One-pot practical preparation of novel propargylic aryl and heteroaryl sulfides and sulfones

Article abstract of DOI:10.1055/s-2005-922750

A one-pot preparation of functionalized propargylic aryl and hetero aryl sulfides from primary alcohols and thiols through the formation of the corresponding iodide or tosylate compounds is presented. The corresponding sulfones are prepared by subsequent

Full text of DOI:10.1055/s-2005-922750

LETTER
3067
One-Pot Practical Preparation of Novel Propargylic Aryl and Heteroaryl
Sulfides and Sulfones
N
ovel Propargyli
a
c
Sulfides
a
r
nd Sulfo
l
nes o Bonini,* Lucia Chiummiento, Valeria Videtta
Dipartimento di Chimica, Università degli Studi della Basilicata, Via N. Sauro 85, 85100 Potenza, Italy
Fax +39(0971)202223; E-mail: bonini@unibas.it
Received 30 September 2005
Several synthetic methods for preparing simple and not
functionalized propargylic sulfides have been reported:
the most utilized is the Williamson-type reaction between
propargylic bromides, iodides, or mesylates with thiols in
the presence of inorganic bases9 or catalyzed by transition
metal.10
Abstract: A one-pot preparation of functionalized propargylic aryl
and hetero aryl sulfides from primary alcohols and thiols through
the formation of the corresponding iodide or tosylate compounds is
presented. The corresponding sulfones are prepared by subsequent
MCPBA oxidation.
Key words: thiols, sulfides, sulfones, oxidation, propargylic alco-
hol
1. activation
2. R'SH
OH
SR'
R
R
Organosulfur compounds are generally useful inter-
mediates for building highly functionalized biologically
and medicinally relevant natural products.1
1a: R = TMS
1b: R = CH2OTBS
1c: R = Et
oxidation
SO2R'
In particular, aromatic and heterocyclic sulfides and relat-
ed compounds are widely used as central nervous system
(CNS) agents.2 Heteroaromatic sulfur-containing deriva-
tives were also successfully used as antitumoral and cyto-
toxic compounds.3 In the class of propargylic compounds,
R
Scheme 1 General preparation of sulfides and sulfones.
heteroaromatic sulfides like compounds A (Figure 1) Initially, we have attempted the preparation of the corre-
were reported to possess certain memory improving and sponding tosylate of commercial alcohol 1a and of the
anticonvulsant activity.2 Propargylic sulfones like com- monoprotected 1,4-but-2-yndiol 1b11 under classical con-
pounds B are a simple class of compounds that cleave ditions, e.g. TsCl in pyridine (Scheme 1).12 However, the
DNA in a pH-dependent fashion4 and similar molecules standard protocol gave disappointing results in terms of
exhibit high DNA intercalating and alkylating activity.5
purity and isolated yields.
A second attempt with NaOH utilization in the reaction
medium afforded the desilylated product for compound
1a and the corresponding tosylate of 1b in good yields.
SHet
SO2Ar
HO
TMS
A
B
With the goal to avoid the use of NaOH for base-sensitive
substrate and in general to perform the reactions in a direct
one-pot synthesis procedure, we finally used and tested
two different approaches to sulfides: a) via iodide forma-
tion with alcohol 1a and 1c (both commercial products;
method A); b) via tosylate (method B) for the alcohol 1b13
(Scheme 2 and Table 1).
Figure 1
Sulfides and their oxidation products, sulfoxides and
sulfones, are important reagents and/or quite useful inter-
mediates in organic synthetic applications.6 In fact, aryl
and heteroaryl sulfoxides are useful moieties in asymmet-
ric synthesis,7 instead their corresponding sulfones are
powerful tools for double bond formation in the classical
and modified Julia olefination.8
The corresponding iodides of 1a,c were prepared using I2
in the presence of imidazole and PPh3, at reflux tempera-
ture, with complete conversion of starting materials after
one hour reaction time.
Because research on these sulfur compounds is widely
studied, considering their important biological activities,
highly selective and efficient methods are desired for the
preparation of propargylic or allenylic sulfides and
sulfones.
In a typical procedure 1.2 equivalents of thiols 3a–c were
added to the organic solution (CH2Cl2 or toluene) of per-
formed iodides or tosylates 2a–c and the reaction was
stirred at room temperature (3–4 h) until TLC indicated
complete consumption of the corresponding iodide or to-
sylate. Under these conditions, the desired sulfides 4a–i
were isolated in variable yields (from 37% up to 89%),
according to the type of thiol and of propargylic alcohol
used (Table 1).14,15
SYNLETT 2005, No. 20, pp 3067–3070
Advanced online publication: 28.11.2005
DOI: 10.1055/s-2005-922750; Art ID: G29805ST
© Georg Thieme Verlag Stuttgart · New York
1
9
.1
2
.2
0
0
5

