Alkylidene[1,3]dithiolane-1,3-dioxides as potent Michael-type acceptors

Article abstract of DOI:10.1055/s-2006-948202

Nucleophilic additions of enolates, piperidine and methanol to easily prepared alkylidene[1,3]dithiolane-1,3-dioxides afforded the respective adducts with good yields. Selectivities were strongly dependant from the steric hindrance of the substrate and re

Full text of DOI:10.1055/s-2006-948202

LETTER
2043
Alkylidene[1,3]dithiolane-1,3-dioxides as Potent Michael-Type Acceptors
Nucleophilic
A
d
o
ditions to 2-
b
Alkylidened
i
ithiolan
a
e
-1,3-dioxi
s
des Wedel, Joachim Podlech*
Institut für Organische Chemie, Universität Karlsruhe (TH), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax +49(721)6087652; E-mail: joachim.podlech@ioc.uka.de
Received 3 May 2006
Dedicated to Hansgeorg Schnöckel on the occasion of his 65th birthday
O
S
O
S
Abstract: Nucleophilic additions of enolates, piperidine and meth-
anol to easily prepared alkylidene[1,3]dithiolane-1,3-dioxides af-
forded the respective adducts with good yields. Selectivities were
strongly dependant from the steric hindrance of the substrate and
reached 92:8 to ≥ 98:2 in additions to the phenyl-substituted bissulf-
oxide product.
S
R
S
S
R
S
O
O
O
O
R
1
2
3
Figure 1
Key words: nucleophilic additions, sulfoxides, thioacetals, Umpol-
ung, stereoelectronic effects
were mandatory for our investigations had not been pub-
lished before our work.
Alkylidenebissulfoxides1 have repeatedly been used in or-
ganic synthesis due to their electron-deficient double
bond.2 Since unsymmetrically substituted sulfoxides are
chiral, these reactions can be led diastereoselectively. Ag-
garwal and co-workers used very successfully dithiane-
and dithiolane-derived bissulfoxides of type 2 and 3 in ep-
oxidations, cyclopropanations and cycloadditions
(Figure 1).3 The cleavage of the auxiliary liberating a car-
bonyl compound is achieved, for example, by Pummerer
reaction.3b,4 Malacria, Fensterbank et al. used bis(tolyl-
sulfinyl)alkenes of type 1 in Michael-type additions and
achieved excellent selectivities in the addition of enolates,
cuprates and amines.5 The stereoselectivities were ex-
plained in accordance to an X-ray crystallographic analy-
sis of 1 (R = Ph) showing a p-stacking of the toluene
moieties leaving only one side of the molecule free for an
attack of the nucleophiles. Recently, we presented
dithiane-derived bissulfoxides 2 as acceptors for nucleo-
philic additions and found high selectivities in the addi-
tion of enolates thought steric hindrance (X-ray
crystallographic analysis of 2, R = Ph) should be negligi-
ble.6 We think that stereoelectronic effects have a signifi-
cant influence and should be particularly considered in
explanations of selectivities. The method presented by us
has been used in an umpoled reaction for the synthesis of
1,4-dicarbonyl compounds.
We found that the previously used synthetic protocol6,7 es-
tablished for the dithiane-derived substrates 2 (Peterson
olefination of dithiane and subsequent stereoselective ox-
idation of the sulfide moieties) is not applicable here.
Deprotonation of dithiolane would induce a cyclorever-
sion giving rise to the formation of ethene and dithiofor-
mate.9 Consequently, we tested a method introduced by
Okuyama et al. starting with ethane-1,2-dithiol and an
acyl chloride.9 Though yields were in the range of only
33–67%, this method could be used for the convenient and
cheap synthesis of ample amounts of alkylidenedithio-
lanes 4 (Scheme 1).
