Efficient palladium catalyzed synthesis of heteroaromatic sulfoxides

Article abstract of DOI:10.1016/j.tetlet.2007.07.165

The present Letter describes the efficient synthesis of novel heteroaromatic sulfoxides by means of a palladium catalyzed heteroarylation of sulfenate anions. Triazolopyridine, pyridine and thiophene sulfoxides can be obtained under mild conditions and in high yield from the corresponding heteroaryl bromides.

Full text of DOI:10.1016/j.tetlet.2007.07.165

Tetrahedron Letters 48 (2007) 6896–6899
Efficient palladium catalyzed synthesis of heteroaromatic sulfoxides
a
a
Franc¸oise Colobert,a, Rafael Ballesteros-Garrido, Frederic R. Leroux,
*
´ ´
b
b,
*
´
Rafael Ballesteros and Belen Abarca
aLaboratoire de Ste´re´ochimie, Universite´ Louis Pasteur (ECPM), CNRS, 25 rue Becquerel, F-67087 Strasbourg Cedex 2, France
b
` ` `
´
Departament de Quı´mica Organica, Facultat de Farmacia, Universitat de Valencia, Av. Vicente Andres, s/n, 46100 Burjassot,
`
Valencia, Spain
Received 1 July 2007; accepted 25 July 2007
Available online 28 July 2007
Abstract—The present Letter describes the efficient synthesis of novel heteroaromatic sulfoxides by means of a palladium catalyzed
heteroarylation of sulfenate anions. Triazolopyridine, pyridine and thiophene sulfoxides can be obtained under mild conditions and
in high yield from the corresponding heteroaryl bromides.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Aryl sulfoxides are highly important compounds for
medicinal and pharmaceutical chemistry.1 Chiral sul-
fur-containing species have a great importance and high
potential as chiral ligands for asymmetric catalysis,
and they also have a promising future for the develop-
ment of a number of new symmetric heterogeneous or
homogeneous reactions.2 Their preparation relies gener-
ally on the stereospecific substitution of optically active
sulfinates with Grignard reagents (the Andersen
method).3
S
O
O
N
i
N
N
N
N
N
N
N
N
N
20%
S
Li
i = BuLi, toluene, -40 °C, 15 min
O
1
In the framework of our studies dealing with the synthe-
sis of triazolopyridine systems as molecular chemosen-
sors for metal ions, anions, and amino acids as well as
fluorescence captors,4 and as precursors of 2,6-disubsti-
tuted pyridines,5 we were interested in the preparation of
sulfoxide bearing [1,2,3]triazolo[1,5-a]pyridines 1. Re-
cently, we showed that this compound is obtained in
low yield after metalation of the corresponding triazolo-
pyridine with butyllithium at ꢀ40 ꢁC in toluene followed
by trapping with (R)-(ꢀ)-menthyl p-toluenesulfinate
(Scheme 1).6
N
N
N
N
N
N
N
N
Li
2
N
N
S
N
O
56%
Scheme 1.
remaining lithiated triazolopyridine. Neither the mode
of addition (normal or inverse addition), nor the
modification of solvent and temperature improved the
situation considerably. Similarly, electron-deficient
heteroaromatics like pyridines cannot afford the
2-(p-toluenesulfoxide)-substituted analogs by the classi-
cal Andersen method. For example, 2-bromopyridine
gives after bromine/lithium exchange followed by trap-
ping with (S)-(ꢀ)-menthyl p-toluenesulfinate essentially
the dimerization product as shown by Oae and
Fukurawa.7
The major problem is the formation of various side
products, mainly the dimerization of the triazolopyri-
dine unit affording the coupling product 2. Its formation
can be explained by means of a nucleophilic substitution
of the introduced p-toluenesulfoxide substituent by
*
Corresponding authors. Tel.: +33 3 90 24 27 44; fax: +33 3 90 24 27
42 (F.C.); e-mail: fcolober@chimie.u-strasbg.fr
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.165

