ortho-metalation of enantiopure aromatic sulfoxides and stereocontrolled addition to imines

Article abstract of DOI:10.1021/jo052358p

Enantiopure aromatic (phenyl, naphthyl) and heteroaromatic (pyridyl, quinolyl, diazinyl) sulfoxides have been synthesized by reaction of (5)-tert-butyl tert-butanethiosulfinate with aryl- or heteroaryllithium derivatives. The ortho-directed metalation of

Full text of DOI:10.1021/jo052358p

ortho-Metalation of Enantiopure Aromatic Sulfoxides and
Stereocontrolled Addition to Imines
Nicolas Le Fur,† Ljubica Mojovic,† Nelly Ple´,† Alain Turck,*,† Vincent Reboul,‡ and
Patrick Metzner‡
Laboratoire de Chimie Organique Fine et He´te´rocyclique, UMR CNRS 6014, IRCOF, INSA, B.P. 08,
76131 Mont Saint Aignan, France, and Laboratoire de Chimie Mole´culaire et Thioorganique,
UMR CNRS 6507, ENSICAEN-UniVersite´ de Caen, 14050 Caen, France
alain.turck@insa-rouen.fr
ReceiVed NoVember 15, 2005
Enantiopure aromatic (phenyl, naphthyl) and heteroaromatic (pyridyl, quinolyl, diazinyl) sulfoxides have
been synthesized by reaction of (S)-tert-butyl tert-butanethiosulfinate with aryl- or heteroaryllithium
derivatives. The ortho-directed metalation of the sulfoxides was performed with lithium bases. Subsequent
addition of the lithiated intermediates to N-tosylimines afforded tosylaminoalkyl tert-butylsulfinyl arenes.
In most cases a complete asymmetric induction was highlighted in favor of (S,S) isomers. Heating the
aminosulfoxides provided an original cyclization to form novel cyclic sulfenamides. A novel enantiopure
synthesis of a benzylamine was described. An application of an enantiopure aminosulfoxide as N,S ligand
for the asymmetric catalysis of allylic nucleophilic substitution has been successfully tested.
Introduction
provide both ortho-directed metalation6 and a stereogenic
element (Scheme 1).
An efficient and largely developed strategy for the stereo-
controlled creation of C-C bonds involves a sequence of
deprotonation and addition of a prochiral electrophile. The first
step is activated by an electron-withdrawing group (such as a
carbonyl, an imine, a hydrazone, a sulfoxide, etc.), which may
incorporate a chiral auxiliary. We became interested in a similar
strategy in the aromatic series, using the sulfinyl group1-5 to
Some stereogenic ortho-directing groups have been studied:
oxazolines,7 masked aldehydes,8-10 amides,11-13 sulfonamides,14
(2) Mikolajczyk, M.; Drabowicz, J.; Kielbasinski, P. Chiral Sulfur
Reagents (Applications in Asymmetric and StereoselectiVe Synthesis); CRC
Press: Boca Raton, 1997.
(3) Allin, S. M.; Shuttleworth, S. J.; Page, P. C. B. Organosulfur
Chemistry-Synthetic and Stereochemical Aspects; Page, P. C. B., Ed.;
Academic Press: London, 1998; Vol. 2, pp 97-155.
(4) Ferna´ndez, I.; Khiar, N. Chem. ReV. 2003, 103, 3651-3706.
(5) Legros, J.; Dehli, J. R.; Bolm, C. AdV. Synth. Catal. 2005, 347, 19-
31.
† UMR CNRS 6014, IRCOF, INSA.
‡ UMR CNRS 6507, ENSICAEN-Universite´ de Caen.
(1) Solladie´, G. StereoselectiVe Synthesis (Houben-Weyl); Helmchen, G.,
Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Georg Thieme:
Stuttgart, 1996; Vol. E21, pp 1056-1076.
(6) Whisler, M. C.; MacNeil, S. L.; Snieckus, V.; Beak, P. Angew. Chem.,
Int. Ed. 2004, 43, 2206-2225.
10.1021/jo052358p CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/01/2006
J. Org. Chem. 2006, 71, 2609-2616
2609

Le Fur et al.
SCHEME 1. Deprotonation of Aryl Sulfoxides and Addition
of Prochiral Electrophiles
FIGURE 1. Enantiopure (S)-sulfoxides.
and also sulfoxides.15-17 The prochiral electrophiles used were
aldehydes or ketones (leading to chiral alcohols), and the best
asymmetric induction (excluding sulfoxides) was observed by
Matsui12,13 with amides (de ) 80%). In the course of our studies
on the synthesis and metalation of diazine and benzodiazine
sulfoxides,16,18,19 we observed that the addition of the metalated
species to aldehydes took place in some cases with a remarkable
asymmetric induction. Surprisingly, imines (leading to attractive
chiral amines) were not used previously as prochiral electro-
philes. This prompted us to use imines as electrophile with
aromatic substrates, such as phenyl and naphthyl sulfoxides.
This opens the way to a new class of bidentate ligands with
nitrogen and sulfur coordination sites for asymmetric
catalysis.20-23
Preparation of Sulfoxides. We wished to prepare a variety
of sulfoxides bearing an aryl and a tert-butyl group. The latter
was chosen as it provides steric hindrance, relative to the
conventional p-tolyl group, and avoids any competition with
proton abstraction of a primary or secondary alkyl group or that
of another aromatic substituent.
SCHEME 2. Synthesis of Enantiopure Sulfoxides 1-5
Numerous methods have been developed to prepare enan-
tiopure sulfoxides, among which the SN2 Andersen’s reaction
of menthyl sulfinate with organolithiums or Grignards is
extremely popular.2,26,27 It is however restricted to the synthesis
of p-tolyl substrates.
For the preparation of alkyl sulfoxides, two main methods
have emerged. Alcudia and Khiar4,28 used DAG (diacetone-D-
glucosyl) alkanesulfinates, or more recently DGG,29 instead of
menthyl sulfinate. Ellman30-32 employed tert-butyl tert-butane-
thiosulfinate as a chiral source. Based upon preliminary results
of the Bolm group,33 oxidation of tert-butyl disulfide by
hydrogen peroxide in the presence of 0.5% of an imine derived
from (1R,2S)-1-amino-2-indanol and VO(acac)2 and subsequent
crystallization provided32 (S)-tert-butyl tert-butanethiosulfinate
6 in essentially enantiopure form (ee g 99%). This method has
attractive features: low cost of the substrates, low loadings of
the catalyst and ligand, easy procedure and scale-up, and
availability of both enantiomers.