3068
C. Bonini et al.
LETTER
The best results were obtained with heteroaromatic mer-
captans. In fact, treatment of benzenethiol 3a with 1a–c
gave the corresponding aryl propargyl known sulfides
4a,2,3,10a,16 4d and 4g (entries 1, 4 and 7) in 37%, 60% and
44%, respectively (diphenyldisulfide was detected but no
traces of starting material).
OH
a
X
SR'
b
R
R
R
4a–i
1a–c
2a–c
not isolated
c
In contrast, when the 2-mercaptobenzothiazole 3b (entries
2 and 5) was used with propargylic alcohols 1a,b, sulfides
4b2,3 and 4e were obtained in 72% and 82% yield, respec-
tively. Surprisingly, this trend has not been followed in
the preparation of sulfide 4h (entry 8), which was isolated
in 49% yield, although many attempts were made to in-
crease the overall yields. In good to high isolated yields
heteroaromatic propargylic sulfides were obtained (en-
tries 3, 6 and 9) using 1-phenyl-1H-tetrazole-5-thiol 3c
with the alcohols 1a–c (75%, 89% and 79% yield).
R = TMS, CH2OTBS, Et
X = I, OTs
R' = Ph, BT, PT
SO2R'
R
5a–i
N
S
N
N
N
SH
BT-SH =
Ph-SH
PT-SH =
SH
Ph
N
3a
3b
3c
Scheme 2 Reagents and conditions: (a) i. method A: X = I, I2, PPh3,
imidazole, CH2Cl2, reflux. ii. method B: X = OTs, TsCl, NaOH,
toluene, r.t.; (b) 3a–c, r.t.; (c) MCPBA, CH2Cl2, r.t.
Table 1 Preparation of Sulfides 4 and Sulfones 5
Entry
1
Propargylic alcohol 1
Thiol 3
Sulfide 4 (yield, %)a
Sulfone 5 (yield, %)b
1a
3a
SO2-Ph
S-Ph
TMS
TMS
4a (37)c,d
5a (100)
2
1a
3b
SO2-BT
S-BT
TMS
TMS
4b (72)c
5b (100)
3
4
5
6
7
8
9
1a
1b
1b
1b
1c
1c
1c
3c
3a
3b
3c
3a
3b
3c
S-PT
SO2-PT
TMS
4c (75)c
TMS
5c (100)e
S-Ph
SO2-Ph
TBSO
TBSO
4d (60)f,d
5d (100)
S-BT
S-PT
SO2-BT
SO2-PT
TBSO
TBSO
4e (82)f
5e (100)
TBSO
TBSO
4f (89)f
5f (92)e
SO2-Ph
S-Ph
S-BT
S-PT
4g (44)c
4h (49)c
4i (79)c
5g (84)
5h (100)
5i (95)e
SO2-BT
SO2-PT
a Yield of isolated sulfide.
b Yield of isolated sulfone.
c Prepared according to method A.
d Better yield was obtained according to the conditions reported below (vide infra).
e Unstable product.
f Prepared according to method B.
Synlett 2005, No. 20, 3067–3070 © Thieme Stuttgart · New York