F. Colobert et al. / Tetrahedron Letters 48 (2007) 6896–6899
6897
Recently, Poli et al. reported on the palladium catalyzed
O
S
Pd2(dba)3
Xantphos
O
synthesis of arylic sulfoxides. These authors could show
that in situ generated sulfenate anions8 from b-sulfinyl
esters can provide under biphasic conditions several aryl
sulfoxides. The sulfoxides were obtained in good yields
from the corresponding aryl iodides. However, the use
of arylbromides was unsuccessful.9
O
Het
S
Het-X +
pTol
Toluene / H2O
reflux
20-80% aq. KOH
O
Scheme 2.
pyridine (entry 2)13 gave compound 314 in 95% yield and
again without traces of the corresponding dimer.
Encouraged by these results, we decided to apply this
new methodology for the preparation of [1,2,3]triaz-
olo[1,5-a]pyridine sulfoxides starting from the corre-
sponding halides. The C–S coupling reaction was
performed under biphasic conditions in a toluene/water
mixture at 85 ꢁC (Scheme 2).10
In order to determine the scope and limitations of this
methodology we applied it to various heteroaromatic
compounds (triazolopyridines, pyridines, thiophenes
and pyrimidines). Due to their lower cost and commer-
cial availability we decided to use heteroaryl bromides as
substrates. The corresponding sulfoxides were obtained
in good yields as depicted in Table 1. 2-Bromopyridine,
The brominated triazolopyridine11 afforded compound
1 in an yield of 82% without any trace of dimerization
(entry 1).12 3-(60-Iodopyridin-20-yl)-[1,2,3]triazolo[1,5-a]-
Table 1. C–S coupling of various heteroaryl bromides via Scheme 2a
Entry
Heteroaryl halide
Product
Yieldb (%)
1
1
82
N
N
N
N
Br
I
S
N
O
N
2
3
4
5
6
7
8
3
4
5
6
7
8
9
95
63
82
75
69
50
41
N
S
N
N
N
N
N
O
N
N
N
S
N
Br
Br
O
N
N
N
N
S
O
S
Br
Br
O
S
S
S
O
S
S
S
Br
Br
O
N
N
N
S
N
O
N
N
9
10
11
31
52
N
N
S
Br
N
O
10
Br
N
S
O
O
O
a Reagents and conditions: aryl halide (1.0 equiv), b-sulfinylester (1.3 equiv), Pd2dba3 (5 mol %), xantphos (10 mol %), KOH (50% aqueous solution)
in 1:1 toluene/H2O at 85 ꢁC.
b Yields are given for isolated products.

6898
F. Colobert et al. / Tetrahedron Letters 48 (2007) 6896–6899
Table 2. C–S coupling of heteroaryl dibromides via Scheme 2a
Entry
1
Heteroaryl halide
Product
Yieldb (%)
74
pTol
pTol
pTol
pTol
12
S
N
S
Br
Br
N
Br
O
O
O
S
2
3
13
13
84
30
pTol
N
N
Br
Cl
N
N
S
O
O
S
Br
pTol
S
O
a Reagents and conditions: aryl halide (1.0 equiv), b-sulfinylester (1.3 equiv), Pd2dba3 (5 mol %), xantphos (10 mol %), KOH (50% aqueous solution)
in 1:1 toluene/H2O at 85 ꢁC.
b Yields are given for isolated products.
1
for example, afforded 63% of sulfoxide 4 (entry 3)
contaminated with 35% of 2,20-bipyridyl. In contrast
to the triazolopyridine substrates, the dimerization
could not be completely avoided on 2-bromopyridine.
We realized, that the dimerization occurred on the
2-bromopyridine and not on the final sulfoxide 4, as
with the Andersen method. Actually, when 2-bromo-
pyridine was submitted to the coupling reaction without
sulfoxide-source, 2,20-bipyridine was obtained in an
yield of 33%. In contrary, 3- and 4-bromopyridines
afforded the corresponding sulfoxides 5 and 6 in a
yield of 82% and 75%, respectively (entries 4 and 5).