O
HClO4
+
R
HS
SH
Ac2O
S
Cl
Et3N
S
R
S
S
R
+
–
ClO4
33–67%
H
4
Scheme 1
Stereoselective oxidation of the sulfide moieties was
achieved by slight modification of the protocol presented
previously6,10 avoiding basic conditions during the work-
up process (Scheme 2, Table 1). Enantio- and diastereo-
selective oxidation with cumene hydroperoxide, diethyl
tartrate (DET) and tetraisopropoxy titanate yielded the re-
spective bissulfoxides in yields of 55–67%. The enantio-
meric excess was determined for the phenyl-substituted
bissulfoxide by means of a chiral shift reagent (a-meth-
oxyphenylacetic acid, MPA)11 to be 94%. The purity
could be improved to ≥ 98% ee by a single recrystalliza-
tion.
In this letter we wish to report on the utilization of dithio-
lane-derived substrates 3 as strong Michael-type accep-
tors.
Cycloadditions with the parent methylene[1,3]dithiolane-
1,3-dioxide 3a (R = H) have been thoroughly investigated
by Aggarwal et al.3a,b,7 and the methyl derivative 3c
(R = Me) has been proposed as an intermediate once.8
Nevertheless, a synthesis for substituted substrates which
SYNLETT 2006, No. 13, pp 2043–2046
1
7
.0
8
.2
0
0
6
Advanced online publication: 09.08.2006
DOI: 10.1055/s-2006-948202; Art ID: G16006ST
© Georg Thieme Verlag Stuttgart · New York
The dithiolane-derived alkylidenebissulfoxides turned out
to be much more reactive than the respective dithiane-

2044
T. Wedel, J. Podlech
LETTER
S
R
S
S
R
S
PhC(Me2)OOH
O
O
(+)-DET, Ti(Oi-Pr)4
3
4
55–67%
ee ~94%
(R = Ph)
Scheme 2
Table 1
Synthesis of Dithiolane-Derived Bissulfoxides 3
Entry
Compd
3b
R
Yield (%)
55a
1
2
3
4
5
Ph
3c
Me
Et
67b
3d
66c
3e
i-Pr
t-Bu
65
3f
63
a 94% ee; ≥ 98% ee after a single recrystallization.
b Formation of the methanol adduct (33%, 85:15).12
c Formation of the methanol adduct (16%, 88:12) and of 2-propen-1-
yl[1,3]dithiolan-1,3-dioxide (14%).12
Figure 2 Structure of 3c (bottom) and its methanol adduct (7c,
major isomer) as formed during chromatography of 3c with MeOH
(co-crystal)13
derived substrates what caused some problems already
during the work-up process. Chromatography with
dichloromethane and methanol on silica gel led to a sig-
nificant addition of methanol to the electron-deficient
double bond. The methanol adducts to 3c and 3d were iso-
lated with 33% and 16% yield, respectively. The selectiv-
ity in these additions was about 85:15.
ONa
S
R
S
O
O
S
R
S
Ph
–78 °C, THF, 20 min
80–86%
O
O
3
O
Ph
5
The structure of the methyl derivative 3c could be re-
vealed by X-ray crystallographic analysis of a co-crystal
formed with its methanol adduct 7c (major isomer,
Figure 2).13 In this view nucleophilic attack to 3c should
be possible preferentially from top left or bottom right (no
oxygen prevents attack of the nucleophile) where an at-
tack from the left should be less likely, especially for sub-
stituents bulkier than the methyl group.
Scheme 3
We tested addition of the acetophenone enolate prepared
from acetophenone and sodium hexamethyldisilazide
(NaHMDS) and found that in fact best results were ob-
tained with the bulky phenyl-substituted substrate 3b
leading to only one diastereomer (≥ 98:2, Scheme 3,
Table 2, entry 1). Selectivities dropped with smaller sub-
stituents and – not astonishingly – almost vanished with a
small methyl group present (55:45, entry 5). Here the nu-
cleophile has to discriminate between a hydrogen atom
and a marginally bulkier methyl group. Nevertheless, ap-
proach is preferred from the bottom (orientation as seen in
Figure 2) which could be proven by X-ray crystallograph-
ic analyses of the enolate adduct 5b (Figure 3) and the
methanol adduct 7c (Figure 2).13
Figure 3 Structure of acetophenone adduct 5b in the crystal13
The further-tested piperidine and malonate anion added to
the bissulfoxide 3b with high yields and selectivities (en-
tries 6 and 7). This finding again proved the high reactiv-
Synlett 2006, No. 13, 2043–2046 © Thieme Stuttgart · New York

LETTER
Nucleophilic Additions to 2-Alkylidenedithiolane-1,3-dioxides
2045
Br
Table 2 Addition of Nucleophiles to Bissulfoxides 3
10
S
*
S
–
MeO2C
CO2Me
S
S
O
O
Entry Educt
Nu
Product Yield (%) dr
O
O
CO2Me
quant.
