General route to racemic and enantiomeric carbo- and heterocyclic vinyl sulfoxides via tandem Michael addition/Horner olefination of α-phosphorylvinyl sulfoxides

Article abstract of DOI:10.1021/jo061463b

A new one-pot synthesis of heterocyclic and carbocyclic vinyl sulfoxides has been developed which involves reaction of α-phosphorylvinyl sulfoxides with carbonyl compounds bearing oxygen, nitrogen, and carbon nucleophilic centers. Use of optically active α-phosphorylvinyl p-tolyl sulfoxides in this tandem Michael addition/Horner olefination reaction leads to the corresponding optically active cyclic sulfoxides. In this way, a variety of optically active chromene, pyrrolizine, chinoline, and cyclopentene sulfoxides have been efficiently prepared.

Full text of DOI:10.1021/jo061463b

General Route to Racemic and Enantiomeric Carbo- and
Heterocyclic Vinyl Sulfoxides via Tandem Michael Addition/Horner
†
Olefination of r-Phosphorylvinyl Sulfoxides
,‡
†
,‡
§
Marian Mikołajczyk,* Jerzy A. Krysiak, Wanda H. Midura,* Michał W. Wieczorek, and
Ewa R o´ z˘ ycka-Sokołowska§
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of
Heteroorganic Chemistry, 90-363 Lodz Sienkiewicza 112, Poland and Institute of Chemistry and
EnVironmental Protection, Jan Długosz Academy,42-200 Cz e¸ stochowa, Al. Armii Krajowej 13/15, Poland
marmikol@bilbo.cbmm.lodz.pl
ReceiVed July 14, 2006
A new one-pot synthesis of heterocyclic and carbocyclic vinyl sulfoxides has been developed which
involves reaction of R-phosphorylvinyl sulfoxides with carbonyl compounds bearing oxygen, nitrogen,
and carbon nucleophilic centers. Use of optically active R-phosphorylvinyl p-tolyl sulfoxides in this tandem
Michael addition/Horner olefination reaction leads to the corresponding optically active cyclic sulfoxides.
In this way, a variety of optically active chromene, pyrrolizine, chinoline, and cyclopentene sulfoxides
have been efficiently prepared.
Introduction
may be further functionalized via their R-lithiated derivatives.2,3
In the last two decades interest in this class of compounds was
mainly connected with the use of optically active vinyl
R,â-Unsaturated sulfoxides are versatile reagents and useful
building blocks in the synthesis of biologically active and natural
1
products. They display three main types of reactivity: (a)
(1) (a) Drabowicz, J.; Kiełbasinski, P.; Mikołajczyk, M. In The Synthesis
electrophilic addition to the carbon-carbon double bond, (b)
of Sulfones and Sulfoxides and Cyclic Sulfides; Patai, S., Rappoport, Z.,
Stirling, C. J. M., Eds.; John Wiley and Sons: New York, 1994; pp 109-
388. (b) Posner, G. H. The Chemistry of Sulphones and Sulphoxides; Patai,
S., Rappoport, Z., Stirling, C. J. M., Eds.; John Wiley and Sons: New York,
Michael addition of carbon and various heteroatom nucleophiles,
and (c) cycloaddition reactions.1d From the viewpoint of
synthetic applications, it is important to note that vinyl sulfoxides
1988; pp 823-849. (c) Oae, S.; Uchida, Y. The Chemistry of Sulphones
and Sulphoxides; Patai, S., Rappoport, Z., Stirling, C. J. M., Eds.; John
Wiley and Sons: New York, 1988; pp 583-664. (d) Drabowicz, J.;
Kiełbasinski, P.; Mikołajczyk, M. In The Chemistry of Sulphones and
Sulphoxides; Patai, S., Rappoport, Z., Stirling, C. J. M., Eds.; John Wiley
and Sons: New York, 1988; pp 349-360.
(2) Posner, G. M.; Tang, P.-W.; Mallamo, J. P. Tetrahedron Lett. 1978,
42, 3995-3998.
*
To whom correspondence should be addressed. Phone: +48426815832.
Fax: +48426847126.
†
This paper is dedicated to the late Professor Leopold Horner, the pioneer
of the organic chemistry and stereochemistry of phosphorus.
‡
Polish Academy of Sciences.
Jan Długosz Academy.
§
10.1021/jo061463b CCC: $33.50 © 2006 American Chemical Society
8
818
J. Org. Chem. 2006, 71, 8818-8823
Published on Web 10/10/2006

Carbo- and Heterocyclic Vinyl Sulfoxides
SCHEME 1. General Approaches to Optically Active
Acyclic Vinyl Sulfoxides
SCHEME 2. Selected Syntheses of Optically Active
Cycloalkenyl Sulfoxides
SCHEME 3. Synthesis of Cyclic Vinyl Sulfoxides by
Tandem Michael Addition/Horner Olefination Reaction of
Sulfoxides 1
sulfoxides in asymmetric synthesis.4-7 This is due to the
presence of the sulfinyl group which has been shown to be one
of the most efficient chiral auxiliaries.
