Addition of thiols to sulfonylacetylenes: Synthetic applications

Article abstract of DOI:10.1055/s-2006-926396

The addition of propane-1,3-dithiol to p-toluenesulfonylacetylene affords the dithioacetal 1. This compound is a useful building block for the synthesis of new functionalized sulfanylvinylsulfonyl derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926396

PAPER
1339
Addition of Thiols to Sulfonylacetylenes: Synthetic Applications
A
dditionof Thio
o
S
ulfony
c
lacetylenesío Medel, Joaquin Plumet*
Departamento de Química Organica I, Facultad de Química, Universidad Complutense, 28040 Madrid, Spain
Fax +34(91)3944100; E-mail: plumety@quim.ucm.es
Received 28 October 2005; revised 25 November 2005
Dedicated to Professor Victor Riera on the occasion of his 70th birthday
SO2Tol
Abstract: The addition of propane-1,3-dithiol to p-toluenesulfo-
nylacetylene affords the dithioacetal 1. This compound is a useful
building block for the synthesis of new functionalized sulfanylvi-
nylsulfonyl derivatives.
TolO2S
S
S
S
SR
Key words: dithioacetals, base-induced, ring-opening, S-alkyla-
tion, sulfanylvinylsulfonyl derivatives
1
2
Figure 1 Compounds 1 and 2
presence of NaH (1.1 equiv) in THF as solvent
(Scheme 2).7
The base-catalyzed addition of thiols to acetylenic sul-
fones has been scarcely studied despite the fact that the
first report of this reaction was published as early as in
1964.1 Some examples concerning the regio-2 and
stereoselectivity3 of this reaction have been reported and
the process has been used for the protection of the thiol
functionality.4 Concerning the stereochemistry of this re-
action we have recently reported that it may be controlled
depending on the reaction conditions (Scheme 1).5
SO2Tol
NaH/THF
SO2Tol
+
+
HS
SH
S
S
0 °C to r.t.
75%
1
SO2Tol
O
NaH/THF
0 °C, 80%
HO
RS
H
SO2Tol
H
SO2Tol
SH
neutral media
S
3
RSH
+
SO2Tol
RS
H
H
Scheme 2
basic media
(NaH/THF)
SO2Tol
The 1,3-dithianyl group attached to a carbon atom bearing
one or two electron-withdrawing groups such as ester,8
ketone9 or TMS10 undergoes dithiane ring-cleavage with
concomitant substitution reaction on the anionic sulfur
atom (Scheme 3).
Scheme 1
On the basis of these precedents, we have considered the
synthetic uses of cyclic thioacetals such as 16 in order to
obtain the hitherto unknown highly functionalized E-sul-
fanylvinylsulfonyl derivatives 2 (Figure 1).
Similar reactions have been observed in related a,b-unsat-
urated acetals and ketals.11 To the best of our knowledge,
this reaction has never been applied to derivatives such as
1 or 3 with an arylsulfonyl group as electron-withdrawing
substituent. Thus, we decided to explore the behavior of
The synthesis of thioacetal 1 and oxathioacetal 3 was
achieved by the reaction of propane-1,3-dithiol and 2-
mercaptoethanol with p-toluenesulfonylacetylene in the
S
S
Z
S
S
Z
S
Z
S
S
Z
E
base
()n
()n
()n
()n
R
R
SE
R
R
n = 0, 1; R = H, alkyl, aryl, electron-withdrawing group
Scheme 3
SYNTHESIS 2006, No. 8, pp 1339–1342
x
x
.
x
x
.2
0
0
6
Advanced online publication: 27.03.2006
DOI: 10.1055/s-2006-926396; Art ID: Z21105SS
© Georg Thieme Verlag Stuttgart · New York

1340
R. Medel, J. Plumet
PAPER
Table 1 Sequential Base-Induced Ring-Opening–S-Alkylation of Dithioacetal 1
SO2Tol
TolO2S
a) base (1.1 equiv)
S
S
S
SR
b) RX (2.0 equiv), THF
–78 °C to r.t.