ONa
1
2
3
4
5
6
3b, R = Ph
5b
5f
5e
5d
5c
6
80
≥ 98:2
Ph
Ph
CO2Me
3b
Ph
ONa
single isomer
3f, R = t-Bu
3e, R = i-Pr
3d, R = Et
3c, R = Me
3b, R = Ph
86
92:8
Scheme 4
Ph
ONa
82
71:29
67:33
55:45
92:8
The high reactivity of these alkylidenebissulfoxides de-
rived from dithiolanes opens new possibilities for the ad-
dition of poor nucleophiles. Investigations in this
direction are now on the way in our laboratories.
Ph
ONa
81
Ph
ONa
85
Ph
General Procedure for the Preparation of Alkylidenedithio-
lanes
Quant.
Ethane-1,2-dithiol (2.83 g, 30 mmol, 1 equiv) was added dropwise
at 0 °C to the respective acid chloride (1 equiv) and stirring was con-
tinued for 30 min at this temperature. Then, HClO4 (70%, 3.1 mL,
36 mmol, 1.2 equiv) was carefully added dropwise. An exothermic
reaction started after 0.5–5 min. The mixture was stirred for 30 min
at r.t., cooled to 0 °C and freshly distilled Ac2O (15 mL) was care-
fully added dropwise. The dithiolanylium salt was precipitated with
anhyd Et2O (50 mL) and filtrated under argon. The red needles were
washed with Et2O (3 × 20 mL) and dissolved in anhyd MeCN (30
mL). Afterwards, Et3N was added until the red color disappeared
and the solvents were removed at reduced pressure. The resulting
oil was dissolved in sat. aq NH4Cl solution (40 mL) and the solution
was extracted with EtOAc (3 × 20 mL). The combined organic lay-
ers were dried (Na2SO4 and K2CO3), the solvents were removed and
the residue was distilled by bulb-to-bulb distillation.
N
H
7
8
3b, R = Ph MeOHa
7b
8
Quant.
92
90:10
94:6
3b, R = Ph
MeO2C
MeO2C
b
9
3b, R = Ph Bu2CuLi
9
9
a Alox, pH 9, MeOH, r.t., 2 h.
b Only a single isomer was detected.
ity of the herein presented substrates. While the dithiane-
derived compound 2 (R = Ph) gave only a poor 20% yield
when reacted for 48 hours in piperidine as the solvent, bis-
2-Benzyliden[1,3]dithiolane (4b)9
1H NMR (250 MHz, CDCl3): d = 3.31–3.36 (m, 2 H), 3.52–3.56 (m,
sulfoxide 3b cleanly gave the adduct 6 with only two 2 H), 6.65 (s, 1 H, C=CHPh), 7.12–7.19, 7.30–7.43 (2 m, 5 H, Ph).
equivalents piperidine at –78 °C for 30 minutes (Table 2,
General Procedure for the Preparation of Alkylidenedithiolane
entry 6). We think that this astonishingly high reactivity is
Dioxides
due to an especially favorable stereoelectronic stabiliza-
(+)-Diethyl tartrate (2 equiv, traces of H2O removed by azeotropic
tion of the intermediate carbanion by the two axial S=O
distillation with toluene) and freshly distilled Ti(Oi-Pr)4 (0.5 equiv)
were dissolved at r.t. under argon in anhyd CH2Cl2 (5 mL/mmol)
and stirred for 30 min. The alkylidenedithiolane (1 equiv) in CH2Cl2
bonds (n → S–O-s*).14,15 Investigations and calculations
on the influence of stereoelectronic effects in this and si-
milar substrates are now under investigation and will be (1 mL/mmol) was added, the mixture was cooled to –40 °C and
stirred for 2 h. Cumene hydroperoxide (technical grade, 80%, 4
published elsewhere.