The aromatic moieties of the sulfoxides that we selected are
benzene, naphthalene, pyridine, quinoline, and diazine (Figure
1). Compounds 1 and 2 were prepared previously24,25 in the
respective (S) and (R) enantiomeric form by other methods,
whereas enantiopure 3-5, or their antipodes, were not reported
previously.
(7) Meyers, A. I.; Hanagan, M. A.; Trefonas, L. M.; Baker, R. J.
Tetrahedron 1991, 39, 1991-1999.
Results and Discussion
(8) Commerc¸on, M.; Mangeney, P.; Tejero, T.; Alexakis, A. Tetra-
hedron: Asymmetry 1990, 1, 287-290.
The synthesis of sulfoxides 1-5 was achieved (Scheme 2,
Table 1) by standard halogen-lithium exchange between iodo-
or bromo-arene derivatives and butyllithium at low temperature
(entries 1-4), or by ortho-directed metalation (entry 5), followed
by addition of thiosulfinate 6.
The yields were good (76-97%, entries 1-3), except for
3-bromoquinoline (entry 4), for which some quinoline was
obtained (32%). In all cases the enantiomeric excess was g
99%. For products 1 and 2, their RD and comparison with
literature data24,25 showed that their stereochemistry is (S), thus
arising from inversion of the thiosulfinate sulfur atom config-
uration, in agreement with previous observations.31,32
(9) Asami, M.; Mukaiyama, T. Chem. Lett. 1980, 17-20.
(10) Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay, T.;
Simson, M.; Seebach, D. Synthesis 1993, 1271-1290.
(11) Beak, P.; Tse, A.; Hawkins, J.; Chen, C.-W.; Mills, S. Tetrahedron
1983, 39, 1983-1989.
(12) Matsui, S.; Uejima, A.; Suzuki, Y.; Tanaka, K. J. Chem. Soc., Perkin
Trans. 1 1993, 701-705.
(13) Matsui, S.; Uejima, A.; Suzuki, Y.; Tanaka, K. Nippon Kagaku
Kaishi 1996, 2, 154-159; Chem. Abstr. 1993, 495244.
(14) Takahashi, H.; Tsubuki, T.; Higashiyama, K. Chem. Pharm. Bull.
1991, 39, 260-265.
(15) Ogawa, S.; Furukawa, N. J. Org. Chem. 1991, 56, 5723-5726.
(16) Pollet, P.; Turck, A.; Ple´, N.; Que´guiner, G. J. Org. Chem. 1999,
64, 4512-4515.
(17) Snieckus, V.; Beaulieu, F.; Mohri, K.; Han, W.; Murphy, C. K.;
Davis, F. A. Tetrahedron Lett. 1994, 35, 3465-3468.
(18) Turck, A.; Ple´, N.; Pollet, P.; Que´guiner, G. J. Heterocycl. Chem.
1998, 35, 429-436.
(26) Allin, S. M. Organosulfur Chemistry-Synthetic and Stereochemical
Aspects; Page, P. C. B., Ed.; Academic Press: London, 1998; Vol. 2, pp
41-61.
(19) Le Fur, N.; Mojovic, L.; Ple´, N.; Turck, A.; Marsais, F. Tetrahedron
2005, 61, 8924-8931.
(27) Khiar, N.; Fernandez, I.; Alcudia, A.; Alcudia, F. AdVances in Sulfur
Chemistry; Rayner, C., Ed.; JAI Press: Greenwich, CT, 2000; Vol. 2, pp
57-115.
(20) Masdeu-Bulto´, A. M.; Die´gueza, M.; Martin, E.; Go´mez, M. Coord.
Chem. ReV. 2003, 242, 159-201.
(21) Bayo´n, J. C.; Claver, C.; Masdeu-Bulto´, A. M. Coord. Chem. ReV.
1999, 193-195, 73-145.
(28) Fernandez, I.; Khiar, N.; Llera, J. M.; Alcudia, F. J. Org. Chem.
1992, 57, 6789-6796.
(22) Dai, L. X.; Tu, T.; You, S. L.; Deng, W. P.; Hou, X. L. Acc. Chem.
Res. 2003, 36, 659-667.
(29) Ferna´ndez, I.; Valdivia, V.; Gori, B.; Alcudia, F.; AÄ lvarez, E.; Khiar,
N. Org. Lett. 2005, 7, 1307-1310.
(23) Hiroi, K.; Suzuki, Y.; Abe, I.; Hasegawa, Y.; Suzuki, K. Tetrahe-
dron: Asymmetry 1998, 9, 3797-3817.
(30) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984-995.
(24) Rebiere, F.; Ricard, O. S. L.; Kagan, H. B. J. Org. Chem. 1991,
56, 5991-5999.
(31) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J. A. J. Am.
Chem. Soc. 1998, 120, 8011-8019.
(25) Baker, R. W.; Hockless, D. C. R.; Pocock, G. R.; Sargent, M. V.;
Skelton, B. W.; Sobolev, A. N.; Twiss E.; White, A. H. J. Chem. Soc.,
Perkin Trans. 1 1995, 2615-2629.
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(33) Bolm, C.; Bienewald, F. Angew. Chem., Int. Ed. Engl. 1995, 34,
2640-2642.
2610 J. Org. Chem., Vol. 71, No. 7, 2006

ortho-Metalation of Enantiopure Aromatic Sulfoxides
TABLE 1. Preparation of (S)-Sulfoxides 1-4
entry
starting material
metalating agent
solvent
temp (°C)
time (h)
product
yield (%)
ee (S)
1
2
3
4
5
iodobenzene
1-bromonaphthalene
3-bromopyridine
3-bromoquinoline
3,6-dimethoxypyridazine
n-BuLi
n-BuLi
n-BuLi
t-BuLi
LTMP
THF
THF
THF
Et2O
THF
-75
-75
-100
-100
-75
0.5
0.5
0.5
2
1
2
3
4
5
85
86
76
37
97
g99
g99
g99
g99
g99
1.5
SCHEME 3. Metalation and Deuteration of Sulfoxides 2
and 3
The pyridazine sulfoxide 5 was synthesized by ortho-directed
metalation of 3,6-dimethoxypyridazine followed by reaction of
thiosulfinate 6. The yield and the enantiomeric purity were
excellent.
