A divergent approach to highly substituted benzothiepinones and to 2,3-dihydrothieno[2,3-b]thiopyran-4-ones

Article abstract of DOI:10.1016/j.tetasy.2010.06.006

The radical addition-transfer of S-(2-fluoro-phenacyl)xanthates can be used to construct rapidly benzothiepinones, including libraries of complex aza-bridged derivatives, and highly functionalized 2,3-dihydrothieno[2,3-b] thiopyran-4-ones.

Full text of DOI:10.1016/j.tetasy.2010.06.006

Tetrahedron: Asymmetry 21 (2010) 1649–1665
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Tetrahedron: Asymmetry
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A divergent approach to highly substituted benzothiepinones and to
2,3-dihydrothieno[2,3-b]thiopyran-4-ones
*
Peter Boutillier, Béatrice Quiclet-Sire, Syeda Nahid Zafar, Samir Z. Zard
Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, F-91128 Palaiseau, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The radical addition-transfer of S-(2-fluoro-phenacyl)xanthates can be used to construct rapidly benzo-
thiepinones, including libraries of complex aza-bridged derivatives, and highly functionalized 2,3-dihy-
drothieno[2,3-b]thiopyran-4-ones.
Received 15 March 2010
Accepted 3 June 2010
Available online 26 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
This paper is dedicated with respect and
admiration to professor Henri B. Kagan on
the occasion of his 80th birthday
1. Introduction
vating effect of the ketone group should greatly facilitate this
transformation. This indeed proved to be the case, as previously re-
Seven-membered rings fused to aromatic nuclei represent
highly privileged structures in medicinal chemistry.1 Whereas
the nitrogen-based structures, such as the medicinally significant
benzazepines, have been very extensively studied, the related sul-
fur analogues have received much less attention, despite the fact
that a few such derivatives have proved to be valuable drugs. For
example, Diltiazem 1 is a benzothiazepine calcium channel blocker
that has been in clinical use for at least three decades for the treat-
ment of hypertension, angina pectoris and certain types of arrhyth-
mia. Benzothiepines of general structure 2 have recently been
reported to be potent inhibitors of the apical sodium co-dependent
bile acid transporter (ASBT); they inhibit the re-absorption of bile
acid and could therefore lower the serum LDL cholesterol (Fig. 1).2
One reason for the relatively limited studies on benzothiepinon-
es is the shortage of general methods for constructing such com-
pounds. In most cases, the synthetic routes have relied on
intramolecular Friedel–Crafts reactions or on Dieckmann-type ring
closures.3 While very useful, these approaches are severely con-
strained by the limited availability of appropriately substituted
precursors. In the course of our work on the degenerative radical
xanthate addition-transfer reaction, a simple route to benzothiepi-
nones soon became apparent.4
ported.5 We now present further results in this area and especially
the development of an efficient, convergent route to complex poly-
cyclic architectures. The benzothiepine structure 7 represents in
fact a very interesting scaffold, with several modification points
OMe
O
O
S
Bu
Bu
S
N
Me2N
OCOCH3
OH
O
X
Me2N
1
2
R
Figure 1.
O
F
O
F
R'
R
F
R
F
R'
S
S
peroxide
OEt
5
3a, X = Cl, R = H
3b, X = Cl, R = Me
4a, X = SCSOEt, R = H
4b, X = SCSOEt, R = Me
H2NCH2CH2NH2
Our approach is portrayed in Scheme 1. Thus, radical addition of
xanthate 4 to an olefin would produce an adduct 5, which should
be easily aminolysed into the corresponding thiol 6. In the pres-
ence of base, this thiol should readily engage in a nucleophilic aro-
matic substitution of the ortho-fluorine to give benzothiepine 7.
The high nucleophilicity of the thiolate anion and the strongly acti-
O
O
R
R
F
R'
SH
Base
F
S
F
R'
6
7
* Corresponding author. Tel.: +33 1693 34872; fax: +33 1693 33851.
E-mail address: zard@poly.polytechnique.fr (S.Z. Zard).
Scheme 1.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.06.006

1650
P. Boutillier et al. / Tetrahedron: Asymmetry 21 (2010) 1649–1665
well positioned around the molecule: the aromatic ketone, the ring
sulfur, the remaining activated fluorine atom and the numerous
functional groups that can be introduced via the olefinic partner.
corresponding thiols 6, which were not purified, but subjected to
the action of DBU in THF to give the desired benzothiepinones
7a–j mostly in good yield (Fig. 2). In the case of adduct 5b with al-
lyl trimethylsilane, the yield of cyclised material 7b was low, in
part because of a fluoride-induced ring opening which produced
thiol 8 as the main side-product (Scheme 2).7
2. Results and discussion
A Friedel–Crafts reaction of 1,3-difluorobenzene with chloro-
acetyl chloride and aluminium trichloride afforded 2-chloro-20,40-
O
O
O
O
F
CO2Et
AcNH
S
F
SH
SiMe3
7b
F
8
CO2Et
R
SCSOEt
Scheme 2.
F
F
F
F
SCSOEt
5p, 76%
A very simple access to benzothiepinones 7 with many varied
substituents is now in hand and these in turn can act as versatile
scaffolds for further elaborations. One illustration is with deriva-
tive 7f containing a protected secondary amine. The presence of
the neighbouring aromatic ketone should allow the construction
of another ring by implementing an intramolecular Mannich reac-
tion. However, as depicted in Scheme 3, a preliminary reaction
conducted with formaldehyde furnished as the main product an
interesting sulfonium derivative 10 in modest yield, instead of
the expected Mannich product 9.
OMe
OMe
5a, R = n-C6H13–, 82%
O
5b, R = –CH2SiMe3, 85%
5c, R = –(CH2)8CO2Me, 80%
5d, R = –CH2Ph, 99%
5e, R = –CH2OAc, 85%
F
F
F
5f, R = n-C6F13–, 42% (64%)
5g, R = –CH2NHAc, 87%
5h, R = –CH2NHBoc, 78%
5i, R = –CH2NMeBoc, 94%
5j, R = –OCOCMe3, 80%
5k, R = –CH2PO(OEt)2, 81%
5l, R = –CH(OEt)2, 85%
SCSOEt
5q, 80%
O
SCSOEt
Me
Me
F
5m, R = –CH2OEt, 62%
5n, R = –CH2N(Boc)CH2CO2Et, 80%
5o, R = –(CH2)8CH2OAc, 85%
O
O
5r, 80%
O
O
N
Me
Me Me
OMe
F
F
F
S
S
O
9
7f
Paraformaldehyde
HCl
F
O
Me
F
F
N
Boc
PO(OEt)2
Me
F
O
F
Cl
mCPBA
SCSOEt
5s, 72%
Boc
S
N
CH2Cl2
O
10, 39%
N
F
F
Me
SCSOEt
5t, 97%
O
O
R
1) CF3CO2H
F
S
O
2) Et3N, RCHO
R
Me
N
7a, R = n-C6H13–, 85%
F
F
7b, R = –CH2SiMe3, 18%
7c, R = –(CH2)8CO2Me, 46%
7d, R = –CH2Ph, 61%
S
S
O
O
O
S
O
N
Boc
11
7e, R = –CH2NHBoc, 61%
7f, R = –CH2NMeBoc, 61%
7g, R = –CH2CH(OEt)2, 52%
12a, R = H, 62%
12b, R = p-methoxyphenyl-, 19%
Me
7h, 82%
MeO
O
OMe
Scheme 3.
O
Me
Me
In order to suppress this reaction pathway, the sulfide was oxi-
O
dised to the corresponding sulfone 11 before deprotection and
treatment with formaldehyde. In the absence of a nucleophilic sul-
fur, the Mannich reaction proceeded as expected and furnished tri-
cyclic derivative 12a in 62% yield. By replacing formaldehyde with
p-anisaldehyde, the corresponding derivative 12b was obtained in
rather modest yield. This compound was obtained as only one dia-
stereoisomer, with the stereochemistry assigned tentatively as
shown on the basis of NMR spectroscopy and on steric consider-
ations. Not unexpectedly, the methoxyphenyl substituent occupies
an equatorial orientation, with respect to the newly formed piper-
idine ring.
Compounds 12a and 12b may be considered as analogues of
eptazocine 13 and cytisine 14, two important biologically active
natural products (Fig. 3). Cytisine, in particular, is a potent nicotinic
receptor ligand, and hundreds of analogues have been prepared as
probes in the study of the central nervous system and as potential
therapeutic agents.8 Difluorobenzo derivative 15 and Varenicline
O
Me
Me
F
S
7i, 71%
Boc
F
S
N
OMe
7j, 55%
Figure 2.
difluoroacetophenone 3 in 90% yield,6 and this was smoothly con-
verted into nicely crystalline xanthate 4a (94%) by treatment with
potassium O-ethyl xanthate in acetone. Xanthate 4b was prepared
by a similar sequence from 2,4-difluorotoluene. The radical addi-
tion of these xanthates to various olefins proceeded smoothly
and furnished the desired adducts 5a–t in high yield (Fig. 2). Ami-
nolysis of the xanthate group with ethylenediamine afforded the

P. Boutillier et al. / Tetrahedron: Asymmetry 21 (2010) 1649–1665
1651
16, which has entered clinical phase studies, are two analogues
recently described by chemists at Pfizer as drugs to combat addic-
tion to smoking.9
or a cyclopropyl group and various heteroaromatic side chains is
noteworthy. The present expedient approach to such intricate
and pharmacologically appealing structures associates flexibility
and convergence. Furthermore, by choosing the appropriate initial
olefin, other reactions besides the Mannich reaction could in prin-
ciple be considered to augment the complexity.
O
N
In an attempt at combining the cleavage of the xanthate with
the fluorine substitution into one operation, we exposed xanthate
5a to the action of potassium carbonate in a 9:1 mixture of aceto-
nitrile and t-butanol. The corresponding benzothiepinone 7a was
indeed formed but only to a very small extent. The major com-
pound turned out to be tricyclic dihydrothieno[2,3-b]-benzothio-
pyranone 19a, isolated in 92% yield (Scheme 5). This unexpected
transformation most logically proceeds by the mechanism outlined
in Scheme 6. Under the modified conditions, the formation of the
enolate 20 of the ketone is faster than cleavage of the xanthate.
The proximity of the enolate to the xanthate group encourages a
nucleophilic attack on the thiocarbonyl group leading to thiolate
21a, which is in equilibrium with open form 21b. The thiolate
group in the former is well positioned for a nucleophilic aromatic
substitution of the fluorine giving observed product 19 following
elimination of ethanol. We very recently stumbled across a trans-
formation akin to the one described in the present study, which
leads to aliphatic analogues by a Michael addition instead of the
fluorine substitution.10
HO
F
N
Me
N
Me
H
14, (–)-Cytisine
13, Eptazocine
F
N
N
N
H
N
H
15
16, Varenicline
Figure 3.
The Mannich reaction did not proceed well starting with deriv-
ative 7e, which gives rise to a primary amine upon removal of the
Boc-group. We therefore continued our study with 7j, where the N-
p-methoxybenzyl group can be removed if an unsubstituted piper-
idine moiety is desired in the end product. Thus, oxidation of 7j
furnished the corresponding sulfone 17, and treatment with triflu-
oroacetic acid followed by triethylamine and an aldehyde gave the
desired tricyclic structure. In this manner, a small library of deriv-
atives 18a–g could be prepared, as shown by the examples dis-
played in Scheme 4. The facile introduction of a trifluoromethyl
O
O
S
K2CO3
C6H13
t-BuOH/CH3CN
(1:9)
S
mCPBA
7j
F
F
F
CH2Cl2
S
C6H13
S
reflux
19a, 92%
5a
O
O
R
EtO
1) CF3CO2H
N-PMB
Scheme 5.
2) Et3N, RCHO
F
F
S
O
Boc-N
S
O
O
O
18
O
F
O
17, 90%
OMe
O
EtO
S
K2CO3
CF3
O
S
F
F
F
F
N-PMB
N-PMB
S
5
R
S
20
R
F
S
F
S
O
O
EtO
O
O
18a, 45%
18b, 65%
O
O
F
O
C5H11
O
O
– F
R
R
N-PMB
S
N-PMB
18c, 60%
S
F
S
S
OEt
F
S
OEt
S
F
F
S
O
O
O
O
18d, 43%
21a
O
O
– EtOH
R
Me
S
O
O
F
O
N
N-PMB
N-PMB
R
OEt
21b
S
S
F
F
F
S
S
S
O
O
18e, 95%
18f, 70%
19
N
Scheme 6.
O
Thieno[2,3-b]-benzothiopyrans and their dihydro derivatives
are quite rare substances, presumably because of a lack of gener-
ally applicable synthetic approaches. Two early patent applications
mentioning their synthesis and use in the preparation of drugs for
treating psychotic disturbances11 were followed by a brief study by
N-PMB
F
S
O
18g, 97%
O
Scheme 4.

1652
P. Boutillier et al. / Tetrahedron: Asymmetry 21 (2010) 1649–1665
Majumdar et al.12 and by a report on the benzo-fused series.13 The
very few routes described in the literature all rely on a preformed
benzothiopyranone ring to which the thiophene or dihydrothioph-
ene ring is then attached. This limits severely the variety of acces-
sible structures.
S
O
S
O
F
K2CO3
OAc
MeCN /t-BuOH
OEt
F
F
In contrast, the present serendipitous radical-based synthesis of
thieno[2,3-b]-benzothiopyrans is extremely short, only two steps
from xanthates 4a and 4b and lends itself very easily to structural
modifications. The numerous examples collected in Figure 4 give
an idea of the possibilities. In the case of derivative 5b, the cleavage
of the silyl group by the liberated fluoride anion was much less se-
vere and a good yield (70%) of the corresponding thieno[2,3-b]-
benzothiopyranone 19b could be secured. Interestingly, when xan-
thate 5e was subjected to the same conditions, a different product
was formed in moderate yield, which was identified as episulfide
22 (Scheme 7). In this case, the equilibrium, which exists between
the closed and open thiolates 23a and 23b, is driven towards the
intermediate episulfide 24 by substitution of the acetate group.
Nucleophilic aromatic substitution of the fluoride by the other sul-
fur then furnishes the observed product.
22, 44%
5e
SCSOEt
K2CO3
– F
S
O
F
O
F
H
EtO
S
OEt
S
F
F
F
S
24
OAc
AcO
O
O
F
S
EtO
S
S
O
OEt
SiMe3
F
F
S
O
23a
OAc
23b
S
F
F
F
S
19b, 74%
Scheme 7.
S
S
Ph
O
F
F
S
19c, 60%
NHR
attack. Thus, no reduction with sodium borohydride occurred
when compound 19m was exposed to sodium borohydride in a
mixture of methanol and THF at room temperature (Scheme 8).
However, upon heating to reflux, a smooth reaction took place
but instead of the expected carbinol 25 methoxy-substituted deriv-
ative 26 was isolated in excellent yield (96%). Clearly, the ketone
exerted a sufficiently activating effect to allow nucleophilic substi-
tution of the remaining fluorine. It was indeed possible to intro-
duce a much more interesting trifluoroethoxy group by heating
19m in trifluoroethanol in the presence of potassium carbonate.
The trifluoroethoxide anion is only a very modest nucleophile,
yet the substitution proved quite efficacious nevertheless and
derivative 27 was obtained in 73% yield. Finally, a more classical
O
S
S
19d, R = Ac, 96%
PO(OEt)2
19e, R = Boc, 59%
O
S
OEt
19f, 61%
S
OEt
S
O
19g, 95%
OEt
CO2Et
O
S
S
N
Boc
F
F
S
19h, 70%
S
F
F
S
O
19i, 72%
(CH2)8OAc
O
AcNH CO2Et
CO2Et
S
MeO
19j, 90%
S
S
MeO
OH
MeO
H
19k, 90%
O
S
Me
O
MeO
Me
25
S
F
S
O
19m
O
S
NaBH4
F
F
Me
Me
MeOH / THF 2:1
19l, 92%
MeO
CF3CH2OH
K2CO3
O
S
O
S
F
S
19m, 77%
O
MeO
S
Boc
N-PMB
Morpholine
K2CO3
(EtO)2OP
S
RO
S
F
F
Me
F
MeO
MeO
19n, 52%
26, R = Me-, 96%
27, R = CF3CH2-, 73%
O
S
S
S
19o, 60%
S
N
O
28, 70%
Figure 4.
We further observed the ketone group in these thieno[2,3-b]-
benzothiopyranones to be rather unreactive towards nucleophilic
Scheme 8.

P. Boutillier et al. / Tetrahedron: Asymmetry 21 (2010) 1649–1665
1653
substitution with morpholine afforded compound 28 in equally
4.2. General procedure for the preparation of addition products 5
good yield.
A solution of xanthate (n mmol) and olefin (2n mmol) in cyclo-
hexane or ethyl acetate (1 mL/mmol) was refluxed for 15 min. un-
der nitrogen atmosphere. Lauroyl peroxide (DLP, 5 mol %) was then
added to the refluxing solution followed by additional portions (2%
or 2.5%) every 20 min or 1 h 30 min until there was complete con-
sumption of the starting xanthate. The reaction mixture was then
cooled to room temperature, concentrated under reduced pressure
and the residue thus obtained was purified by flash chromatogra-
phy on a silica gel column.
3. Conclusion
In summary, we have presented some unconventional ap-
proaches to a variety of highly functionalized scaffolds of potential
pharmacological interest. The combination of the radical and ionic
reactions of xanthates offers both flexibility and convergence and
allows the introduction of tremendous diversity into the struc-
tures. We have also uncovered an unusual synthesis of thie-
no[2,3-b]-benzothiopyranones which opens an easy access to
numerous new derivatives and which will hopefully facilitate the
study of their chemistry.
4.2.1. Dithiocarbonic acid S-{1-[3-(2,4-difluorophenyl)-3-oxo-
propyl]-heptyl} ester O-ethyl ester 5a
The reaction was run in cyclohexane (3 mL) with xanthate 4a
(0.828 g, 3 mmol), octene (0.7 mL, 4.5 mmol) and DLP (11%). Flash
chromatography on a silica gel column using a gradient petroleum
ether/diethyl ether: 96:4 gave the addition product 5a (0.955 g) as a
yellow oil in 82% yield. 1H NMR (200 MHz, CDCl3) d 7.93 (1H, ddd,
JH–H = 8.5 Hz, JH–F = 8.5 and 6.7 Hz, CHAr), 6.99–6.81 (2H, m, 2CHAr),
4.62 (2H, q, J = 7.1 Hz, OCH2CH3), 3.81 (1H, m, CHS), 3.11 (2H, m,
CH2), 2.25 (1H, m, CHH), 2.02 (1H, m, CHH), 1.77–1.65 (2H, CH2),
1.52–1.35 (2H, CH2), 1.40 (3H, t, J = 7.1 Hz, OCH2CH3), 1.28 (6H, br
s), 0.88 (3H, m). 13C NMR (50 MHz, CDCl3) d 214.3 (CS), 195.6 (d,
JC–F = 4.0 Hz, CO), 165.6 (dd, JC–F = 257.0 and 12.0 Hz, CF), 162.7
(dd, JC–F = 257.0 and 12.5 Hz, CF), 132.6 (dd, JC–F = 10.0 and 3.5 Hz,
CHAr), 122.1 (d, JC–F = 13.0 Hz, CqAr), 112.0 (d, JC–F = 21.5 Hz, CHAr),
104.6 (t, JC–F = 26.5 Hz, CHAr), 69.6 (OCH2CH3), 50.9 (CHS), 40.5 (d,
JC–F = 7.0 Hz, COCH2), 34.6 (CH2), 31.6 (CH2), 29.0 (CH2), 28.4 (CH2),
26.8 (CH2), 22.5 (CH2), 13.9 (CH3), 13.6 (CH3). IR (neat) 1688,
1610 cmꢀ1. MS (CI) 406 (M+NH4)+, 389 (M+H)+.
4. Experimental
4.1. General conditions
All reactions were carried out under an inert atmosphere.
Commercial reagents were used as received without further puri-
fication. All products were purified by using silica gel (SDS, Silica
60 A. C. C. 40–63 lm) or by crystallisation. Analytical TLC was
carried out on Merck silica gel plates using short wave
(254 nm) UV light, 1% aq KMnO4 solution to visualise compo-
nents. NMR spectra were recorded in CDCl3 using a Bruker
AMX400 operating at 400 MHz for 1H and 100 MHz for 13C. The
chemical shifts are expressed in parts per million (ppm) refer-
enced to residual chloroform. 1H NMR data are reported as fol-
lows: d, chemical shift; multiplicity (recorded as: s, singlet; br
s, broad singlet; d, doublet; t, triplet; q, quadruplet; qt, quintu-
plet; ht, heptuplet; dd, double doublet; ddd, double double dou-
blet; dddd, double double double doublet; dt, double triplet; ddt,
double double triplet; dq, double quadruplet; tt, triple triplet; td;
triple doublet; tdd, triple double doublet; m, multiplet), coupling
constants (J are given in Hertz, Hz) and integration. Infrared
Absorption spectra were recorded as thin films or as solutions
in CCl4 with a Perkin–Elmer 1600 Fourier Transform Spectropho-
tometer. Mass spectra were recorded with an HP 5989B mass
spectrometer via direct introduction for chemical positive ionisa-
tion (CI) using ammonia as the reagent gas. Melting points were
determined by a Reichert microscope apparatus and are uncor-
rected. HRMS were performed on JEOL JMS-GcMate II, GC/MS
system spectrometer. Microanalyses were carried out at the ‘Ser-
vice de Microanalyses’ in the Institut de Chimie des Substances
Naturelles in Gif-sur-Yvette.
4.2.2. Dithiocarbonic acid S-[4-(2,4-difluorophenyl)-4-oxo-1-
trimethylsilylmethyl-butyl] ester O-ethyl ester 5b
The reaction was run in cyclohexane (3 mL) with xanthate 4a
(0.828 g, 3 mmol), allyl trimethylsilane (0.9 mL, 6 mmol) and DLP
(7%). Flash chromatography on a silica gel column using a gradient
petroleum ether/ethyl acetate (98:2) afforded the addition product
5b (0.995 g) as a yellow oil in 85% yield. 1H NMR (400 MHz, CDCl3)
d 7.93 (1H, ddd, JH–H = 8.5 Hz, JH–F = 8.5 and 7.0 Hz, CHAr), 6.96 (1H,
m, CHAr), 6.87 (1H, m, CHAr), 4.62–4.58 (2H, m, OCH2CH3), 3.95
(1H, m, CHS), 3.18–3.02 (2H, m, CH2CO), 2.27 (1H, m, CHH), 1.95
(1H, m, CHH), 1.39 (3H, t, J = 7.1 Hz, OCH2CH3), 1.17 (1H, dd, J =
14.8 and 6.9 Hz, CHHSiMe3), 1.05 (1H, dd, J = 14.8 and 8.3 Hz,
CHHSiMe3), 0.09 (9H, s, SiMe3). 13C NMR (100 MHz, CDCl3) d
214.2 (CS), 195.7 (d, JC–F = 4.3 Hz, CO), 165.6 (dd, JC–F = 257.0 and
12.3 Hz, CF), 162.7 (dd, JC–F = 257.0 and 12.5 Hz, CF), 132.6 (m,
CHAr), 122.0 (d, JC–F = 13.0 Hz, CqAr), 112.l (d, JC–F = 21.3 Hz, CHAr),
104.6 (t, JC–F = 24.3 Hz, CHAr), 69.5 (OCH2CH3), 48.1 (CHS), 40.5 (d,
JC–F = 7.5 Hz, CH2CO), 31.0 (CH2), 23.5 (CH2), 13.7 (OCH2CH3), ꢀ0.8
4.1.1. Dithiocarbonic acid S-[2-(2,4-difluorophenyl)-2-oxo-ethyl]
ester O-ethyl ester 4a
To a solution of 2,4-difluorophenacyl chloride 3a6a (15.45 g,
81.0 mmol) in acetone (162 mL) was added portionwise and under
nitrogen potassium O-ethylxanthogenate (15.52 g, 97.0 mmol).
The reaction was monitored by tlc and, upon completion, ice water
was added. The resulting precipitate was filtered off and dried to
afford xanthate 4a (20.91 g) as pale yellow crystals in 93% yield.
(SiMe3). IR (neat) 1688, 1610 cmꢀ1
.
4.2.3. Methyl 13-(2,4-difluorophenyl)-10-(ethoxycarbonothioyl-
thio)-13-oxotridecanoate 5c
The reaction was run in ethyl acetate (1.8 mL) with xanthate 4a
(0.5 g, 1.8 mmol) undec-10-enoic acid methyl ester (2 equiv,
0.713 g) and DLP (10%). Flash chromatography on a silica gel col-
1H NMR (400 MHz, CDCl3) d 7.96 (1H, ddd, JH–H = 8.6 Hz, JH–F
=
8.6 and 6.6 Hz, CHAr), 7.01 (1H, m, CHAr), 6.93 (1H, m, CHAr),
4.63 (2H, q, J = 7.1 Hz, OCH2CH3), 4.57 (2H, d, JH–F = 3.1 Hz, CH2S),
1.41 (3H, t, J = 7.1 Hz, OCH2CH3). 13C NMR (100 MHz, CDCl3) d
212.8 (CS), 188.8 (d, JC–F = 4.7 Hz, CO), 166.1 (dd, JC–F = 258.0 and
12.4 Hz, CF), 162.5 (dd, JC–F = 257.1 and 12.6 Hz, CF), 132.9 (m,
CHAr), 122.1 (d, JC–F = 10.1 Hz, CqAr), 112.5 (d, JC–F = 20.3 Hz, CHAr),
104.7 (t, JC–F = 26.5 Hz, CHAr), 70.6 (OCH2CH3), 46.7 (d, JC–F = 9.0 Hz,
CH2S), 13.6 (OCH2CH3). IR (nujol) 1686, 1610 cmꢀ1. MS (CI) 294
(M+NH4+), 277 (M+H+).
umn using
a gradient petroleum ether/diethyl ether (95:5)
afforded the addition product 5c (0.682 g) as a yellow oil in 80%
yield. 1H NMR (400 MHz, CDCl3) d 7.92 (dt, 1H, JH–F = 6.7 Hz,
JH–H = 8.6 Hz, CHAr), 6.95 (m, 1H, CHAr), 6.86 (ddd, 1H, JH–H
=
2.4 Hz, JH–F = 8.7 Hz, JH–F = 11.1 Hz, CHAr), 4.61 (m, 2H, OCH2CH3),
3.79 (m, 1H, CHS), 3.66 (s, 3H, CO2CH3), 3.09 (tt, 2H, J = 4.6 Hz,
J = 3.8 Hz, CH2CO), 2.29 (t, 2H, J = 7.5 Hz, CH2CO2CH3), 2.22 (m,
1H, CHHCHS), 1.97 (m, 1H, CHHCHS), 1.69 (dd, 2H, J = 7.3 Hz,
J = 15.2 Hz, CHSCH2), 1.59 (m, 2H, CH2), 1.45 (m, 1H, CHHCH2),