equiv; diluted with CH2Cl2 to twice the volume) was added within
1 h. The solution was warmed to –20 °C and stored for 15 h in a
freezer (lower than –20 °C). H2O (20 equiv) was added and the mix-
The unintended formation of methanol adducts during
chromatography of 3c and 3d prompted us to test this ad-
dition with better defined reaction conditions. While the ture was stirred vigorously for 1 h at r.t. The slurry was kept for 1 h
in an ultrasonication bath and the resulting suspension was filtered
reaction of 3b with sodium methanolate was very sluggish
through a sinter glass (G2) covered with a Celite® pad (1.5 cm). The
below –20 °C and led to decomposition of the substrate
filter cake was washed repeatedly with small amounts of CH2Cl2.
The solvents were removed and the pure bissulfoxide was obtained
by chromatography on SiO2 (CH2Cl2–acetone, 2:1).
above that temperature, we achieved a quantitative addi-
tion of methanol to the bissulfoxide 3b in the presence of
basic alumina within two hours (→ 7b, dr 90:10, entry 7).
Only a poor 9% yield was obtained in the addition of a bu-
tyl cuprate, however with high selectivity, a single isomer
9 was detected in the product fraction (entry 9).
(1R,3R)-2-Benzylidene[1,3]dithiolane-1,3-dioxide (3b)
Colorless crystals, mp 146–148 °C (CH2Cl2–hexane); Rf = 0.32
20
(CH2Cl2–acetone, 2:1); [a]D –676 (c 1.0, CHCl3). IR (DRIFT):
2986 (m), 2934 (m), 2044 (m), 1883 (m), 1599 (m), 1494 (m), 1447
(m), 1404 (m), 1395 (m), 1207 (m), 1094 (m), 1026 (s, S=O) cm–1.
UV (EtOH): lmax (e) = 200 (22600), 290 nm (20100). 1H NMR (400
The initially formed anion in the addition of nucleophiles
could be trapped when a leaving group was present in the
molecule (Scheme 4).16 Spiro compound 10 was formed MHz, CDCl3): d = 3.62–3.67 (m, 1 H), 3.76–3.93 (m, 3 H), 7.50–
7.57, 7.81–7.84 (2 m, 5 H, Ph), 8.10 (s, 1 H, C=CHPh). 13C NMR
as a single diastereoisomer with quantitative yield.
(100 MHz, CDCl3): d = 49.5 (t), 52.1, (t), 129.3 (d), 130.6 (d), 132.2
(d), 132.8 (s), 150.7 (d), 153.5 (s). MS (EI, 70 eV, 70 °C): m/z
Synlett 2006, No. 13, 2043–2046 © Thieme Stuttgart · New York

2046
T. Wedel, J. Podlech
LETTER
(3) (a) Aggarwal, V. K.; Drabowicz, J.; Graininger, R. S.;
(%) = 226 (8) [M+], 198 (17), 150 (17), 134 (100) [M+ – C7H8], 118
(31), 114 (20), 102 (34), 96 (23), 88 (62), 77 (40). HRMS (EI): m/z
calcd for C10H10O232S2: 226.0122; found: 226.0119. Anal. Calcd for
C10H10O2S2 (226.32): C, 53.07; H, 4.45. Found: C, 52.87; H, 4.69.
Gültekin, Z.; Lightowler, M.; Spargo, P. L. J. Org. Chem.
1995, 60, 4962. (b) Aggarwal, V. K.; Gültekin, Z.; Grainger,
R. S.; Adams, H.; Spargo, P. L. J. Chem. Soc., Perkin Trans.
1 1998, 2771. (c) Aggarwal, V. K.; Barrell, J. K.; Worral, J.