1
2
Entry
Base
Time (h)
Electrophile
MeI
Product (R)
2a (Me)
2b (Bn)
2c
Yield (%)a
Yield (%)a of recovered 1
1
2
3
LDA
LDA
LDA
18
18
18
75
–
6
BnOMs
CH2Br
35b
60
20
H2C
2c
4
5
6
BuLi
LDA
BuLi
4
18
4
65
64
48
10
20
18
CH2Br
CH2Br
H2C
2d
H2C
2d
CH2Br
H2C
7
8
LDA
LDA
LDA
LDA
18
18
2
MeOCH2Br
2e (CH2OMe)
2f (CH2CO2Me)
2g (CH2COPh)
4d
75
36
30
24
–
MeOCOCH2Br
PhCOCH2Br
Me3SiCl
20
c
9
–
10
18
–
a Isolated yields.
b The reaction with BnBr under different experimental conditions gave 25–28% of compound 2b and 36–46% of recovered starting material.
c Almost 50% of starting material was recovered in different experiments.
d Compound 4 was the only isolated product. The stereochemistry of the double bond was confirmed by NOE experiment. For a discussion on
the mechanism of this silicon migration, see ref. 10a.
TolO2S
TMS
S
SH
4
compounds 1 and 3 towards basic reagents in the presence It should be pointed out that only E-diastereoisomers were
of representative electrophiles.
obtained and that these products constitute new function-
alized sulfanylvinylsulfonyl derivatives, suitable building
blocks for further useful transformations.12
The reaction of compound 3 with different basic reagents
(LDA, organolithium derivatives) in the presence of dif-
ferent electrophilic reagents afforded complex reaction In summary, a new aspect of the addition reaction of thiols
mixtures from which we were unable to isolate any iden- to sulfonylacetylene has been considered: the sequence
tifiable product with the exception of starting material. In ring-opening–S-alkylation reactions of dithioacetals 1,
sharp contrast, the reaction of compound 1 with LDA or giving new functionalized sulfanylvinylsulfonyl deriva-
BuLi under different experimental conditions gave rise to tives.
the expected product arising from the sequence ring-open-
ing–S-alkylation process. The results are given in Table 1.
Synthesis 2006, No. 8, 1339–1342 © Thieme Stuttgart · New York

PAPER
Addition of Thiols to Sulfonylacetylenes
1341
Reagents obtained from commercial sources were used as received,
and solvents were dried prior to use. Silica gel 60 F254 was used for
TLC, and the spots were detected with UV or KMnO4 solution.
Flash column chromatography was carried out on silica gel 60.
Melting points were determined on a Büchi 512 apparatus and are
uncorrected. IR spectra were recorded on a Perkin-Elmer 781 spec-
trophotometer. 1H and 13C NMR spectra were recorded on a Bruker
AM-300 instrument at 300 (1H) and 75 MHz (13C) in CDCl3 solu-
tion, with Me4Si as internal reference; d in ppm. Elemental analyses
were performed at the Universidad Complutense de Madrid.
1H NMR (CDCl3, 300 MHz): d = 1.94 (q, J = 7.1 Hz, 2 H), 2.05 (s,
3 H), 2.43 (s, 3 H), 2.58 (t, J = 6.8 Hz, 2 H), 2.90 (t, J = 7.3 Hz, 2
H), 6.20 (d, J = 14.6 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.69 (d,
J = 14.9 Hz, 1 H), 7.75 (d, J = 8.5 Hz, 2 H).
13C NMR (CDCl3, 75 MHz): d = 15.8, 22.0, 27.8, 31.2, 33.2, 122.7,
127.8, 130.3, 138.6, 144.5, 145.0.
Anal. Calcd for C13H18O2S3: C, 51.62; H, 6.00; O, 10.58; S, 31.80.
Found: C, 51.56; H, 5.92; O, 10.70; S, 31.78.