Acyclic, optically active vinyl sulfoxides may be easily
prepared by two general methods. The first is based on the
Andersen reaction of (-)-(S)-menthyl p-toluenesulfinate with
8
vinyl Grignard reagents or alkynylmagnesium bromides fol-
lowed by stereoselective reduction of the resulting 1-alkynyl
sulfoxides to the corresponding vinyl sulfoxides of a required
9
E- and Z-geometry (Scheme 1).
cyclic and carbocyclic vinyl sulfoxides that is based on the use
The second convenient synthesis elaborated in our laboratory
involves the Horner olefination reaction of (+)-(S)-dimethoxy-
phosphorylmethyl p-tolyl sulfoxide10 or the Wittig reaction of
of chiral (S)-R-(diethoxyphosphoryl)vinyl p-tolyl sulfoxides
14,15
1
as starting reagents.
(
S)-(p-toluenesulfinyl)methyltriphenylphosphonium ylide with
11
carbonyl compounds (Scheme 1). However, the synthetic
approaches to optically active, cyclic vinyl sulfoxides are few
in number and devised for the synthesis of specific structures.
Thus, for example, the widely used (+)-(S)-2-(p-toluene-
sulfinyl)-2-cyclopentenone has been prepared by Posner from
cyclopentenone in five steps involving bromination, ketalization,
lithiation, Andersen reaction, and carbonyl deprotection, Scheme
1
2
2
.
Recently, a novel method for the synthesis of optically active
-cycloalkenyl sulfoxides has been developed by Tanaka et al.,
13
Results and Discussion
1
wherein the key step involves intramolecular alkylation of â-(ω-
haloalkyl)vinyl sulfoxides. However, this approach is somewhat
lengthy because it requires first the synthesis of acyclic vinyl
sulfoxides followed by their multistep elaboration to â-(ω-
haloalkyl) analogues.
R-Phosphorylvinyl sulfoxides 1 have been shown to be potent
Michael acceptors due to the presence of two electron-
withdrawing phosphoryl and sulfinyl groups bonded to the
14
olefinic R-carbon atom. As the nucleophilic addition to 1
generates the corresponding R-phosphonate carbanion, which
can react with carbonyl compounds, reactions of R-phospho-
rylvinyl sulfoxides 1 with carbonyl reagents bearing a nucleo-
philic center in a â- or γ-position to the carbonyl group can
provide a useful means for the synthesis of heterocyclic and
carbocyclic vinylic sulfoxides as depicted in Scheme 3.
In accord with our expectations, this new tandem Michael
addition/Horner olefination reaction was found to afford a
variety of cyclic vinylic sulfoxides. The examples discussed be-
low demonstrate the scope and usefulness of this methodology.
Initially, the method was tested with racemic R-(diethoxy-
phosphoryl)vinyl methyl sulfoxide 2 and 2-hydroxybenzalde-
hyde (eq 1). The latter was first converted into the sodium salt
by sodium hydride in a THF solution and then treated with the
sulfoxide (()-2. After refluxing the reaction mixture 1 h and
In this paper we wish to disclose a new general approach to
the synthesis of optically active mono- and condensed hetero-
(
3) Okamura, H.; Mitsuhira, Y.; Miura, M.; Takei, H. Chem. Lett. 1978,
5
17-520.
(
4) Carre n˜ o, M. C. Chem. ReV. 1995, 95, 7-1760.
(5) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P. Tetra-
hedron: Asymmetry 1997, 8, 1339-1367.
6) Mikołajczyk, M.; Drabowicz, J.; Kiełbasinski, P. Chiral Sulfur
(
Reagents: Applications in Asymmetric and StereoselectiVe Synthesis; CRC
Press: Boca Raton, 1997; pp 144-194.
(
7) Pellissier, H. Tetrahedron 2006, 62, 5559-5601.
(8) (a) Abbot, D. J.; Colonna, S.; Stirling, C. J. M. J. Chem. Soc., D
1
971, 472-473; Perkin Trans. 1 1976, 492-498. (b) Posner, G. H.; Tang,
P. W. J. Org. Chem. 1978, 43, 4131-4136.
9) Kosugi, H.; Kitaoka, M.; Tagami, K.; Takahashi, A.; Uda, H. J. J.
Org. Chem. 1987, 52, 1078-1082.
10) Mikołajczyk, M.; Midura, W. H.; Grzejszczak, S.; Zatorski, A.;
Chefczynska, A. J. Org. Chem. 1978, 43, 473-478.
11) Mikołajczyk, M.; Perlikowska, W.; Omelanczuk, J.; Cristau, H.-J.;
Perraud-Darcy, A. J. Org. Chem. 1998, 63, 9716-9722.
12) Frye, L. L.; Kogan, T. P.; Mallamo, J. P.; Posner, G. H. Org. Synth.