Sulfoxide substituted thiophenes were obtained, using
2- or 3-bromothiophene, in an yield of 69% and 50%,
respectively (entries 6 and 7). 2-Bromopyrimidine as well
as 5-bromopyrimidine underwent the coupling reaction
more reluctantly affording the sulfoxide in 41% and
31% yields (entries 8 and 9). When 2-acetyl-6-bromo-
pyridine was used as starting material, sulfoxide 11
was obtained in an yield of 52%.15 This compound
reflects the utility of the C–S coupling method, as it
cannot be obtained by the classical Andersen method
involving a halogen/metal exchange.
a ratio dl/meso of 66:33 (measured by H NMR) for
12 and a diastereomeric ratio of 55:44 for 13. Thus,
we can deduce that there is no chiral induction due to
the first introduced sulfoxide group.
In order to check the selectivity of bromine versus chlo-
rine, we replaced 2,5-dibromopyridine by 2-chloro-5-
bromopyridine. Bis-sulfoxide 13 was obtained in an
yield of 30%. However, 3-chloropyridine revealed to
be unreactive towards the C–S coupling when we
screened different reaction conditions and ligands. In
fact, the first introduction of the sulfoxide group on
2-chloro-5-bromopyridine occurs on the position of
the bromine atom, which renders the pyridine ring more
electron-deficient, facilitating the second introduction of
a sulfoxide, now on the position of the chlorine atom
(Table 2, entry 3).
In conclusion, we could show that hetaryl bromides and
b-sulfinyl esters undergo very efficiently the palladium
catalyzed C–S coupling under biphasic conditions
affording the pharmaceutically important class of
heteroaromatic sulfoxides and bis-sulfoxides. Applying
this methodology, hetaryl sulfoxides become accessible,
which cannot be obtained by means of the classical
Andersen method. We could extend this approach on
electron-deficient hetaryl chlorides.
Due to our interest in chiral fluorescence captors we next
decided to develop new target molecules bearing two
sulfoxide groups. When 2,6-dibromopyridine was sub-
mitted to the C–S coupling using 1.3 equiv of sulfoxide-
source, only the corresponding bis-sulfoxides 12 was
obtained in an yield of 74% (Table 2, entry 1).16
Acknowledgements
We are grateful to the CNRS and Ministerio de Edu-
No traces of mono-sulfoxide were detected. The yield
decreased to 48% when 2 equiv of b-sulfinylester was
used. Thus, the best coupling conditions for mono-
and bis-sulfoxides are those described in Scheme 2.
Analogously, 2,5-dibromopyridine afforded bis-sulfox-
ide 13 (entry 2) in an yield of 84%.17 The sulfoxides were
obtained as mixtures of the possible enantiomeric diaste-
reomers (dl and meso). In their Letter, Poli et al.9
reported on the C–S coupling of 1,2-diiodobenzene.
The authors obtained the bis-sulfoxide in a 45% yield
and a ratio dl/meso of 90:10. In our case we obtained
´
cacion y Ciencia (Spain) for its financial support (project
CTQ2006-15672-C05-03). R.B.G. is much grateful to
`
the Ministere de la Recherche for an MRT grant.
References and notes
1. For reviews, see: (a) Legros, J.; Dehli, J. R.; Bolm, C. Adv.
Synth. Catal. 2005, 347, 19; (b) Bentley, R. Chem. Soc.
´
Rev. 2005, 34, 609; (c) Fernandez, I.; Khiar, N. Chem. Rev.
2003, 103, 3651.