Metalation of Aromatic Sulfoxides and Reaction with
N-Tosylimines. Though sulfoxides have attracted a great deal
of attention in asymmetric synthesis,4,34 the metalation of the
aryl substrates remains under exploited. This group is potentially
enhancing the acidity of the ortho hydrogen atoms and stabiliz-
ing the resulting species by coordination to the metal. The first
reports are by Furukawa et al. on the pyridine series.35-37
Deprotonation was effected by LDA, and the intermediates were
quenched by a variety of electrophiles. Further studies by
Snieckus and his group17,38 were carried out in the benzene series
using n-BuLi. They reported that the sulfinyl group is a more
efficient ortho-directing group than OMOM, CONEt2, and
NHBoc. The naphthalene series has also been explored but has
led to moderate yields.39,40
The reported lithiated sulfoxides were submitted to the
reaction of a variety of electrophiles. With racemic sulfoxides
and aldehydes, the diastereoselectivity of the addition was
usually modest: for tert-butylsulfinylbenzene and 2-chloro-4-
tolylylsulfinylbenzene,15 de’s were in the range of 10-38%.
For 2-arylsulfinylpyridines,36 de’s varied from 5% to 74%. Our
group has examined two other series in the enantiopure form,
3-pyridine and pyridazine. Pollet16 has demonstrated that the
induction can be made complete by employing hindered
aldehydes (de > 98%).
TABLE 2. Optimization of the Metalation of Naphthyl and
Pyridyl Sulfoxides 2 and 3
racemic
entry sulfoxide
time
deuteration
base
equiv (h) product incorporationa (%)
1
2
3
4
5
6
2
2
2
3
3
3
LDA
LTMP
LTMP
LDA
LDA
LDA
2.2
2.2
3.2
1.2
1.2
2.1
1
1
1
1
2
1
7
7
7
8
8
8
39
58
90
70
60
90
1
a Content of deuterium was determined by H NMR.
SCHEME 4. Metalation of Sulfoxides 1-3 and Addition of
N-Tosylimines
From these observations we anticipated that addition of the
lithiated sulfoxides to imines could lead41-43 to C-C bond
formation with a higher degree of stereocontrol, as compared
to aldehydes, as a result of (i) the presence of a substituent on
the heteroatom of the electrophile, and (ii) the possible introduc-
tion of a lithium coordinating substituent on the nitrogen atom,
such as a sulfonyl group.
Prior to the addition of imines, we needed to carry out the
metalation of sulfoxides 1-5. Deprotonation of racemic 1 has
been reported38 with n-BuLi. For the naphthalene sulfoxide 2,
the modest yields reported39 led us to optimize the reaction
conditions by carrying out deprotonation with LDA and LTMP
in THF at -78 °C, followed by quenching with EtOD (Scheme
3). We observed that an excess of LTMP afforded a 90%
deuterium incorporation (Table 2). The more activated pyridine
sulfoxide 3 could be deprotonated at C4 by 2.2 equiv of LDA.
Diazine 5 has been previously metalated by LTMP.16
The reactivity of the resulting metalated sulfoxides was first
tested with unactivated N-alkyl or phenyl imines. The addition
did not take place. We pursued our study with imines bearing
an electron-withdrawing group on the nitrogen atom. We chose
the N-tosyl group, in connection with its steric hindrance (sp3
tetrasubstituted sulfur atom) and presence of oxygen atoms for
coordination to lithium with potentially ordered transition states.
Phenyl sulfoxide 1 was lithiated as indicated above and
submitted to N-tosyl imines44 of benzaldehyde 9 (R ) Ph) or
isobutyraldehyde 10 (R ) i-Pr) for 1.5 h at -78 °C (Scheme
4). The awaited tosylamino-sulfoxides 11 and 12 were obtained
in 63-80% yields (Table 3, entries 1 and 2).
(34) Hanquet, G.; Colobert, F.; Lanners, S.; Solladie´, G. ARKIVOC 2003,
328-401.
(35) Furukawa, N.; Shibutani, T.; Fujihara, H. Tetrahedron Lett. 1989,
30, 7091-7094.
(36) Shibutani, T.; Fujihara, H.; Furukawa, N. Tetrahedron Lett. 1991,
32, 2943-2946.
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32, 2947-2948.
(38) Quesnelle, C.; Iihama, T.; Aubert, T.; Perrier, H.; Snieckus, V.
Tetrahedron Lett. 1992, 33, 2625-2628.
(39) Baker, R. W.; Pocock, G. R.; Sargent, M. V.; Twiss, E. Tetrahe-
dron: Asymmetry 1993, 4, 2423-2426.
(40) Nakamura, S.; Yasuda, H.; Watanabe, Y.; Toru, T. J. Org. Chem.
2000, 65, 8640-8650.
(41) Risch, N.; Arend, M. StereoselectiVe Synthesis (Houben-Weyl);
Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Georg
Thieme: Stuttgart, 1996; Vol. E21, pp 1908-1929.
(42) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895-
1946.
With the tosylimine of benzaldehyde 9 (R ) Ph, entry 1), a
modest diastereoisomeric excess of 60% was observed, and the
(43) Bloch, R. Chem. ReV. 1998, 98, 1407-1438.
(44) Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75-77.
J. Org. Chem, Vol. 71, No. 7, 2006 2611

Le Fur et al.
TABLE 3. Metalation of Sulfoxides 1-3 and Addition of
N-Tosylimines
sulf-
entry oxide
deprotonation
conditionsa
imineb
R
yield dec eed
product (%) (%) (%)
1
2
3
4
5
6
1
1
2
2
3
3
n-BuLi (1.2 equiv) Ph
n-BuLi (1.2 equiv) i-Pr 12
11a, 11b 63
60e 99
80 >98 99
64 >98 99
66 >98 99
79 >98 99
67 >98 99
LTMP (3.2 equiv)
LTMP (3.2 equiv)
LDA (2.1 equiv)
LDA (2.1 equiv)
Ph
i-Pr 14
Ph 15
i-Pr 16
13
a -78 °C for 1 h. b -78 °C for 1.5 h. c Diastereomeric excess (SS/SR)
was measured by 1H NMR on the crude product. d Enantiomeric excess
(SS/RR) was determined by enantioselective HPLC (Chiralpak AD column).
e Diastereomers were separated by column chromatography.
FIGURE 2. Enantioenriched isothiazolines.