LETTER
Novel Propargylic Sulfides and Sulfones
3069
(5) (a) Gupta, R.; Xie, G.; Lown, J. W. Gene 1994, 149, 81.
(b) Dai, W.-M.; Fong, K. C. Tetrahedron Lett. 1995, 36,
5613. (c) Dai, W.-M.; Fong, K. C.; Danjo, H.; Nishimoto, S.-
I.; Solow, M.; Mak, W. L.; Yeung, M. L. Bioorg. Med.
Chem. Lett. 1996, 6, 1093. (d) Dai, W.-M.; Chow, C. W.;
Zhou, L.; Ishii, A.; Lau, C. W.; Li, Q.; Hamaguchi, W.;
Nishimoto, S.-I. Bioorg. Med. Chem. Lett. 1999, 9, 2789.
(6) (a) Braverman, S.; Zafrani, Y.; Gottlieb, H. E. Tetrahedron
Lett. 2000, 41, 2675. (b) Braverman, S.; Zafrani, Y.;
Gottlieb, H. Tetrahedron 2001, 57, 9177. (c) Braverman,
S.; Cherkinsky, M.; Birsa, M. L.; Zafrani, Y. Eur. J. Org.
Chem. 2002, 3198.
In order to improve the overall yields of the phenyl prop-
argyl sulfides 4a, 4d and 4g, benzenethiol sodium salt
with 18-crown-6-ether has successively been used as a
new variant in the S-propargylation. Much-improved re-
sults have been achieved (Scheme 3) for phenyl propargyl
sulfides 4a and 4d (74% and 100%).17 Only 2-pentyn-1-ol
(1c) still gave the corresponding sulfide 4g in similar 33%
yield.
a, b
OH
SPh
R
(7) Fernández, I.; Khiar, N. Chem. Rev. 2003, 103, 3651; and
references therein.
R
1a–c
4 a 74%
4 d 100%
4 g 33%
(8) (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002,
2563. (b) Alonso, D. A.; Fuensanta, M.; Nájera, C.; Varea,
M. J. Org. Chem. 2005, 70, 6404; and references therein.
(9) (a) Denmark, S. E.; Harmata, M. A.; White, K. S. J. Org.
Chem. 1987, 52, 4031. (b) Zaragoza, F. Tetrahedron 2001,
57, 5451.
Scheme 3 Reagents and conditions: (a) conditions of Scheme 2; (b)
PhSNa, 18-crown-6-ether, r.t.
(10) (a) Kondo, T.; Kanda, Y.; Baba, A.; Fukuda, K.; Nakamura,
A.; Wada, K.; Morisaki, Y.; Mitsudo, T. J. Am. Chem. Soc.
2002, 124, 12960. (b) Tsutsumi, K.; Fujimoto, K.;
Yabukami, T.; Kawase, T.; Morimoto, T.; Kakiuchi, K. Eur.
J. Org. Chem. 2004, 504; and references therein.
(c) Georgy, M.; Boucard, V.; Campagne, J.-M. J. Am. Chem.
Soc. 2005, 127, 14180.
(11) We have prepared 1b using TBSCl/pyridine obtaining the
monoprotected diol with 55% vs. 30% yield reported in:
Padwa, A.; Lipka, H.; Watterson, S. H.; Murphree, S. S. J.
Org. Chem. 2003, 68, 6238.
(12) Greene, T. W.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis; Wiley-Interscience: New York, 1999,
3rd ed.
(13) The corresponding iodide was isolated in minor yield (70%
vs. 79%) with respect to the tosylate.
With these novel sulfides in hand, we envisioned the op-
portunity to prepare the corresponding sulfones. After
some attempts with different oxidants (oxone,18 H2O2/cat-
alyst,19 or MCPBA20), the use of MCPBA for the oxida-
tion of the functionalized sulfides 4a–i was found to be the
most efficient and practical method. Sulfones 5a–i have
been prepared and isolated, in the majority of cases, quan-
titatively and without need of purification. With respect to
PT sulfones 5c,f,i, the recovery of the crude material was
also satisfactory, but a decrease in the yield was observed
due to the unstable products.
In conclusion, the synthetic strategy depicted in Scheme 2
and Scheme 3 appears extremely valuable for providing,
in one-pot simple procedures, new functionalized propar-
gylic aromatic and heteroaromatic sulfides. The synthetic
utility of the method is further illustrated by the transfor-
mation of sulfides to their corresponding sulfones in ex-
cellent yields, as new synthetically important