(E)-2-{[3-Benzylsulfanyl)propyl]sulfanyl}vinyl 4-Methylphenyl
Sulfone (2b)
1,3-Dithian-2-ylmethyl 4-Methylphenyl Sulfone (1)
Pale-yellow oil.
To a solution of propane-1,3-dithiol (0.1 mL, 1 mmol) in THF (5 mL)
at 0 °C, was added NaH (60% in mineral oil, 44 mg, 1.1 mmol). Af-
ter stirring for 10 min, a solution of p-toluenesulfonylacetylene (198
mg, 1.1 mmol) in THF (5 mL) was added and the mixture was
stirred for 3 h at r.t. The reaction was quenched with phosphate buff-
er and extracted with CH2Cl2. The organic extracts were collected
and dried (MgSO4), filtered and concentrated under reduced pres-
sure. The crude reaction product was purified by column chroma-
tography on silica gel using a mixture of hexane–EtOAc (5:1) as
eluent affording 276 mg (96%) of 1 as a white solid; mp 107–108
°C.
IR (CHCl3): 2925.8, 1454.2, 1317.3, 1269.1 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.86 (q, J = 7.1 Hz, 2 H), 2.43 (s,
3 H), 2.49 (t, J = 6.9 Hz, 2 H), 2.82 (t, J = 7.3 Hz, 2 H), 3.68 (s, 2
H), 6.16 (d, J = 14.5 Hz, 1 H), 7.23–7.34 (m, 7 H), 7.67 (d, J = 14.5
Hz, 1 H), 7.76 (d, J = 8.4 Hz, 2 H).
13C NMR (CDCl3, 75 MHz): d = 22.0, 28.0, 30.2, 31.3, 36.6, 122.7,
127.6, 127.8, 129.0, 129.2, 130.3, 138.4, 138.6, 144.5, 145.0.
Anal. Calcd for C19H22O2S3: C, 60.28; H, 5.86; O, 8.45; S, 25.41.
Found: C, 60.33; H, 5.91; O, 8.39; S, 25.50.
IR (KBr): 2902.7, 1317.3, 1151.4, 732.9 cm–1.
4-Methylphenyl (E)-2-{[3-(2-Prop-2-ynylsulfanyl)propyl]-
sulfanyl}vinyl Sulfone (2c)
Pale-yellow oil.
IR (CHCl3): 3286.5, 2922.0, 1595.0, 1301.9 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.74–1.94 (m, 1 H), 1.98–2.16 (m,
1 H), 2.45 (s, 3 H), 2.84 (dt, J = 9.7, 3.4 Hz, 4 H), 3.50 (d, J = 6.6
Hz, 2 H), 4.46 (t, J = 6.6 Hz, 1 H), 7.35 (d, J = 8.3 Hz, 2 H), 7.82
(d, J = 8.1 Hz, 2 H).
1H NMR (CDCl3, 300 MHz): d = 1.96 (q, J = 7.1 Hz, 2 H), 2.25 (t,
J = 2.6 Hz, 1 H), 2.41 (s, 3 H), 2.75 (t, J = 6.9 Hz, 2 H), 2.89 (t,
J = 7.1 Hz, 2 H), 3.20 (d, J = 2.6 Hz, 2 H), 6.18 (d, J = 14.7 Hz), 1
H, 7.31 (d, J = 8.2 Hz, 2 H), 7.67 (d, J = 14.7 Hz, 1 H), 7.73 (d,
J = 8.2 Hz, 2 H).
13C NMR (CDCl3, 75 MHz): d = 21.5, 24.6, 29.3, 38.9, 60.7, 128.0,
129.7, 136.3, 144.9.
Anal. Calcd for C12H16O2S3: C, 49.97; H, 5.59; O, 11.09; S, 33.35.
Found: C, 50.09; H, 5.48; O, 10.99; S, 33.40.