1654
P. Boutillier et al. / Tetrahedron: Asymmetry 21 (2010) 1649–1665
1.39 (t, 3H, J = 7.1 Hz, OCH2CH3), 1.28 (br s, 9H, CHHCH2, 4CH2).
NMR (100 MHz, CDCl3) d 214.4 (CS), 195.9 (d, JC–F = 4.7 Hz, CO),
174.2 (CO2Me), 165.7 (dd, JC–F = 12.3 Hz, JC–F = 256.9 Hz, CF),
2H, J = 3.1 Hz, J = 7.1 Hz, CH2CO), 2.62 (m, 1H, CHHCHS), 2.04 (m,
1H, CHHCHS), 1.41 (t, 3H, J = 7.1 Hz, OCH2CH3). 13C NMR
(100 MHz, CDCl3) d 210.5 (CS), 194.8 (CO, d, JC–F = 4.7 Hz), 166.1
(dd, JC–F = 12.4 Hz, JC–F = 257.7 Hz, CF), 162.9 (dd, JC–F = 12.5 Hz,
JC–F = 257.5 Hz, CF), 132.8 (dd, JC–F = 4.2 Hz, JC–F = 10.6 Hz, CHAr),
121.7 (Cq, dd, JC–F = 3.6 Hz, JC–F = 13.1 Hz), 119.0 (CF), 118.7 (CF),
162.7 (dd, JC–F = 12.5 Hz, JC–F = 257.4 Hz, CF), 132.6 (dd, JC–F
4.2 Hz, J = 10.5 Hz, CHAr), 122.10 (Cq, dd, JC–F = 3.6 Hz, JC–F
=
=
13.2 Hz), 112.2 (dd, JC–F = 3.4 Hz, JC–F = 21.4 Hz, CHAr), 104.7 (dd,
JC–F = 25.4 Hz, JC–F = 27.8 Hz, CHAr), 69.8 (OCH2CH3), 51.4, 50.8
(CHS, OCH3), 40.6 (d, JC–F = 7.6 Hz, CH2CO), 34.5 (CH2), 34.0 (CH2),
29.3 (CH2), 29.2 (CH2), 29.1 (CH2), 29.0 (CH2), 28.3 (CH2), 26.8
117.0 (CF), 115.8 (CF), 113.0 (CF), 112.4 (dd, JC–F = 3.3 Hz, JC–F
=
21.4 Hz, CHAr), 110.4 (CF), 104.9 (dd, JC–F = 25.5 Hz, JC–F = 27.8 Hz,
CHAr), 71.4 (OCH2CH3), 51.5 (CHS), 39.5 (d, JC–F = 8.5 Hz, CH2CO),
22.1 (CH2), 13.6 (OCH2CH3). IR (CDCl3) 1687, 1611 cmꢀ1. MS (CI)
623 MH+, 640 MH+NH3+. HRMS (EI+) 622.0104 (Measured mass),
622.0117 (Calculated mass).
(CH2), 24.9 (CH2), 13.7 (OCH2CH3). IR (CDCl3) 1740, 1690, 1609.
MS (CI) 475 MH+, 492 MH+NH3
.
+
4.2.4. S-5-(2,4-Difluorophenyl)-5-oxo-1-phenylpentan-2-yl-O-
ethylcarbonodithioate 5d
4.2.7. S-1-Acetamido-5-(2,4-difluorophenyl)-5-oxopentan-2-yl
O-ethyl carbonodithioate 5g
The reaction was run in cyclohexane (2.1 mL) with xanthate 4a
(0.60 g, 2.1 mmol), allyl benzene (4.2 mmol, 0.55 mL) and DLP
(12.5%). Flash chromatography on a silica gel column using a gra-
dient petroleum ether/diethylether (97:3) afforded the addition
The reaction was run in ethyl acetate (7.2 mL) with xanthate 4a
(2.0 g, 7.2 mmol), N-allylacetamide (2 equiv, 0.71 g) and DLP (10%).
Flash chromatography on a silica gel column using a gradient
petroleum ether/diethyl ether (1:1) afforded the addition product
5g (2.35 g) as a yellow oil in 87% yield. 1H NMR (400 MHz, CDCl3)
d 7.91 (dt, 1H, JH–F = 6.6 Hz, JH–H = 8.6 Hz, CHAr), 6.94 (m, 1H,
CHAr), 6.85 (ddd, 1H, JH–H = 2.4 Hz, JH–H = 8.6 Hz, JH–F = 11.1 Hz,
CHAr), 5.99 (s, 1H, NH), 4.62 (q, 2H, J = 7.1 Hz, OCH2CH3), 3.93
(m, 1H, CHS), 3.64 (td, 1H, J = 5.9 Hz, J = 14.0 Hz, CHHNHAc), 3.52
(m, 1H, CHHNHAc), 3.14 (dt, 2H, J = 3.1 Hz, J = 7.1 Hz, CH2CO),
2.22 (m, 1H, CHHCHS), 1.97 (m, 4H, CHHCHS, COCH3), 1.40 (t, 3H,
J = 7.1 Hz, OCH2CH3). 13C NMR (100 MHz, CDCl3) d 213.5 (CS),
product 5d (0.82 g) as
a
yellow oil in 99% yield. 1H NMR
(400 MHz, CDCl3) d 7.88 (dt, 1H, JH–F = 6.7 Hz, JH–H = 8.6 Hz, CHAr),
7.30 (m, 4H, CHPh), 7.23 (m, 1H, CHPh), 6.93 (m, 1H, CHAr), 6.84
(ddd, 1H, JH–H = 2.4 Hz, JH–H = 8.7 Hz, JH–F = 11.1 Hz, CHAr), 4.62
(m, 2H, OCH2CH3), 4.03 (m, 1H, CHS), 3.20 (dd, 1H, J = 6.0 Hz,
J = 13.9 Hz, CHHPh) 3.08 (m, 2H, CH2CO), 2.90 (dd, 1H, J = 8.5 Hz,
J = 13.9 Hz, CHHPh) 2.21 (m, 1H, CHHCHS) 1.93 (m, 1H, CHHCHS)
1.40 (t, 3H, J = 7.1 Hz, OCH2CH3). 13C NMR (100 MHz, CDCl3) d
213.9 (CS), 195.7 (CO), 165.8 (dd, JC–F = 12.3 Hz, JC–F = 257.0 Hz,
CF), 162.7 (dd, JC–F = 12.5 Hz, JC–F = 257.5 Hz, CF), 138.3 (Cq),
132.6 (dd, JC–F = 4.3 Hz, JC–F = 10.5 Hz, CHAr), 129.3 (CHPh), 128.5
(CHPh), 126.7 (CHPh), 122.0 (Cq, dd, JC–F = 3.6 Hz, J = 13.2 Hz),
195.7 (d, JC–F = 4.7 Hz, CO), 170.3 (COCH3), 165.9 (dd, JC–F
12.3 Hz, JC–F = 257.3 Hz, CF), 162.8 (dd, JC–F = 12.5 Hz, JC–F
=
=
257.7 Hz, CF), 132.7 (dd, JC–F = 4.2 Hz, JC–F = 10.5 Hz, CHAr), 122.0
(Cq, dd, JC–F = 3.6 Hz, JC–F = 13.1 Hz), 112.3 (dd, J = 3.4 Hz,
J = 21.4 Hz, CHAr), 104.9 (dd, J = 25.4 Hz, J = 27.8 Hz, CHAr), 70.4
(OCH2CH3), 50.8 (CHS), 42.9 (CH2NHAc), 40.4 (d, JC–F = 7.8 Hz,
CH2CO), 25.6 (d, JC–F = 1.8 Hz, CH2CHS), 23.3 (CH3CO), 13.8
(OCH2CH3). IR (CDCl3) 1681, 1611 cmꢀ1. MS (CI) 376 MH+, 393
MH+NH3+. HRMS (EI+) 375.0774 (Measured mass), 375.0774 (Cal-
culated mass).
112.2 (dd, JC–F = 3.4 Hz, JC–F = 21.4 Hz, CHAr), 104.8 (dd, 1H, JC–F
=
25.4 Hz, JC–F = 27.8 Hz, CHAr), 70.7 (OCH2CH3), 51.7 (CHS), 41.5
(CH2Ph), 40.8 (CH2CO), 26.8 (CH2CHS), 14.1 (OCH2CH3). IR (CCl4)
1691, 1607 cmꢀ1. MS (CI) 395 MH+, 412 MH+NH3+. HRMS (EI+)
[MꢀSCSOEt] 274.1172 (Measured mass), 274.1169 (Calculated
mass).
4.2.5. Acetic acid 5-(2,4-difluorophenyl)-2-ethoxythiocarbon-
ylsulfanyl-5-oxo-pentyl ester 5e
4.2.8. Dithiocarbonic acid S-[1-(tert-butoxycarbonylamino-met
hyl)-4-(2,4-difluorophenyl)-4-oxo-butyl] ester O-ethyl ester 5h
The reaction was run in cyclohexane (5 mL) with xanthate 4a
(1.38 g, 5 mmol), allyl amine Boc derivative (1.18 g, 7.5 mmol)
and DLP (13%). Flash chromatography on a silica gel column using
a gradient petroleum ether/diethyl ether (8:2) afforded the addi-
tion product 5h (1.69 g) as a pale yellow and viscous oil in 78%
The reaction was run in cyclohexane (5 mL) with xanthate 4a
(1.38 g, 5 mmol), allyl acetate (1.09 mL, 10 mmol) and DLP (9%).
Flash chromatography on a silica gel column using a gradient
petroleum ether/ethyl acetate (9:1) afforded the addition product
5e (1.33 g) as a yellow oil in 71% yield. 1H NMR (200 MHz, CDCl3)
d 7.87 (1H, m, CHAr), 6.95–6.76 (2H, m, 2CHAr), 4.60–4.52 (2H, m,
OCH2CH3), 4.32–4.16 (2H, m, CH2OAc), 3.98 (1H, m, CHS), 3.09–
3.04 (2H, m, CH2CO), 2.22 (1H, m, CHH), 1.99 (1H, m, CHH), 1.36–
1.29 (3H, m, OCH2CH3). 13C NMR (50 MHz, CDCl3) d 212.7 (CS),
195.2 (CO), 170.3 (OCOCH3), 165.7 (dd, JC–F = 256.4 and 12.4 Hz,
CF), 162.6 (dd, JC–F = 257.5 and 12.5 Hz, CF), 132.6 (m, CHAr),
yield. 1H NMR (400 MHz, CDCl3) d 7.93 (1H, ddd, JH–H = 8.5 Hz, JH–F
8.5 and 7.0 Hz, CHAr), 6.96 (1H, ddd, JH–H = 8.5 and 2.5 Hz, JH–F
=
=
8.0 Hz, CHAr), 6.87 (1H, ddd, JH–H = 2.5 Hz, JH–F = 11.0 and 8.8 Hz,
CHAr), 4.90 (1H, m, NH), 4.63 (2H, q, J = 7.1 Hz, OCH2CH3), 3.92
(1H, m, CHS), 3.53 (1H, m, CHHN), 3.41 (1H, m, CHHN), 3.15 (2H,
m, COCH2), 2.23 (1H, m, CHHCHS), 1.97 (IH, m, CHHCHS), 1.43
(9H, s, Me3), 1.41 (3H, t, J = 7.1 Hz, OCH2CH3). 13C NMR (100 MHz,
122.0 (m, CqAr), 112.2 (d, JC–F = 21.7 Hz, CHAr), 104.7 (t, JC–F
26.5 Hz, CHAr), 70.1 (OCH2CH3), 65.5 (CH2OAc), 48.8 (CHS), 40.3
(d, C–F = 7.6 Hz, COCH2), 24.9 (CH2), 20.6 (OCOCH3), 13.6
(OCH2CH3). IR (neat) 1745, 1688, 1611 cmꢀ1
=
J
CDCl3) d 213.4 (CS), 195.7 (d, JC–F = 4.2 Hz, CO), 165.8 (dd, JC–F =
.
257.0 and 12.2 Hz, CF), 162.8 (dd, JC–F = 257.0 and 12.5 Hz, CF),
155.9 (NCO), 132.7 (m, CHAr), 121.9 (d, JC–F = 10.7 Hz, CqAr),
112.2 (d, JC–F = 21.0 Hz, CHAr), 104.8 (t, JC–F = 26.3 Hz, CHAr), 79.6
4.2.6. S-1-(2,4-Difluorophenyl)-5,5,6,6,7,7,8,9,10,10,10-undeca-
fluoro-8,9-dimethyl-1-oxodecan-4-yl O-ethyl carbonodithioate
5f
The reaction was run in ethyl acetate (3.6 mL) with xanthate 4a
(1.0 g, 3.6 mmol), perfluoro (hexyl)ethylene (2 equiv, 1.6 mL) and
DLP (12.5%). Flash chromatography on a silica gel column using a
gradient petroleum ether/ethyl acetate (9:1) afforded the addition
product 5f (0.94 g) as a yellow oil in 42% (64%) yield. 1H NMR
(400 MHz, CDCl3) d 7.95 (dt, 1H, JH–F = 6.7 Hz, JH–H = 8.6 Hz, CHAr),
(CqMe3), 70.2 (OCH2CH3), 51.2 (CH, CHS), 43.8 (CH2N), 40.5 (d, JC–F
=
7.3 Hz, CH2CO), 28.4 (Me3), 25.4 (CH2), 13.7 (OCH2CH3). IR (neat)
1714, 1690, 1610. MS (CI) 451 (M+NH4)+, 434 (M+H)+.
4.2.9. Dithiocarbonic acid S-[1-(tert-butoxycarbonylamino-me
thyl)-4-(2,4-difluorophenyl)-4-oxo-butyl] ester O-ethyl ester 5i
The reaction was run in cyclohexane (6 mL) with xanthate 4a
(1.66 g, 6 mmol), allyl methylamine Boc derivative (1.54 g,
9 mmol) and DLP (11%). Flash chromatography on a silica gel col-
umn using a gradient petroleum ether/diethyl ether (8:2) afforded
6.97 (m, 1H, CHAr), 6.87 (ddd, 1H, JH–H = 2.4 Hz, JH–H = 8.6 Hz, JH–F
11.1 Hz, CHAr), 4.83 (m, 1H, CHS), 4.64 (m, 2H, OCH2CH3), 3.21 (dt,
=