TABLE 4. Cyclization of the Aminosulfoxides 11, 12, 15, and 16
into Isothiazolines 20-23
SCHEME 5. Metalation of Sulfoxide 5 and Addition of
N-Tosylimine 9
aminosulfoxide
product
yield (%)
configuration
ee (%)
11a (S,S)
11b (S,R)
12 (S,S)
15 (S,S)
16 (S,S)
20a
20b
21
22
23
93
93
85
83
89
(S)
(R)
(S)
(S)
(S)
98
99
97
99
95
and a sulfenic acid 19, The amino group attacks the electrophilic
sulfenic acid, followed by elimination of H2O. The formation
of sulfenic acids from sulfoxides is classical but normally takes
place at higher temperatures. The present structure may present
specific features, possibly an electronic effect and/or a hydrogen
bond stabilizing47 the intermediate 19.
SCHEME 6. Formation of 18
This unprecedented and facile formation of isothiazolines and
the interest of this structure led us to investigate the thermolytic
behavior of previous aminosulfoxides 11-16. Heating in toluene
for 20 min nicely provided cyclic sulfenamides 20-23 in very
good yields and excellent enantiomeric excesses (Table 4, Figure
2).
The new structures 11-16, 18, and 20-23 offer interesting
synthetic possibilities. We have briefly explored the reductive
cleavage of the stereogenic sulfur moiety as a synthesis of
enantiopure amines. The reaction of sulfoxide 12 with freshly
prepared Raney nickel in boiling ethanol was very slow. We
then attempted the Raney nickel reduction of sulfenamide 21
and observed that it took place rapidly at room temperature to
afford amine 24 in quantitative yield (the sulfonamide being
untouched) and 99% ee. The overall transformation of 12 into
24 could also be performed without isolation of 21 in 81% yield
(Scheme 7).
two diastereoisomers 11a and 11b were easily separated by
column chromatography with silica gel. Furthermore the enan-
tiomeric excess measured for each diastereoisomer was 99%.
Thus, no racemization of the sulfoxide occurred during the
metalation process.45 With an aliphatic tosylimine 10 (R ) i-Pr,
entry 2), the yield was increased and the asymmetric induction
was excellent (de >98%). The (S) configuration of the new
stereogenic center will be established hereunder.
Naphthyl and pyridyl sulfoxides 2 and 3 were deprotonated
and imines 9 and 10 were added to the reaction mixture. Good
yield of adducts 13-16 were isolated. We were rewarded to
observe that a single diastereomer was detected by NMR. Their
enantiomeric purity is 99%.
A similar sequence was carried out with pyridazine sulfoxide
5. Instead of the expected adduct 17, we isolated a cyclic
sulfenamide 18 (Scheme 5).
The formation of 18 can be explained by the following
pathway (Scheme 6). The aminosulfoxide 17 undergoes a 1,2-
elimination or [2,3] sigmatropic process46 leading to isobutene
Tosylamine 24 is a known product48 and the optical rotation
indicated that we obtained the (S) isomer. As the initial sulfur
configuration is (S), we assign an (S,S) structure to the
aminosulfoxide 12 and propose by analogy that the major
diastereomer 11 and compounds 12-16 have the same (S,S)
stereochemistry.
A preliminary test was carried out to show that aminosul-
foxides could be used as N,S chiral ligands for asymmetric
organometallic catalysis (Figure 3). This type of bidentate
coordination for soft transition metals is still under-
developed.23,49-57
(47) Ishii, A.; Komiya, K.; Nakayama, J. J. Am. Chem. Soc. 1996, 118,
12836-12837.
(48) Soeta, T.; Nagai, K.; Fujihara, H.; Kuriyama, M.; Tomioka, K. J.
Org. Chem. 2003, 68, 9723-9727.
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Chem. 1974, 52, 761-766.
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Synthesis; Trost, B. M., Fleming, I., Winterfeldt, E., Eds.; Pergamon
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3848.
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van Leeuwen, P. W. N. M. J. Org. Chem. 2000, 65, 3010-3017.
2612 J. Org. Chem., Vol. 71, No. 7, 2006

ortho-Metalation of Enantiopure Aromatic Sulfoxides
showed a good enantiomeric excess (86%) in favor of the (R)
isomer.
Discussion
We have used with success the sequence of aromatic sulfoxide
deprotonation and addition to activated imines. The ortho-
metalation was applied to a variety of sulfoxides using n-BuLi
or lithium dialkylamides.
FIGURE 3. Complexes of N,S-bidentate ligands.
SCHEME 7. Synthesis of an Enantiopure Tosylamine
We have reported the first investigation of the behavior of
sulfinylaryllithiums toward imines. As anticipated, it was
necessary to activate the electrophiles. The choice of N-tosyl
imines led to good yields (63-80%) of aminosulfoxides 11-
16.
Except for the case of phenyl sulfoxide 1 and the imine 9 of
benzaldehyde, the adducts 12-16 were produced as single
diastereoisomers and enantiomers. This stands in contrast with
the known reaction of aldehydes, which does lead to an efficient
C-C bond formation, but with poorer diastereoselectivities.
The (S) stereochemistry of the newly formed carbon center
was established by chemical correlation. Reductive desulfiny-
lation of sulfenamide 21 provides a new access to amine 24
and potentially to a variety of benzylic amines.
Our results confirm the power of the sulfinyl group to direct
the metalation and to control the approach of an electrophile.
As indicated in the introduction, this strategy has been developed
in the aliphatic series, including reaction with imines.41,62-68
For aromatic compounds, the closest structures are those
investigated by Garcia-Ruano and his group,69,70 which involved
sulfinylbenzenes, but the metalation was achieved in a benzylic
position and then reacted with tosylimine 9. In this case the
diastereoselectivity is modest (de ) 38%).
SCHEME 8. Enantioselective Allylic Nucleophilic
Substitution
Our access to aminosulfoxides 11-16, with (S,S) configu-
ration, deserves some comment. Examination of possible
approaches of the sulfinyl carbanion and the imine led us to
the observation that a pseudo-cyclic chair type transition state
does not lead to the observed configuration. We propose a
different model, involving (i) a concerted four-membered
transition state, as proposed by Garcia Ruano for the reaction
of a sulfinyl benzylic carbanion with imines,69,71 and (ii)
coordination of the lithium atom with both the tert-butylsulfinyl
oxygen atom and one of the two sulfonylimine oxygen atoms.