13C NMR (CDCl3, 75 MHz): d = 19.6, 22.0, 27.9, 30.6, 31.3, 71.9,
2-{[(4-Methylphenyl)sulfonyl]methyl}-1,3-oxathiolane (3)
To a solution of 2-mercaptoethanol (0.07 mL, 1 mmol) in THF (5 mL)
at 0 °C, was added NaH (60% in mineral oil, 44 mg, 1.1 mmol). Af-
ter stirring 10 min, a solution of p-toluenesulfonylacetylene (198
mg, 1.1 mmol) in THF (5 mL) was added and the mixture was
stirred for 20 min at 0 °C. The reaction was quenched with phos-
phate buffer and extracted with CH2Cl2. The organic extracts were
collected and dried (MgSO4), filtered and concentrated under re-
duced pressure. The crude reaction product was purified by column
chromatography on silica gel using a mixture of hexane–EtOAc
(5:1) as eluent affording 206 mg (80%) of 3. This compound had
been previously obtained in 9% isolated yield.4a
80.0, 122.7, 127.8, 130.3, 138.5, 144.5, 144.9.
Anal. Calcd for C15H18O2S3: C, 55.18; H, 5.56; O, 9.80; S, 29.46.
Found: C, 55.12; H, 5.60; O, 9.72; S, 29.50.
(E)-2-{[3-Allylsulfanyl)propyl]sulfanyl}vinyl 4-Methylphenyl
Sulfone (2d)
Pale-yellow oil.
IR (CHCl3): 2923.9, 1635.5, 1315.4 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.88 (q, J = 7.0 Hz, 2 H), 2.41 (s,
3 H), 2.51 (t, J = 6.9 Hz, 2 H), 2.86 (t, J = 7.1 Hz, 2 H), 3.46 (d,
J = 7.1 Hz, 2 H), 5.05 (d, J = 17.3 Hz, 1 H), 5.07 (d, J = 9.6 Hz, 1
H), 5.66–5.80 (m, 1 H), 6.18 (d, J = 14.5 Hz, 1 H), 7.31 (d, J = 8.1
Hz, 2 H), 7.67 (d, J = 14.7 Hz, 1 H), 7.73 (d, J = 8.1 Hz, 2 H).
Base-Induced Ring-Opening–S-Alkylation of Dithioacetal 1;
General Procedure
13C NMR (CDCl3, 75 MHz): d = 21.4, 27.5, 28.9, 30.7, 34.5, 117.2,
To a solution of n-BuLi (1.1 equiv, 1.6 M solution in hexane) cooled
to –78 °C or LDA [generated by stirring a solution of diisopropyl-
amine (1.1 equiv) and n-BuLi (1.1 equiv, 1.6 M solution in hexane)
in THF for 30 min at –78 °C under argon] were added successively
the corresponding electrophile (2 equiv, see Table 1) and 1
(1 equiv) dissolved in THF (0.1 M of 1). The resulting solution was
stirred for the time indicated in Table 1 and allowed to reach r.t. The
reaction was quenched with brine and extracted with EtOAc. The
organic layer was dried (MgSO4) and evaporated under reduced
pressure. The resulting crude was purified by silica gel chromatog-
raphy eluting with hexane–EtOAc system of appropriate polarity to
afford compounds 2a–g and 4 (Table 1).
122.1, 127.2, 129.7, 133.9, 138.1, 143.9, 144.4.
Anal. Calcd for C15H20O2S3: C, 54.84; H, 6.14; O, 9.74; S, 29.28.
Found: C, 54.80; H, 6.21; O, 9.80; S, 29.21.
(E)-2-{[3-[(Methoxymethyl)sulfanyl]propyl}sulfanyl)vinyl
4-Methylphenyl Sulfone (2e)
Pale-yellow oil.