P. Boutillier et al. / Tetrahedron: Asymmetry 21 (2010) 1649–1665
1655
the addition product 5i (2.22 g) as a yellow oil in 83% yield. 1H
NMR (200 MHz, CDCl3) d 7.92 (1H, ddd, JH–H = 8.6 Hz, JH–F = 8.6
and 6.8 Hz, CHAr), 7.00–6.80 (2H, m, 2 CHAr), 4.62 (2H, q, J =
7.1 Hz, OCH2CH3), 4.04 (1H, m, CHS}, 3.70 (1H, m, CHHN), 3.37
(1H, m, CHHN), 3.18–3.05 (2H, m, COCH2), 2.95 (3H, s, NMe},
2.28 (1H, m, CHHCHS), 1.88 (1H, m, CHHCHS), 1.50 (9H, br s,
Me3), 1.41 (3H, t, J = 7.1 Hz, OCH2CH3). 13C NMR (50 MHz, CDCl3)
d 213.7 (CS), 195.5 (CO), 165.7 (dd, JC–F = 257.0 and 12.1 Hz CF),
162.6 (dd, JC–F = 257.5 and 12.2 Hz, CF), 155.6 (NCO), 132.6 (m,
CHAr), 122.2 (d, JC–F = 12, CqAr), 112.2 (d, JC–F = 21.4 Hz, CHAr),
104.7 (t, JC–F = 26.6 Hz, CHAr), 79.9 (CqMe3), 70.1 (OCH2CH3), 52.4
(broad, CH2N), 49.3 (CHS), 40.4 (d, JC–F = 6.5 Hz, COCH2), 34.8
(NCH3), 29.6 (Me3), 28.4 (CH2), 13.7 (OCH2CH3). IR (neat) 1693,
gradient petroleum ether/diethyl ether (2:3) afforded the addition
product 5l (1.24 g) as a colourless oil in 85% yield. 1H NMR
(400 MHz, CDCl3) d 7.91 (dt, 1H, JH–F = 6.8 Hz, JH–H = 8.6 Hz, CHAr),
6.93 (m, 1H, CHAr), 6.84 (ddd, 1H, JH–H = 2.4 Hz, JH–H = 8.7 Hz, JH–F
=
11.0 Hz, CHAr), 4.61 (m, 3H, CH(OEt)2, OCH2CH3), 4.12 (m, 1H,
CHS), 3.64 (m, 4H, 2OCH2CH3), 3.16 (m, 2H, CH2CO), 2.41 (m, 1H,
CHHCHS), 2.01 (m, 1H, CHHCHS), 1.39 (t, 1H, J = 7.1 Hz, OCH2CH3),
1.21 (dt, 6H, J = 7.1 Hz, (CH3)2). 13C NMR (100 MHz, CDCl3) d 214.9
(CS), 196.2 (CO, d, JC–F = 4.7 Hz), 165.7 (dd, JC–F = 12.2 Hz, JC–F
=
256.6 Hz, CF), 162.7 (dd, JC–F = 12.6 Hz, JC–F = 257.5 Hz, CF), 132.7
(dd, JC–F = 4.3 Hz, J = 10.5 Hz, CHAr), 122.3 (Cq, dd, JC–F = 3.5 Hz,
JC–F = 13.2 Hz), 112.1 (dd, JC–F = 3.4 Hz, JC–F = 21.4 Hz, CHAr), 104.8
(dd, JC–F = 25.4 Hz, JC–F = 27.8 Hz, CHAr), 104.1 (CH(OEt)2), 70.2
(OCH2CH3), 64.6 (OCH2CH3), 63.8 (OCH2CH3), 53.4 (CHS), 40.7 (d,
JC–F = 7.7 Hz, CH2CO), 22.7 (CH2), 15.2 (OCH2CH3), 15.3 (OCH2CH3),
13.8 (CH3). IR (CDCl3) 1685, 1609 cmꢀ1. MS (CI) 361 MH+ꢀEtOH.
HRMS (EI+) 406.1091 (Measured mass), 406.1084 (Calculated
mass).
1610 cmꢀ1
.
4.2.10. 4-(2,4-Difluorophenyl)-1-(ethoxycarbonothioylthio)-4-
oxobutyl pivalate 5j
The reaction was run in ethyl acetate (3.6 mL) with xanthate 4a
(1.0 g, 3.6 mmol), vinyl pivalate (2 equiv, 1.0 mL) and DLP (7.5%).
Flash chromatography on a silica gel column using a gradient petro-
leum ether/ethyl acetate (9:1) afforded the addition product 5j
(1.16 g) as a yellow oil in 80% yield. 1H NMR (400 MHz, CDCl3) d
7.94 (dt, 1H, JH–F = 6.6 Hz, JH–H = 8.6 Hz, CHAr), 6.96 (m, 1H, CHAr),
6.86 (ddd, 1H, JH–H = 2.4 Hz, JH–H = 8.6 Hz, JH–F = 11.1 Hz, CHAr),
6.68 (t, 1H, J = 6.6 Hz, CHS), 4.62 (m, 2H, OCH2CH3), 3.08 (dt, 2H,
J = 3.1 Hz, J = 7.2 Hz, CH2CO), 2.37 (m, 2H, J = 7.1 Hz, CH2CHS), 1.40
(t, 3H, J = 7.2 Hz, OCH2CH3), 1.19 (s, 9H, (CH3)3). 13C NMR
(100 MHz, CDCl3) d 210.1 (CS), 194.6 (d, JC–F = 4.6 Hz, CO), 176.7
4.2.13. Dithiocarbonic acid S-[4-(2,4-difluorophenyl)-1-ethoxy-
methyl-4-oxo-butyl] ester O-ethyl ester 5m
The reaction was run in cyclohexane (8 mL) with xanthate 4a
(1.38 g, 5 mmol), allyl ethyl ether (1.7 mL, 15 mmol) and DLP
(13%). Flash chromatography on a silica gel column using a gradi-
ent petroleum ether/diethyl ether (9:1) afforded the addition prod-
uct 5m (1.12 g) as a pale yellow oil in 62% yield. 1H NMR (200 MHz,
CDCl3) d 7.94 (1H, ddd, JH–H = 8.5 Hz, JH–F = 8.5 and 7.0 Hz, CHAr),
7.02–6.82 (2H, m, 2CHAr), 4.62 (2H, q, J = 7.1 Hz, OCH2CH3), 4.00
(1H, m, CHS), 3.73 (1H, dd, J = 10.0 and 4.2 Hz, CHSCHHO), 3.62–
3.48 (m, 3H, CHSCHHO, OCH2), 3.19–3.10 (2H, m, COCH2), 2.35
(IH, m, CHHCHS), 2.05 (1H, m, CHHCHS), 1.40 (3H, t, J = 7.1 Hz,
OCH2CH3), 1.18 (3H, t, J = 7.0 Hz, CH2OCH2CH3). 13C NMR
(50 MHz, CDCl3) d 213.7 (CS), 195.2 (d, JC–F = 4.0 Hz, CO), 165.5
(Cq, dd, JC–F = 257.0 and 12.5 Hz, CF), 162.5 (Cq, dd, JC–F = 257.0
and 12.5 Hz, CF), 132.4 (dd, JC–F = 10.0 and 4.0 Hz, CHAr), 121.9
(d, JC–F = 13.0 Hz, CqAr), 111.8 (CH, d, JC–F = 21.5 Hz, CHAr), 104.4
(t, JC–F = 26.5 Hz, CHAr), 72.0 (CH2O), 69.6 (OCH2CH3), 66.3
(OCH2), 49.7 (CHS), 40.3 (d, JC–F = 7.5 Hz, COCH2), 25.2 (CH2), 14.8,
13.4 (CH3). IR (neat) 1687, 1610 cmꢀ1. MS (CI) 380 (M+NH4)+,
363 (M+H)+.
(OCO), 166.0 (dd, JC–F = 12.4 Hz, JC–F = 257.4 Hz, CF), 162.9 (dd, JC–F
=
12.5 Hz, JC–F = 257.3 Hz, CF), 132.8 (dd, JC–F = 4.2 Hz, JC–F = 10.6 Hz,
CHAr), 121.8 (Cq, dd, JC–F = 3.5 Hz, JC–F = 13.1 Hz), 112.4 (dd, JC–F
3.3 Hz, JC–F = 21.4 Hz, CHAr), 104.8 (dd, JC–F = 25.5 Hz, JC–F
=
=
27.7 Hz, CHAr), 80.0 (CHOCO), 70.2 (OCH2CH3), 39.0 (d,
JC–F =8.3 Hz, CH2CO), 38.9 (Cq), 28.4 (d, JC–F = 1.8 Hz, CH2CHS), 27.0
(C(CH3)3), 13.7 (OCH2CH3). IR (CDCl3) 1739, 1691, 1614 cmꢀ1. MS
(CI) 422 MH+NH3+. HRMS (EI+) [MꢀSCSOEt] 284.1209 (Measured
mass), 284.1224 (Calculated Mass).
4.2.11. 5-(2,4-Difluorophenyl)-2-ethoxythiocarbonylsulfanyl-5-
oxo-pentyl-phosphonic acid diethyl ester 5k
The reaction was run in cyclohexane (5 mL) with xanthate 4a
(1.38 g, 5 mmol), allyl phosphonate (1.78 g, 10 mmol) and DLP
(11%). Flash chromatography on a silica gel column using a gradi-
ent petroleum ether/diethyl ether (8:2) afforded the addition prod-
uct 5k (1.84 g) as a yellow oil in 81% yield. 1H NMR (200 MHz,
CDCl3) d 7.90 (1H, ddd, JH–H = 8.6 Hz, JH–F = 8.6 and 6.6 Hz, CHAr),
6.93 (1H, dddd, JH–H = 8.6 and 2.5 Hz, JH–F = 7.6 and 0.7 Hz, CHAr),
6.84 (1H, ddd, JH–H = 2.5 Hz, JH–F = 11.1 and 8.7 Hz, CHAr), 4.61
(2H, q, J = 7.1 Hz, OCH2CH3), 4.17–4.07 (5H, m, CHS, 2POCH2CH3),
3.16–3.06 (2H, m, COCH2), 2.58–2.00 (4H, m, CH2, CH2P), 1.40
4.2.14. Ethyl-2-(tert-butoxycarbonyl(5-(2,4-difluorophenyl)-
2(ethoxycarbonothioylthio)-5-oxopentyl) amino)acetate 5n
The reaction was run in ethyl acetate (3.6 mL) with xanthate 4a
(1.0 g, 3.6 mmol), ethyl 2-(allyl (tert-butoxycarbonyl) amino) ace-
tate (2 equiv, 1.75 g) and DLP (10%). Flash chromatography on a sil-
ica gel column using a gradient petroleum ether/ethyl acetate (9:1)
afforded the addition product 5n (1.49 g) as a yellow oil in 80%
yield. 1H NMR (400 MHz, CDCl3)
d 7.91 (tt, 1H, J = 6.3 Hz,
J = 8.6 Hz, CHAr), 6.94 (m, 1H, CHAr), 6.85 (m, 1H, CHAr), 4.61 (q,
2H, J = 7.1 Hz, OCH2CH3), 4.19 (m, 2H, OCH2CH3), 4.08 (d, 1H,
J = 12.4 Hz, NCHHCO2Et), 4.01 (d, 1H, J = 6.7 Hz, NCHHCHS), 3.88
(m, 2H, NCHHCO2Et, CHS), 3.34 (m, 1H, NCHHCHS), 3.13 (m, 2H,
CH2CO), 2.34 (m, 1H, CHHCHS), 1.93 (m, 1H, CHHCHS), 1.43 (m,
12H, C(CH3)3, OCH2CH3), 1.27 (t, 1H, J = 7.2 Hz, OCH2CH3). 13C
NMR (100 MHz, CDCl3) d 213.8; 214.0 (CS), 195.8; 195.6 (CO, d,
(3H, t, J = 7.1 Hz, OCH2CH3), 1.31 (6H, dt, JH–H = 7.1 Hz, JH–P
2.3 Hz, 2POCH2CH3). 13C NMR (50 MHz, CDCl3) d 212.6 (CS), 195.1
(CO), 165.6 (dd, JC–F = 257.0 and 12.0 Hz, CF), 162.1 (dd, JC–F
=
=
257.0 and 12.0 Hz, CF), 132.5 (dd, JC–F = 10.5 and 4.5 Hz, CHAr),
121.9 (d, JC–F = 12.5 Hz, CqAr), 112.0 (d, JC–F = 21.5 Hz, CHAr),
104.6 (t, JC–F = 26.5 Hz, CHAr), 69.8 (OCH2CH3), 61.8, 61.7 (d, JC–P
=
6.0 Hz, 2POCH2CH3), 44.9 (CHS), 40.3 (d,. JC–F = 7.4 Hz, COCH2),
31.7 (d, JC–P = 137.5 Hz, CH2P), 27.9 (CH2), 16.2 (d, JC–P = 5.5 Hz,
2POCH2CH3)13.5 (OCH2CH3). IR (neat) 1687, 1609 cmꢀ1. MS (CI)
455 (M+H)+.
JC–F = 4.6 Hz; d, JC–F = 4.7 Hz), 170.1; 170.0 (OCO), 165.8 (ddd, JC–F =
8.3 Hz, JC–F = 12.1 Hz, JC–F = 256.9 Hz, CF), 162.8 (ddd, JC–F = 3.5 Hz,
JC–F = 12.9 Hz, JC–F = 257.6 Hz, CF), 155.5 (NCO), 132.7 (dd,
JC–F = 4.3 Hz, JC–F = 10.5 Hz, CHAr), 122.2 (Cq), 112.2 (ddd, JC–F
=
2.6 Hz, JC–F = 11.7 Hz, JC–F = 20.7 Hz, CHAr), 104.8 (m, CHAr), 81.1;
80.7 (C(CH3)3), 70.2; 70.3 (OCH2CH3), 61.1 (OCH2CH3), 52.0; 51.4
(NCH2CO2Et), 49.9; 49.8 (CHS), 49.6; 49.2 (NCH2CHS), 40.83;
40.57 (d, JC–F = 7.2 Hz; d, JC–F = 7.1 Hz, CH2CO), 28.4; 28.2 (CH3)3,
25.3; 24.9 (CH2CHS), 14.4; 14.2 (OCH2CH3), 13.8 (OCH2CH3). IR
(CDCl3) 1746, 1690, 1611 cmꢀ1. MS (CI) 420 M+ꢀBoc, 520 MH+.
4.2.12. S-5-(2,4-Difluorophenyl)-1,1-diethoxy-5-oxopentan-2-yl
O-ethyl carbonodithioate 5l
The reaction was run in ethyl acetate (3.6 mL) with xanthate 4a
(1.0 g, 3.6 mmol), 4,4-diethoxy-but-1-ene (2.0 equiv, 1.03 g) and
DLP (12.5%). Flash chromatography on a silica gel column using a

1656
P. Boutillier et al. / Tetrahedron: Asymmetry 21 (2010) 1649–1665
HRMS (EI+) 519.1574 (Measured mass), 519.1561(Calculated
mass).
257.4 Hz, CF), 152.4 (Cq), 147.2 (Cq), 132.3 (dd, JC–F = 4.2 Hz,
JC–F = 10.5 Hz, CHAr), 131.7 (Cq), 123.4 (CHPh), 122.3 (CHPh),
121.8 (Cq, dd, JC–F = 3.6 Hz, JC–F = 13.2 Hz), 111.8 (dd, JC–F = 3.3 Hz,
JC–F = 21.4 Hz, CHAr), 110.8 (CHPh), 104.4 (dd, JC–F = 25.5 Hz,
JC–F = 27.8 Hz, CHAr), 69.5 (OCH2CH3), 60.2 (OCH3), 55.3 (OCH3),
50.7 (CHS), 40.4 (d, J = 7.5 Hz, CH2CO), 34.5 (CH2), 27.3 (CH2),
13.4 (CH3). IR (CDCl3) 1690, 1607 cmꢀ1. MS (CI) 455 MH+, 472
MH+NH3+. HRMS (EI+) 454.1086 (Measured mass), 454.1084 (Cal-
culated mass).
4.2.15. Acetic acid 13-(2,4-difluorophenyl)-10-ethoxythiocarbon
ylsulfanyl-13-oxo-tridecyl ester 5o
The reaction was run in cyclohexane (5 mL) with xanthate 4a
(1.38 g, 5 mmol), olefin (1.59 g, 7.5 mmol) and DLP (7%). Flash
chromatography on a silica gel column using a gradient petroleum
ether/diethyl ether (9:1) afforded the addition product 5o (1.84 g)
as a pale yellow oil in 85% yield. 1H NMR (200 MHz, CDCl3) d 7.92
(1H, ddd, JH–H = 8.5 Hz, JH–F = 8.5 and 7.0 Hz, CHAr), 6.96 (1H, ddd,
JH–H = 8.5 and 2.5 Hz, JH–F = 8.0, CHAr), 6.87 (1H, ddd,
JH–H = 2.5 Hz, JH–F = 11 and 9.0 Hz, CHAr), 4.63 (1H, q, 7.1 Hz,
OCHHCH3), 4.60 (1H, q, 7.1 Hz, OCHHCH3), 4.05 (2H, t, J = 6.7,
CH2OAc), 3.80 (1H, m, CHS), 3.10 (2H, m, COCH2), 2.22 (1H, m,
CHHCHS), 2.05 (3H, s, OCOCH3), 1.98 (1H, m, CHHCHS), 1.73–1.67
(2H, m), 1.63–1.59 (2H, m), 1.46–1.38 (2H, m), 1.40 (3H, t,
J = 7.1 Hz, OCH2CH3), 1.28 (10H, br s, 5CH2). 13C NMR (50 MHz,
CDCl3) d 214.4 (CS), 195.8 (d, JC–F = 4.0 Hz, CO), 171.0 (OCOCH3),
165.7 (dd, JC–F = 257.0 and 12.5 Hz, CF), 162.6 (dd, JC–F = 257.0
and 12.5 Hz, CF), 132.6 (dd, JC–F = 10.5 et 4.0 Hz, CHAr), 122.2 (d,
JC–F = 13.0 Hz, CqAr), 112.1 (d, JC–F = 21.5 Hz, CHAr), 104.7 (t,
JC–F = 26.5 Hz, CHAr), 69.7 (OCH2CH3), 64.5 (CH2OAc), 50.9 (CHS),
40.5 (d, JC–F = 7.5 Hz, COCH2), 34.6, 29.3, 29.2, 28.6, 28.4, 26.8,
25.9 (CH2), 20.9 (OCOCH3), 13.7 (OCH2CH3). IR (neat) 1738, 1687,
1610 cmꢀ1. MS (CI) 506 (M+NH4)+, 489 (M+H)+.
4.2.18. S-1-(2,4-Difluorophenyl)-6-(5,5-dimethyl-1,3-dioxan-2-
yl)-6-methyl-1-oxoheptan-4-yl O-ethyl carbonodithioate 5r
The reaction was run in ethyl acetate (3.6 mL) with xanthate 4a
(1.0 g, 3.6 mmol), 5,5-dimethyl-2-(2-methylpent-4-en-2-yl)-1,3-
dioxane (2.0 equiv, 1.4 g) and DLP (12.5%). Flash chromatography
on a silica gel column using a gradient petroleum ether/diethyl
ether (2:3) afforded the addition product 5r (1.36 g) as a colourless
oil in 80% yield. 1H NMR (400 MHz, CDCl3) d 7.92 (dt, 1H,
JH–F = 6.7 Hz, JH–H = 8.6 Hz, CHAr), 6.95 (m, 1H, CHAr), 6.85 (ddd,
1H, JH–H = 2.4 Hz, JH–H = 8.7 Hz, JH–F = 11.1 Hz, CHAr), 4.62 (m, 2H,
OCH2CH3), 4.13 (s, 1H, CHOCH2CCH3), 3.94 (m, 1H, CHS), 3.58 (d,
2H, J = 11.0 Hz, OCH2C(CH3)2), 3.38 (dd, 2H, J = 1.6 Hz, J = 11.0 Hz,
OCH2C(CH3)2), 3.09 (m, 2H, CH2CO), 2.21 (m, 1H, CHHCHS), 2.01
(m, 1H, CHHCHS), 1.75 (dq, 2H, J = 5.8 Hz, J = 15.1 Hz,
CHSCH2C(CH3)), 1.40 (t, 3H, J = 7.1 Hz, OCH2CH3), 1.14 (s, 3H,
CH2CCH3), 1.02 (s, 3H, CCH3), 0.99 (s, 3H, CCH3), 0.70 (s, 3H,
CH2CCH3). 13C NMR (100 MHz, CDCl3) d 214.5 (CS), 196.2 (CO, d,
JC–F = 4.7 Hz), 165.7 (dd, JC–F = 12.3 Hz, JC–F = 256.8 Hz, CF), 162.7
(dd, JC–F = 12.5 Hz, JC–F = 257.5 Hz, CF), 132.7 (dd, JC–F = 4.3 Hz,
JC–F = 10.5 Hz, CHAr), 122.3 (Cq, dd, JC–F = 3.6 Hz, JC–F = 13.2 Hz),
112.2 (dd, JC–F = 3.4 Hz, JC–F = 21.4 Hz, CHAr), 106.5 (CHOCH2CCH3),
104.8 (dd, JC–F = 25.4 Hz, JC–F = 27.8 Hz, CHAr), 77.33, 77.36
(2OCH2C(CH3)2), 69.7 (OCH2CH3), 46.5 (CHS), 41.4 (CH2C(CH3)2),
40.6 (d, J = 7.6 Hz, CH2CO), 38.3 (C(CH3)2), 31.8 (d, JC–F = 1.6 Hz,
CH2CHS), 30.2 (C(CH3)2), 23.0 (CH3), 22.7 (CH3), 22.4 (CH3), 21.8
(CH3), 13.8 (OCH2CH3). IR (CDCl3) 1681, 1606 cmꢀ1. MS (CI) 475
MH+, 492 MH+NH3+. HRMS (EI+) [MꢀSCSOEt] 354.2019 (Measured
mass), 354.2007 (Calculated mass).
4.2.16. 2-Acetylamino-2-[5-(2,4-difluorophenyl)-2-ethoxythio-
carbonylsulfanyl-5-oxo-pentyl] -malonic acid diethyl ester 5p
The reaction was run in cyclohexane (2 mL) with xanthate 4a
(0.552 g, 2 mmol), olefin (0.771 g, 3.0 mmol) and DLP (7%). Flash
chromatography on a silica gel column using a gradient petroleum
ether/ethyl acetate (6:4) afforded the addition product 5p (1.16 g)
contaminated with the olefin in excess (ratio: 9:1) in 76% NMR
yield. 1H NMR (400 MHz, CDCl3) d 7.88 (1H, ddd, JH–H = 8.2 Hz,
JH–F = 8.2 and 7.0 Hz, CHAr), 6.92 (1H, m, CHAr), 6.90 (1H, s, NH),
6.83 (1H, m, CHAr), 4.58 (2H, q, J = 7.1 Hz, OCH2CH3), 4.25–4.17
(4H, m, 2CO2CH2CH3), 3.78 (1H, m, CHS), 3.12–2.95 (2H, m, COCH2),
2.91 (1H, dd, J = 15.5 and 3.4 Hz, CHHCNHAc), 2.70 (1H, dd, J = 15.5
and 10.2 Hz, CHHCNHAc), 2.12 (1H, m, CHHCHS), 2.04 (3H, s,
NHCOCH3), 2.01 (IH, m, CHHCHS), 1.36 (3H, t, J = 7.1 Hz, OCH2CH3),
1.26–1.21 (6H, m, 2CO2CH2CH3). 13C NMR (100 MHz, CDCl3) d
213.6 (CS), 195.6 (d, JC–F = 4.7 Hz, ArCO), 169.6, 167.9, 167.5
(3CO), 165.7 (dd, JC–F = 257.0 and 12.2 Hz, CF), 162.7 (dd,
JC–F = 257.0 and 12.5 Hz, CF), 132.6 (m, CHAr), 122.0 (d,
4.2.19. tert-Butyl-5-(2,4-difluorophenyl)-2-(ethoxycarbon-
othioylthio)-5-oxopentyl(4-methoxybenzyl) carbamate 5t
The reaction was run in ethyl acetate (3.6 mL) with xanthate 4a
(1.0 g, 3.6 mmol), tert-butyl allyl(4-methoxybenzyl)carbamate
(2.0 equiv, 2.0 g) and DLP (12.5%). Flash chromatography on a silica
gel column using a gradient petroleum ether/ethyl acetate (9:1)
afforded the addition product 5t (1.93 g) as a yellow oil in 97%
yield. 1H NMR (400 MHz, CDCl3) d 7.91 (dt, 1H, JH–F = 6.7 Hz,
JH–H = 8.6 Hz, CHAr), 7.21 (m, 2H, 2CHAr), 6.95 (m, 1H, CHPh),
6.86 (m, 3H, CHAr, CHPh), 4.61 (q, 2H, J = 7.1 Hz, OCH2CH3), 4.56
(d, 1H, J = 5.7 Hz, NCHHPh), 4.43 (m, 1H, NCHHPh), 4.04 (m, 1H,
SCH), 3.78 (s, 3H, OCH3), 3.60 (m, 1H, NCHHCHS), 3.32 (dd, 1H,
J = 7.2 Hz, J = 14.4 Hz, NCHHCHS), 3.09 (m, 2H, CH2CO), 2.23 (m,
1H, CHHCHS), 1.88 (m, 1H, CHHCHS), 1.48 (m, 9H, C(CH3)3), 1.38
(t, 3H, J = 7.1 Hz, OCH2CH3). 13C NMR (100 MHz, CDCl3) d 213.9
(CS), 195.8 (CO), 165.7 (dd, JC–F = 11.6 Hz, JC–F = 256.4 Hz, CF),
162.7 (dd, JC–F = 12.4 Hz, JC–F = 257.9 Hz, CF), 158.9 (Cq), 155.8
(NCO), 132.6 (dd, JC–F = 4.1 Hz, JC–F = 10.5 Hz, CHAr), 130.2 (Cq),
129.3; 128.8 (CHPh), 122.1 (Cq, dd, JC–F = 3.5 Hz, JC–F = 6.2 Hz),
113.9 (CHPh), 112.1 (d, JC–F = 21.4 Hz, CHAr), 104.7 (dd,
JC–F = 25.6 Hz, JC–F = 27.6 Hz, CHAr), 80.3; 80.4 (OC(CH3)3), 70.1
(OCH2CH3), 55.2 (OCH3), 49.5 (CHS), 49.3 (NCH2Ph), 40.5 (CH2CO),
29.6 (NCH2CHS), 28.4 (C(CH3)3), 25.7; 25.2 (CH2CHS), 13.7
(OCH2CH3). IR (CDCl3) 1686, 1611 cmꢀ1. MS (CI) 454 M+ꢀBoc,
554 MH+. HRMS (EI+) 553.1777 (Measured mass), 553.1768 (Calcu-
lated mass).
JC–F = 12.6 Hz, CqAr), 112.2 (d, JC–F = 21.2 Hz, CHAr), 104.8 (t, JC–F
=
26.6 Hz, CHAr), 70.2 (OCH2CH3), 65.4 (CqNHAc), 63.1 (CO2CH2CH3),
62.7 (CO2CH2CH3), 46.1 (CHS), 40.2 (d, JC–F = 7.6 Hz, COCH2), 36.1
(CH2), 30.5 (CH2), 23.0 (NHCOCH3), 14.0 (CH3), 13.7 (CH3).
4.2.17. S-5-(2,4-Difluorophenyl)-1-(2,3-dimethoxyphenyl)-5-
oxopentan-2-yl-O-ethyl-carbonodithi-oate 5q
The reaction was run in ethyl acetate (3.6 mL) with xanthate 4a
(1.0 g, 3.6 mmol), 1-allyl-2,3-dimethoxybenzene (2 equiv, 1.2 g)
and DLP (12.5%). Flash chromatography on a silica gel column
using a gradient petroleum ether/diethyl ether (4:2) afforded the
addition product 5q (1.31 g) as a yellow oil in 80% yield. 1H NMR
(400 MHz, CDCl3) d 7.88 (dt, 1H, JH–F = 6.7 Hz, JH–H = 8.6 Hz, CHAr),
6.99 (t, 1H, J = 7.91, CHPh), 6.93 (m, 1H, CHAr), 6.87 (m, 1H, CHPh),
6.82 (m, 2H, CHAr, CHPh), 4.59 (q, 2H, J = 7.1 Hz, OCH2CH3), 4.08
(m, 1H, CHS), 3.85 (s, 6H, 2OCH3), 3.14 (m, 2H, CH2Ph), 3.05 (d,
2H, J = 7.6 Hz, CH2CO), 2.18 (m, 1H, CHHCHS), 1.99 (m, 1H,
CHHCHS), 1.39 (t, 3H, J = 7.1 Hz, OCH2CH3). 13C NMR (100 MHz,
CDCl3) d 213.4 (CS), 195.2 (CO, d, JC–F = 4.6 Hz), 165.3 (dd, JC–F
12.2 Hz, JC–F = 256.5 Hz, CF), 162.3 (dd, JC–F = 12.5 Hz, JC–F
=
=