We shall take as model the simplest sulfoxide: (S)-tert-
butylsulfinylbenzene 1. Figure 4 represents the isolated lithiated
molecule in the most stable conformation according to ab initio
DFT calculations. A strong lithium-oxygen interaction was
noticed (O-Li bond order, 0.49). The sulfoxide and the lithium
We tested 12 as a ligand for the catalytic asymmetric allylic
nucleophilic substitution.58-61 1,3-Diphenyl-2-propenyl acetate
25 was reacted with the anion of methyl malonate under standard
conditions in the presence of a palladium catalyst and 10% of
our ligand 12 (Scheme 8). Allylic ester 26 was indeed produced
1
with a 95% substitution rate (determined by H NMR spec-
troscopy of the crude product), and enantioselective HPLC
(51) Hiroi, K.; Watanabe, K.; Abe, I.; Koseki, M. Tetrahedron Lett. 2001,
42, 7617-7619.
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J. Org. Chem, Vol. 71, No. 7, 2006 2613

Le Fur et al.
ligands have been reported recently,20,22 but their potential has
not yet been fully explored.
The unexpected conversion of amino sulfoxides into isothia-
zolines 20-23 brings a promise for further transformations,
including reductive cleavage of the sulfenamide moiety to chiral
amino thiols.78-83
FIGURE 4. Lithiated sulfoxide 1.
Aminosulfoxides 12-16 are also potential precursors of
enantioenriched sultames, after oxidation of the sulfur atom and
deprotection of the N-tosyl group. The latter compounds
represent an important class of chiral auxiliaries84-87
Conclusion
We have synthesized various aromatic enantiopure sulfoxides
by reaction of lithio derivatives with tert-butanethiosulfinate with
moderate to good yields with an excellent optical purity (g99%).
The enantiopure sulfoxides have been metalated and reacted
with N-tosylated imines for the first time. Excellent asymmetric
inductions have been observed on the new chiral center, except
in one case. We have highlighted an original thermal cyclization
to analogues of benzisothiazoline. The reduction of the cyclized
product allowed the preparation of an enantioenriched amine
with a good yield. An example of use as N,S(O) chiral ligand
for asymmetric catalysis has also been described. Further studies
and applications are in due course.
FIGURE 5. Proposed model.
atom form a flat five-membered ring, coplanar with the benzene
ring. The lower face of these rings is clearly hindered by the
tert-butyl group, so that an electrophile will approach from the
upper face.
The imine has an (E)-configuration and a conformation in
which the tolyl group is anti to the NdC bond (along the N-S
bond).72 With these elements, we assume two modes of attack,
A and B (Figure 5).
The face of attack of the imine does not appear well
differentiated by the interaction of R imine group with the
aromatic ring of the sulfoxide. The tolylsulfonyl group provides
a significant difference between A and B. It is a bulky group,
as suggested by the conformational energy73 of 2.5 kcal/mol
for SO2Me.74 For the approach B the interaction is severe with
the sulfinyl group. In a model A the tolylsulfonyl is located
away from the sulfinyl favoring such an approach, leading to
the (S,S) diastereomer, in agreement with the experimental.
The results reported here provide a nice entry to the new
aminosulfoxides 12-16. The sequence is rather straightforward
(2 steps from the sulfoxide) and practical. The Ellman enan-
tioenriched thiosulfinate 6 is available32 in large scale and is
easily prepared in the laboratory with low cost (0.52% ligand
loading for the enantioselective oxidation).
The only precedent of structures 12-16 that we are aware
of is in the naphthyl series. The Toru group75 investigated the
addition of methyllithium to racemic [1-(2,4,6-triisopropyl-
phenylsulfinyl)-2-naphthyl]methanimines. They obtained a struc-
ture, similar to 13 and 14, interestingly possessing an opposite
relative stereochemistry.
Aminosulfoxides 12-16 are potential bidentate ligands for
asymmetric synthesis mediated by transition metals. One
example has been reported here, showing an enantioselectivity
that is one of the highest among N,S(O) ligands.23,49,76 One of
the present strategies to improve catalytic systems is to develop
ligands, which are not phosphines, to avoid some of the
difficulties that can be met.77 Among novel ligands, the choice
of N,S(O) moieties has been rarely examined.50-57More N,S
Experimental Section
General Procedure for Direct Lithiation by Lithium Alkyl-
amide (LTMP or LDA). A solution of n-butyllithium (1.6 or 2.5
in hexane) was added to cold (-50 °C), stirred, and anhydrous
tetrahydrofuran (10 mL) under an atmosphere of nitrogen. Then
2,2,6,6-tetramethylpiperidine (TMPH) or diisopropylamine (DI-
PAH) was added. The mixture was warmed to 0 °C. After 20 min,
the temperature was lowered to -78 °C, and the substrate to
metalate dissolved in 5 mL of THF was added. After stirring for 1
h at -78 °C, the corresponding sulfonylimine was introduced, and
stirring was continued for 1.5 h at -78 °C. Hydrolysis was then
carried out at -78 °C using a mixture of water, ethanol, and
tetrahydrofuran (1/4/5). The reaction solution was warmed to room
temperature, and the solvent was evaporated. The aqueous layer
was extracted with dichloromethane, and the combined organic
layers were dried over magnesium sulfate and evaporated. The crude
product was purified by column chromatography on silica gel.
[1S,(S)S]-(-)-N-[(2-tert-Butylsulfinylphenyl)phenylmethyl]-4-
methylbenzenesulfonamide (11a) and [1R,(S)S]-(-)-N-[(2-tert-
Butylsulfinylphenyl)phenylmethyl]-4-methylbenzenesulfona-
mide (11b). Metalation of 1 (0.2 g, 1.10 mmol) according to the
general procedure for direct lithiation with 1.6 M n-BuLi (0.83 mL,
1.32 mmol), followed by reaction with the sulfonylimine 9 (R )
Ph) (0.43 g, 1.65 mmol), gave after purification by column
(78) Kang, J.; Kim, D. S.; Kim, J. I. Synlett 1994, 842-844.
(79) Arink, A. M.; Braam, T. W.; Keeris, R.; Jastrzebski, J. T. B. H.;
Benhaim, C.; Rosset, S.; Alexakis, A.; van Koten, G. Org. Lett. 2004, 6,
1959-1962.
(80) Harfouche, J.; Herault, D.; Tommasino, M. L.; Pellet-Rostaing, S.;
Lemaire, M. Tetrahedron: Asymmetry 2004, 15, 3413-3418.
(81) Tseng, S.-L.; Yang, T.-K. Tetrahedron: Asymmetry 2005, 16, 773-
782.
(82) Kim, J. Y.; Livinghouse, T. Org. Lett. 2005, 7, 1737-1739.