985, 64, 196-206.
13) Maezaki, N.; Izumi, M.; Yuyama, S.; Sawamoto, H.; Iwata, Ch.;
Tanaka, T. Tetrahedron 2000, 56, 7927-7945.
(
(
(
(14) (a) Mikołajczyk, M.; Midura, W. H. Tetrahedron: Asymmetry 1992,
3, 1515-1518. (b) Midura, W. H.; Krysiak, J. A. Tetrahedron 2004, 60,
12217-12229.
(15) Sulfoxide (+)-(S)-1b has been prepared according to the procedure
elaborated for the dimethoxyphosphoryl analog;16 for details of the
preparation of (+)-1b, see Experimental Section of this paper.
(
1
(
J. Org. Chem, Vol. 71, No. 23, 2006 8819

Mikołajczyk et al.
SCHEME 4. Synthesis of Enantiopure Pyrrolizine
typical workup, (()-3-methylsulfinyl-2H-chromene 3a was
isolated in 67% yield.
Sulfoxides 5
When sulfoxide (+)-(S)-1a was condensed with salicylic
aldehyde under the same reaction conditions, the expected
chromene 3b was obtained in low yield. However, using toluene
as solvent and refluxing the reaction mixture for 3 h led to (+)-
In this context, it is interesting to point out that a very similar
isomerization of 2-(phenylsulfonyl)-3H-pyrrolizine to 6-(phen-
ylsulfonyl)-3H-pyrrolizine has been described by Flitsch and
Lubisch, who were able to obtain and characterize both
(
S)-3-p-toluenesulfinyl-2H-chromene 3b in 56% yield (eq 2).
1
7
Reaction of the sulfoxide (+)-(S)-1a with aliphatic hydroxy-
tautomers.
aldehydes was found to occur under milder conditions and more
efficiently. For example, its reaction with the sodium salt of
R-hydroxyacetaldehyde, generated in situ from the dimer upon
treatment with sodium hydride in THF, gave, after stirring for
When (+)-(S)-1a and pyrrole-2-carbaldehyde were reacted
under the conditions elaborated above, the corresponding
annulation product (-)-5b was obtained in 74% yield. In a
similar way, starting from (+)-(S)-1b led to the pyrrolizine
sulfoxide (-)-5c in 77% yield (Scheme 4).
6
h at room temperature, (+)-(S)-3-p-toluenesulfinyl-2,5-dihy-
drofuran 4 in 88% yield (eq 3).
1
Also in this case, H NMR spectra indicated that the
products obtained have the structure of 5b and 5c and not
5
b′ and 5c′, which were preliminarily formed as shown in
Scheme 4. To unequivocally confirm the product structure we
took advantage of the fact that the pyrrolizine sulfoxide (-)-
5
b is crystalline and determined its crystal and molecular
structure by X-ray diffraction. Inspection of bond lengths in
both five-membered heterocyclic rings revealed that the chiral
sulfinyl group is attached to the ring with two carbon-carbon
double bonds. With regard to stereostructure of the sulfoxide
(
-)-5b, the X-ray data corroborated its absolute configuration
In the next step aminoaldehydes and aminoketones were used
as reaction partners in the tandem reaction of R-phosphorylvinyl
sulfoxides 1. As in the case of hydroxyaldehydes, the reaction
conditions were determined using racemic sulfoxide 2. It was
found that treatment of pyrrole-2-carbaldehyde with an excess
of sodium hydride and then with (()-2 in benzene gave, after
S at sulfur with full enantiomeric purity because Flack’s
parameter was found to be zero. Most probably, other optically
active cyclic vinyl sulfoxides obtained in this work are also
enantiopure because the reaction conditions used for their
preparation could not cause racemization of the chiral sulfoxide
moiety.
Reaction of (+)-(S)-1a with o-aminoacetophenone requires
special comment for two reasons. First, it was performed using
a different experimental procedure. Second, it afforded two
rather unexpected products. Since both reagents did not react
under conditions elaborated for the synthesis of pyrrolizine
sulfoxides 5, we found that it was advantageous to add, in the
first place, aminoketone to the sulfoxide (+)-(S)-1a in the
presence of triethylamine in a benzene solution. Then, the
diastereomeric adducts (δP)21.8 and 20.3 ppm; 9:1) isolated
in the crude state were dissolved in DMF, treated with sodium
hydride, and refluxed for 2 h. This procedure resulted in
formation of two products which were identified as (-)-(S)-4-
methyl-3-p-toluenesulfinyl-chinoline 7 and 4-hydroxymethyl-
3
h reflux, the expected cyclic product in 40% isolated yield.
1
13
Its spectral properties ( H and C NMR) indicated, however,
that we obtained (()-6-methylsulfinyl-3H-pyrrolizine 5a and
not the tautomeric form 5a′, which is a primary cyclic product
formed as a result of the Horner olefination reaction (eq 4).