P. Boutillier et al. / Tetrahedron: Asymmetry 21 (2010) 1649–1665
1657
4.3. General procedure for the preparation of benzothiepinones
7
1471, 1445, 1383, 1251, 1211, 1152, 1118 1065, 1008, 937. MS
(CI) 283 MH+. HRMS (EI+) 282.0921 (Measured mass), 282.0910
(Calculated mass). Compound 8: 1H NMR (400 MHz, CDCl3) d 7.88
(dd, 1H, JH–F = 5.9 Hz, JH–H = 8.7 Hz, CHAr), 7.21 (m, 1H, CHAr),
6.93 (m, 1H, CHAr), 5.87 (tdd, 1H, J = 6.6 Hz, J = 10.2 Hz,
J = 16.8 Hz, CH@CH2), 5.04 (m, 2H, CH@CH2), 4.26 (s, 1H, SH),
3.02 (t, 2H, J = 7.4 Hz, CH2CO), 2.47 (m, 2H, CH2CH@CH2). 13C
NMR (100 MHz, CDCl3) d 199.0 (CO), 164.82 (d, JC–F = 255.5 Hz,
To a degassed solution of xanthate (n mmol) in a 1:1mixture of
ethanol and diethyl ether (n mL) was added ethylenediamine (4n
mmol). The reaction mixture was stirred under nitrogen at room
temperature for 20–30 min and then diluted with water. After
extraction with diethyl ether the combined organic layers were
washed with aqueous ammonium chloride and brine, respectively,
dried over magnesium sulfate and concentrated under vacuum.
The residue thus obtained was taken up in THF (10n mL) and
DBU (1.1 equiv) was added to the solution. The reaction mixture
was heated to reflux until there was complete consumption of
the starting material and then was washed with aqueous ammo-
nium chloride and extracted with diethyl ether. The organic layers
were washed with brine, dried over magnesium sulfate and evap-
orated under vacuum. Finally, the residue was purified by column
chromatography.
CF), 143.6 (Cq, d, JC–F = 8.6 Hz), 137.1 (CH@CH2), 132.6 (d, JC–F
9.9 Hz, CHAr), 131.4 (Cq), 115.6 (CH@CH2), 113.81 (d, JC–F
=
=
25.2 Hz, CHAr), 111.8 (d, JC–F = 21.9 Hz, CHAr), 39.0 (CH2CO), 28.2
(CH2). IR (CDCl3) 1672, 1597 cmꢀ1. HRMS (EI+) 210.0501 (Measured
mass), 210.0515 (Calculated mass).
4.3.3. 9-(8-Fluoro-5-oxo-2,3,4,5-tetrahydro-benzo[b]thiepin-2-
yl)-nonanoic acid methyl ester 7c
The reaction was carried out with xanthate 5c (0.2 g,
0.42 mmol) and ethylenediamine (0.1 mL, 4 mmol) in a 1:1 mix-
ture of ethanol and diethyl ether (0.42 mL). After 20 min, the mix-
ture was treated according to the general procedure (THF, 4.2 mL
and DBU, 0.07 mL) to furnish after purification on a silica gel col-
umn (petroleum ether/diethyl ether 3:2) the bicyclic product 7c
(0.070 g) as a colourless oil in 46% yield. 1H NMR (400 MHz, CDCl3)
d 7.83 (dd, 1H, JH–F = 6.1 Hz, JH–H = 8.7 Hz, CHAr), 7.15 (dd, 1H,
JH–H = 2.5 Hz, JH–F = 9.0 Hz, CHAr), 6.93 (dt, 1H, JH–H = 2.5 Hz,
JH–F = 8.3 Hz, CHAr), 3.65 (s, 3H, CO2CH3), 3.34 (dt, 1H, J = 6.7 Hz,
J = 11.5 Hz, CHHCO), 2.94 (dt, 1H, J = 6.7 Hz, J = 12.3 Hz, CHS), 2.68
(ddd, 1H, J = 3.2 Hz, J = 5.2 Hz, J = 11.6 Hz, CHHCO), 2.34 (m, 1H,
CHHCO2CH3), 2.28 (m, 2H, CHHCO2CH3, CHHCHS), 1.92 (m, 1H,
CHHCHS), 1.62 (m, 4H, CH2CH2CH2), 1.48 (m, 1H, CHHCH2), 1.36
(m, 1H, CHHCH2), 1.26 (s, 8H, 4CH2). 13C NMR (100 MHz, CDCl3) d
201.9 (CO), 174.3 (CO2CH3), 163.6 (d, JC–F = 255.3 Hz, CF), 143.9
4.3.1. 8-Fluoro-2-hexyl-3,4-dihydro-2H-benzo[b]thiepin-5-one 7a
The reaction was carried out with xanthate 5a (0.388 g,
1.0 mmol) and ethylenediamine (0.270 mL, 4 mmol) in a 1:1 mix-
ture of ethanol and diethyl ether (1 mL). After 20 min, the mixture
was treated according to the general procedure (THF, 10 mL and
DBU, 0.170 mL) to furnish after purification on a silica gel column
(petroleum ether/diethyl ether 95:5) the bicyclic product 7a
(0.224 g) as a colourless oil in 80% yield. 1H NMR (400 MHz, CDCl3)
d 7.84 (1H, ddd, JH–H = 8.7 Hz, JH–F = 6.1, CHAr), 7.16 (1H, dd, JH–H
2.5 Hz, JH–F = 9.0, CHAr), 6.94 (1H, ddd, JH–H = 2.5 and 8.7 Hz, JH–F
=
=
8.0 Hz, CHAr), 3.35 (1H, ddd, J = 11.5, J = 6.7 Hz, COCHH), 2.95 (1H,
dddd, J = 5.3, J = 12.5, J = 6.8, J = 6.8 Hz, CHS), 2.68 (1H, ddd,
J = 11.5 Hz, J = 5.3 Hz, J = 3.2 Hz, COCHH), 2.35 (1H, dddd,
J = 12.8 Hz, J = 5.3 Hz, J = 11.5 Hz, J = 5.3 Hz, CHH), 1.94 (1H, dddd,
J = 12.8 Hz, J = 12.5 Hz, J = 6.7 Hz, J = 3.2 Hz, CHH), 1.65–1.60 (2H,
m, CH2), 1.48 (1H, m), 1.38 (1H, m), 1.26 (6H, m), 0.88–0.84 (3H,
(Cq, d, JC–F = 9.2 Hz), 135.0 (Cq, d, JC–F = 2.8 Hz), 132.5 (d, JC–F
9.6 Hz, CHAr), 117.2 (d, JC–F = 23.1 Hz, CHAr), 113.7 (d, JC–F
=
=
21.8 Hz, CHAr), 51.5, 51.3 (CHS, OCH3), 40.4 (CH2CO), 35.9
(CH2CO2CH3), 35.3 (CH2), 34.1(CH2), 29.28 (CH2), 29.25 (CH2),
29.18 (CH2), 29.15 (CH2), 27.4 (CH2), 24.9 (CH2). IR (CDCl3) 1728,
1673, 1594 cmꢀ1. MS (CI) 367 MH+. HRMS (EI+) 366.1684 (Mea-
sured mass), 366.1665 (Calculated mass).
m, CH3). 13C NMR (100 MHz, CDCl3) d 201.6 (CO), 163.5 (d, JC–F
255.0 Hz, CF), 143.9 (d, JC–F = 9.Hz, CF), 134.9 (CqAr), 132.4 (d,
C–F = 9.5 Hz, CHAr), 117.1 (d, JC–F = 23.0 Hz, CHAr), 113.6 (d, JC–F
22.0 Hz, CHAr), 51.3 (CHS), 40.3, 35.8, 35.3, 31.6, 29.0, 27.4, 22.5
=
J
=
(CH2), 14.0 (CH3). IR (neat) 1681, 1597 cmꢀ1
. MS (CI) 298
(M+NH4)+, 281 (M+H)+. Anal. Calcd for C16H21FOS: C, 68.53; H,
7.55. Found: C, 68.35; H, 7.48.
4.3.4. 2-Benzyl-8-fluoro-3,4-dihydro-2H-benzo[b]thiepin-5-one
7d
The reaction was carried out with xanthate 5d (0.5 g,
1.26 mmol) and ethylenediamine (0.34 mL, 4 mmol) in a 1:1 mix-
ture of ethanol and diethyl ether (1.26 mL). After 20 min, the mix-
ture was treated according to the general procedure (THF, 12 mL
and DBU, 0.2 mL) to furnish after purification on a silica gel column
(petroleum ether/diethyl ether (95:5) the bicyclic product 7d
(0.220 g) as a colourless oil in 61% yield. 1H NMR (400 MHz, CDCl3)
d 7.84 (dd, 1H, JH–F = 6.1 Hz, JH–H = 8.8 Hz, CHAr) 7.29 (m, 2H, CHPh)
7.23 (m, 1H, CHAr) 7.15 (m, 3H, CHPh) 6.96 (m, 1H, CHAr) 3.27 (m,
2H, CH2Ph), 3.05 (dd, 1H, CHHCO, J = 6.8 Hz, J = 13.9 Hz) 2.89 (dd,
1H, CHHCO, J = 7.7 Hz, J = 13.9 Hz), 2.69 (m, 1H, CHS) 2.26 (m, 1H,
CHHCHS) 1.98 (m, 1H, CHHCHS). 13C NMR (100 MHz, CDCl3) d
4.3.2. 8-Fluoro-2-methylsilanylmethyl-3,4-dihydro-2H-benzo
[b]thiepin-5-one 7b and 1-(4-fluoro-2-mercaptophenyl)pent-4-
en-1-one 8
The reaction was carried out with xanthate 5b (0.25 g,
0.64 mmol) and ethylenediamine (0.17 mL, 4.0 mmol) in a 1:1 mix-
ture of ethanol and diethyl ether (0.64 mL). After 20 min, the mix-
ture was treated according to the general procedure (THF, 6.4 mL
and DBU, 0.10 mL) to furnish after purification on a silica gel col-
umn (petroleum ether/diethyl ether 97:3) the bicyclic product 7b
(0.032 g) as a colourless oil in 18% yield and the olefinic product
8 (0.012 g) as a colourless oil in 9% yield. Compound 7b: 1H NMR
(400 MHz, CDCl3) d 7.85 (dd, 1H, JH–F = 6.1 Hz, JH–H = 8.8 Hz, CHAr),
201.7 (CO), 163.6 (d, JC–F = 255.6 Hz, CF), 142.9 (Cq, d, JC–F
9.2 Hz), 137.9 (Cq), 135.1 (Cq, d, JC–F = 2.9 Hz), 132.5 (d, JC–F
=
=
7.13 (dd, 1H, JH–H = 2.5 Hz, JH–F = 9.0 Hz, CHAr) 6.93 (ddd, 1H, JH–H
=
2.5 Hz, JH–F = 7.8 Hz, JH–H = 8.8 Hz, CHAr), 3.36 (dt, 1H, J = 6.8 Hz,
J = 11.5 Hz, CHHCO), 3.08 (m, 1H, SCH), 2.66 (ddd, 1H, J = 2.9 Hz,
J = 5.3 Hz, J = 11.5 Hz, CHHCO), 2.39 (m, 1H, CHHCHS), 1.95 (m,
1H, CHHCHS), 1.14 (dd, 1H, J = 6.5 Hz, J = 14.6 Hz, CHHSiMe3),
1.00 (dd, 1H, J = 8.8 Hz, J = 14.6 Hz, CHHSiMe3), 0.03 (s, 9H, CH3).
13C NMR (100 MHz, CDCl3) d 201.9 (CO), 163.6 (d, JC–F = 255.3 Hz,
CF), 144.7 (Cq, d, JC–F = 9.1 Hz), 134.5 (Cq, d, JC–F = 2.8 Hz), 132.5
(d, JC–F = 9.6 Hz, CHAr), 116.7 (d, JC–F = 23.1 Hz, CHAr), 113.7 (d,
JC–F = 21.8 Hz, CHAr), 49.0 (CHS), 40.8 (CH2CO), 39.1 (CH2), 24.9
(CH2), ꢀ0.71 (SiCH3). IR (CDCl3) 2954, 2856, 2251, 1673, 1595,
9.6 Hz, CHAr), 129.1 (CHPh), 128.5 (CHPh), 126.9 (CHPh), 117.5
(d, JC–F = 23.1 Hz, CHAr), 114.0 (d, JC–F = 21.7 Hz, CHAr), 51.7
(CHS), 41.6 (CH2Ph), 40.2 (CH2CO), 34.9 (CH2CHS). IR (CDCl3)
1691, 1608 cmꢀ1. MS (CI) 287 MH+, 304 MH+NH3+. HRMS (EI+)
286.0836 (Measured mass), 286.0828 (Calculated mass).
4.3.5. (8-Fluoro-5-oxo-2,3,4,5-tetrahydro-benzo[b]thiepin-2-
ylmethyl)-carbamic acid tert-butyl ester 7e
The reaction was carried out with xanthate 5h (0.433 g,
1.0 mmol) and ethylenediamine (0.270 mL, 4 mmol) in a 1:1 mix-