IR (CHCl3): 2925.8, 2856.4, 1448.4, 1301.9 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.95 (q, J = 7.3 Hz, 2 H), 2.41 (s,
3 H), 2.66 (t, J = 7.1 Hz, 2 H), 2.88 (t, J = 7.1 Hz, 2 H), 3.31 (s, 3
H), 4.58 (s, 2 H), 6.18 (d, J = 14.9 Hz, 1 H), 7.30 (d, J = 8.1 Hz, 2
H), 7.68 (d, J = 15.3 Hz, 1 H), 7.74 (d, J = 8.5 Hz, 2 H).
13C NMR (CDCl3, 75 MHz): d = 21.5, 28.4, 29.7, 30.8, 55.7, 75.5,
122.3, 127.3, 129.8, 138.2, 143.9, 144.5.
4-Methylphenyl (E)-2-{[3-Methylsulfanyl)propyl]sulfanyl}-
vinyl Sulfone (2a)
Pale-yellow oil.
IR (CHCl3): 2923.9, 2852.5, 1550.7, 1139.9 cm–1.
Synthesis 2006, No. 8, 1339–1342 © Thieme Stuttgart · New York

1342
R. Medel, J. Plumet
PAPER
Anal. Calcd for C14H20O3S3: C, 50.57; H, 6.06; O, 14.44; S, 28.93.
Found: C, 50.62; H, 5.99; O, 14.39; S, 29.84.
thiols, sulfinates and related nucleophiles is considered in pp
5276–5277.
(2) Selling, H. A. Tetrahedron 1975, 31, 2387.
(3) Tichenor, G. J. W.; Truce, W. E. J. Org. Chem. 1972, 37,
2391.
(4) (a) Arjona, O.; Iradier, F.; Medel, R.; Plumet, J. J. Org.
Chem. 1999, 64, 6090. (b) Arjona, O.; Medel, R.; Rojas, J.
K.; Costa, A. M.; Vilarrasa, J. Tetrahedron Lett. 2003, 44,
6369.
Methyl ({[3-({(E)-2-[(4-Methylphenyl)sulfonyl]vinyl}-
sulfanyl)propyl]sulfanyl}acetate( 2f)
Pale-yellow oil.
IR (CHCl3): 2952.8, 2925.8, 1733.9, 1301.9, 1143.7 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.96 (q, J = 7.0 Hz, 2 H), 2.44 (s,
3 H), 2.73 (t, J = 6.9 Hz, 2 H), 2.89 (t, J = 7.1 Hz, 2 H), 3.20 (s, 2
H), 3.74 (s, 3 H), 6.18 (d, J = 14.7 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 2
H), 7.68 (d, J = 14.7 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 2 H).
(5) Medel, R.; Monterde, M. I.; Plumet, J.; Rojas, J. K. J. Org.
Chem. 2005, 70, 735.
(6) For the synthesis of oxathianes and dithianes by
stereoselective addition–cyclization of hydroxythiols and
dithiols to electron-poor acetylenes, see: (a) De Lucci, O.;
Marchioro, C.; Modena, G.; Lucchini, V. Tetrahedron Lett.
1985, 26, 4539. (b) De Lucci, O.; Marchioro, C.; Modena,
G.; Lucchini, V.; Valle, G. J. Org. Chem. 1986, 51, 1457.
For the synthesis of acyclic and the cyclic thioacetal 5
(Figure 2) by base-catalyzed addition of ethanedithiol to
arylsulfonylacetylenes, see: (c) Buso, M.; De Lucci, O.;
Modena, G. Tetrahedron Lett. 1987, 28, 107. (d) Cossu, S.;
De Lucci, O.; Fabris, F.; Ballini, R.; Bosica, G. Synthesis
1996, 1481.
13C NMR (CDCl3, 75 MHz): d = 21.6, 27.4, 30.7, 31.2, 33.2, 52.5,
122.4, 127.4, 129.9, 138.1, 144.1, 144.4, 170.6.
Anal. Calcd for C15H20O4S3: C, 49.97; H, 5.59; O, 17.75; S, 26.68.
Found: C, 50.05; H, 5.61; O, 17.70; S, 26.61.