Most probably, isomerization of 5a′ to the thermodynamically
more stable 5a occurred under basic conditions and at elevated
temperatures.
(
16) Midura, W. H.; Mikołajczyk, M. Tetrahedron Lett. 2002, 43, 3061-
065.
17) Flitsch, W.; Lubish, W. Chem. Ber. 1984, 117, 1424-1435.
3
(
8820 J. Org. Chem., Vol. 71, No. 23, 2006

Carbo- and Heterocyclic Vinyl Sulfoxides
SCHEME 5. Synthesis of Optically Active Chinoline
Sulfoxide 7
Formation of N-hydroxy-pyrroles 10 in this reaction indicates
that Michael addition of the monooxime anion takes place by
means of nitrogen as the nucleophile. Our findings are in accord
with the results of Schweizer and Kopay, who obtained
N-hydroxy-pyrroles in a closely related tandem reaction of
vinyltriphenylphosphonium bromide with monooximes. Interest-
ingly, both tandem reactions represent the only way reported
to construct the N-hydroxypyrrole ring.
2
0
Finally, we focused our interest on the tandem reaction with
carbonyl compounds bearing a carbanionic center in hopes of
finding a new approach to 1-cycloalkenyl sulfoxides. In fact,
when sulfoxide (+)-(S)-1a was added to the sodium salt of
diethyl 2-(2-oxopropyl)malonate in a THF solution with stirring
for 3 h at room temperature, the annulation product 11 was
isolated in excellent yield (eq 8).
chinoline 8 and isolated in 32% and 45% yield, respectively
(see Scheme 5).
Their formation can reasonably be explained by assuming
that the expected annulation product 6 is air oxidized to the
chinoline sulfoxide (-)-(S)-7.18 On the other hand, under forced
and basic conditions 6 most probably undergoes isomerization
to the corresponding allylic sulfoxide 9 which in turn undergoes
[
2,3]-sigmatropic rearrangement followed by air oxidation to
1
9
alcohol 8 (eq 6).
Similarly, treatment of the sodium salt of the same malonate
with racemic 1-(diethoxyphosphoryl)propen-1-yl p-tolyl sul-
foxide 12 resulted in formation of the corresponding cyclopen-
tenyl sulfoxide (()-13 in 87% yield (eq 9). This compound was
obtained as a 3:1 mixture of two diastereomers due to generation
of a new stereogenic center at C5 in the product.
Continuing our work on the synthesis of cyclic vinyl
sulfoxides, we also selected ketone monooximes as components
of the tandem reaction. Due to the ambident character of the
monooxime anion, its addition to 1 could be expected to occur
through attack of nitrogen or oxygen on the olefinic â-carbon
atom to give, after intramolecular Horner reaction, the corre-
sponding pyrrole or 6H-oxazine derivatives. We found that
treatment of the racemic sulfoxide 1a with the sodium salt of
monooximes of butan-2,3-dione and 2-phenylpropan-1,2-dione
in a DMF solution at room temperature gave N-hydroxy-2,3-
dimethyl-4-(p-toluenesulfinyl)pyrrole 10a (81% yield) and
N-hydroxy-3-methyl-2-phenyl-4-(p-toluenesulfinyl)pyrrole 10b
(78% yield) (eq 7).
Conclusions
In conclusion, a new and efficient method for the synthesis
of cyclic (hetero- and carbocyclic) vinyl sulfoxides has been
developed which is based on the tandem Michael addition/
Horner olefination reaction of R-phosphorylvinyl sulfoxides and
carbonyl compounds bearing nucleophilic centers. Using opti-
cally active R-phosphorylvinyl sulfoxides this approach delivers
a series of enantiomeric cyclic vinyl sulfoxides in which the
chiral sulfinyl group is bonded to the chromene, pyrrolizine,
chinoline, and cyclopentene rings. All of these sulfoxides are
(
18) Aromatization of the dihydrochinoline ring by atmospheric oxygen
is a well-known process, see, for example: (a) Barton, J. W.; Pearson, N.
D. J. Chem. Soc., Perkin Trans.1 1987, 1541-1545. (b) Gellerman, G.;
Babad, M.; Kashman, Y. Tetrahedron Lett. 1993, 34, 1822-1830. (c) Uno,
H.; Okada, S.; Shirashi, Y.; Shimokawa, K.; Suzuki, H. Chem. Lett. 1988,
1
165-1168.
(19) For excellent review on [2,3]-sigmatropic rearrangement of allyl
sulfoxides, see: Braverman, S. In The Chemistry of Suphones and
Sulphoxides; Patai, S., Rappoport, Z., Stirling, C. J. M., Eds.; John Wiley
and Sons: New York, 1988; pp 717-757.
(20) Schweizer, E. E.; Kopay, Ch. M. J. Org. Chem. 1972, 37, 1561-
1564.
