An efficient and straightforward access to sulfur substituted [2.2]paracyclophanes: Application to stereoselective sulfenate salt alkylation

Article abstract of DOI:10.1021/ol800161m

A straightforward and high-yielding access to various [2.2]paracyclophanes possessing a sulfur-based functional group is reported, the key step being a S_EAr reaction mediated by a sulfonium salt. The versatility of the methodology was exemplified by an original application in sulfenate salt chemistry, from which a remarkable chirality transfer was observed.

Full text of DOI:10.1021/ol800161m

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1271-1274
An Efficient and Straightforward Access
to Sulfur Substituted
[2.2]Paracyclophanes: Application to
Stereoselective Sulfenate Salt Alkylation
Jean-Franc
Jana Sopkova´
¸
ois Lohier,† Florian Foucoin,† Paul-Alain Jaffre`s,‡ Jose´ I. Garcia,§
|
−
de Oliveira Santos, Ste´phane Perrio,*,† and Patrick Metzner†
Laboratoire de Chimie Mole´culaire et Thio-organique, ENSICAEN, UniVersite´ de Caen
Basse-Normandie, CNRS, 6 BouleVard du Mare´chal Juin, 14050 Caen, France,
Laboratoire de Chimie Electrochimie Mole´culaire Chimie Analytique, UniVersite´ de
Bretagne Occidentale, CNRS, 6 AVenue Le Gorgeu, 29238 Brest, France,
Departamento de Qu´ımica Orga´nica, Instituto de Ciencia de Materiales de Aragon,
UniVersidad de Zaragoza-CSIC, 50009 Zaragoza, Spain, and Centre d’Etudes et de
Recherche sur le Me´dicament de Normandie, UniVersite´ de Caen Basse-Normandie, 5
Rue Vaube´nard, 14032 Caen, France
stephane.perrio@ensicaen.fr
Received January 24, 2008
ABSTRACT
A straightforward and high-yielding access to various [2.2]paracyclophanes possessing a sulfur-based functional group is reported, the key
step being a SEAr reaction mediated by a sulfonium salt. The versatility of the methodology was exemplified by an original application in
sulfenate salt chemistry, from which a remarkable chirality transfer was observed.
[2.2]Paracyclophane 1 is the parent molecule for a fascinating
family of compounds consisting of two benzene rings held
face-to-face by two ethano bridges at the para positions
(Figure 1). The strong electronic interaction between the
arene fragments combined with rigidly defined geometric
relationships between substituents gives rise to the unique
properties of these molecules, with successful application
in various areas, including polymers, materials, and planar
chiral catalysts.1 Considering the great potential of these
systems, it is however surprising that research in this field
is still in its infancy when compared to the analogous
ferrocenyl or η6-arene transition metal complexes. The most
† Laboratoire de Chimie Mole´culaire et Thio-organique.
‡ Laboratoire de Chimie Electrochimie Mole´culaire Chimie Analytique.
§ Instituto de Ciencia de Materiales de Aragon.
Figure 1. [2.2]Paracyclophane and sulfur derivatives.
| Centre d’Etudes et de Recherche sur le Me´dicament de Normandie.
10.1021/ol800161m CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/15/2008

significant reason appears to be the lack of attractive
strategies for the preparation of functionalized structures,
associated also to a limited number of commercially available
starting materials.
As sulfenates are normally converted into sulfoxides upon
quenching with soft electrophiles13 (S-alkylation), the inves-
tigation we suggest using paracyclophane-based species could
provide a diastereoselective version of this reaction. Com-
pared to the successful but scarce precedents, an obvious
originality concerns the unprecedented use of planar chirality
as element of stereocontrol.14 Full accounts on this work are
provided in this manuscript.