intermediates in organic chemistry.
(14) General Procedure for Preparation of Sulfides 4a–c,
4g–i (Method A).
To a stirred solution of propargyl alcohol 1a,c (1 equiv, 0.78
mmol) in CH2Cl2 (13 mL) were added PPh3 (251 mg, 0.96
mmol), imidazole (158 mg, 2.32 mmol) and I2 (237 mg, 0.94
mg). The reaction mixture was raised to reflux. After 1 h, a
complete conversion of alcohol to the corresponding iodide
was observed by TLC control. The reaction temperature was
cooled to r.t. and thiol 3a–c (0.94 mmol) was added. After
complete conversion to sulfide (3 h), the reaction mixture
was hydrolyzed with a sat. aq solution of NH4Cl. The
organic layer was washed with brine, dried over Na2SO4 and
concentrated in vacuo. The crude mixture was purified by
column chromatography on silica gel.
Acknowledgment
We would like to thank the University of Basilicata and the MIUR
(FIRB-Progettazione, preparazione e valutazione biologica e far-
macologica di nuove molecole organiche quali potenziali farmaci
innovativi grant) for financial support.
(15) General Procedure for Preparation of Sulfides 4d–f
(Method B).
References
To a stirred solution of propargylic alcohol 1b (202 mg, 1.01
mmol) in toluene (0.9 mL) at 0 °C Bu4NI (39 mg, 0.10
mmol), 2 N solution of NaOH (1.5 mL), and a dropwise
solution of TsCl (202 mg, 1.06 mmol) in toluene (0.4 mL)
were added. The mixture was stirred for 3 h at r.t. and after
the complete formation of the corresponding tosylate, thiol
3a–c (1.08 mmol) was added. After additional 2 h the
aqueous layer was extracted with EtOAc, while the organic
layer was washed with H2O. The combined organic layers
were dried over Na2SO4 and concentrated in vacuo. The
crude mixture was purified by column chromatography on
silica gel.
(1) Metzner, P.; Thuillier, A. In Sulfur Reagents in Organic
Chemistry; Academic Press: London U.K., 1994.
(2) Abele, R.; Zvejniece, L.; Abele, E.; Rubina, K.; Arsenyan,
P.; Vandish, M.; Pudova, O.; Dambrova, M.; Domracheva,
I.; Shestakova, I.; Popelis, J.; Lukevics, E. Appl. Organomet.
Chem. 2004, 18, 181.
(3) Abele, R.; Abele, E.; Rubina, K.; Dzenitis, O.; Arsenyan, P.;
Shestakova, I.; Nesterova, A.; Domracheva, I.; Popelis, J.;
Grinberga, S.; Lukevics, E. Chem. Heterocycl. Compd.
2002, 38, 867.
(4) (a) Nicolaou, K. C.; Skokotas, G.; Maligres, P.; Zuccarello,
G.; Schweiger, E. J.; Toshima, K.; Wendeborn, S. Angew.
Chem., Int. Ed. Engl. 1989, 28, 1272. (b) Nicolaou, K. C.;
Wendeborn, S.; Maligres, P.; Isshiki, K.; Zein, N.; Ellestad,
G. Angew. Chem., Int. Ed. Engl. 1991, 30, 418.
(16) (a) Nicolaou, K. C.; Zipkin, R. E.; Petasis, N. A. J. Am.
Chem. Soc. 1982, 104, 5558. (b) Bacci, J. P.; Greenman, K.
L.; Van Vranken, D. L. J. Org. Chem. 2003, 68, 4955.
Synlett 2005, No. 20, 3067–3070 © Thieme Stuttgart · New York

3070
C. Bonini et al.
LETTER
(17) With our procedure the propargylic sulfides 4a and 4b have
been prepared in higher yields than in the other older
procedures reported in ref. 2, 3 and 10a.
(18) (a) Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22,
1287. (b) Webb, K. S. Tetrahedron Lett. 1994, 35, 3457.
(19) Blakemore, P. R.; Kocienski, P. J.; Morley, A.; Muir, K. J.
Chem. Soc., Perkin Trans. 1 1999, 955.
(20) (a) Nicolaou, K. C.; Magolda, R. L.; Sipio, W. J.; Barnette,
W. E.; Lysenko, Z.; Joullie, M. M. J. Am. Chem. Soc. 1980,
102, 3784. (b) Davis, F. A.; Zhou, P. Tetrahedron Lett.
1994, 35, 7525.
Synlett 2005, No. 20, 3067–3070 © Thieme Stuttgart · New York