2-{[3-({(E)-2-[(4-Methylphenyl)sulfonyl]vinyl}sulfanyl)-
propyl]sulfanyl}-1-phenylethanone (2g)
White solid; mp 60–61 °C.
IR (KBr): 2922.0, 2360.7, 1278.7, 1143.7 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.96 (q, J = 7.0 Hz, 2 H), 2.43 (s,
3 H), 2.66 (t, J = 6.9 Hz, 2 H), 2.89 (t, J = 7.1 Hz, 2 H), 3.78 (s, 2
H), 6.18 (d, J = 14.7 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.48 (t,
J = 8.0 Hz, 2 H), 7.60 (t, J = 7.1 Hz, 1 H), 7.67 (d, J = 14.7 Hz, 1
H), 7.75 (d, J = 8.2 Hz, 2 H), 7.97 (d, J = 7.9 Hz, 2 H).
SO2Tol
S
S
13C NMR (CDCl3, 75 MHz): d = 21.6, 27.3, 30.7, 30.7, 36.8, 122.3,
127.4, 128.7, 129.9, 133.6, 134.9, 138.1, 144.0, 144.4, 194.2.
5
Anal. Calcd for C20H22O3S3: C, 59.08; H, 5.45; O, 11.81; S, 23.66.
Found: C, 58.98; H, 5.51; O, 11.87; S, 23.60.
Figure 2 Thioacetal 5
3-{[(E)-2-[(4-Methylphenyl)sulfonyl]-2-(trimethylsilyl)-
vinyl]sulfanyl}propane-1-thiol (4)
Pale-yellow oil.
IR (CHCl3): 2927.7, 1251.7, 1137.9 cm–1.
(7) The reaction of propane-1,3-dithiol and p-
toluenesulfonylacetylene in presence of Me3P (THF) affords
a mixture of compounds 6 and 7 (mixture of diastereomers)
(Figure 3).
1H NMR (CDCl3, 300 MHz): d = 0.16 (s, 9 H), 1.40 (t, J = 8.1 Hz,
1 H), 2.04 (q, J = 7.0 Hz, 2 H), 2.43 (s, 3 H), 2.68 (s, J = 7.0 Hz, 2
H), 3.07 (t, J = 7.0 Hz, 2 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.66 (d,
J = 8.1 Hz, 2 H), 8.34 (s, 1 H).
S
SH
S
S
SO2Tol
SO2Tol
SO2Tol
13C NMR (CDCl3, 75 MHz): d = –0.9, 21.5, 22.8, 34.0, 34.1, 127.1,
129.5, 134.8, 139.3, 143.3, 157.8.
6
7
Figure 3 Compounds 6 and 7
Anal. Calcd for C15H24O2S3Si: C, 49.96; H, 6.71; O, 8.87; S, 26.67;
Si, 7.79. Found: C, 49.89; H, 6.65; O, 8.82; S, 26.62; Si, 7.85.
(8) Kruse, C. G.; Janse, A. C. V.; Dert, V.; Van der Gen, A. J.
Org. Chem. 1979, 44, 2916.
(9) Marshal, J. A.; Sertz, D. E. J. Org. Chem. 1975, 40, 534.
(10) (a) Hase, T. A.; Latineen, L. Tetrahedron Lett. 1981, 22,
3285. (b) Hase, T. A.; Latineen, L. J. Organomet. Chem.
1982, 240, 9.
Acknowledgment
Ministerio de Ciencia y Tecnología of Spain (Project BQU2003-
04967) is gratefully thanked for financial support.
(11) Mroskowski, C.; Manna, S.; Falck, J. R. Tetrahedron Lett.
1984, 25, 519.
(12) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon:
London, 1993.
References
(1) (a) Stirling, C. J. M. J. Chem. Soc. 1964, 5856. (b) For a
review on the chemistry of acetylenic and allenic sulfones,
see: Back, T. G. Tetrahedron 2001, 57, 5263; the addition of
Synthesis 2006, No. 8, 1339–1342 © Thieme Stuttgart · New York