1658
P. Boutillier et al. / Tetrahedron: Asymmetry 21 (2010) 1649–1665
ture of ethanol/diethyl ether (1 mL). After 20 min, the mixture was
treated according to the general procedure (THF, 10 mL and DBU,
0.170 mL) to furnish after purification on a silica gel column
(petroleum ether/ethyl acetate 8:2) the bicyclic product 7e
(0.251 g) as a white solid in 77% yield. 1H NMR (400 MHz, CDCl3)
d 7.82 (1H, dd, JH–H = 8.7 Hz, JH–F = 6.1 Hz, CHAr), 7.17 (1H, dd,
JH–H = 2.4 Hz, JH–F = 8.8 Hz, CHAr), 6.98 (1H, ddd, JH–H = 2.4 and
8.7 Hz, JH–F = 8.8 Hz, CHAr), 5.01 (1H, m, NH), 3.47 (1H, m, COCHH),
3.28–3.10 (3H, m, CHS, CH2NHBoc), 2.75 (1H, m, COCHH), 2.34 (1H,
m, CHH), 1.88 (1H, m, CHH), 1.40 (9H, s, CMe3). 13C NMR (100 MHz,
CDCl3) d 201.6 (CO), 163.7 (d, JC–F = 256.0 Hz, CF), 155.7 (NCO),
140.5 (CqS, d, JC–F = 9.6 Hz), 135.8 (CqAr), 132.6 (d, JC–F = 8.9 Hz,
CHAr), 118.4 (d, JC–F = 23.1 Hz, CHAr), 114.6 (d, JC–F = 21.9 Hz,
CHAr), 79.9 (CqMe3), 51.4 (CHS), 44.2 (CH2NHBoc), 40.0 (COCH2),
31.8 (CH2), 28.4 (CMe3).
ether/diethyl ether (3:2) the bicyclic product 7h (1.70 g) as a col-
ourless oil in 82% yield. 1H NMR (400 MHz, CDCl3) d 7.82 (dd, 1H,
JH–F = 6.1 Hz, JH–H = 8.8 Hz, CHAr), 7.14 (dd, 1H, JH–F = 2.5 Hz,
JH–F = 9.0 Hz, CHAr), 6.94 (m, 2H, CHAr, CHPh), 6.81 (dd, 1H,
J = 1.4 Hz, J = 8.2 Hz, CHPh), 6.71 (dd, 1H, J = 1.4 Hz, J = 7.7 Hz,
CHPh), 3.84 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.30 (m, 2H,CH2CO),
3.02 (dd, 1H, J = 7.1 Hz, J = 13.6 Hz, CHHPh), 2.91 (dd, 1H,
J = 7.7 Hz, J = 13.6 Hz, CHHPh), 2.68 (m, 1H, CHS), 2.25 (m, 1H,
CHHCHS), 1.98 (m, 1H, CHHCHS). 13C NMR (100 MHz, CDCl3) d
201.5 (CO), 163.3 (d, JC–F = 255.2 Hz, CF), 152.5 (Cq), 147.1 (Cq),
142.7 (Cq, d, JC–F = 9.1 Hz), 135.1(Cq, d, JC–F = 2.8 Hz), 132.2 (d, JC–F
=
9.6 Hz, CHAr), 131.6 (Cq), 123.6 (CHPh), 122.3 (CHPh), 117.3 (d,
JC–F = 23.1 Hz, CHAr), 113.6 (d, JC–F = 21.7 Hz, CHAr), 111.1 (CHPh),
60.3 (OCH3), 55.4 (OCH3), 50.8 (CHS), 40.1 (CH2CO), 35.6 (CH2Ph),
34.7 (CH2). IR (CDCl3) 1676, 1595 cmꢀ1. MS (CI) 347 MH+, 364
MH+NH3+. HRMS (EI+) 346.0699 (Measured mass), 346.1039 (Cal-
culated mass).
4.3.6. (8-Fluoro-5-oxo-2,3,4,5-tetrahydro-benzo[b]thiepin-2-
ylmethyl)-methyl-carbamic acid tert-butyl ester 7f
The reaction was carried out with xanthate 5i (1.34 g,
3.0 mmol) and ethylenediamine (0.8 mL, 12 mmol) in a 1:1 mix-
ture of ethanol/diethyl ether (3 mL). After 30 min, the mixture
was treated according to the general procedure (THF, 30 mL and
DBU, 0.490 mL) to furnish after purification on a silica gel column
(petroleum ether/ethyl acetate 8:2) the bicyclic product 7f
(0.661 g) as a yellow oil in 65% yield. 1H NMR (400 MHz, CDCl3) d
7.85 (1H, dd, JH–H = 8.6 Hz, JH–F = 6.2 Hz, CHAr), 7.18 (1H, dd,
JH–H = 2.4 Hz, JH–F = 8.8 Hz, CHAr), 7.00 (1H, ddd, JH–H = 2.4 and
8.6 Hz, JH–F = 8.1 Hz, CHAr), 3.46–3.40 (2H, m), 3.33–3.25 (2H, m),
2.87 (3H, s, NCH3), 2.77 (1H, td, J = 4.7 and 12.6 Hz, COCHH), 2.29
(1H, m, CHH), 1.91 (1H, m, CHH), 1.44 (9H, s, 3Me). 13C NMR
(50 MHz, CDCl3) d 201.4 (CO), 163.7 (d, JC–F = 255.7 Hz, CF), 155.7
(NCO), 141.3 (CqS), 135.8 (CqAr), 132.5 (d, JC–F = 9.3 Hz, CHAr),
118.2 (d, JC–F = 23.0 Hz, CHAr), 114.4 (CH, d, JC–F = 21.8 Hz, CHAr),
80.0 (CqMe3), 52.5 (CH2NMeBoc), 49.3 (CHS), 40.0 (COCH2), 35.3
(NCH3), 32.0 (CH2), 28.4 (3Me). MS (CI) 357 (M+NH4)+, 340 (M+H)+.
4.3.9. 2-(2-(5,5-Dimethyl-1,3-dioxan-2-yl)-2-methylpropyl)-8-
fluoro-3,4-dihydrobenzo[b]thiepin-5(2H)-one 7i
The reaction was carried out with xanthate 5r (0.55 g,
1.16 mmol) and ethylenediamine (0.31 mL, 4 mmol) in a 1:1 mix-
ture of ethanol and diethyl ether (1.16 mL). After 20 min, the mix-
ture was treated according to the general procedure (THF, 11.6 mL
and DBU, 0.2 mL) to furnish after purification on a silica gel column
(petroleum ether/diethyl ether (95:5) the bicyclic product 7i
(0.301 g) as a colourless oil in 71% yield. 1H NMR (400 MHz, CDCl3)
d 7.81 (dd, 1H, JH–F = 6.1 Hz, JH–H = 8.8 Hz, CHAr), 7.11 (dd, 1H,
JH–H = 2.5 Hz, JH–F = 9.0 Hz, CHAr), 6.91 (ddd, 1H, JH–H = 2.5 Hz,
JH–F = 8.0 Hz, JH–H = 8.6 Hz, CHAr), 4.02 (s, 1H, CH(OEt) 2), 3.52 (m,
2H, OCH2CCH3), 3.30 (m, 3H, OCH2CCH3, CHHCO), 3.07 (m, 1H,
CHS) 2.61 (m, 1H, CHHCO), 2.34 (tdd, 1H, J = 5.3 Hz, J = 10.9 Hz,
J = 13.1 Hz, CHHCHS), 1.94 (ddt, 1H, J = 3.1 Hz, J = 6.7 Hz,
J = 13.0 Hz, CHHCHS), 1.74 (dd, 1H, J = 7.3 Hz, J = 15.0 Hz,
CHHC(CH3)2), 1.63 (dd, 1H, J = 3.9 Hz, J = 15.1 Hz, CHHC(CH3)2),
1.07 (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.89 (s, 3H, CH3), 0.65 (s, 3H,
4.3.7. 2-Diethoxymethyl-8-fluoro-3,4-dihydro-2H-
benzo[b]thiepin-5-one 7g
CH3). 13C NMR (100 MHz, CDCl3) d 201.6 (CO), 163.4 (d, JC–F
253.5 Hz, CF), 144.1 (Cq, d, JC–F = 9.1 Hz), 134.8 (Cq, d, JC–F
=
=
The reaction was carried out with xanthate 5l (0.1 g, 0.25 mmol)
and ethylenediamine (0.06 mL, 4 mmol) in a 1:1 mixture of ethanol
and diethyl ether (0.24 mL). After 20 min, the mixture was treated
according to the general procedure (THF, 2.5 mL and DBU, 0.03 mL)
to furnish after purification on a silica gel column (petroleum
ether/diethyl ether (2:3) the bicyclic product 7g (0.038 g) as a col-
ourless oil in 52% yield. 1H NMR (400 MHz, CDCl3) d 7.85 (dd, 1H,
JH–F = 6.1 Hz, JH–H = 8.8 Hz, CHAr), 7.19 (dd, 1H, JH–H = 2.5 Hz,
2.7 Hz), 132.3 (d, JC–F = 9.6 Hz, CHAr), 116.9 (d, JC–F = 23.0 Hz,
CHAr), 113.6 (d, JC–F = 21.8 Hz, CHAr), 106.7 (CH(OEt) 2), 77.2
(2OCH2CCH3) 2), 47.3 (CHS), 42.8 (CH2C(CH3)2), 40.2 (CH2CO),
38.4 (CH2CHS), 37.9 (C(CH3)2CH(OEt)2), 30.0 (C(CH3)2), 22.9 (CH3),
22.8 (CH3), 22.4 (CH3), 21.6 (CH3). IR (CDCl3) 1680, 1591 cmꢀ1
.
MS (CI) 367 MH+. HRMS (EI+) 366.1660 (Measured mass),
366.1665 (Calculated mass).
JH–F = 8.9 Hz, CHAr), 6.96 (ddd, 1H, JH–H = 2.5 Hz, JH–F = 7.9 Hz, JH–H
=
4.3.10. 8-Fluoro-5-oxo-2,3,4,5-tetrahydro-1-benzothiepin-2-
ylmethyl)-(4-methoxy-benzyl)carbamic acid tert-butyl ester 7j
The reaction was carried out with xanthate 5t (03.5 g,
6.4 mmol) and ethylenediamine (1.7 mL, 4 mmol) in a 1:1 mixture
of ethanol and diethyl ether (6.4 mL). After 20 min, the mixture
was treated according to the general procedure (THF, 64 mL and
DBU, 1.1 mL) to furnish after purification on a silica gel column
(petroleum ether/diethyl ether (95:5) the bicyclic product 7j
(1.56 g) as a colourless oil in 55% yield. 1H NMR (400 MHz, CDCl3)
d 7.86 (dd, 1H, JH–H = 8.65, JH–F = 6.1 Hz, CHAr), 7.16 (m, 3H, CHAr,
2CHPh), 7.02 (m, 1H, CHAr), 6.81 (m, 2H, CHPh), 4.57 (m, 1H,
NCHHPh), 4.33 (m, 1H, NCHHPh), 3.80 (OMe), 3.29 (m, 4H, CHS,
NCH2CHS, CHHCO), 2.73 (m, 1H, CHHCO), 2.27 (m, 1H, CHHCHS),
1.86 (m, 1H, CHHCHS), 1.51 (s, 9H, (CH3)3). 13C NMR (100 MHz,
CDCl3) d 201.6 (CO), 163.7 (d, JH–F = 255.7 Hz, CF), 159.0 (Cq),
155.8 (NCO), 142.2; 141.5 (Cq, m), 135.8; 135.2 (Cq, m), 132.5 (d,
8.7 Hz, CHAr), 4.59 (d, 1H, J = 4.1 Hz, CH(OEt)2), 3.70 (m, 2H,
OCH2CH3), 3.52 (m, 2H, OCH2CH3), 3.33 (m, 1H, CHS), 3.18 (m,
1H, CHHCO), 2.73 (m, 1H, CHHCO), 2.35 (m, 1H, CHHCHS), 2.24
(m, 1H, CHHCHS), 1.21 (m, 6H, 2OCH2CH3). 13C NMR (100 MHz,
CDCl3) d 201.9 (CO), 163.7 (d, JC–F = 255.6 Hz, CF), 142.8 (Cq, d, JC–F
=
9.1 Hz), 135.5 (Cq, d, JC–F = 2.8 Hz), 132.6 (d, JC–F = 9.6 Hz, CHAr),
117.8 (d, JC–F = 23.1 Hz, CHAr), 114.1 (d, JC–F = 21.7 Hz, CHAr),
103.4 (CH (EtO)2), 64.3 (OCH2CH3), 63.9 (OCH2CH3), 53.8 (CHS),
39.8 (CH2), 28.6 (CH2), 15.3 (CH3), 15.2 (CH3). IR (CDCl3) 1676,
1597 cmꢀ1. MS (CI) 253 MH+ꢀCH3CH2OH. HRMS (EI+) 298.1049
(Measured mass), 298.1039 (Calculated mass).
4.3.8. 2-(2,3-Dimethoxy-benzyl)-8-fluoro-3,4-dihydro-2H-
benzo[b]thiepin-5-one 7h
The reaction was carried out with xanthate 5q (2.8 g, 6.0 mmol)
and ethylenediamine (1.62 mL, 4 mmol) in a 1:1 mixture of ethanol
and diethyl ether (6.0 mL). After 20 min, the mixture was treated
according to the general procedure (THF, 60 mL and DBU, 0.9 mL)
to furnish after purification on a silica gel column (petroleum
JH–F = 9.5 Hz, CHAr), 129.9 (Cq), 129.2; 128.5 (CHPh), 118.1 (t, JH–F =
25.4 Hz, CHAr), 114.3 (d, JH–F = 21.7 Hz, CHAr), 114.0 (CHPh), 80.5
(C(CH3)3), 55.3 (OCH3), 51.1 (NCH2Ph), 50.3 (CHS), 50.0; 49.8
(NCH2CHS), 40.0 (CH2), 32.7; 32.2 (CH2), 28.4 (CH3)3. IR (CDCl3)

P. Boutillier et al. / Tetrahedron: Asymmetry 21 (2010) 1649–1665
1659
1689, 1598 cmꢀ1. HRMS (EI+) 445.1742 (Measured mass), 445.1723
(Calculated mass).
J = 6.9 Hz, CHPh), 6.87 (d, 2H, J = 8.2 Hz, CHPh), 4.63 (d, 1H,
J = 15.5 Hz, NCHHPh), 4.32 (d, 1H, J = 15.3 Hz, NCHHPh), 3.80 (s,
3H, OCH3), 3.62 (m, 3H, CHS, NCH2CHS), 3.00 (m, 2H, CH2CO),
2.17 (m, 1H, CHHCHS), 1.82 (m, 1H, CHHCHS), 1.46 (s, 9H,
4.3.11. 9-Fluoro-2-methyl-2,3,3a,4,5,10b-hexahydro-1H-10bk4-
thia-2-aza-benzo[e]azulen-6-one 10
C(CH3)3). 13C NMR (100 MHz, CDCl3) d 200.7 (CO), 163.9 (d, JC–F
=
To a solution of bicyclic product 7f (0.576 g, 1.7 mmol) in etha-
nol (5 mL) were added a few drops of concentrated HCl. After
30 min the solution was concentrated and the residue dissolved
in ethanol (5 mL). To this solution was added p-formaldehyde
(0.510 g, 17 mmol). The reaction mixture was refluxed for 15 h.
The same quantity of p-formaldehyde was added every 5 h until to-
tal consumption of the starting material. A solution of sodium
hydroxide (1 M) was added and the resulting solution was ex-
tracted with diethyl ether four times. The organic layers were
washed with brine, dried over MgSO4 and evaporated under re-
duced pressure to give the yellowish salt 10 (0.19 g) after chroma-
tography on a silica gel column (petroleum ether/dichloromethane/
ethyl acetate/triethylamine) 9:0.5:0.5 in 39% yield. 1H NMR
(400 MHz, CDCl3) d 7.26 (1H, dd, JH–H = 8.4 Hz, JH–F = 5.9 Hz, CHAr),
258.6 Hz, CF), 159.2 (Cq), 155.9 (NCO), 137.9 (Cq, d, JC–F = 6.8 Hz),
133.9 (Cq), 132.5 (d, JC–F = 8.1 Hz, CHAr), 128.8 (CHPh), 121.5 (d,
JC–F = 21.3 Hz, CHAr), 115.5 (d, JC–F = 25.3 Hz, CHAr), 114.1 (CHPh),
81.0 (C(CH3)3), 62.0 (CHS), 55.2 (OCH3), 51.1 (NCH2Ph),
45.5(NCH2CHS), 38.0 (CH2CO), 28.3 (C(CH3)3), 23.4 (CH2). IR (CDCl3)
1703, 1598 cmꢀ1. HRMS (EI+) 477.1640 (Measured mass), 477.1621
(Calculated mass).
4.4.3. 5-Fluoro-12-methyl-2,2-dioxo-2 k6-thia-12-aza-tricyclo
[8.3.1.03,8]tetradeca-3(8),4,6-trien-9-one 12a
To a solution of sulfone 11 (0.04 g, 0.1 mmol) in dry dichloro-
methane (0.75 mL) was added CF3COOH (0.25 mL). The reaction
mixture was stirred at room temperature until complete consump-
tion of the starting sulfone. After concentrating the reaction mix-
ture under reduced pressure without heating, Et3N (0.1 mL) was
added and the reaction mixture was stirred at room temperature
for 5 min. To the residue, obtained after evaporation of Et3N under
nitrogen stream, were added acetic acid (1.0 mL) and p-formalde-
hyde (1.5 equiv, 0.004 g). The reaction mixture was refluxed until
there was no more intermediate product and then evaporated un-
der reduced pressure. The residue thus obtained was purified on
silica gel (petroleum ether/diethyl ether (9:1) to afford an amor-
phous solid 12a (0.013 g) in 48% yield. 1H NMR (400 MHz, CDCl3)
d 7.75 (dd, 1H, JH–F = 2.5 Hz, JH–H = 8.3 Hz, CHAr), 7.58 (dd, 1H,
JH–H = 5.2 Hz, JH–F = 8.4 Hz, CHAr), 7.21 (m, 1H, CHAr), 3.45 (m,
2H, CHSO2, CHCO), 3.00 (m, 2H, NCH2CHSO2), 2.62 (d, 1H,
J = 12.9 Hz, NCHHCHCO), 2.46 (dd, 1H, J = 2.8 Hz, J = 12.8 Hz,
NCHHCHCO), 2.26 (m, 1H, CHHCHSO2), 2.11 (m, 1H, CHHCHSO2),
1.90 (s, 3H, NCH3). 13C NMR (100 MHz, CDCl3) d 203.7 (CO), 163.6
7.18 (1H, dd, JH–H = 2.4 Hz, JH–F = 8.9 Hz CHAr), 7.00 (1H, ddd, JH–H
=
2.4 and 8.4 Hz, JH–F = 8.4 Hz, CHAr), 3.75 (1H, m, CHS), 3.52 (1H, d,
J = 11.2 Hz, CHHCO), 3.47 (1H, d, J = 10.7 Hz, NCHHS), 3.40 (1H, d,
J = 10.7 Hz, NCHHS), 2.84 (1H, dd, J = 1.5 and 12.3 Hz, MeNCHH),
2.40 (1H, dd, J = 1.8 et 15.0 Hz, CHH), 2.31 (1H, dd, J = 2.3 and
12.3 Hz, MeNCHH), 2.27 (3H, s, NMe), 1.89(1H, d, J = 11.2 Hz,
CHHCO), 1.85 (IH, dd, J = 4.6 and 15.0 Hz, CHH). 13C NMR
(100 MHz, CDCl3) d 210.4 (CO), 163.6 (d, JC–F = 253.3 Hz, CF), 139.4
(CqAr), 135.1 (d, JC–F = 8.6 Hz, ArCqS), 131.0 (d, JC–F = 9.0 Hz, CHAr),
118.6 (d, JC–F = 23.0 Hz, CHAr), 114.5 (d, JC–F = 21.4 Hz, CHAr), 68.8
(SCH2), 60.4 (NCH2CH), 59.9 (CH2CO), 46.3 (NCH3), 39.6 (CHS),
31.5(CH2). MS (CI) 252 (M+H)+.
4.4. General procedure for the preparation of sulfones
To a sulfide (n mol) solution in dichloromethane (10n mL/
mmol) was added m-CPBA (2.7–3 equiv) at 0 °C and the reaction
mixture was stirred at room temperature. After complete con-
sumption of the starting sulfide, the reaction mixture was diluted
with dichloromethane and washed with saturated aqueous solu-
tions of Na2S2O3 and NaHCO3. The combined organic layers were
dried over MgSO4.
(d, J = 256.5 Hz, CF), 143.9 (Cq, d, JC–F = 2.0 Hz), 134.0 (Cq, d, JC–F =
3.7 Hz), 132.1 (d, JC–F = 8.2 Hz, CHAr), 118.7 (d, JC–F = 20.8 Hz,
CHAr), 112.2 (d, J = 26.3 Hz, CHAr), 59.6 (CHSO2), 53.9, 52.5
(NCH2CHSO2, NCH2CHCO), 47.7 (CHCO), 45.0 (NCH3), 26.0 (CH2).
IR (CDCl3) 1684, 1598 cmꢀ1. HRMS (EI+) 283.0671 (Measured
mass), 283.0678 (Calculated mass).
4.4.4. 5-Fluoro-12-(4-methoxy-benzyl)-2,2-dioxo-2k6-thia-12-
aza tricyclo[8.3.1.03,8]tetradeca-3(8),4,6-trien-9-one 18a
4.4.1. 8-Fluoro-1,1,5-trioxo-2,3,4,5-tetrahydro-1H-1 k6-1-benzot
hiepin-2-lmethylmethyl-carbamic acid tert-butyl ester 11
The reaction was run with sulfide 7f (0.24 g, 0.73 mmol) and m-
CPBA (3.0 equiv, 0.378 g) in CH2Cl2 (7.3 mL). A white amorphous
solid 11 (0.254 g) was isolated in 94% yield. 1H NMR (400 MHz,
CDCl3) d 7.74 (m, 2H, CHAr), 7.43 (m, 1H, CHAr), 3.64 (m, 3H,
NCH2CHS, CHS), 3.06 (m, 2H, CH2CO), 2.94 (s, 3H, NCH3), 2.24 (m,
1H, CHHCHS), 1.88 (m, 1H, CHHCHS), 1.44 (s, 9H, C (CH3)3). 13C
NMR (100 MHz, CDCl3) d 200.8 (CO), 164.1 (d, JC–F = 258.8 Hz, CF),
156.2 (NCO), 138.0 (Cq), 132.7 (d, JC–F = 7.1 Hz, CHAr), 130.2 (Cq),
121.7 (d, JC–F = 21.4 Hz, CHAr), 115.7 (d, JC–F = 22.2 Hz, CHAr), 80.6
(C(CH3)3), 61.9 (CHS), 48.0 (NCH2), 38.2 (CH2CO), 35.7 (NCH3),
28.4 (C(CH3)3), 23.3 (CH2). IR (CDCl3) 1694, 1597 cmꢀ1. MS (CI)
372 MH+. HRMS (EI+) 371.1235 (Measured mass), 371.1203 (Calcu-
lated mass).
To a solution of sulfone 17 (0.26 g, 0.55 mmol) in dry dichloro-
methane (4.2 mL) was added CF3COOH (1.4 mL). The reaction mix-
ture was stirred at room temperature until complete consumption
of the starting sulfone. After concentrating the reaction mixture
under reduced pressure without heating, Et3N (0.5 mL) was added
and the reaction mixture was stirred at room temperature for
5 min. To the residue, obtained after evaporation of Et3N under a
nitrogen stream, were added CH3COOH (5.0 mL), dioxane
(5.0 mL) and p-formaldehyde (2 equiv, 0.031 g). The reaction mix-
ture was refluxed until there was no more intermediate product
and then evaporated under reduced pressure. The residue thus ob-
tained was purified on silica gel (petroleum ether/diethyl ether
(9:1) to afford a white amorphous solid 18a (0.096 g) in 45% yield.
1H NMR (400 MHz, CDCl3) d 7.80 (dd, 1H, JH–F = 2.5 Hz, JH–H
=
8.3 Hz, CHAr), 7.52 (dd, 1H, JH–H = 5.2 Hz, JH–F = 8.4 Hz, CHAr),
7.27 (m, 1H, CHAr), 6.64 (d, 2H, J = 8.6 Hz, CHPh), 6.38 (d, 2H,
J = 8.5 Hz, CHPh), 3.76 (s, 3H, OMe), 3.58 (dd, 1H, J = 1.4 Hz,
J = 12.9 Hz, NCHHCHSO2), 3.51 (m, 1H, CHSO2,), 3.28 (d, 1H,
J = 12.8 Hz, NCHHPh), 3.09 (m, 1H, CHCO), 3.01 (m, 2H, NCHHPh,
NCHHCHCO), 2.71 (dd, 1H, J = 1.2 Hz, J = 12.7 Hz, NCHHCHCO),
2.52 (dd, 1H, J = 3.2 Hz, J = 12.9 Hz, NCHHCHSO2), 2.17 (m, 2H,
CH2CHSO2). 13C NMR (100 MHz, CDCl3) d 203.2 (CO), 163.8 (d,
JC–F = 256.8 Hz, CF), 159.1 (Cq), 143.9 (Cq, d, JC–F = 9.4 Hz), 134.1
4.4.2. 8-Fluoro-1,1,5-trioxo-2,3,4,5-tetrahydro-1H-1 k6-1-benzot
hiepin-2-ylmethyl)-(4-methoxy-benzyl)-carbamic acid tert-
butyl ester 17
The reaction was run with sulfide 7j (1.2 g, 2.7 mmol) and m-
CPBA (3.0 equiv, 1.39 g) in CH2Cl2 (27 mL). A yellow amorphous so-
lid 17 (1.16 g) was isolated in 90% yield. 1H NMR (400 MHz, CDCl3)
d 7.73 (dd, 1H, JH–F = 5.2 Hz, JH–H = 7.8 Hz, CHAr), 7.69 (dd, 1H,
JH–H = 2.6 Hz, JH–F = 7.6 Hz, CHAr), 7.42 (m, 1H, CHAr), 7.17 (d, 2H,