(83) Braga, A. L.; Alves, E. F.; Silveira, C. C.; Zeni, G.; Appelt, H. R.;
Wessjohann, L. A. Synlett 2005, 588-594.
(84) Kim, B. H.; Curran, D. P. Tetrahedron 1993, 49, 293-318.
(85) Liu, Z.; Takeuchi, Y. Heterocycles 2002, 56, 693-709.
(86) Hirano, S.; Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6, 727-
729.
(72) Charette, A. B.; Giroux, A. Tetrahedron Lett. 1996, 37, 6669-6672.
(73) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; John Wiley: New York, 1994; pp 690-700.
(74) Eliel, E. L.; Kandasamy, D. J. Org. Chem. 1976, 41, 3899-3904.
(75) Nakamura, S.; Yasuda, H.; Toru, T. Tetrahedron: Asymmetry 2003,
13, 1509-1518.
(76) Hiroi, K.; Suzuki, Y.; Kaneko, Y.; Kato, F.; Abe, I.; Kawagishi, R.
Polyhedron 2000, 19, 525-528.
(77) Vries, J. G. d.; Vries, A. H. M. d. Eur. J. Org. Chem. 2003, 799-
811.
(87) Ahn, K. H.; Kim, S.-K.; Ham, C. Tetrahedron Lett. 1998, 39, 6321-
6322.
2614 J. Org. Chem., Vol. 71, No. 7, 2006

ortho-Metalation of Enantiopure Aromatic Sulfoxides
chromatography (silica gel with Et2O/cyclohexane (4/1) as eluent)
a mixture of two diastereoisomers (ratio 80:20 determined by H
NMR). A subsequent purification by column chromatography (silica
gel with dichloromethane/ethyl acetate (9/1) as eluent) gave in a
first fraction the major diastereoisomer 11a (243 mg, 50%) as a
white solid, mp 160 °C. The ee was 99% by HPLC (Chiralpak AD
(C); 142.6 (C); 141.0 (C); 138.7 (C); 133.3 (C); 133.0 (CH); 132.4
(C); 129.7 (C); 129.6 (CH); 128.8 (CH); 128.7 (CH); 127.5 (CH);
127.3 (CH); 127.1 (CH); 126.8 (CH); 126.5 (CH); 126.0 (CH);
124.6 (CH); 60.0 (C); 57.4 (CH); 25.4 (CH3); 21.3 (CH3). IR (KBr)
(cm-1): 2786-3027, 1340, 1163, 1007. Anal. Calcd for C28H29-
NO3S2: C, 68.40; H, 5.94; N, 2.85; S, 13.04. Found: C, 68.10; H,
6.12; N, 3.04; S, 12.79.
1
column, 1 mL/min, 80:20 heptane/i-PrOH, λ ) 230 nm, t1R,(S)R
)
15.4 min, t1S,(S)S ) 18.7 min). [R]20D ) -149 (c 0.68, CHCl3). 1H
NMR (CDCl3): δ 7.79 (m, 1H); 7.67 (m, 1H); 7.52 (d, J ) 8.3
Hz, 2H); 7.37 (m, 2H); 7.10 (d, J ) 7.9 Hz, 2H); 7.03 (m, 3H);
6.92 (m, 2H); 6.10 (d, J ) 6.8 Hz, 1H); 6.01 (d, J ) 6.8 Hz, 1H);
2.36 (s, 3H); 1.22 (s, 9). 13C NMR (CDCl3): δ 143.4 (C); 140.6
(C); 139.6 (C); 137.5 (C); 131.7 (CH); 129.4 (CH); 128.7 (CH);
128.0 (CH); 127.8 (CH); 127.4 (CH); 127.1 (CH); 127.0 (CH);
126.8 (CH); 58.0 (CH); 57.8 (C); 23.2 (CH3); 21.5 (CH3). IR (KBr)
(cm-1): 2868-3085, 1458, 1332, 1160, 1003, 670. Anal. Calcd
for C24H27NO3S2: C, 65.28; H, 6.16; N, 3.17; S, 14.52. Found: C,
65.51; H, 5.64; N, 2.96; S, 12.80.
[1S,(S)S]-(-)-N-[2-Methyl-1-(1-tert-butylsulfinylnaphthalen-
2-yl)propyl]-4-methylbenzenesulfonamide (14). Metalation of 2
(0.15 g, 0.65 mmol) according to the general procedure for direct
lithiation with 2.5 M n-BuLi (0.83 mL, 2.07 mmol) and TMPH
(0.35 mL, 2.07 mmol), followed by reaction with the sulfonylimine
10 (R ) i-Pr) (0.47 g, 2.1 mmol), gave after purification by column
chromatography (silica gel with dichloromethane/acetone (95/5) as
eluent) 14 (197 mg, 66%) as a single diastereoisomer (ratio >99:1
determined by 1H NMR) and as a white solid, mp 170 °C. The ee
was 99% by HPLC (Chiralpak AD column, 1 mL/min, 80:20
heptane/i-PrOH, λ ) 230 nm, t1R,(S)R ) 14.4 min, t1S,(S)S ) 17.8
1
A second fraction gave the minor diastereoisomer 11b (62 mg,
13%) as a white solid, mp 160 °C. The ee was 99% by HPLC
(Chiralpak AD column, 1 mL/min, 80:20 heptane/i-PrOH, λ ) 230
nm, t1R,(S)S ) 15.6 min, t1S,(S)R ) 19.8 min). [R]20D ) -135 (c 0.93,
min). [R]20 ) -157 (c 0.29, CHCl3). H NMR (CDCl3): δ 9.34
D
(m, 1H); 7.69 (m, 4H); 7.51 (d, J ) 8.7 Hz, 1H); 7.41 (m, 2H);
7.15 (d, J ) 8.3 Hz, 2H); 5.75 (d, J ) 8.3 Hz, 1H); 5.22 (m, 1H);
2.31 (m, 4H); 1.24 (s, 9H); 0.82 (d, J ) 6.8 Hz, 3H); 0.55 (d, J )
6.8 Hz, 3H). 13C NMR (CDCl3): δ 143.9 (C); 143.4 (C); 138.3
(C); 133.8 (C); 133.6 (C); 132.4 (CH); 130.4 (C); 129.9 (CH); 128.6
(CH); 127.3 (CH); 127.2 (CH); 126.9 (CH); 126.9 (CH); 124.1
(CH); 61.0 (C); 59.6 (CH); 36.0 (CH); 26.2 (CH3); 21.9 (CH3);
20.7 (CH3); 15.8 (CH3). IR (KBr) (cm-1): 3140, 2898-2965, 1474,
1330, 1162, 1095, 1045, 1012, 670. Anal. Calcd for C25H31NO3S2:
C, 65.61; H, 6.83; N, 3.06; S, 14.01. Found: C, 66.06; H, 6.97; N,
3.08; S, 14.45.