J. Org. Chem, Vol. 71, No. 23, 2006 8821

Mikołajczyk et al.
potentially interesting as starting materials for further asym-
metric transformations.
General Procedure for the Preparation of Pyrrazoline Sul-
foxides 5. To a solution of pyrrole-2-carbaldehyde (94 mg, 1 mmol)
in benzene (10 mL) was added 50% NaH (48 mg, 2 mmol,
suspension in mineral oil). The mixture was stirred for 0.5 h, and
a solution of vinyl sulfoxide [(()-2, (+)-1a, (+)-1b] (1 mmol) in
benzene (5 mL) was added. After 3 h reflux, the reaction was
quenched by addition of aqueous ammonium chloride solution (15
Experimental Section
(+)-(S)-1-(Diethoxyphosphoryl-2-phenyl)vinyl p-Tolyl Sul-
foxide (1b). To a solution of benzaldehyde (1.06 g, 10 mmol) in
benzene (30 mL) was added piperidine (340 mg, 4 mmol), and the
mixture was refluxed for 0.5 h. Then, to a resulting solution cooled
to room temperature was added (+)-(S)-R-diethoxyphophorylmethyl
p-tolyl sulfoxide (2.9 g, 10 mmol) and acetic acid (0.25 g, 4.1
mmol). The reaction mixture was refluxed for 2 days. After solvent
mL). The water phase was extracted with CHCl
and combined organic phases were dried over anhydrous MgSO
3
(3 × 10 mL),
4
.
Evaporation of solvents gave the crude product 5, which was
purified by chromatography (acetone/benzene, 1:25).
(()-6-Methanesulfinyl-3H-pyrrolizine (5a). Yellow oil (80 mg,
1
evaporation, water (20 mL) and CH
the remaining oil. The organic layer was dried over anhydrous
MgSO and evaporated in a vacuum. The residue obtained as a
2
Cl
2
(20 mL) were added to
48%); H NMR (200 MHz, CDCl
3
) δ 2.82 (s, 3H), 4.46-4.49 (m,
2H), 6.11 (s, 1H), 6.30 (m, 1H), 6.96 (m, 1H), 7.29 (dd, 1H, J )
1.4 and 2.8 Hz); 13C NMR (50 MHz, CDCl
) δ 38.1, 49.2, 106.1,
108.1, 119.0, 122.9, 142.3, 148.9. Anal. Calcd for C NOS
4
3
yellow oil was purified by column chromatography (hexane/ethyl
8 9
H
acetate, 5:1) to give the pure sulfoxide 1b as a colorless oil (3.6 g,
(167.22): C, 57.46; H, 5.42; N, 8.38; S, 19.17. Found: C, 57.34;
H, 5.22; N, 8.63; S, 18.99.
20
31
9
5%); [R]
D
+77 (c ) 0.21, acetone); P NMR (81 MHz, CDCl
δ 12.3; H NMR (200 MHz, CDCl ) δ 1.12 (t, 3H, J ) 7.1 Hz),
.16 (t, 3H, J ) 7.1 Hz), 2.38 (s, 3H), 3.50-4.03 (m, 4H), 7.17 (d,
3
)
1
3
(
S)-6-(p-Toluenesulfinyl)-3H-pyrrolizine (5b). After crystal-
lization from a mixture of petroleum ether/methylene chloride (3:
1
1
13
3
H, J ) 41.4 Hz), 7.21-7.64 (m, 9H); C NMR (50 MHz, CDCl )
1
) the product 5b was obtained in the form of yellow crystals (180
δ 19.6, 21.7, 61.4 (d, J ) 7.2 Hz), 126.4, 128.5, 129.2, 134.8 (d,
J ) 181.3 Hz), 140.4, 146.6, 150.4 (d, J ) 7.5 Hz). Anal. Calcd
20
1
mg, 74%); mp 123-125 °C; [R]
NMR (200 MHz, CDCl ) δ 2.39 (s, 3H), 4.44 (m, 2H), 5.93 (s,
3
D
-37.5 (c ) 0.22, acetone); H
for C19
0.04; H, 6.23; S, 8.39.
()-3-Methanesulfinyl-2H-chromene (3a). To a solution of
23 4
H O PS (378.36): C, 60.31; H, 6.13; S, 8.47. Found: C,
1
6
H), 6.26 (dt, 1H, J ) 2.1 and 6.1 Hz), 6.49 (dt, 1H, J ) 2.1 and
6
13
.1 Hz), 7.27 and 7.53 (AA′BB′ system, 4H and 1H); C NMR
) δ 21.3, 52.3, 95.8, 119.8, 122.9, 124.5, 128.1,
28.9, 129.3, 130.5, 140.2, 142.8. Anal. Calcd for C14
(
(50 MHz, CDCl
3
salicylaldehyde (61 mg, 0.5 mmol) in THF (20 mL) 50% NaH (24
mg, 1 mmol, suspension in mineral oil) in THF (5 mL) was added.