1660
P. Boutillier et al. / Tetrahedron: Asymmetry 21 (2010) 1649–1665
(Cq, d, JC–F = 4.0 Hz), 132.9 (d, JC–F = 8.2 Hz, CHAr), 130.0 (CHPh),
128.1 (Cq), 118.8 (d, JC–F = 21.2 Hz, CHAr), 113.6 (CHPh), 112.5 (d,
JC–F = 26.3 Hz, CHAr), 61.8 (NCH2Ph), 59.7 (CHSO2), 55.3 (OMe),
51.5, 51.2 (NCH2CHSO2, NCH2CHCO), 47.7 (CHCO), 26.4
(CH2CHSO2). IR (CDCl3) 1684, 1612 cmꢀ1. MS (CI) 390 MH+. HRMS
(EI+) 389.1093 (Measured mass), 389.1097 (Calculated mass).
(100 MHz, CDCl3) d 203.4 (CO), 163.8 (d, JC–F = 256.9 Hz, CF), 158.9
(Cq), 143.0 (Cq, d, JC–F = 6.8 Hz), 133.7 (Cq, d, JC–F = 4.0 Hz), 133.0
(d, JC–F = 8.1 Hz, CHAr), 130.1 (CHPh), 128.6 (Cq), 118.9 (d, JC–F
=
21.2 Hz, CHAr), 113.5 (CHPh), 113.0 (d, JC–F = 26.2 Hz, CHAr), 61.7
(CHSO2), 59.1 (NCH), 58.8 (NCH2Ph), 55.3 (OMe), 52.9 (CHCO),
44.0 (NCH2CHSO2), 22.2 (CH2), 8.0 (CH2), 5.9 (CH), 0.8 (CH2). IR
(CDCl3) 1677, 1612 cmꢀ1. MS (CI) 430 MH+ HRMS (EI+) 429.1373
(Measured mass), 429.1410 (Calculated mass).
4.4.5. 5-Fluoro-12-(4-methoxy-benzyl)-2,2-dioxo-11-trifluoro
methyl-2k6-thia-12-azatricyclo[8.3.1.03,8]tetradeca-3(8),4,6-
trien-9-one 18b
4.4.7. 5-Fluoro-12-(4-methoxy-benzyl)-2,2-dioxo-11-pentyl-2
k6-thia-12-azatricyclo[8.3.1.03,8] tetradeca-3(8),4,6-trien-9-one
18d
To a solution of sulfone 17 (0.03 g, 0.06 mmol) in dry dichloro-
methane (0.45 mL) was added CF3COOH (0.15 mL). The reaction
mixture was stirred at room temperature until complete consump-
tion of the starting sulfone. After concentrating the reaction mix-
ture under reduced pressure without heating, Et3N (60 lL) was
added and the reaction mixture was stirred at room temperature
for 5 min. To the residue, obtained after evaporation of Et3N under
To a solution of sulfone 17 (0.1 g, 0.21 mmol) in dry dichloro-
methane (1.5 mL) was added CF3COOH (0.5 mL). The reaction mix-
ture was stirred at room temperature until complete consumption
of the starting sulfone. After concentrating the reaction mixture un-
der reduced pressure without heating, Et3N (0.2 mL) was added and
the reaction mixture was stirred at room temperature for 5 min. To
the residue, obtained after evaporation of Et3N under a nitrogen
stream, were added CH3COOH (2.0 mL), dioxane (2.0 mL) and tri-
fluoroacetaldehyde methyl hemiacetal (4 equiv, 0.11 g). The reac-
tion mixture was refluxed until there was no more intermediate
product and then evaporated under reduced pressure. The residue
thus obtained was purified on silica gel (petroleum ether/diethyl
ether (9:1) to afford a yellow oily product 18b (0.062 g) in 65% yield.
1H NMR (400 MHz, CDCl3) d 7.62 (m, 2H, CHAr), 7.35 (m, 1H, CHAr),
6.65 (d, 2H, J = 8.6 Hz, CHPh), 6.31 (d, 2H, J = 8.5 Hz, CHPh), 3.78 (s,
3H, OCH3), 3.60 (m, 1H, NCHHCHSO2), 3.51 (m, 3H, NCH2Ph, CHSO2),
3.37 (m, 2H, NCHHCHSO2, CHCO), 3.23 (q, 1H, JH–F = 8.8 Hz,
NCHCF3), 2.89 (d, 1H, J = 15.9 Hz, CHHCHSO2), 2.57 (td, 1H,
J = 5.8 Hz, J = 15.9 Hz, CHHCHSO2). 13C NMR (100 MHz, CDCl3) d
199.9 (CO), 164.2 (d, JC–F = 258.3 Hz, CF), 159.3 (Cq), 142.5 (Cq, d,
a
nitrogen stream, were added CH3COOH (0.2 mL), dioxane
(0.4 mL) and hexanal (2 equiv, 0.01 mL).The reaction mixture was
heated at 60 °C until there was no more intermediate product
and then evaporated under reduced pressure. The residue thus ob-
tained was purified on silica gel (petroleum ether/diethyl ether
(9:1) to afford a light yellow oily product 18d (0.012 g) in 43%
yield. 1H NMR (400 MHz, CDCl3) d 7.65 (dd, 1H, JH–F = 2.4 Hz, JH–H
=
8.3 Hz, CHAr), 7.59 (dd, 1H, JH–H = 5.3 Hz, JH–F = 8.4 Hz, CHAr), 7.30
(m, 1H, CHAr), 6.62 (d, 2H, J = 8.4 Hz, CHPh), 6.26 (d, 2H, J = 8.4 Hz,
CHPh), 3.77 (s, 3H, OMe), 3.39 (m, 1H, CHSO2), 3.31 (d, 1H,
J = 13.5 Hz, NCHHCHSO2), 3.23 (br s, 2H, NCH2Ph), 3.04 (bd, 1H,
J = 5.7 Hz, CHCO), 2.94 (dd, 1H, J = 3.4 Hz, J = 13.5 Hz, NCHHCHSO2),
2.83 (bd, 1H, J = 15.5 Hz, CHHCHSO2), 2.51 (bd, 1H, J = 10.3 Hz,
NCHCHCO), 2.38 (td, 1H, J = 5.7 Hz, J = 15.6 Hz, CHHCHSO2), 1.27
(m, 8H, 4CH2), 0.89 (t, 3H, J = 6.7 Hz, CH3). 13C NMR (100 MHz,
CDCl3) d 203.3 (CO), 163.9 (d, JC–F = 256.8 Hz, CF), 159.0 (Cq),
143.5 (d, JC–F = 7.0 Hz, Cq), 133.6 (Cq, d, J = 3.7 Hz), 133.2 (d,
JC–F = 6.8 Hz), 133.5 (d, JC–F = 8.4 Hz, CHAr), 132.2 (Cq, d, JC–F
4.0 Hz), 128.9 (m, CF3), 130.7 (CHPh), 126.9 (Cq), 119.6 (d, JC–F
=
=
21.2 Hz, CHAr), 113.8 (CHPh), 113.5 (d, JC–F = 26.2 Hz, CHAr), 58.8
(NCH2Ph), 58.5 (CHSO2), 55.9 (d, JC–F = 25.1 Hz, NCHCF3), 55.3
(OCH3), 46.0 (CHCO), 43.8 (NCH2CHSO2), 21.9 (CH2CHSO2). IR
(CDCl3) 1684, 1612 cmꢀ1. MS (CI) 458 MH+. HRMS (EI+) 457.0973
(Measured mass), 457.0971 (Calculated mass).
JC–F = 8.1 Hz, CHAr), 130.3 (CHPh), 128.2 (Cq), 118.8 (d, JC–F
=
21.2 Hz, CHAr), 113.6 (CHPh), 112.6 (d, JC–F = 26.1 Hz, CHAr), 59.3
(CHSO2), 58.1 (NCH2Ph), 55.5, 55.3 (NCH, OMe), 49.7 (CHCO), 44.1
(NCH2CHSO2), 32.0 (CH2), 26.8 (CH2), 22.6 (CH2), 21.4 (CH2), 21.3
(CH2), 14.0 (CH3). IR (CDCl3) 1678, 1598 cmꢀ1 MS (CI) 460 MH+.
HRMS (EI+) 459.1880 (Measured mass), 459.1880 (Calculated
mass).
4.4.6. 11-Cyclopropyl-5-fluoro-12-(4-methoxy-benzyl)-2,2-
dioxo-2k6-thia-12-aza tricyclo [8.3.1.03,8]tetradeca-3(8),4,6-
trien-9-one 18c
To a solution of sulfone 17 (0.1 g, 0.20 mmol) in dry dichloro-
methane (1.35 mL) was added CF3COOH (0.45 mL). The reaction
mixture was stirred at room temperature until there was complete
consumption of the starting sulfone. After concentrating the reac-
tion mixture under reduced pressure without heating, Et3N
(0.18 mL) was added and the reaction mixture was stirred at room
temperature for 5 min. To the residue, obtained after evaporation of
Et3N under a nitrogen stream, were added CH3COOH (1.8 mL), diox-
ane (1.0 mL) and cyclopropanaldehyde (2 equiv, 0.01 mL). The reac-
tion mixture was refluxed until there was no more intermediate
product and then evaporated under reduced pressure. The residue
thus obtained was purified on silica gel (petroleum ether/diethyl
ether (9:1) to afford an off white solid 18c (0.051 g) in 60% yield.
Recrystallisation from (AcOEt, PE). Mp 179–181 °C. 1H NMR
(400 MHz, CDCl3) d 7.62 (td, 2H, JH–F = 4.1 Hz, JH–H = 8.3 Hz, CHAr),
7.33 (m, 1H, CHAr), 6.63 (d, 2H, J = 8.6 Hz, CHPh), 6.24 (d, 2H,
J = 8.6 Hz, CHPh), 3.77 (s, 3H, OMe), 3.44 (d, 2H, J = 13.0 Hz,
NCH2Ph), 3.35 (dd, 2H, J = 2.8 Hz, J = 13.4 Hz, NCHHCHSO2, CHSO2),
3.27 (d, 1H, J = 5.8 Hz, CHCO), 3.07 (dd, 1H, J = 3.8 Hz, J = 13.6 Hz,
NCHHCHSO2), 2.91 (dd, 1H, J = 1.5 Hz, J = 15.5 Hz, CHHCHSO2),
2.52 (td, 1H, J = 5.7 Hz, J = 15.5 Hz, CHHCHSO2), 1.89 (d, 1H,
J = 9.8 Hz, NCHCHCO), 1.12 (m, 1H, NCHCHcyclopr), 0.77 (m, 1H,
CHHcyclopr), 0.53 (ddd, 1H, J = 5.2 Hz, J = 9.0 Hz, J = 14.0 Hz,
CHHcyclopr), 0.32 (dt, 1H, J = 5.0 Hz, J = 10.0 Hz, CHHcyclopr),
ꢀ0.02 (dt, 1H, J = 5.1 Hz, J = 10.7 Hz, CHHcyclopr). 13C NMR
4.4.8. 5-Fluoro-12-(4-methoxy-benzyl)-2,2-dioxo-11-thiophen-
3-yl-2k6-thia-12-aza-tricyclo[8.3.1.03,8]tetradeca-3(8),4,6-trien-
9-one 18e
To a solution of sulfone 17 (0.05 g, 0.10 mmol) in dry dichloro-
methane (0.75 mL) was added CF3COOH (0.25 mL). The reaction
mixture was stirred at room temperature until there was complete
consumption of the starting sulfone. After concentrating the reac-
tion mixture under reduced pressure without heating, Et3N
(0.1 mL) was added and the reaction mixture was stirred at room
temperature for 5 min. To the residue, obtained after evaporation
of Et3N under nitrogen stream, were added CH3COOH (1.0 mL), diox-
ane (1.0 mL) and 3-thiophenaldehyde (2 equiv, 0.024 g).The reac-
tion mixture was refluxed until there was no more intermediate
product and then evaporated under reduced pressure. The residue
thus obtained was purified on silica gel (petroleum ether/diethyl
ether (9:1) to afford an off white solid 18e (0.044 g) in 95% yield.
Recrystallisation from (EtOAc, PE). Mp 173–175 °C. 1H NMR
(400 MHz, CDCl3) d 7.77 (dd, 1H, JH–F = 2.6 Hz, JH–H = 8.3 Hz, CHAr),
7.63 (dd, 1H, JH–H = 5.2 Hz, JH–F =8.4 Hz, CHAr), 7.37 (dd, 1H,
J = 2.9 Hz, J = 5.0 Hz, CHthp), 7.33 (m, 1H, CHAr), 7.11 (dd, 1H,
J = 1.3 Hz, J = 2.8 Hz, CHthp), 6.95 (dd, 1H, J = 1.3 Hz, J = 5.0 Hz,
CHthp), 6.60 (d, 2H, J = 8.6 Hz, CHPh), 6.19 (d, 2H, J = 8.6 Hz, CHPh),

P. Boutillier et al. / Tetrahedron: Asymmetry 21 (2010) 1649–1665
1661
3.87 (s, 1H, NCH), 3.77 (s, 3H, OMe), 3.62 (m, 1H, CHSO2), 3.46 (m, 2H,
NCH2CHSO2), 3.15 (m, 3H, CHCO, NCH2Ph), 2.93 (d, 1H, J = 15.7 Hz,
CHHCHSO2), 2.63 (m, 1H, CHHCHSO2). 13C NMR (100 MHz, CDCl3)
d 202.6 (CO), 163.9 (d, JC–F = 257.1 Hz, CF), 159.0, (Cq), 142.9 (Cq d,
JC–F = 6.9 Hz), 138.5 (Cq), 133.3 (d,, JC–F = 8.0 Hz, CHAr), 130.2 (CHPh),
128.1 (Cq), 127.9 (CHthp), 126.4 (CHthp), 123.0 (CHthp), 119.2 (d,
JC–F = 21.3 Hz, CHAr), 113.5 (CHPh), 112.8 (d, JC–F = 26.2 Hz, CHAr),
59.3 (CHSO2), 58.5 (NCH2Ph), 55.3 (OCH3), 54.6 (NCH), 53.0 (CHCO),
J = 1.4 Hz, J = 4.6 Hz, CHpyr), 7.74 (m, 2H, CHAr), 7.47 (dd, 1H,
JH–H = 2.2 Hz, JH–F = 8.3 Hz, CHAr), 7.39 (dd, 2H, J = 1.4 Hz,
J = 4.7 Hz,CHpyr) 6.65 (d, 2H, J = 8.6 Hz, CHPh), 6.25 (d, 2H,
J = 8.6 Hz, CHPh), 3.98 (br s, 2H, CHSO2, NCHPyr), 3.72 (s, 3H,
OMe), 3.56 (dd, 1H, J = 4.2 Hz, J = 14.1 Hz, NCHHCHSO2), 3.19 (d,
1H, J = 14.1 Hz, CHHCHSO2), 3.13 (d, 1H, J = 13.1 Hz, CHHPh), 3.07
(d, 1H, J = 13.0 Hz, CHHPh), 2.98 (d, 1H, J = 3.8 Hz, CHCO), 2.61
(m, 2H, CH2CHSO2).13C NMR (100 MHz, DMSO) d 202.8 (CO),
162.6 (d, JC–F = 253.2 Hz, CF), 158.1(Cq), 149.5 (CHpyr), 148.4
(Cq), 140.8 (d, J = 7.0 Hz, Cq), 133.5 (Cq, d, JC–F = 3.7 Hz), 132.8 (d,
JC–F = 8.6 Hz, CHAr), 129.8 (CHPh), 128.1(Cq), 123.4 (CHpyr), 119.6
45.2 (NCH2CHSO2), 21.8 (CH2CHSO2). IR (CDCl3) 1681, 1612 cmꢀ1
.
MS (CI) 472 MH+. HRMS (EI+) 471.0974 (Measured mass),
471.0974 (Calculated mass).
(d, JC–F = 21.7 Hz, CHAr), 112.9 CHPh), 111.57 (d, 1H, JC–F
=
4.4.9. 5-Fluoro-12-(4-methoxy-benzyl)-11-(3-methyl-pyridin-2-
yl)-2,2-dioxo-2k6-thia-12-aza-tricyclo[8.3.1.03,8]tetradeca-
3(8),4,6-trien-9-one 18f
26.3 Hz, CHAr), 57.8, 57.7 (NCHCHCO, CHSO2), 57.2 (NCH2Ph),
54.7 (OCH3), 52.0 (CHCO), 42.9 (NCH2SO2), 20.8 (CH2CHSO2). IR
(nujol) 1678, 1615, 1596 cmꢀ1. MS (CI) 467 MH+. HRMS (EI+)
466.1361 (Measured mass), 466.1363 (Calculated mass).
To a solution of sulfone 17 (0.05 g, 0.1 mmol) in dry dichloro-
methane (0.75 mL) was added CF3COOH (0.25 mL). The reaction
mixture was stirred at room temperature until there was complete
consumption of the starting sulfone. After concentrating the reac-
tion mixture under reduced pressure without heating, Et3N
(0.1 mL) was added and the reaction mixture was stirred at room
temperature for 5 min. To the residue, obtained after evaporation
of Et3N under a nitrogen stream, were added CH3COOH (1.0 mL),
dioxane (1.0 mL) and 6-methyl-2-pyridincarboxaldehyde (2 equiv,
0.024 mg). The reaction mixture was refluxed until there was no
more intermediate product and then evaporated under reduced
pressure. The residue thus obtained was purified on silica gel
(petroleum ether/diethyl ether (9:1) to afford a yellow oil 18f
(0.033 g) in 70% yield. 1H NMR (400 MHz, CDCl3) d 7.79 (dd, 1H,
JH–F = 2.6 Hz, JH–H = 8.3 Hz, CHAr), 7.64 (dd, 1H, JH–H = 5.2 Hz,
JH–F = 8.4 Hz, CHAr), 7.50 (t, 1H, J = 7.7 Hz, CHPyr), 7.33 (m, 1H,
CHAr), 7.07 (d, 1H, J = 7.7 Hz, CHPyr), 6.67 (d, 1H, J = 7.6 Hz, CHPyr),
6.59 (d, 2H, J = 8.6 Hz, CHPh), 6.17 (d, 2H, J = 8.6 Hz, CHPh), 4.22
(dd, 1H, J = 3.9 Hz, J = 12.9 Hz, NCHHCHSO2), 3.77 (s, 3H, OMe),
3.66 (m, 1H, CHSO2), 3.54 (br s, 1H, NCHPyr), 3.36 (m, 2H,
NCHHCHSO2, CHHCHSO2), 3.16 (m, 2H, NCHHPh, CHCO), 3.10 (d,
1H, J = 13.0 Hz, NCHHPh), 2.82 (dd, 1H, J = 1.3 Hz, J = 14.9 Hz,
CHHCHSO2), 2.57 (s, 3H, CH3).13C NMR (100 MHz, CDCl3) d 203.1
(CO), 164.0 (d, JC–F = 256.6 Hz, CF), 159.3 (Cq), 158.9 (Cq), 158.0
(Cq), 143.3 (Cq, d, J = 6.6 Hz), 136.7 (CHPyr), 133.4 (Cq, d,
J = 3.9 Hz), 133.1 (d, JC–F = 8.2 Hz, CHAr), 130.1 (CHPh), 128.6 (Cq),
122.1 (CHPyr), 120.5 (CHPyr), 118.9 (d, JC–F = 21.3 Hz, CHAr),
113.5 (CHPh), 112.7 (d, JC–F = 26.1 Hz, CHAr), 60.3 (CHSO2), 58.3
(NCH2Ph), 57.8 (NCH), 55.3 (OMe), 52.4 (CHCO), 45.2 (NCH2CHSO2),
24.9 (CH3), 21.3 (CH2CHSO2). IR (CDCl3) 1682, 1598 cmꢀ1. MS (CI)
481MH+. HRMS (EI+) 480.1502 (Measured mass), 480.1519 (Calcu-
lated mass).
4.4.11. 7-Fluoro-2-hexyl-1,2-dihydro-4H-thieno[2,3-
b][1]benzothiopyran-4-one 19a
The reaction was carried out with xanthate 5a (0.155 g,
0.4 mmol) and potassium carbonate (0.280 g, 2 mmol) in a 9:1
mixture of CH3CN/t-BuOH (4 mL). After 1 h 45 min, the mixture
was treated according to the general procedure to furnish after
purification on a silica gel column (petroleum ether/dichlorometh-
ane 5:5) the tricyclic product 19a (0.119 g) as white crystals in 92%
yield. Mp 84–85 °C (recrystallisation from Et2O at 0 °C). 1H NMR
(200 MHz, CDCl3) d 8.51 (1H, dd, JH–H = 9.6 Hz, JH–F = 6.0 Hz, CHAr),
7.26–7.15 (2H, m, 2CHAr), 4.05 (1H, m, CHS), 3.52 (1H. dd, J = 16.0
and 8.6 Hz, CHHCHS), 3.17 (1H, dd, J = 16.0 and 6.5 Hz, CHHCHS),
1.85–1.71 (2H, m, CH2), 1.45–1.21 (8H, m, 4CH2), 0.89 (3H, m,
CH3). 13C NMR (100 MHz, CDCl3) d 174.2 4 (CO), 163.6 (d, JC–F
=
255.0 Hz, CF), 152.5 (SCqS), 138.3 (d, JC–F = 9.5 Hz, ArCqS), 131.5
(d, JC–F = 9.4 Hz, CHAr), 130.5, 127.3 (2Cq), 115.7 (d, JC–F = 22.3 Hz,
CHAr), 111.8 (d, JC–F = 24.7 Hz, CHAr), 52.1 (CHS), 40.5, 36.5, 31.6,
28.9, 27.9, 22.5 (CH2), 14.0 (CH3). IR (CC14) 1622, 1598 cmꢀ1. MS
(CI) 323 (M+H)+. Anal. Calcd for C17H19FOS2: C, 63.32; H, 5.94.
Found: C, 62.91; H, 5.91.
4.4.12. 7-Fluoro-2-trimethylsilylmethyl-1,2-dihydro-4H-
thieno[2,3-b)][1]benzothiopyran-4-one 19b
The reaction was carried out with xanthate 5b (0.390 g,
1 mmol) and potassium carbonate (0.690 g, 5 mmol) in a 9:1 mix-
ture of CH3CN/t-BuOH (10 mL). After 5 h 30 min, the mixture was
treated according to the general procedure to furnish after purifica-
tion on a silica gel column (petroleum ether/dichloromethane 5:5)
the tricyclic product 19b (0.240 g) as beige crystals in 74% yield.
Mp 119–120 °C (recrystallisation from iPr2O at ꢀ20 °C). 1H NMR
(400 MHz, CDCl3) 8.40 (1H, dd, JH–H = 8.8 Hz, JH–F = 5.9 Hz, CHAr),
7.12–7.06 (2H, m, 2CHAr), 4.22 (1H, m, CHS), 3.49 (1H, dd, J = 8.0
and 15.6 Hz, CHHCHS), 2.97 (1H, dd, J = 8.6 and 15.6 Hz, CHHCHS),
1.23 (1H, dd, J = 8.5 and 14.5 Hz, CHHSiMe3), 1.17 (1H, dd, J = 7.0
and 14.5 Hz, CHHSiMe3), 0.05 (9H, s, SiMe3). 13C NMR (100 MHz,
CDCl3) d 173.9 (CO), 163.3 (d, JC–F = 255.1 Hz, CF), 153.0 (SCqS),
138.1 (d, JC–F = 9.7 Hz, ArCqS), 131.4 (d, JC–F = 9.6 Hz, CHAr), 130.7,
4.4.10. 5-Fluoro-12-(4-methoxy-benzyl)-2,2-dioxo-11-pyridin-
4-yl-2k6-thia-12-aza-tricyclo[8.3.1.03,8]tetradeca-3(8),4,6-trien-
9-one 18g
To a solution of sulfone 17 (0.05 g, 0.1 mmol) in dry dichloro-
methane (0.75 mL) was added CF3COOH (0.25 mL). The reaction
mixture was stirred at room temperature until there was complete
consumption of the starting sulfone. After concentrating the reac-
tion mixture under reduced pressure without heating, Et3N
(0.1 mL) was added and the reaction mixture was stirred at room
temperature for 5 min. To the residue, obtained after evaporation
of Et3N under a nitrogen stream, were added CH3COOH (1.0 mL),
dioxane (1.0 mL) and 4-pyridinecarboxaldehyde (2 equiv,
0.02 mL).The reaction mixture was refluxed until there was no
more intermediate product and then evaporated under reduced
pressure. The residue thus obtained was purified on silica gel
(petroleum ether/diethyl ether (9:1) to afford a light yellow solid
product 18g (0.045 g) in 97% yield. Recrystallisation from (EtOAc,
PE). Mp 191–192 °C. 1H NMR (400 MHz, DMSO) d 8.56 (dd, 2H,
127.2 (2Cq), 115.7 (d, JC–F = 22.1 Hz, CHAr), 111.7 (d, JC–F
=
24.7 Hz, CHAr), 50.2 (CHS), 43.0 (CH2), 24.6 (CH2SiMe3), ꢀ1.0
(SiMe3). IR (CC14) 1621, 1597. MS (CI) 325 (M+H)+. Anal. Calcd
for C15H17FOS2Si: C, 55.52; H, 5.28. Found: C, 55.39; H, 5.27.
4.4.13. 2-Benzyl-7-fluoro-2,3-dihydro-thieno[2,3-
b]thiochromen-4-one 19c
The reaction was carried out with xanthate 5d (0.514 g,
1.30 mmol) and potassium carbonate (0.897 g, 5 mmol) in a 9:1
mixture of CH3CN/t-BuOH (13 mL). After 3 h 30 min, the mixture
was treated according to the general procedure to furnish after
purification on a silica gel column (petroleum ether/diethyl ether