Symmetrical sulfoxide 715 was activated by triflic anhy-
dride to give a highly electrophilic intermediate, which was
further reacted with unsubstituted [2.2]paracyclophane 1 to
produce the corresponding sulfonium trifluoromethane-
sulfonate 8 (Figure 2). Subsequent treatment with Et3N
In this regard, very few derivatives incorporating a sulfur
function, even in racemic form, have been described so far.2-6
As a prominent example, (()-[2.2]paracyclophane-4-thiol 2
was mentioned2 for the first time in 2001, the few syntheses
of which still suffering from multistep derivatization reactions
and low overall yields.7 To overcome these severe shortcom-
ings, we were interested in developing a precursor that could
facilitate the synthesis of a variety of sulfur-containing [2.2]-
paracyclophanes, including previously cited thiol 2 but also
related sulfides8 3. â-Sulfanyl ester 4 was postulated as a
suitable candidate for the following criteria. In principle, it
should be prepared from simple paracyclophane 1 using an
elegant but surprisingly overlooked SEAr reaction mediated
by a sulfonium salt.9,10 Conversion into 2 and 3 should then
be directly secured according to a retro-Michael pathway.9
Having a current interest into sulfenate salts11 (sulfur
nucleophiles with general structure R1SO-), oxidation of 4
into the analogous sulfinyl compound 5 could also permit a
straightforward extension toward this unusual chemistry.12
Figure 2. Intermediates in the synthesis of 4.
(1) (a) Modern Cyclophane Chemistry; Gleiter, R., Hopf, H., Eds; Wiley-
VCH: Weinheim, 2004. (b) Gibson, S. E.; Knight, J. D. Org. Biomol. Chem.
2003, 1, 1256-1269. (c) Bra¨se, S.; Dahmen, S.; Ho¨fener, S.; Lauterwasser,
F.; Kreis, M.; Ziegert, R. E. Synlett 2004, 2647-2669.
induced a single â-elimination-based dealkylation and de-
livered the pivotal intermediate 4 in 75% yield. Conversion
of 4 into the targeted compounds 2-5 was then cleanly
achieved as detailed below. Reaction with t-BuOK with
subsequent acidification afforded thiol 2 in 89% yield,
thereby providing by far the most elegant access2 to this
compound. Use of alkyl halides as alternative electrophilic
partners furnished also, in a single procedural step, the
analogous sulfides 3 (85-93% yield). Finally, oxidation of
(2) Thiol: (a) Kane, V. V.; Gerdes, A.; Grahn, W.; Ernst, L.; Dix, I.;
Jones, P. G.; Hopf, H. Tetrahedron Lett. 2001, 42, 373-376. (b) Kreis,
M.; Bra¨se, S. AdV. Synth. Catal. 2005, 47, 313-319.
(3) Sulfides: (a) Menichetti, S.; Faggi, C.; Lamanna, G.; Marrocchi, A.;
Minuti, L.; Taticchi, A. Tetrahedron 2006, 62, 5626-5631. (b) Pelter, A.;
Mootoo, B.; Maxwell, A.; Reid, A. Tetrahedron Lett. 2001, 42, 8391-
8394. (c) Marchand, A.; Maxwell, A.; Mootoo, B.; Pelter, A.; Reid, A.
Tetrahedron 2000, 56, 7331-7338. (d) Hou, X.-L.; Wu, X.-W.; Dai, L.-
X.; Cao, B.-X.; Sun, J. J. Chem. Soc., Chem. Commun. 2000, 1195-1196.
(4) Sulfoxides: (a) Hitchcock, P. B.; Rowlands, G. J.; Seacome, R. J.
Org. Biomol. Chem. 2005, 3, 3873-3876. (b) Hitchcock, P. B.; Rowlands,
G. J.; Parmar, R. J. Chem. Soc., Chem. Commun. 2005, 4219-4221. (c)
Reich, H. J.; Yelm, K. E. J. Org. Chem. 1991, 56, 5672-5679.
(5) Sulfonamides: Braddock, D., C.; MacGilp, I. D.; Perry, B. G. AdV.
Synth. Catal. 2004, 346, 1117-1130.