M.; Alexander, R. J. Org. Chem. 1998, 63, 7128.
(d) Aggarwal, V. K.; Roseblade, S. J.; Barrell, J. K.;
Alexander, R. Org. Lett. 2002, 4, 1227. (e) Aggarwal, V.
K.; Roseblade, S.; Alexander, R. Org. Biomol. Chem. 2003,
1, 684.
General Procedure for the Addition of Acetophenone Enolate to
Alkylidenedithiolane Dioxides
To a solution of acetophenone (1.4 equiv) in THF (10 mL/mmol)
was added at –78 °C NaHMDS (1.2 equiv, 2 M in hexane). The so-
lution was transferred via a cannula after 45 min at –78 °C to a pre-
cooled (–78 °C) solution of the bissulfoxide (1.0 equiv in THF, 15
mL/mmol). After 10 min, an excess MeOH (ca .0.5 mL) was added,
the solution was poured into sat. NH4Cl solution (20 mL/mmol), ex-
tracted with EtOAc (2 × 20 mL), CH2Cl2 (2 × 20 mL), and dried
(Na2SO4, K2CO3). The solvents were removed and the selectivity
was determined by 1H NMR or 13C NMR of the crude product (in-
tegration of the acetal proton). The residue was purified by chroma-
tography on SiO2.
(4) Wipf, P.; Graham, T. H. Org. Biomol. Chem. 2005, 3, 31.
(5) (a) Brebion, F.; Delouvrié, B.; Nájera, F.; Fensterbank, L.;
Malacria, M.; Vaissermann, J. Angew. Chem. Int. Ed. 2003,
52, 5342; Angew. Chem. 2003, 115, 5500. (b) Brebion, F.;
Goddard, J. P.; Fensterbank, L.; Malacria, M. Synthesis
2005, 2449. (c) Brebion, F.; Goddard, J.-P.; Gomez, C.;
Fensterbank, L.; Malacria, M. Synlett 2006, 713. (d) See
also: Midura, W. H.; Krysiak, J. A.; Cypryk, M.;
Mikołajczyk, M.; Wieczorek, M. W.; Filipczak, A. D. Eur.
J. Org. Chem. 2005, 653.
(6) Wedel, T.; Podlech, J. Org. Lett. 2005, 7, 4013.
(7) (a) Aggarwal, V. K.; Grainger, R. S.; Adams, H.; Spargo, P.
L. J. Org. Chem. 1998, 63, 3481. (b) Aggarwal, V. K.;
Grainger, R. S.; Newton, G. K.; Spargo, P. L.; Hobson, A.
D.; Adams, H. Org. Biomol. Chem. 2003, 1, 1884.
(8) Chou, W.-C.; Yang, S.-A.; Fang, J.-M. J. Chem. Soc., Perkin
Trans. 1 1994, 603.
(3R,1¢R,3¢R)-3-{1,3-Dioxo[1,3]dithiolan-2-yl}-1,3-diphenyl-pro-
pan-1-one (5b)
Selectivity ≥ 98:2; colorless crystals; mp 184 °C (CH2Cl2–acetone);
Rf = 0.19 (CH2Cl2–acetone, 2:1); [a]D +88.3 (c 0.8, CHCl3).