1662
P. Boutillier et al. / Tetrahedron: Asymmetry 21 (2010) 1649–1665
8:2) the tricyclic product 19c (0.255 g) as light pink crystals in 60%
yield. 1H NMR (400 MHz, CDCl3) d 8.52 (dd, 1H, JH–F = 5.9 Hz, JH–H
16.1 Hz, CHHCHS), 3.16 (1H, dd, J = 6.9 and 16.1 Hz, CHHCHS),
2.36–2.22 (2H, m, CH2P), 1.40–1.29 (6H, m, 2P(O)OCH2CH3). 13C
NMR (50 MHz, CDCl3) d 173.7 (CO), 163.3 (d, JC–F = 255.2 Hz, CF),
151.8 (SCqS), 137.9 (d, JC–F = 9.6 Hz, ArCqS), 131.2 (d, JC–F = 9.6 Hz,
CHAr), 129.5, 127.0 (2Cq), 115.6 (d, JC–F = 22.3 Hz, CHAr), 111.7 (d,
JC–F = 24.9 Hz, CHAr), 61.9 (d, JC–P = 6.0 Hz, 2P(O)OCH2CH3), 45.2
(d, JC–P = 2.6 Hz CHS), 41.4 (d, JC–P = 11.5 Hz, CH2), 32.8 (d,
JC–P = 139.9 Hz, CH2P), 16.2 (d, JC–P = 5.4 Hz, 2P(O)OCH2CH3). IR
(CC14) 1623, 1598 cmꢀ1. MS (CI) 389 (M+H)+. Anal. Calcd for
=
9.6 Hz, CHAr), 7.33 (m, 2H, CHPh), 7.22 (m, 5H, CHAr, CHPh), 4.29
(tt, 1H, J = 6.5 Hz, J = 8.4 Hz, CHS) 3.47 (dd, 1H, J = 8.4 Hz,
J = 16.1 Hz, CHHPh) 3.32 (dd, 1H, J = 5.9 Hz, J = 16.1 Hz, CHHPh),
3.12 (dd, 1H, J = 6.7 Hz, J = 14.0 Hz, CHHCCO), 3.04 (dd, 1H,
J = 8.5 Hz, J = 13.9 Hz, CHHCCO). 13C NMR (100 MHz, CDCl3) d
174.5 (CO), 163.6 (d, JC–F = 255.3 Hz, CF), 152.6 (Cq), 138.4 (Cq, d,
JC–F = 9.7 Hz), 138.1 (Cq), 131.6 (d, JC–F = 9.6 Hz, CHAr), 130.3 (Cq),
129.1 (2 CHPh), 128.8 (2CHPh), 127.4 (Cq, d, JC–F = 2.3 Hz), 127.1
(CHPh), 116.0 (d, JC–F = 22.2 Hz, CHAr), 112.0 (d, JC–F = 24.9 Hz,
CHAr), 53.0 (CHS), 42.4 (CH2), 40.0 (CH2). IR (CDCl3) 1620, 1596,
cmꢀ1. MS (CI) 329 MH+. HRMS (EI+) 328.0392 (Measured mass),
328.0392 (Calculated mass).
C16H18FNO4PS2: C, 49.48; H, 4.67. Found: C, 49.09; H, 4.62.
4.4.17. 2-Diethoxymethyl-7-fluoro-2,3-dihydro-thieno[2,3-
b]thiochromen-4-one 19g
The reaction was carried out with xanthate 5l (0.100 g,
0.24 mmol) and potassium carbonate (0.165 g, 5 mmol) in a 9:1
mixture of CH3CN/t-BuOH (2.4 mL). After 3 h 30 min, the mixture
was treated according to the general procedure to furnish after
purification on a silica gel column (petroleum ether/diethyl ether
4:1) the tricyclic product 19g (0.077 g) as light brown crystals in
95% yield. 1H NMR (400 MHz, CDCl3) d 8.52 (dd, 1H, JH–F = 5.9 Hz,
JH–H = 9.6 Hz, CHAr), 7.20 (m, 2H, CHAr), 4.59 (d, 1H, J = 7.8 Hz,
CH(OEt)2), 4.22 (ddd, 1H, J = 6.8 Hz, J = 7.8 Hz, J = 9.5 Hz, CHS),
3.73 (m, 2H, OCH2CH3), 3.62 (m, 2H, OCH2CH3), 3.48 (dd, 1H,
J = 9.5 Hz, J = 16.5 Hz, CHHCCO), 3.38 (dd, 1H, J = 6.7 Hz,
J = 16.5 Hz, CHHCCO), 1.25 (m, 3H, OCH2CH3), 1.22 (m, 3H,
OCH2CH3). 13C NMR (100 MHz, CDCl3) d 174.2 (CO), 163.6 (d,
JC–F = 255.4 Hz, CF), 152.4 (Cq), 138.2 (Cq, d, JC–F = 9.6 Hz), 131.5
(d, JC–F = 9.6 Hz, CHAr), 130.3 (Cq), 127.2 (Cq, d, JC–F = 2.3 Hz),
115.9 (d, JC–F = 22.2 Hz, CHAr), 111.9 (d, JC–F = 24.9 Hz, CHAr),
104.1 (CH(OEt)2), 63.7 (OCH2CH3), 62.5 (OCH2CH3), 52.7 (CHS),
36.2 (CH2), 15.3 (2CH3). IR (CDCl3) 1623, 1599 cmꢀ1. MS (CI) 341
MH+. HRMS (EI+) 340.0612 (Measured mass), 340.0603 (Calculated
mass).
4.4.14. N-(7-Fluoro-4-oxo-2,3-dihydro-4H-thieno[2,3-
b]thiochromen-2-ylmethyl)-acetamide 19d
The reaction was carried out with xanthate 5g (.050 g,
0.13 mmol) and potassium carbonate (0.089 g, 5 mmol) in a 9:1
mixture of CH3CN/t-BuOH (1.3 mL). After 3 h 30 min, the mixture
was extracted with diethyl ether, which furnished an off white
crystalline tricyclic product 19d (0.038 g) in 96% yield. 1H NMR
(400 MHz, DMSO) d 8.52 (dd, 1H, JH–F = 5.9 Hz, JH–H = 9.6 Hz, CHAr),
7.22 (m, 2H, CHAr), 5.9 (br s, 1H, NHAc), 4.23 (ddt, 1H, J = 3.8 Hz,
J = 6.4 Hz, J = 8.3 Hz, CHS), 3.54 (td, 1H, J = 6.3 Hz, J = 13.6 Hz,
CHHCCO), 3.38 (m, 3H, CHHCCO, CH2NH), 2.01 (s, 3H, Ac). 13C
NMR (100 MHz, DMSO) d 173.1 (CO), 169.5 (COCH3), 162.8 (d, JC–F
=
252.4 Hz, CF), 151.3 (Cq), 137.6 (Cq, d, JC–F = 10.4 Hz), 130.7 (d,
JC–F = 9.9 Hz, CHAr), 129.6 (Cq), 126.7 (Cq, d, JC–F = 2.2 Hz), 116.0
(d, JC–F = 22.7 Hz, CHAr), 112.7 (d, JC–F = 25.7 Hz, CHAr), 49.6
(CHS), 42.9 (CH2), 37.3 (CH2), 22.3 (COCH3). IR (nujol) 1650, 1616,
1591 cmꢀ1. MS (CI) 310 MH+. HRMS (EI+) 309.0287 (Measured
mass), 309.0294 (Calculated mass).
4.4.15. 2-(tert-Butoxycarbonylamino-methyl)-7-fluoro-1,2-
dihydro-4H-thieno[2,3-b)][1] benzo thio pyran-4-one 19e
The reaction was carried out with xanthate 5h (0.433 g,
1 mmol) and potassium carbonate (0.690 g, 5 mmol) in a 9:1 mix-
ture of CH3CN/t-BuOH (10 mL). After 45 min, the mixture was trea-
ted according to the general procedure to furnish after purification
on a silica gel column (petroleum ether/dichloromethane 8:2,
7.5:2.5) the tricyclic product 19e (0.216 g) as pale yellow crystals
in 59% yield. Mp 155–156 °C (recrystallisation from ethyl acetate
at ꢀ20 °C). 1H NMR (400 MHz, CDCl3) 8.43 (1H, dd, JH–H = 9.6 Hz,
JH–F = 5.9 Hz, CHAr), 7.16–7.12 (2H, m, 2CHAr), 5.35 (1H, m, NH),
4.17 (1H, m, CHS), 3.39–3.27 (4H, m, NCH2, CH2), 1.40 (9H, s,
4.4.18. 2-Ethoxymethyl-7-fluoro-1,2-dihydro-4H-thieno[2,3-b]
[1]benzothiopyran-4-one 19h
The reaction was carried out with xanthate 5m (0.362 g,
1 mmol) and potassium carbonate (0.690 g, 5 mmol) in a 9:1 mix-
ture of CH3CN/t-BuOH (10 mL). After 2 h 15 min, the mixture was
treated according to the general procedure to furnish after purifica-
tion on a silica gel column (gradient petroleum ether/ethyl acetate
8:2) the tricyclic product 19h (0.207 g) as yellow orange needles in
70% yield. Mp 89–90 °C (recrystallisation from iPr2O at ꢀ20 °C). 1H
NMR (400 MHz, CDCl3) 8.51 (1H, dd, JH–H = 9.6 Hz, JH–F = 6.0 Hz,
CHAr), 7.22–7.18 (2H, m, 2CHAr), 4.21 (1H, m, CHS), 3.66 (1H, dd,
J = 6.1 et 9.7 Hz, CHHOEt)), 3.55 (1H, dd, J = 8.5 and 9.7 Hz,
CHHOEt), 3.54 (2H, q, J = 7.0 Hz, OCH2CH3), 3.45 (1H, dd, J = 9.1
and 16.3 Hz, CHHCHS), 3.29 (1H, dd, J = 5.3 and 16.3 Hz, CHHCHS),
1.21 (3H, t, J = 7.0 Hz, OCH2CH3). 13C NMR (100 MHz, CDCl3) d 174.4
CMe3). 13C NMR (100 MHz, CDCl3) d 174.4 (CO), 163.5 (d, JC–F
=
256.0 Hz, CF), (155.8 NHCO), 152.0 (SCqS), 138.3 (d, JC–F = 9.7 Hz,
ArCqS), 131.5 (d, JC–F = 9.5 Hz, CHAr), 129.9, 127.1 (2Cq), 115.9 (d,
JC–F = 22.0 Hz, CHAr), 111.9 (d, JC–F = 24.8 Hz, CHAr), 79.8 (CqMe3),
50.3 (CHS), 45.2 (NCH2), 37.7 (CH2), 28.3 (Me3). IR (CC14) 1721,
(CO), 163.5 (d, JC–F = 255.4 Hz, CF), 152.6 (SCqS), 138.2 (d, JC–F
=
9.8 Hz, ArCqS), 131.5 (d, JC–F = 9.6 Hz, CHAr), 129.9, 127.2 (2Cq),
115.9 (d, JC–F = 22.2 Hz, CHAr), 111.9 (d, JC–F = 24.8 Hz, CHAr), 73.2
(CH2OEt), 66.9 (OCH2CH3), 36.8 (CH2), 15.1 (OCH2CH3). IR (CC14)
1622, 1598 cmꢀ1. MS (CI) 297 (M+H)+. Anal. Calcd for C14H13FO2S2:
C, 56.73; H, 4.42. Found: C, 56.72; H, 4.35.
1622, 1599 cmꢀ1
.
MS (CI) 368 (M+H)+. Anal. Calcd for
C17H18FNO3S2: C, 57.57; H, 4.94. Found: C, 57.78; H, 4.95.
4.4.16. 7-Fluoro-4-oxo-1,2-dihydro-4H-thieno[2,3-b][1]
benzothiopyran-2-ylmethyl-phosphonic acid diethyl ester 19f
The reaction was carried out with xanthate 5k (0.4543 g,
1 mmol) and potassium carbonate (0.690 g, 5 mmol) in a 9:1 mix-
ture of CH3CN/t-BuOH (10 mL). After 2 h 45 min, the mixture was
treated according to the general procedure to furnish after purifica-
tion on a silica gel column (gradient dichloromethane/ethyl acetate
5:5, 3:7) the tricyclic product 19f (0.236 g) as yellow crystals in
61% yield. Mp 99–100 °C (recrystallisation from ethyl acetate at
ꢀ20 °C). 1H NMR (200 MHz, CDCl3) 8.45 (1H, dd, JH–H = 9.7 Hz,
JH–F = 5.8 Hz, CHAr), 7.21–7.13 (2H, m, 2 CHAr), 4.32 (1H, m,
CHS), 4.20–4.04 (4H, m, 2P(O)OCH2CH3), 3.58 (1H, dd, J = 8.4 and
4.4.19. [tert-Butoxycarbonyl-(7-fluoro-4-oxo-2,3-dihydro-4H-
thieno[2,3-b][1]benzothiopyran-2-ylmethyl)-amino]-acetic
acid ethyl ester 19i
The reaction was carried out using xanthate 5n (0.200 g,
0.38 mmol) in ethanol (0.38 mL) and ethyl acetate (2%) with DBU
(1.1 equiv). After stirring at room temperature until complete con-
sumption of starting adduct, the reaction mixture was extracted
with diethyl ether. A light yellow oily tricyclic product 19i
(0.124 g) was obtained in 72% yield. The pure compound was a
mixture of rotamers. 1H NMR (400 MHz, CDCl3) d 8.48 (br s, 1H,