(6) Sulfonic acid: (a) van Lindert, H. C. A.; Koeberg-Telder, A.;
Cerfontain, H. Recl. TraV. Chim. Pays-Bas 1992, 111, 379-388. (b) van
Lindert, H. C. A.; van Doorn, J. A.; Bakker, B. H.; Cerfontain, H. Recl.
TraV. Chim. Pays-Bas 1996, 115, 167-178.
(7) The sulfur atom was introduced via a Newman-Kwart reaction,
treatment of lithiated species with elemental sulfur or a Pd-catalysis with
triisopropylsilanethiol. See ref 2.
16
4 with H2O2 gave the sulfenate precursor 5 in 96% yield
as an inseparable 3:2 diastereoisomeric mixture. Attractive
features of the syntheses include introduction of the sulfur
moiety on the paracyclophane core in an extremely simple
way with stable and readily available reagents, convenient
protocols appropriate for scalability, and straightforward
purifications.
(()-[2.2]Paracyclophane-4-sulfenic acid salt was generated
in THF by deprotonation of 5 with t-BuOK at low temper-
ature (-78 °C), followed by a spontaneous retro-Michael
reaction. After in situ quenching with alkyl halides, we were
delighted to uniformly isolate in excellent yields the antici-
pated sulfoxides as single diastereoisomers 9a-c (Table 1,
entries 1-3).17 The (SP,SS)* configuration was unambigu-
(8) To the best of our knowledge, only the t-butylsulfanyl derivative of
3 (alkyl ) t-Bu) has been described so far. See ref 4a.
(9) (a) Becht, J.-M.; Wagner, A.; Mioskowski, C. J. Org. Chem. 2003,
68, 5758-5761. (b) Becht, J.-M.; Wagner, A.; Mioskowski, C. Tetrahedron
Lett. 2004, 45, 7031-7033.
(10) It was previously shown that the aromatic sulfonation of 1 with
sulfur trioxide, in the presence of 1,4-dioxane, proceeds cleanly to afford
[2.2]paracyclophane-4-sulfonic acid. See ref 6.
(11) (a) Sandrinelli, F.; Perrio, S.; Beslin, P. J. Org. Chem. 1997, 62,
8626-8627. (b) Sandrinelli, F.; Perrio, S.; Averbuch-Pouchot, M.-T. Org.
Lett. 2002, 4, 3619-3622. (c) Sandrinelli, F.; Fontaine, G.; Perrio, S.; Beslin,
P. J. Org. Chem. 2004, 69, 6916-6919. (d) Sandrinelli, F.; Boudou, C.;
Caupe`ne, C.; Averbuch-Pouchot, M.-T.; Perrio, S.; Metzner, P. Synlett 2006,
3289-3293. (e) Boudou, C.; Berge`s, M.; Sagnes, C.; Sopkova´-de Oliveira
Santos, J.; Perrio, S.; Metzner, P. J. Org. Chem. 2007, 72, 5403-5406.
(12) (a) Caupe`ne, C.; Boudou, C.; Perrio, S.; Metzner, P. J. Org. Chem.
2005, 70, 2812-2815. (b) Maitro, G.; Prestat, G.; Madec, D.; Poli, G. J.
Org. Chem. 2006, 71, 7449-7454. (c) Maitro, G.; Vogel, S.; Prestat, G.;
Madec, D.; Poli, G. Org. Lett. 2006, 8, 5951-5954. (d) Colobert, F.;
Ballesteros-Garrido, R.; Leroux, F. R.; Ballesteros, R.; Abarca, B.
Tetrahedron Lett. 2007, 48, 6896-6899. (e) Maitro, G.; Vogel, S.; Sadaoui,
M.; Prestat, G.; Madec, D.; Poli, G. Org. Lett. 2007, 9, 5493-5496.
(13) For a review: O’Donnell, J. S.; Schwan, A. L. J. Sulfur Chem. 2004,
25, 183-211.
(14) Excellent diastereocontrols were already reported using isoborneol,
cysteine and (R)-phenylethylamine derivatives. See ref 13.
(15) This compound was prepared in a 93% overall yield by Michael
addition of 3-sulfanylpropanoic acid methyl ester on methyl acrylate,
followed by oxidation with NaIO4. See Supporting Information.