20
IR (DRIFT): 2978 (m), 1680 (s, C=O), 1596 (m), 1452 (m), 1412
(m), 1377 (w), 1301 (w), 1229 (m), 1027 (s, S=O) cm–1. 1H NMR
(400 MHz, CDCl3): d = 3.53–3.56 (m, 1 H), 3.66–3.74 (m, 3 H),
3.79–3.90 (m, 2 H), 3.98–4.04 (m, 1 H, H-3), 4.44 (dd, 1 H, J = 11.8,
1.1 Hz, H-2¢), 7.25–7.45, 7.51–7.55, 7.85–7.87 (3 m, 10 H, 2 Ph).
13C NMR (100 MHz, CDCl3): d = 37.8 (d), 43.6 (t), 50.7 (t), 52.1
(t), 97.4 (d), 128.1 (d), 128.2 (d), 128.4 (d), 128.6 (d), 129.1 (d),
133.4 (d), 136.4 (s), 139.5 (s), 196.6 (s). MS (EI, 70 eV, 190 °C):
m/z (%) = 346 (11) [M+], 221 (22), 210 (31), 107 (14), 105 (100)
[C7H5O+], 77 (28). HRMS (EI): m/z calcd for C18H18O332S2:
346.0697; found: 346.0695. Anal. Calcd for C18H18O3S2 (226.32):
C, 62.40; H, 5.24. Found: C, 62.13; H, 5.47.
(9) Okuyama, T.; Fujiwara, W.; Fueno, T. Bull. Chem. Soc. Jpn.
1986, 59, 453.
(10) (a) Aggarwal, V. K.; Steele, R. M.; Ritmaleni; Barrell, J. K.;
Grayson, I. J. Org. Chem. 2003, 68, 4087. (b) Further
methods for the oxidation of sulfides are summarized in:
Bäckvall, J.-E. In Modern Oxidation Methods; Bäckvall, J.-
E., Ed.; Wiley-VCH: Weinheim, 2004, 193. (c) Legros, J.;
Dehli, J. R.; Bolm, C. Adv. Synth. Catal. 2005, 347, 19.
(d) Kowalski, P.; Mitka, K.; Ossowska, K.; Kolarska, Z.
Tetrahedron 2005, 61, 1933.
(11) (a) Buist, P. H.; Marecak, D.; Holland, H. L.; Brown, F. M.
Tetrahedron: Asymmetry 1995, 6, 7. (b) Buist, P. H.;
Behrouzian, B. Magn. Res. Chem. 1996, 34, 1013.
(12) The formation of methanol adducts and of the prop-1-enyl
derivative was avoided when CH2Cl2–acetone (2:1) was
used as eluent in the chromatography.
Acknowledgment
We are deeply indebted to Dr. Wolfgang U. Frey (University of
Stuttgart) for the X-ray crystal structure analyses. We thank Prof.
Dr. W. Klopper (University of Karlsruhe) and Prof. Dr. E. Juaristi
(Mexico) for inspiring discussions.
(13) CCDC 603241 (co-crystal of 3c and 7c) and CCDC 603242
(5c) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
References and Notes
(1) (a) A comprehensive review on bissulfoxides has been
published: Delouvrié, B.; Fensterbank, L.; Nájera, F.;
Malacria, M. Eur. J. Org. Chem. 2002, 3507. (b) See also:
Fernández, I.; Khiar, N. Chem. Rev. 2003, 103, 3651.
(2) (a) Posner, G. H. In Asymmetric Synthesis. Stereo-
differentiating Addition Reactions, Part A, Vol. 2; Morrison,
J. D., Ed.; Academic Press: New York, 1983, 225.
(b) Kahn, S. D.; Hehre, W. J. J. Am. Chem. Soc. 1986, 108,
7399. (c) Posner, G. H.; Weitzberg, M.; Hamill, T. G.;
Asirvatham, E.; Cun-Heng, H.; Clardy, J. Tetrahedron 1986,
42, 2919.
www.ccdc.cam.ac.uk/data_request/cif.
(14) (a) Roux, M. V.; Temprado, M.; Jiménez, P.; Dávalos, J. Z.;
Notario, R.; Martín-Valcárcel, G.; Garrido, L.; Guzmán-
Mejía, R.; Juaristi, E. J. Org. Chem. 2004, 69, 5454.
(b) Juaristi, E.; Notario, R.; Roux, M. V. Chem. Soc. Rev.
2005, 34, 347.
(15) Klopper, W.; Bihlmeier, A.; Kordel, E. personal
communication.
(16) Perkin, W. H. Ber. Dtsch. Chem. Ges. 1884, 17, 54.
Synlett 2006, No. 13, 2043–2046 © Thieme Stuttgart · New York