P. Boutillier et al. / Tetrahedron: Asymmetry 21 (2010) 1649–1665
1663
CHAr), 7.19 (br s, 2H, CHAr), 4.33 (br s, 1H, CHS), 4.11 (m, 2H,
OCH2CH3), 3.97 (m, 2H, NCH2CO), 3.61 (t, 1H, J = 14.2 Hz,
NCHHCHS), 3.39 (m, 2H, NCHHCHS, CHHCCO), 3.28 (m, 1H,
CHHCCO), 1.44, 1.41 (2s, 9H, (CH3)3), 1.25 (s, 3H, OCH2CH3). 13C
mixture of CH3CN/t-BuOH (54.6 mL). After 3 h 30 min, the mixture
was treated according to the general procedure to furnish after
purification on a silica gel column (petroleum ether/diethyl ether
8:2) the tricyclic product 19l (1.95 g) as white crystals in 92% yield.
NMR (100 MHz, CDCl3) d 174.4 (CO), 169.8 (OCO), 163.6 (d, JC–F
=
1H NMR (400 MHz, CDCl3) d 8.52 (dd, 1H, JH–F = 5.9 Hz, JH–H
=
255.2 Hz, CF), 155.4 (NCO), 152.0 (Cq), 138.3 (Cq, dd, JC–F = 6.8 Hz,
JC–F = 8.9 Hz), 131.6 (d, J = 9.6 Hz, CHAr), 130.0; 130.1 (Cq), 127.3
(Cq), 116.0 (dd, JC–F = 8.7 Hz, JC–F = 22.6 Hz, CHAr), 111.9 (d,
JC–F = 5.9 Hz, JC–F = 24.8 Hz, CHAr), 81.1; 81.3 (C(CH3)3), 61.2
(OCH2CH3), 54.2; 53.4 (CH2), 51.7; 50.3 (CH2), 49.9; 49.8 (CHS),
37.9; 37.8 (CH2), 28.3; 28.2 (C(CH3)3), 14.3; 14.2 (OCH2CH3). IR
(CC14) 1752, 1708, 1620, 1599 cmꢀ1. MS (CI) 454 MH+. HRMS
(EI+) 453.1081 (Measured mass), 453.1080 (Calculated mass).
9.6 Hz, CHAr), 7.20 (m, 2H, CHAr), 7.00 (m, 1H, CHPh), 6.85 (dd,
1H, J = 1.4 Hz, J = 8.2 Hz, CHPh), 6.78 (dd, 1H, J = 1.4 Hz, J = 7.6 Hz,
CHPh), 4.38 (ddt, 1H, J = 5.9 Hz, J = 7.1 Hz, J = 8.3 Hz, SCH), 3.87 (s,
3H, OCH3), 3.85 (s, 3H, OCH3), 3.44 (dd, 1H, J = 8.4 Hz, J = 16.0 Hz,
CHHPh), 3.30 (dd, 1H, J = 5.8 Hz, J = 16.1 Hz, CHHPh), 3.11 (dd,
1H, J = 7.0 Hz, J = 13.6 Hz, CHHCCO), 3.05 (dd, 1H, J = 8.4 Hz,
J = 13.6 Hz, CHHCCO). 13C NMR (100 MHz, CDCl3) d 174.4 (CO),
163.5 (d, JC–F = 255.3 Hz, CF), 152.9 (Cq), 152.8 (Cq), 147.4 (Cq),
138.4 (Cq, d, JC–F = 9.7 Hz),131.8 (Cq), 131.6 (d, JC–F = 9.6 Hz, CHAr),
130.3 (Cq), 127.4 (Cq, d, JC–F = 2.4 Hz), 123.9 (CHPh), 122.5 (CHPh),
115.8 (d, JC–F = 22.2 Hz, CHAr), 111.9 (d, JC–F = 24.9 Hz, CHAr), 111.6
(CHPh), 60.6 (OCH3), 55.7 (OCH3), 51.8 (CHS), 40.0 (CH2), 36.9
(CH2). IR (CDCl3) 1620, 1589 cmꢀ1. MS (CI) 389 MH+. HRMS (EI+)
388.0603 (Measured mass), 386.0603 (Calculated mass).
4.4.20. Acetic acid 9-(7-fluoro-4-oxo-1,2-dihydro-4H-thieno
[2,3-b)][1]benzothiopyran-2-yl)-nonyl ester 19j
The reaction was carried out with xanthate 5o (0.488 g,
1 mmol) and potassium carbonate (0.690 g, 5 mmol) in a 9:1 mix-
ture of CH3CN/t-BuOH (10 mL). After 2 h 45 min, the mixture was
treated according to the general procedure to furnish after purifica-
tion on a silica gel column (petroleum ether/dichloromethane/
ethyl acetate 7:2:1) the tricyclic product 19j (0.380 g) as yellow
crystals in 90% yield. Mp 71–72 °C (recrystallisation from iPr2O at
4.4.23. 2-[2-(5,5-Dimethyl-[1,3]dioxan-2-yl)-2-methyl-propyl]-
7-fluoro-2,3-dihydro-thieno[2,3-b]thiochromen-4-one 19m
The reaction was carried out with xanthate 5r (0.210 g,
0.44 mmol) and potassium carbonate (0.303 g, 5 mmol) in a 9:1
mixture of CH3CN/t-BuOH (4.4 mL). After 3 h 30 min, the mixture
was treated according to the general procedure to furnish after
purification on a silica gel column (petroleum ether/diethyl ether
4:1) the tricyclic product 19m (0.138 g) as white crystals in 77%
0 °C). 1H NMR (400 MHz, CDCl3) 8.50 (1H, dd, JH– = 9.6 Hz, JH–F
=
5.9 Hz, CHAr), 7.21–7.16 (2H, m, 2CHAr), 4.04 (2H, t, J = 6.8 Hz,
CH2OAc), 4.03 (1H, m, CHS), 3.50 (1H, dd, J = 8.7 and 15.9 Hz,
CHHCHS), 3.16 (IH, dd, J = 6.4 and 15.9 Hz, CHHCHS), 2.03 (3H, s,
OCOCH3), 1.80–1.75 (2H, m, CH2), 1.62–1.58 (2H, m, CH2), 1.42–
1.36 (2H, m, CH2), 1.28 (10H, br s, 5CH2). 13C NMR (50 MHz, CDCl3)
d 173.8 (CO), 170.6 (OCO), 163.2 (d, JC–F = 254.7 Hz, CF), 152.1
(SCqS), 138.0 (d, JC–F = 9.7 Hz, ArCqS), 132.2 (CH, d, JC–F = 9.4 Hz,
CHAr), 130.3, 127.1 (2Cq), 115.5 (d, JC–F = 22.0 Hz, CHAr), 111.5 (d,
JC–F = 24.7 Hz, CHAr), 64.3 (CH2OAc), 51.8 (CHS), 40.3, 36.3, 29.1,
29.0, 28.4, 27.7, 25.7 (CH2), 20.7 (OCOCH3). IR (CC14) 1741, 1622,
1598 cmꢀ1. MS (CI) 423 (M+H)+. Anal. Calcd for C22H27FO3S2: C,
62.53; H, 6.44. Found: C, 62.39; H, 6.38.
yield. 1H NMR (400 MHz, CDCl3) d 8.51 (dd, 1H, JH–F = 5.9 Hz, JH–H
=
9.6 Hz, CHAr), 7.20 (m, 2H, CHAr), 4.33 (m, 1H, CH(OCH2)2, 4.08 (s,
1H, CHS), 3.61 (m, 3H, CHHCCO, OCH2CCH3), 3.40 (dd, 2H,
J = 2.0 Hz, J = 10.7 Hz, OCH2CCH3), 3.05 (dd, 1H, J = 9.7 Hz,
J = 15.8 Hz, CHHCCO), 2.03 (m, 2H, SCHCH2), 1.16 (s, 3H, CCH3),
0.99 (s, 6H, C(CH3)2), 0.72 (s, 3H, CCH3). 13C NMR (100 MHz, CDCl3)
d 174.1 (CO), 163.5 (d, JC–F = 255.0 Hz, CF), 153.6 (Cq), 138.3 (Cq, d,
JC–F = 9.7 Hz), 131.5 (d, JC–F = 9.6 Hz, CHAr), 130.6 (Cq), 127.4 (Cq, d,
JC–F = 2.3 Hz), 115.8 (d, JC–F = 22.2 Hz, CHAr), 111.9 (d, JC–F
=
4.4.21. 2-Acetylamino-2-(7-fluoro-4-oxo-1,2-dihydro-4H-thieno
[2,3-b][1]benzothiopyran-2-yl-methyl)-malonic acid diethyl
ester 19k
24.9 Hz, CHAr), 106.6 (CHOCH2), 77.3 (OCH2CCH3), 77.2
(OCH2CCH3), 48.9 (CHS), 44.3 (CH2), 42.6 (CH2), 37.9 (Cq), 30.2
(Cq), 23.0 (CH3), 22.9 (CH3), 22.8 (CH3), 21.7 (CH3). IR (CDCl3)
1617, 1590 cmꢀ1. MS (CI) 409 MH+. HRMS (EI+) 408.1225 (Mea-
sured mass), 408.1229 (Calculated mass).
The reaction was carried out with xanthate 5p (0.535 g,
0.7 mmol) and potassium carbonate (0.480 g, 3.5 mmol) in a 9:1
mixture of CH3CN/t-BuOH (10 mL). After 1 h 30 min, the mixture
was treated according to the general procedure to furnish after
purification on a silica gel column (petroleum ether/dichlorometh-
ane/ethyl acetate 2:3:5) the tricyclic product 19k (0.294 g) as
white crystals in 90% yield. Mp 145–146 °C (recrystallisation from
ethyl acetate at ꢀ20 °C). 1H NMR (400 MHz, CDCl3) d 8.32 (1H, dd,
JH–F = 8.8 Hz, JH–F = 5.9 Hz, CHAr), 7.09–7.02 (2H, m, 2CHAr), 4.23–
4.15 (4H, m, 2CO2CH2CH3), 3.87 (1H, m, CHS), 3.42 (1H, dd,
7 = 8.3 and 15.8 Hz, CHHCHS), 2.98 (1H, dd, J = 15.8 Hz, CHHCHS),
2.95–2.86 (2H, m, CH2), 2.05 (3H, s, NHCOCH3), 1.18 (6H, t,
J = 7.1 Hz, CO2CH2CH3). 13C NMR (100 MHz, CDCl3) d 173.8 (CO),
169.8 (CO), 167.3 (CO), 163.3 (d, JC–F = 255.4 Hz, CF), 152.2 (SCqS),
137.8 (d, JC–F = 9.7 Hz, ArCqS), 131.3 (d, JC–F = 9.0 Hz, CHAr), 129.9,
4.4.24. (7-Fluoro-4-oxo-2,3-dihydro-4H-thieno[2,3-b][1]benzo-
thiopyran-2-ylmethyl)-(4-methoxy-benzyl)-carbamic acid tert-
butyl ester 19n
The reaction was carried out with xanthate 5t (0.240 g,
0.38 mmol) and potassium carbonate (0.262 g, 5 mmol) in a 9:1
mixture of CH3CN/t-BuOH (3.8 mL). After 3 h 30 min, the sample
was extracted with diethyl ether. A light yellow amorphous solid
19n (0.096 g) was obtained in 52% yield. The required product
was a mixture of rotamers. 1H NMR (400 MHz, CDCl3) d 8.49 (dd,
1H, JH–F = 5.9 Hz, JH–H = 9.6 Hz, CHAr), 7.19 (m, 2H, CHAr), 7.11 (br
s, 2H, CHPh), 6.83 (d, 2H, J = 8.7 Hz, CHPh), 4.51 (m, 1H, NCHHPh),
4.41 (m, 1H, CHS), 4.23 (m, 1H, NCHHCHS), 3.77 (s, 3H, OMe), 3.47
(m, 1H, NCHHPh), 3.35 (m, 2H, NCHHCHS, CHHCCO), 3.23 (dd, 1H,
J = 4.8 Hz, J = 16.2 Hz, CHHCCO), 1.47 (s, 9H). 13C NMR (100 MHz,
CDCl3) d 174.4 (CO), 163.6 (d, JC–F = 255.5 Hz, CF), 159.0 (Cq),
155.7 (NCO), 152.1 (Cq), 138.3 (Cq, d, JC–F = 9.4 Hz), 131.6; 131.5
(Cq), 130.0 (d, JC–F = 23.3 Hz, CHAr), 128.7 (m, CHPh), 127.37;
127.35 (Cq), 115.9 (d, J = 22.1 Hz, CHAr), 114.1 (CHPh), 111.9 (d,
J = 25.0 Hz, CHAr), 80.6 (C(CH3)3), 55.2 (OCH3), 51.5 (NCH2Ph),
50.8 (NCH2CHS), 49.6 (CHS), 37.8 (CH2), 28.4 (C(CH3)3). IR (CDCl3)
1698, 1622, 1599 cmꢀ1. MS (CI) 488 MH+. HRMS (EI+) 487.1292
(Measured mass), 487.1287 (Calculated mass).
126.9 (2 Cq), 115.8 (d, JC–F = 21.9 Hz, CHAr), 111.7 (d, JC–F
=
25.2 Hz, CHAr), 65.5 (Cq), 63.0 (CO2CH2CH3), 62.8 (CO2CH2CH3),
47.1 (CHS), 41.0 (CH2), 37.9 (CH2), 22.9 (NHCOCH3), 13.8
(CO2CH2CH3). IR (CC14) 1754, 1739, 1692, 1623, 1597 cmꢀ1. MS
(CI) 468 (M+H)+. Anal. Calcd for C21H22FNO6S2: C, 53.95; H, 4.74.
Found: C, 53.89; H, 4.74.
4.4.22. 2-(2,3-Dimethoxy-benzyl)-7-fluoro-2,3-dihydro-thieno
[2,3-b]thiochromen-4-one 19l
The reaction was carried out with xanthate 5q (2.48 g,
5.46 mmol) and potassium carbonate (3.76 g, 5 mmol) in a 9:1

1664
P. Boutillier et al. / Tetrahedron: Asymmetry 21 (2010) 1649–1665
4.4.25. 1,1-Difluoro-2-(7-fluoro-6-methyl-4-oxo-1,2-dihydro-
4H-thieno[2,3-b][1]benzothiopyran-2-yl)-ethylphosphonic acid
diethyl ester 19o
1606, 1583 cmꢀ1. MS (CI) 401 MH+. HRMS (EI+) 400.0799 (Mea-
sured mass), 400.0803 (Calculated mass).
The reaction was carried out with xanthate 5s6b (0.259 g,
0.5 mmol) and potassium carbonate (0.345 g, 2.5 mmol) in a 9:1
mixture of CH3CN/t-BuOH (5 mL). After 3 h, the mixture was trea-
ted according to the general procedure to furnish after purification
on a silica gel column (petroleum ether/dichloromethane/ethyl
acetate 6:4:0 to 4:4:2) the tricyclic product 19o (0.136 g) as beige
crystals in 60% yield. Mp 144–145 °C (recrystallisation from ethyl
4.4.28. 2-(2,3-Dimethoxy-benzyl)-7-(2,2,2-trifluoro-ethoxy)-2,3-
dihydro-thieno[2,3-b][1]benzo-thiopyran-4-one 27
Fifty milligram (0.12 mmol) of starting tricyclic compound 19l
was dissolved in trifluoroethanol. Five equivalents of K2CO3
(89 mg) were added and the mixture was heated at 100 °C. After
1 h there was complete consumption of the starting material. The
reaction mixture was cooled to room temperature, the solvent
was evaporated and the residue diluted in dichloromethane and
washed with water to afford a white solid product 27 (41 mg) in
73% yield. Mp 149–151 °C. 1H NMR (400 MHz, CDCl3) d 8.53 (d,
1H, J = 8.9 Hz, CHAr), 7.09 (dd, 2H, J = 8.9 Hz, J = 2.3 Hz, CHAr,
CHPh), 7.00 (dd, 1H, J = 12.8 Hz, J = 5.0 Hz, CHAr), 6.85 (d, 1H,
J = 8.1 Hz, CHPh), 6.78 (d, 1H, J = 7.4 Hz, CHPh), 4.40 (m, 3H, CHS,
OCH2CF3), 3.86, 3.85 (2s, 6H, 2OCH3), 3.43 (dd, 1H, J = 16.0 Hz,
J = 8.3 Hz, CHHPh), 3.30 (dd, 1H, J = 16.0 Hz, J = 5.7 Hz, CHHPh),
3.08 (m, 2H, CH2CHS). 13C NMR (100 MHz, CDCl3) d 174.7 (CO),
158.7 (Cq), 152.8 (Cq), 152.1 (Cq), 147.4 (Cq), 138.5 (Cq), 131.8
(Cq), 131.0 (CHAr), 130.3 (Cq), 125.9 (Cq), 123.9 (CHPh), 122.9 (d,
J = 277.9 Hz, CF3), 122.5 (CHPh), 115.5 (CHAr), 111.5 (CHAr),
110.0 (CHPh), 65.7 (q, J = 36.7 Hz, CH2CF3), 60.6 (OCH3), 55.7
(OCH3), 51.7 (CHS), 40.0 (CH2Ph), 36.9 (CH2CHS). IR (CDCl3) 1611,
1587 cmꢀ1. HRMS (EI+) 468.0679 (Measured mass), 468.0677 (Cal-
culated mass).
acetate at 0 °C). 1H NMR (200 MHz, CDCl3) d 8.34 (1H, d, JH–F
=
8.0 Hz, CHAr), 7.15 (1H, d, JH–F = 9.1 Hz, CHAr), 4.44 (1H, m, CHS),
4.34–4.26 (4H, m, 2OCH2CH3), 3.66 (1H, dd, J = 8.6 and 16.0 Hz,
CHHCHS), 3.22 (1H, dd, J = 7.8 and 16.0 Hz, CHHCHS), 2.70–2.60
(2H, m, CH2CF2), 2.38 (3H, s, CH3), 1.42–1.38 (6H, m, 2OCH2CH3).
13C NMR (100 MHz, CDCl3) d 174.3 (CO), 162.6 (d, JC–F = 254.9 Hz,
CF), 152.3 (SCqS), 135.1 (d, JC–F = 9.6 Hz, ArCqS), 132.0 (d,
JC–F = 9.6 Hz, CHAr), 129.6, 126.8 (2Cq), 126.1 (CqAr), 119.5 (dt,
JC–P = 215.5, JC–F = 261.3 Hz, CF2), 111.6 (d, JC–F = 26.6 Hz, CHAr),
64.9 (d, JC–P = 6.5 Hz, P(O)CH2CH3), 43.3, 41.3 (CHS, CH2), 40.0 (dt,
JC–P = 15.1 Hz, JC–F = 19.9 Hz, CH2CF2), 16.4 (d, JC–P = 5.0 Hz,
P(O)CH2CH3), 14.7 (ArCH3). IR (CC14) 1626, 1599 cmꢀ1. MS (CI)
4538 (M+H)+. Anal. Calcd for C18H20F3O4PS2: C, 47.78; H, 4.46.
Found: C, 47.66; H, 4.44.
4.4.26. 2-Ethoxy-7-fluoro-3-thiiranylmethyl-thiochromen-4-
one 22
The reaction was carried out with xanthate 5e (0.752 g, 2 mmol)
and potassium carbonate (1.38 g, 10 mmol) in a 9:1 mixture of
CH3CN/t-BuOH (20 mL). After 2 h, the mixture was treated accord-
ing to the general procedure to furnish after purification on a silica
gel column (petroleum ether/dichloromethane/ethyl acetate 9:1)
the episulfide 22 (0.26 g) as a white solid in 44% yield. Mp 113–
115 °C. 1H NMR (200 MHz, CDCl3) d 8.52 (1H, dd, JH–H = 9.7 Hz,
JH–F = 5.9 Hz, CHAr), 7.26–7.18 (2H, m, CHAr), 4.36 (2H, q,
J = 7.0 Hz, OCH2CH3), 3.33–3.11 (2H, m), 2.89 (1H, dd, J = 7.1 and
12.5 Hz), 2.46–2.36 (2H, m), 1.51 (3H, t, J = 7.0 Hz, OCH2CH3). 13C
NMR (100 MHz, CDCl3) d 179.7 (CO), 164.8 (SCqOEt), 163.8 (d,
JC–F = 255.4 Hz, CF), 133.8 (d, JC–F = 9.7 Hz, ArCqS), 132.0 (d,
4.4.29. 2-(2,3-Dimethoxy-benzyl)-7-morpholin-4-yl-2,3-dihydro
-thieno[2,3-b][1]benzothiopyran-4-one 28
Fifty milligrams (0.12 mmol) of the starting tricyclic compound
19l were dissolved in a minimum of morpholine. Five equivalents
of K2CO3 (89 mg) were added to this solution which was heated at
130 °C. After 1 h 30 min there was complete consumption of the
starting material. The reaction mixture was cooled to room tem-
perature, the solvent was evaporated and the residue diluted in
dichloromethane and washed with water to afford a white solid
product 28 (38 mg) in 70% yield. Mp 122–125 °C. 1H NMR
(400 MHz, CDCl3) d 8.36 (d, 1H, J = 9.0 Hz, CHAr), 7.02 (m, 2H, CHAr,
CHPh), 6.84 (d, 1H, J = 7.6 Hz, CHAr), 6.78 (m, 2H, CHPh), 4.34 (m,
1H, CHS), 3.86, 3.84 (2s, 10H, 2OCH3, CH2OCH2), 3.42 (dd, 1H,
J = 15.9 Hz, 8.3 Hz, CHHPh), 3.29 (m, 5H, CH2NCH2, CHHPh), 3.07
(m, 2H, CH2CHS). 13C NMR (100 MHz, CDCl3) d 175.2 (CO), 152.8
(Cq), 152.2 (Cq), 151.1 (Cq), 147.5 (Cq), 138.7 (Cq), 132.1 (Cq),
130.1 (Cq), 130.0 (CHAr), 123.9 (CHPh), 122.7 (Cq), 122.6 (CHPh),
115.1 (CHAr), 111.5 (CHAr), 108.6 (CHPh), 66.6 (CH2OCH2), 60.7
(OCH3), 55.7 (OCH3), 51.5 (CHS), 47.7 (CH2NCH2), 40.2 (CH2Ph),
37.0 (CH2CHS). IR (CDCl3) 1606, 1582 cmꢀ1. HRMS (EI+) 455.1226
(Measured mass), 455.1225 (Calculated mass).
JC–F = 9.5 Hz, CHAr), 126.7 (CqAr), 118.7 (Cq), 115.9 (d, JC–F
=
22.4 Hz, CHAr), 112.1 (CH, d, JC–F = 24.8 Hz, CHAr), 67.7 (OCH2CH3),
33.7 (CHCH2S), 31.2 (CH2), 26.0 (CH2), 15.0 (OCH2CH3), IR (CC14)
1610, 1585 cmꢀ1. MS (CI) 297 (M+H)+. Anal. Calcd for C14H13FO2S2:
C, 56.73; H, 4.42. Found: C, 56.69; H, 4.37.
4.4.27. 2-(2,3-Dimethoxy-benzyl)-7-methoxy-2,3-dihydro-
thieno[2,3-b][1]benzothiopyran-4-one 26
0.1 g (0.25 mmol) of starting tricyclic compound 19l was dis-
solved in MeOH/THF (2:1) solution. NaBH4 (23.6 mg, 2.5 equiv)
was added to this solution which was heated at 90–100 °C. After
1 h 30 min there was complete consumption of the starting mate-
rial. The reaction mixture was cooled to room temperature, the sol-
vent was evaporated and the residue diluted in dichloromethane
and washed with water to afford a white solid product 26
(0.096 g) in 96% yield. Mp 120–122 °C. 1H NMR (400 MHz, CDCl3)
d 8.41 (d, 1H, J = 8.9 Hz, CHAr), 7.01 (m, 2H, CHAr, CHPh), 6.89 (d,
1H, J = 2.40 Hz, CHPh), 6.83 (dd, 1H, J = 8.2 Hz, J = 1.2 Hz, CHAr),
6.77 (dd, 1H, J = 7.6 Hz, J = 1.1 Hz, CHPh), 4.35 (m, 1H, CHS), 3.86,
3.85, 3.84 (3s, 9H, 3 OCH3), 3.42 (dd, 1H, J = 15.9 Hz, J = 8.3 Hz,
CHHPh), 3.28 (dd, 1H, J = 16.0 Hz, J = 5.8 Hz, CHHPh), 3.07 (m, 2H,
CH2CHS). 13C NMR (100 MHz, CDCl3) d 175.1 (CO), 161.4 (Cq),
152.8 (Cq), 151.7 (Cq), 147.5 (Cq), 138.6 (Cq), 132.0 (Cq), 130.6
(CHAr), 130.2 (Cq), 124.5 (Cq), 123.9 (CHPh), 122.6 (CHPh), 115.9
(CHAr), 111.6 (CHAr), 108.5 (CHPh), 60.7 (OCH3), 55.8 (OCH3),
55.7 (OCH3), 51.7 (CHS), 40.2 (CH2Ph), 37.0 (CH2). IR (CDCl3)
Acknowledgement
One of us (S.N.Z.) thanks SFERE-EGIDE for a scholarship.
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