After stirring for 5 min, vinyl sulfoxide (()-2 (113 mg, 0.5 mmol)
in THF (5 mL) was added dropwise. The reaction mixture was
then refluxed for 1 h. After cooling the reaction mixture to room
1
H13NOS
(243.31): C, 69.11; H, 5.39; N, 5.76; S, 13.18. Found: C, 69.34;
H, 5.22; N, 5.83; S, 12.99.
(
S)-5-Phenyl-6-(p-toluenesulfinyl)-3H-pyrrolizine (5c). Brown
20
1
oil (245 mg, 77%); [R]
D
-150 (c ) 0.3, acetone); H NMR (200
temperature an aqueous solution of NH
and the product was extracted with CHCl
combined extracts were dried over anhydrous MgSO
4
Cl (15 mL) was added,
(3 × 10 mL). The
and evapo-
MHz, CDCl ) δ 2.39 (s, 3H), 4.42-4.67 (m, 2H), 5.92 (s, 1H),
3
3
6
.27 (dt, 1H, J ) 2.1 and 6.1 Hz), 6.53 (dt, 1H, J ) 2.1 and 6.1
4
13
Hz), 7.26-7.50 (AA′BB′ system, 4H), 7.33-7.75 (m, 5H);
NMR (50 MHz, CDCl ) δ 21.3, 52.2, 97.3, 119.2, 123.2, 124.7,
27.6, 128.3, 128.5, 129.4, 140.2, 142.1. Anal. Calcd for C20
NOS (319.41): C, 75.20; H, 5.36; N, 4.39; S, 10.04. Found: C,
C
rated to give the crude product 3a, which was purified by column
chromatography on silica gel (benzene/acetone, 1:20); yellow oil,
3
1
17
H -
1
6
(
5 mg (67%); H NMR (200 MHz, CDCl
3
) δ 2.69 (s, 3H), 4.92
AB system, 2H, J ) 12 Hz)), 6.82-7.35 (m, 5H); 13C NMR (50
MHz, CDCl ) δ 38.9, 61.6, 103.9, 116.0, 122.0, 126.1, 127.9, 131.2.
Anal. Calcd for C10 S (194.24): C, 61.83; H, 5.19; S, 16.50.
Found: C, 61.68; H, 5.27; S, 16.45.
S)-3-p-Toluenesulfinyl-2H-chromene (3b). According to the
75.45; H, 5.09; N, 4.44; S, 9.96.
3
Reaction of (+)-1a with o-Aminoacetophenone. To vinyl
10 2
H O
sulfoxide (+)-1a (151 mg, 0.5 mmol) dissolved in benzene (5 mL)
o-aminoacetophenone (67 mg, 0.5 mmol) and 3 drops of triethyl-
amine were added. The mixture was kept at room temperature, and
benzene was evaporated. The crude adduct was dissolved in DMF
(
procedure described above, the sulfoxide (+)-1a (151 mg, 0.5
mmol) and salicylaldehyde (61 mg, 0.5 mmol) in toluene (3 h
reflux) gave the chromene sulfoxide 3b; light-yellow crystals, mp
(3 mL), and NaH (24 mg, 1 mmol, 50% dispersion in oil) was
added. The mixture was refluxed for 2 h. The reaction was quenched
by addition of aqueous ammonium chloride solution (15 mL), and
9
(
4-95 °C, 76 mg (56%); [R]20
D
+84 (c ) 0.21, acetone); H NMR
1
3
500 MHz, CDCl ) δ 2.41 (s, 3H), 4.53 and 6.66 (AB system, 2H,
the water phase was extracted with CHCl
combined extracts were dried over anhydrous MgSO
3
(3 × 10 mL). The
J ) 14.2 Hz), 6.78-7.26 (m, 5H), 7.32 and 7.55 (AA′BB′ system,
4
. After
4
1
H); 13C NMR (50 MHz, CDCl
25.1, 127.4, 128.2, 130.2, 131.5, 135.6, 138.0 142.1, 154.0. Anal.
S (270.32): C, 71.09; H, 5.22; S, 11.86.
Found: C, 70.97; H, 5.11; S, 11.95.
S)-3-p-Toluenesulfinyl-2,5-dihydrofuran (4). To 50% NaH (48
3
) δ 21.4, 61.8, 116.2, 120.8, 122.0,
evaporation of solvents (DMF was removed by Kugelrohr distil-
lation) the reaction products were separated by column chroma-
tography (hexane/ethyl acetate, 10:1).