1
CHCl3). H NMR (CDCl3): δ 7.67 (d, J ) 8.3 Hz, 1H); 7.47 (d,
J ) 8.3 Hz, 2H); 7.25 (m, 8H); 7.05 (d, J ) 8.3 Hz, 2H); 6.07 (d,
J ) 6.8 Hz, 1H); 5.39 (d, J ) 6.8 Hz, 1H); 2.28 (s, 3H); 0.89 (s,
9H). 13C NMR (CDCl3): δ 143.5 (C); 139.9 (C); 139.7 (C); 139.3
(C); 137.2 (C); 131.6 (CH); 129.9 (CH); 129.5 (CH); 129.0 (CH);
128.9 (CH); 128.4 (CH); 128.4 (CH); 127.6 (CH); 127.5 (CH); 57.5
(C); 56.5 (CH); 23.5 (CH3); 21.9 (CH3). IR (KBr) (cm-1): 2922-
3253, 1440, 1328, 1159, 1057, 1028, 669. Anal. Calcd for C24H27-
NO3S2: C, 65.28; H, 6.16; N, 3.17; S, 14.52. Found: C, 64.97; H,
6.47; N, 2.92; S, 12.96.
[1S,(S)S]-(-)-N-[(3-tert-Butylsulfinylpyridin-4-yl)phenylmethyl]-
4-methylbenzenesulfonamide (15). Metalation of 3 (0.15 g, 0.82
mmol) according to the general procedure for direct lithiation with
2.5 M n-BuLi (0.72 mL, 1.8 mmol) and DIPAH (0.25 mL, 1.8
mmol), followed by reaction with the sulfonylimine 9 (R ) Ph)
(0.52 g, 2 mmol), gave after purification by column chromatography
(silica gel with ethyl acetate as eluent) 15 (287 mg, 79%) as a single
[1S,(S)S]-(-)-N-[2-Methyl-1-(2-tert-butylsulfinylphenyl)-
propyl]-4-methylbenzenesulfonamide (12). Metalation of 1 (0.15
g, 0.82 mmol) according to the general procedure for direct lithiation
with 1.6 M n-BuLi (0.62 mL, 0.99 mmol), followed by reaction
with the sulfonylimine 10 (R ) i-Pr) (0.27 g, 1.2 mmol), gave after
purification by column chromatography (silica gel with Et2O as
eluent) 12 (264 mg, 80%) as a single diastereoisomer (ratio >99:1
1
diastereoisomer (ratio >99:1 determined by H NMR) and as a
pale yellow solid, mp 100 °C. The ee was 99% by HPLC (Chiralpak
AD column, 1 mL/min, 75:25 heptane/i-PrOH, λ ) 230 nm, t1R,(S)R
) 9.9 min, t1S,(S)S ) 12.4 min). [R]20D ) -65 (c 1.17, CHCl3). 1H
NMR (CDCl3): δ 8.83 (s, 1H); 8.61 (d, J ) 4.9 Hz, 1H); 7.64 (d,
J ) 5.3 Hz, 1H); 7.52 (d, J ) 8.3 Hz, 2H); 7.15 (m, 6H); 6.77 (d,
J ) 7.5 Hz, 2H); 5.76 (d, J ) 6.0 Hz, 1H); 5.58 (d, J ) 6.0 Hz,
1H); 2.37 (s, 3H); 1.21 (s, 9H). 13C NMR (CDCl3): δ 152.7 (CH);
149.6 (C); 149.2 (CH); 144.5 (C); 138.1 (C); 137.3 (C); 133.9 (C);
130.1 (CH); 129.7 (CH); 129.2 (CH); 128.0 (CH); 127.5 (CH);
121.3 (CH); 58.6 (C); 58.4 (CH); 23.4 (CH3); 22.0 (CH3). IR (KBr)
(cm-1): 2861-3061, 1720, 1333, 1166, 1089, 1027, 577. Anal.
Calcd for C23H26N2O3S2: C, 62.42; H, 5.92; N, 6.33; S, 14.49.
Found: C, 62.74; H, 5.89; N, 6.41; S, 14.56.
1
determined by H NMR) and as a white solid, mp 70 °C. The ee
was 99% by HPLC (Chiralpak AD column, 1 mL/min, 80:20
heptane/i-PrOH, λ ) 230 nm, t1S,(S)S ) 10.7 min, t1R,(S)R ) 12.2
1
min). [R]20 ) -150 (c 0.99, CHCl3). H NMR (CDCl3): δ 7.78
D
(d, J ) 7.7 Hz, 1H); 7.64 (d, J ) 8.3 Hz, 2H); 7.33 (m, 3H); 7.12
(d, J ) 8.3 Hz, 2H); 5.75 (d, J ) 7.5 Hz, 1H); 4.74 (dd, J ) 7.9
and 3.4 Hz, 1H); 2.33 (s, 3H); 2.17 (m, 1H); 1.14 (s, 9H); 0.78 (d,
J ) 6.8 Hz, 3H); 0.55 (d, J ) 6.8 Hz, 3H). 13C NMR (CDCl3): δ
143.8 (C); 141.6 (C); 138.3 (C); 137.8 (C); 131.4 (CH); 129.9 (CH);
127.9 (CH); 127.3 (CH); 127.3 (CH); 127.0 (CH); 59.4 (CH); 57.9
(C); 34.8 (CH); 23.5 (CH3); 21.9 (CH3); 20.4 (CH3); 15.5 (CH3).
IR (KBr) (cm-1): 2894-3138, 1459, 1323, 1158, 1017, 662. Anal.
Calcd for C21H29NO3S2: C, 61.88; H, 7.17; N, 3.44; S, 15.73.
Found: C, 61.89; H, 7.29; N, 3.61; S, 15.42.