(16) An H2O2/2,2,2-trifluoroethanol combination was used: Be´gue´, J.-
P.; Bonnet-Delpon, D.; Crousse, B. Synlett 2004, 18-29.
(17) Previously reported [2.2]paracyclophan-4-yl sulfoxides were syn-
thetized using oxidation or Andersen approaches. See ref 4.
1272
Org. Lett., Vol. 10, No. 6, 2008

Table 1. Sulfoxides by Sulfenate Alkylation
entry precursor
R1X
conditionsa
productb yieldc
1
2
3
4
5
6
5
5
5
5
5
6
BnBr t-BuOK, -78 °C
9a
9b
9c
9a
9a
9a
82
88
90
80
77
72
MeI
EtI
t-BuOK, -78 °C
t-BuOK, -78 °C
BnBr t-BuOK, -40 °C
BnBr t-BuOK, -0 °C
BnBr TBAF, 60 °C
a Commercial 1M t-BuOK or TBAF solutions (1.1 equiv) in THF and
R1X (1.1-2.1 equiv). b No sulfenic ester, which might arise through a
competing O-alkylation of the ambident sulfenate was detected. c Isolated
yield.
ously assigned by X-ray crystallography.18 A perfect dias-
tereoselectivity was observed likely when the reaction was
carried at higher temperatures (entries 4 and 5). Having very
recently identified sulfoxides displaying the 2-(trimethylsi-
lyl)ethyl moiety as an alternative source of sulfenates
according to a fluoride-triggered fragmentation, we also
tested this methodology.19 Treatment of silyl sulfoxide 620
with TBAF in the presence of benzyl bromide led efficiently
to diastereoisomer 9a as the sole reaction product (entry 6).
The remarkably high diastereoselectivity observed can be
accounted for by the preferred conformation of the interme-
diate sulfenate I, with the S-O bond lying in the plane of
the aromatic ring and oriented toward the ortho arene
hydrogen (Scheme of Table 1). If this conformational
preference is maintained in the alkylation transition state,
the nucleophilic attack proceeds from the more readily
available sulfur lone pair, away from the paracyclophane
lower deck. This induction model is fully supported by the
results of a molecular modeling study as summarized in
Figure 3 (see also Supporting Information for additional
comments).21
Figure 3. Calculated (HF/6-31+G*) sulfenate alkylation pathway.
3). Optimal results with diastereoisomeric compositions23 up
to 9:91 were reached using the reagent 11b11d derived from
pinacolone (entries 4-6). The major product 10 being
(SP,RS)* configured, the stereochemical outcome is comple-
mentary to that available with the sulfenate process.
Table 2. Sulfoxides by Thioether Oxidation
entry
sulfide
R1
oxidant
ratio 9:10
yielda
1
2
3
4
6
5
3a
3a
3a
3a
3b
3c
Bn
Bn
Bn
Bn
Me
Et
H2O2
m-CPBA
11ab
42:58
60:40
30:70
16:84
9:91
92
77
68
70
90
82
This approach involving sulfenates was then compared
with the alternative and traditional strategy toward sulfoxides,
based on the oxidation of the corresponding thioethers. As
shown in Table 2, the degree of stereocontrol highly depends
on the reaction conditions. Oxidation of benzyl compound
5a with H2O2 or m-CPBA led to poor diastereoselectivities
(entries 1 and 2), whereas improvement was observed (30:
70 ratio) with the Davis N-sulfonyloxaziridine 11a22 (entry
11bc
11bc
11bc
19:81
a Isolated yield. b (()-trans-3-Phenyl-2-(phenylsulfonyl)loxaziridine. c (()-
trans-3-(t-Butyl)-3-methyl-2-(phenylsulfonyl)oxaziridine.
(18) Crystal structures of 9 showed that the S-O bond is almost in the
same plane than the arene, the oxygen atom oriented towards the ortho
proton (torsional angle values between S-O and C4-C5 ranging from
-8.84 to 1.8°). See Supporting Information.