14 2
Calcd for C16H O
(
S)-4-Methyl-3-(p-toluenesulfinyl)quinoline (7). Red oil (45 mg,
(
20
1
3
2%); [R]
D
-212 (c ) 0.17, acetone); H NMR (200 MHz,
mg, 2 mmol; suspension in mineral oil) in THF (10 mL) was added
glycolaldehyde (60 mg, 1 mmol) dropwise. After vigorous stirring
for 30 min at room temperature a solution of sulfoxide (+)-1a (302
mg, 1 mmol) in THF (10 mL) was added, and the reaction mixture
was stirred for 6 h. Then, saturated ammonium chloride solution
3
CDCl ) δ 2.35 (s, 3H), 2.88 (s, 3H), 7.26 and 7.56 (AA′BB′ system,
4
9
1
H), 7.59-7.67 (m, 1H), 7.75-7.82 (m, 1H), 8.03-8.14 (m, 2H),
.20 (s, 1H); 13C NMR (50 MHz, CDCl
) δ 14.4, 21.3, 111.6, 124.1,
25.0, 127.6, 130.2, 131.0, 130.4, 138.2, 142.7, 145.5, 146.2. MS
3
+
(
EI) m/z 281 [M] . Anal. Calcd for C17
H, 5.37; N, 4.98. Found: C, 72.36; H, 5.67; N, 5.01.
-(Hydroxymethyl)quinoline (8). Red oil (36 mg, 45%), mp
H15NOS (281.36): C, 72.57;
(
5 mL) was added, and the reaction solution was extracted with
CHCl
(3 × 10 mL). The combined organic phases were dried over
MgSO . After solvent evaporation, the crude product was purified
by chromatography on silica gel (hexane/acetone, 24:1) to afford
3
4
4
21
1
9
1-92 °C (lit. 97-98 °C ); H NMR (200 MHz, CDCl
3
) δ 5.23
2
0
(s, 2H), 7.52-7.61 (m, 2H), 7.68-7.76 (m, 1H), 7.93-7.98 (m,
the product 4 as a yellow oil (183 mg, 88%); [R]
D
+83 (c )
) δ 2.38 (s, 3H), 4.39-
.60 (m, 2H), 4.73-4.80 (m, 2H), 6.57 (m, 1H), 7.32 and 7.50
13
1
1H), 8.11-8.16 (m, 1H), 8.87 (d, 1H, J ) 4.4 Hz); C NMR (50
MHz, CDCl ) δ 60.7, 118.1, 123.0, 125.9, 126.8, 129.7, 147.4,
9
147.6, 150.3; MS (CI) m/z 159 [M + H] . Anal. Calcd for C10H -
0
4
6 6
.28, acetone); H NMR (200 MHz, C D
3
+
AA′BB′ system, 4H); 1 C NMR (50 MHz, CDCl
3
(
3
) δ 21.1, 71.9,
6.1, 124.5, 130.5, 131.9, 133.1, 140.2, 142.1. Anal. Calcd for
S (208.27): C, 63.44; H, 5.81; S, 15.39. Found: C, 63.67;
H, 5.70; S, 15.45.
7
C H O
11 12 2
(21) Wender, P. A.; Beckham, S.; Oleary, J. G. Synthesis 1994, 1278-
1283; Philips, A. P. J. Am. Chem. Soc. 1946, 68, 2568-2569.
8822 J. Org. Chem., Vol. 71, No. 23, 2006

Carbo- and Heterocyclic Vinyl Sulfoxides
NO (159.18): C, 75.45; H, 5.70; N, 8.80. Found: C, 75.16; H,
and evaporated to give the crude product 11, which was subjected
7
.54; N, 9.01.
to column chromatography (petroleum ether/acetone, 15:1). The
2
0
General Procedure for the Preparation of N-Hydroxy-
product 11 was obtained pure as a brown oil (2.25 g, 95%); [R]
D
1
pyrroles (10). To a solution of dione monooxime (0.25 mmol) in
DMF (10 mL) 50% NaH (12 mg, 0.5 mmol, dispersion in oil) and
vinyl sulfoxide (()-1a (75 mg, 0.25 mmol) dissolved in DMF (1
mL) were added. The mixture was kept at room temperature for 4
h. After this time aqueous ammonium chloride solution (15 mL)
3
-15.2 (c ) 0.17, acetone); H NMR (200 MHz, CDCl ) δ 1.07
and 1.18 (2xt, 3H, J ) 7.1 Hz), 2.10 (m, 3H), 2.37 (s, 3H), 2.61
(m, 1H), 2.97 (m, 1H), 3.20 (m, 1H), 3.29 (m, 1H), 4.08 (2xq, 4H,
13
J ) 7.1 Hz), 7.26 and 7.38 (AA′BB′ system, 4H); C NMR (50
MHz, CDCl
3
) δ 14.1, 18.7, 21.6, 34.6, 34.8, 51.2, 61.5, 126.3, 124.8,
was added, and the reaction solution was extracted with CHCl
3
(3
24 5
129.4, 134.5, 141.8, 144.6, 169.3. HRMS calcd for C19H O S (M
×
10 mL). The extracts were combined, dried over anhydrous
+ H), 365.1422; found, 365.1427.
4
MgSO , and evaporated. The crude product was purified by column
(
()-4,4-Di(ethoxycarbonyl)-2.5-dimethyl-1-(p-toluenesulfinyl)-
chromatography (hexane/ethyl acetate, 12:1 or 20:1).