[1S,(S)S]-(-)-N-[2-Methyl-1-(3-tert-butylsulfinylpyridin-4-yl)-
propyl]-4-methylbenzenesulfonamide (16). Metalation of 3 (0.15
g, 0.82 mmol) according to the general procedure for direct lithiation
with 2.5 M n-BuLi (0.72 mL, 1.8 mmol) and DIPAH (0.25 mL,
1.8 mmol), followed by reaction with the sulfonylimine 10 (R )
i-Pr) (0.45 g, 2 mmol), gave after purification by column chroma-
tography (silica gel with ethyl acetate as eluent) 16 (223 mg, 67%)
[1S,(S)S]-(-)-N-[(1-tert-Butylsulfinylnaphthalen-2-yl)phenyl-
methyl]-4-methylbenzenesulfonamide (13). Metalation of 2 (0.15
g, 0.65 mmol) according to the general procedure for direct lithiation
with 2.5 M n-BuLi (0.83 mL, 2.07 mmol) and TMPH (0.35 mL,
2.07 mmol), followed by reaction with the sulfonylimine 9 (R )
Ph) (0.59 g, 2.28 mmol), gave after purification by column
chromatography (silica gel with dichloromethane/Et2O (9/1) as
eluent) 13 (203 mg, 64%) as a single diastereoisomer (ratio >99:1
determined by 1H NMR) and as a white solid, mp 210 °C. The ee
was 99% by HPLC (Chiralpak AD column, 1 mL/min, 80:20
1
as a single diastereoisomer (ratio >99:1 determined by H NMR)
and as a pale yellow solid, mp 170 °C. The ee was 99% by HPLC
(Chiralpak AD column, 1 mL/min, 80:20 heptane/i-PrOH, λ ) 230
nm, t1R,(S)R ) 9.8 min, t1S,(S)S ) 18.3 min). [R]20D ) -118 (c 1.01,
1
CHCl3). H NMR (CDCl3): δ 9.14 (s, 1H); 8.74 (d, J ) 5.3 Hz,
heptane/i-PrOH, λ ) 230 nm, t1R,(S)R ) 31.9 min, t1S,(S)S ) 36.0
1H); 7.85 (d, J ) 8.3 Hz, 2H); 7.57 (d, J ) 4.9 Hz, 1H); 7.41 (d,
J ) 7.9 Hz, 2H); 6.49 (d, J ) 7.9 Hz, 1H); 4.83 (m, 1H); 2.57 (s,
3H); 2.47 (m, 1H); 1.43 (s, 9H); 1.07 (d, J ) 6.8 Hz, 3H); 0.79 (d,
J ) 6.8 Hz, 3H). 13C NMR (CDCl3): δ 152.1 (CH); 151.0 (C);
149.0 (CH); 144.2 (C); 137.7 (C); 133.7 (C); 130.0 (CH); 127.3
(CH); 121.4 (CH); 59.2 (CH); 58.4 (C); 34.1 (CH); 23.4 (CH3);
1
min). [R]20 ) -142 (c 0.65, DMSO). H NMR (DMSO-d6): δ
D
9.07 (d, J ) 8.7 Hz, 1H); 8.77 (m, 1H); 7.90 (d, J ) 8.7 Hz, 1H);
7.71 (d, J ) 7.2 Hz, 1H); 7.64 (d, J ) 8.7 Hz, 1H); 7.32 (m, 4H);
7.00 (d, J ) 7.9 Hz, 2H); 6.90 (m, 3H); 6.82 (m, 2H); 6.28 (m,
1H); 2.08 (s, 3H); 1.01 (s, 9H). 13C NMR (DMSO-d6): δ 142.9
J. Org. Chem, Vol. 71, No. 7, 2006 2615

Le Fur et al.
22.0 (CH3); 20.6 (CH3); 15.3 (CH3). IR (KBr) (cm-1): 2967-3166,
1474, 1331, 1159, 1046, 1012, 670. Anal. Calcd for C20H28N2O3S2:
C, 58.79; H, 6.91; N, 6.86; S, 15.70. Found: C, 59.19; H, 7.28; N,
7.02; S, 15.15.
2922-3059, 1468, 1373, 1171, 1029, 673. Anal. Calcd for
C20H19N3O4S2: C, 55.93; H, 4.46; N, 9.78. Found: C, 56.28; H,
4.77; N, 9.46.
(S)-(-)-4,7-Dimethoxy-3-phenyl-2-(toluene-4-sulfonyl)-2,3-di-
hydro-isothiazolo[4,5-d]pyridazine (18). Metalation of 5 (0.16 g,
0.66 mmol) according to the general procedure for direct lithiation
with 2.5 M n-BuLi (0.85 mL, 2.12 mmol) and TMPH (0.35 mL,
2.12 mmol), followed by reaction with the sulfonylimine 9 (R )
Ph) (0.57 g, 2.2 mmol), gave after purification by column
chromatography (silica gel with dichloromethane/cyclohexane (8/
2) as eluent) 18 (155 mg, 55%) as a pale yellow solid, mp < 50
°C. The ee was 75% by HPLC (Chiralcel OD column, 1 mL/min,
90:10 heptane/i-PrOH, λ ) 230 nm, t ) 8.1 min, t ) 10.3 min).
[R]20D ) -292 (c 0.73, CHCl3). 1H NMR (CDCl3): δ 7.68 (d, J )
8.2 Hz, 2H); 7.25 (m, 5H); 7.04 (d, J ) 8.2 Hz, 2H); 6.37 (s, 1H);
3.92 (s, 3H); 3.89 (s, 3H); 2.24 (s, 3H). 13C NMR (CDCl3): δ 158.1
(C); 156.4 (C); 145.9 (CH); 135.8 (C); 134.2 (C); 130.9 (C); 129.5
(CH); 129.5 (CH); 129.2 (CH); 128.9 (CH); 127.4 (CH); 127.0 (C);
71.1 (CH); 55.4 (CH3); 55.3 (CH3); 22.0 (CH3). IR (KBr) (cm-1):
Acknowledgment. We thank the “PunchOrga” Network
(Poˆle Universitaire Normand de Chimie Organique), the “Re´gion
Haute-Normandie”, the “Re´gion Basse-Normandie”, the “Min-
iste`re de la Recherche”, CNRS (Centre National de la Recherche
Scientifique), and the European Union (FEDER funding) for
financial support. We are grateful to Pr. Dupas for the
calculations and to the CRIHAN (Centre de Ressources Infor-
matiques de Haute-Normandie) for technical support.
Supporting Information Available: Detailed experimental
procedures, characterization data, and 1H and 13C NMR spectra of
compounds 1-5, 11-16, 18, 20-23, 24, and 26. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO052358P
2616 J. Org. Chem., Vol. 71, No. 7, 2006