(19) Foucoin, F.; Caupe`ne, C.; Lohier, J.-F.; Sopkova´ -de Oliveira
Santos, J.; Perrio, S.; Metzner, P. Synthesis 2007, 1315-1324.
(20) Sulfoxide 6 was prepared in an 78% overall yield by a regioselective
radical addition of thiol 2 on vinyltrimethylsilane in the presence of a
catalytic amount of AIBN (1%), followed by oxidation. See Supporting
Information.
An interesting stereochemical point also to mention is that
oxidation of the t-butyl sulfide of 3 (R1 ) t-Bu) with both
(22) (a) Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703-
5742. (b) Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A. Org. Synth.
1988, 66, 203-210. (c) Davis, F. A.; Chattopadhyay, S.; Towson, J. C.;
Lal, S.; Reddy, T. J. Org. Chem. 1988, 53, 2087-2089.
(23) A remarkable difference in chemical shift, resulting of the strong
anisotropy of the sulfinyl group, is observed for the signal of one
diastereotopic H2. It occurs in the range of 2.6-2.9 ppm in 9 but is
substantially deshielded at δ ) 4.1-4.2 ppm in 10. See also ref 4a.
(21) Previously reported conformational studies involving calculations
concern exclusively ethenesulfenate species. See ref 13.
Org. Lett., Vol. 10, No. 6, 2008
1273

m-CPBA or NaIO4 was previously shown by Rowlands to
furnish exclusively diastereoisomer 9.4a A probable inter-
pretation for the reversal in diastereoselectivity is illustrated
in Figure 4.24 When R1 ) methyl, ethyl, or benzyl, we
interactions restrict the sulfanyl substituent to the conforma-
tion illustrated, in which neither of the sulfur lone pairs is
on the exo face. Consequently, the oxidant is forced to
approach the endo face past the bridge to afford diastereo-
isomer 9.
In conclusion, we report in this paper an elegant access
to a range of paracyclophanyl thiol, sulfides, and sulfoxides.
The latter were also efficiently prepared as single diastere-
oisomers from the related sulfenate salt. Even if all com-
pounds were produced in racemic forms, the presented
methodology already affords an appreciable synthetic progress
in the area. Access to enantiopure substrates is currently
investigated in our laboratory and will be reported in due
course.
Figure 4. Preferred conformations for thioether oxidation.
Acknowledgment. We acknowledge financial support
from the “Ministe`re de la Recherche”, CNRS (Centre
National de la Recherche Scientifique), the “Re´gion Basse-
Normandie”, and the European Union (FEDER funding). We
also thank Ste´phan Pellinghelli (ENSICAEN), Ce´dric Bou-
dou (CNRS), and Ana¨ıs Prunier (University of Caen Basse
Normandie) for the synthesis of starting materials.
assume that thioether 3 adopts a conformation with the
alkylsulfanyl group lying in the arene plane opposite to the
bridge. One of the sulfur lone pairs is hence exposed on the
exo face of the paracyclophane and reacts selectively with
the oxidant to afford diastereoisomer 10. Switching to a
bulkier substituent such as R1 ) t-Bu, increasing eclipsing
Supporting Information Available: General methods of
the experimental section, full spectroscopic data, X-ray
structure of 9, and sulfenate conformation study. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(24) Similar precedents have already been reported with tricarbonyl(η6-
arene)chromium(0) complexes: (a) Pe´rez-Encabo, A.; Perrio, S.; Slawin,
A. M. Z.; Thomas, S. E.; Wierzchleyski, A. T.; Williams, D. J. J. Chem.
Soc., Chem. Commun. 1993, 1059-1062. (b) Pe´rez-Encabo, A.; Perrio, S.;
Slawin, A. M. Z.; Thomas, S. E.; Wierzchleyski, A. T.; Williams, D. J. J.
Chem. Soc., Perkin Trans. 1 1994, 629-642.
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Org. Lett., Vol. 10, No. 6, 2008