()-2,3-Dimethyl-N-hydroxy-4-(p-toluenesulfinyl)pyrrole (10a).
Red oil (50 mg, 81%); H NMR (200 MHz, CDCl
cyclopent-1-ene (13). According to the procedure described above,
malonate (1.4 g, 6.5 mmol) and vinyl sulfoxide (()-12 (2.06 g,
(
1
3
) δ 1.79 (s,
6
.5 mmol) produced the cyclopentene sulfoxide (()-13 (mixture
3H), 2.01 (s, 3H), 2.36 (s, 3H), 6.33 (s, 1H), 7.38 and 7.21 (AA′BB′
1
of diastereomers in a 3:1 ratio) as a yellow oil (2.14 g, 87%); H
NMR (200 MHz, CDCl ) major diastereomer δ 1.11 (9t, 3H, J )
13
system, 4H), 11.26 (s, 1H); C NMR (50 MHz, CDCl
3
) δ 8.9,
3
9.7, 21.3, 110.6, 115.2, 125.0, 125.7, 129.7, 138.9, 140.8, 152.8;
7
(
(
.2 Hz), 1.14 (d, 3H, J ) 7.1 Hz), 1.19 (d, 3H, J ) 7.2 Hz), 2.14
-
1
IR (film) 3142, 2924, 1688, 1023 cm . Anal. Calcd for C13
NO S (249.32): C, 62.63; H, 6.06; N, 5.62. Found: C, 62.39; H,
.87; N, 5.81.
()-N-Hydroxy-3-methyl-2-phenyl-4-(p-toluenesulfinyl)pyr-
15
H -
m, 3H), 2.42 (s, 3H), 2.79 (dq, 1H, J ) 18.0 and 0.8 Hz), 3.38
2
qdq, 1H, J ) 7.1, 1.6 and 1.3 Hz), 3.50 (ddq, 1H, J ) 18.0, 1.6
5
and 1.4 Hz), 3.90-4.25 (m, 4H), 7.33 and 7.44 (AA′BB′ system,
(
1
4
3
H); H NMR (200 MHz, CDCl
3
) minor diastereomer δ 0.63 (d,
1
role (10b). Red oil (61 mg, 78%); H NMR (200 MHz, CDCl
3
) δ
.04 (s, 3H), 2.39 (s, 3H), 6.44 (s, 1H), 7.18-7.46 (m, 9H), 11.3
s, 1H); 13C NMR (50 MHz, CDCl
) δ 11.0, 21.4, 106.7, 114.7,
25.1, 126.2, 126.7, 129.7, 131.4, 131.5, 134.0, 141.8, 141.9. Anal.
S (311.39): C, 69.43; H, 5.50; N, 4.50.
Found: C, 69.63; H, 5.38; N, 4.31.
R)-4,4-Di(ethoxycarbonyl)-2-methyl-1-(p-toluenesulfinyl)cy-
H, J ) 7.2 Hz), 1.09 (t, 3H, J ) 7.2 Hz), 1.17 (t, 3H, J ) 7.2
Hz), 2.10 (m, 3H), 2.38 (s, 3H), 2.84 (m, 1H), 2.96-3.35 (m, 2H),
.90 (m, 4H), 7.33-7.44 (AA′BB′ system, 4H); C NMR (50 MHz,
CDCl ) δ 13.8, 14.1, 19.7, 21.6, 32.0, 46.8, 58.2, 62.5, 124.5, 126.3,
34.4, 136.5, 141.8, 143.6, 167.5. HRMS calcd for C20 S (M
2
(
1
13
3
3
3
Calcd for C18H17NO
2
1
26 5
H O
+
H), 379.1579; found, 379.1583.
(
clopent-1-ene (11). To a solution of diethyl 2-(2-oxopropyl)-
malonate (1.4 g, 6.5 mmol) in THF (30 mL) 50% NaH (0.299 g,
Supporting Information Available: General experimental
methods, 31P NMR spectrum of (+)-1b, H and/or C NMR spectra
of compounds 3a, 4, 5a-c, 7, 10a,b, and 13, X-ray crystallographic
data in CIF format, and Figure 1 (ORTEP view of (-)-5b with
discussion of bond lengths in the pyrrolizine ring). This material
is available free of charge via the Internet at http://pubs.acs.org.
1
13
13 mmol) was added. After stirring for ca. 20 min, vinyl sulfoxide
(
+)-1a (1.969 g, 6.5 mmol) was slowly added and the deeply red
reaction solution was stirred at room temperature for additional 3
h. Then, a water solution (10 mL) of ammonium chloride was
added. The water phase was extracted with CHCl
and the combined organic phase was dried over anhydrous MgSO
3
(3 × 20 mL),
4
JO061463B
J. Org. Chem, Vol. 71, No. 23, 2006 8823