F. Colobert et al. / Tetrahedron Letters 48 (2007) 6896–6899
6899
2. (a) Pellissier, H. Tetrahedron 2007, 63, 1297; (b) Hanquet,
21.47 (CH3) 10.35 (CH3). MS (E.I): m/z (%) = 273 (3), 271
(40), 243 (63), 226 (35), 195 (30), 139 (100), 120 (36), 104
(60), 91 (42), 77 (67). HRMS for C14H13N3OS: calcd,
271.0779; found, 271.0778.
´
G.; Colobert, C.; Lanners, S.; Solladie, G. Arkivoc 2003,
vii, 328.
3. (a) Andersen, K. K. Tetrahedron Lett. 1962, 3, 93; (b)
Andersen, K. K.; Gaffield, W.; Papanikolau, N. P.; Foley,
J. W.; Perkins, R. I. J. Am. Chem. Soc. 1964, 86, 5637.
4. Chadlaoui, M.; Abarca, B.; Ballesteros, R.; de Arellano,
13. Abarca, B.; Alkorta, I.; Ballesteros, R.; Blanco, F.;
Chadlaoui, M.; Elguero, J.; Mojarrad, F. Org. Biomol.
Chem. 2005, 3, 3905.
C. R.; Aguilar, J.; Aucejo, R.; Garcia-Espana, E. J. Org.
Chem. 2006, 71, 9030.
5. Jones, G.; Mouat, D. J.; Tonkinson, D. J. Chem. Soc.,
Perkin Trans. 1 1985, 2719.
6. Ballesteros-Garrido, R.; Abarca, B.; Ballesteros, R.;
Leroux, F. R.; Colobert, F., in preparation.
7. (a) Oae, S. Tetrahedron Lett. 1984, 25, 2549; (b) Furuk-
awa, N.; Ogawa, S.; Matsumura, K.; Furihara, Y. H. J.
Org. Chem. 1991, 56, 6341; (c) Vinishi, J.; Tanaka, T.;
Wakabayashi, S.; Oae, S. Tetrahedron Lett. 1990, 31, 4625.
14. 3-[60-(Toluene-4-sulfinyl)-pyridin-20-yl]-[1,2,3]triazolo [1,
5-a]pyridine (1b): mp 167–170 ꢁC. 1H NMR (CDCl3,
300 MHz): d = 8.69 (d, J = 7.0 Hz, 1H), 8.37 (d,
J = 8.9 Hz, 1H), 8.27 (dd, J = 7.2, 1.8 Hz, 1H), 7.91 (dd,
J = 7.1, 7.8 Hz, 1H) 7.88 (dd, J = 7.8, 1.8 Hz, 1H), 7.65 (d,
J = 8.1 Hz, 2H) 7.33 (dd, J = 7.0, 8.9 Hz, 1H), 7.2 (d,
J = 8.1 Hz, 2H), 7.0 (dd, J = 7.0, 6.9 Hz, 1H), 2.30 (s, 3H).
13C NMR (CDCl3, 75.5 MHz): d = 165.00 (C), 152.40 (C),
141.90 (C), 141.26 (C), 138.67 (CH), 136.16 (C), 132.19
(C), 129.93 (CH), 126.96 (CH), 125.42 (CH), 125.35 (CH),
121.19 (CH), 120.84 (CH), 116.74 (CH), 116.05 (CH),
21.82 (CH3). MS (E.I): m/z (%) = 336 (3), 334 (40), 306
(75), 258 (65), 215 (10), 199 (5), 183 (86), 167 (100), 139
(80), 113 (20), 91 (44), 78 (47). HRMS for C18H14N4OS:
calcd, 334.0888; found: 334.0904.
15. 1-(6-(p-Tolylsulfinyl)pyridin-2-yl)ethanone (10): mp 140–
144 ꢁC. 1H NMR (CDCl3, 300 MHz): d = 8.12 (dd,
J = 6.3, 2.7 Hz, 1H), 7.90 (m, 2H), 7.60 (d, J = 8.1 Hz,
2H), 7.17 (d, J = 8.1 Hz, 2H), 2.55 (s, 3H), 2.26 (s, 3H).
13C NMR (CDCl3, 75.5 MHz): d = 198.5, 165.8, 153.1,
141.8, 140.5, 138.9, 129.8, 124.6, 122.1, 121.5, 25.5, 21.3.
HRMS for C14H13NO2S: calcd, 259.0667; found:
259.0669.
˜
`
8. Caupene, C.; Boudou, C.; Perrio, S.; Metzner, P. J. Org.
Chem. 2005, 70, 2812.
9. Maitro, G.; Vogel, S.; Prestat, G.; Madec, D.; Poli, G.
Org. Lett. 2006, 8, 5951.
10. General procedure for palladium-catalyzed arylation of
sulfenate anions under biphasic conditions: To a solution
of Pd2(dba)3 (5 mol %) in toluene (0.500 mL) was added
xantphos (10 mol %). The solution was stirred at room
temperature for 5 min. Then, a solution of hetaryl
bromide (0.5 mmol in 1.5 mL of toluene), b-sulfinylester
(0.7 mmol in 1.5 mL of toluene), distilled water (3.5 mL)
and 50% aq KOH solution (10 mmol) were successively
added. The resulting biphasic system was stirred and
heated to reflux. The reaction was monitored by TLC.
Upon completion of the reaction (2–4 h) and cooling to
room temperature, the aqueous phase was extracted with
dichloromethane (3 · 50 mL). The combined organic lay-
ers were dried over anhydrous MgSO4 and the solvent was
removed under reduced pressure. The crude product was
purified by flash chromatography.
16. 2,6-Bis(p-tolylsulfinyl)pyridine (11): oil. 1H NMR (CDCl3,
300 MHz): d = 8.03 (m, 3H), 7.63/7.43 (d, J = 8.1 Hz,
2H), 7.28/7.10 (d, J = 8.0 Hz, 2H), 2.39/2.36 (s, 6H). 13C
NMR (CDCl3, 75.5 MHz): d = 166.8 (C), 141.9/141.4 (C),
140.4/140.2 (C), 140.0 (CH), 130.0/129.7 (CH), 124.8/
124.7 (CH), 119.3/118.9 (CH), 21.4/21.3 (CH3). HRMS
for C19H17NO2S2: calcd, 355.0701; found, 355.0700.
17. 2,5-Bis(p-tolylsulfinyl)pyridine (12): mp 89–92 ꢁC. 1H
NMR (CDCl3, 300 MHz): d = 8.68/8.66 (m, 1H), 8.12
(m, 2H), 7.63/7.52 (d, J = 8.1 Hz, 2H), 7.29/7.23 (d,
J = 8.1 Hz, 2H), 2.38/2.37 (s, 3H). 13C NMR (CDCl3,
75.5 MHz): d = 168.8/168.7 (C), 146.3, (CH) 144.0/143.8
(C), 142.8/142.7 (C), 142.1/142.0 (C), 140.8/149.7 (C),
140.2/140.1 (C), 134.5/134.4 (CH), 130.5/130.0 (CH),
125.5 (CH), 125.0/124.9 (CH), 119.0/118.9 (CH), 21.5
(CH3), 21.4 (CH3). HRMS for C19H17NO2S2: calcd,
355.0701; found, 355.0703.
11. Abarca, B.; Ballesteros, R.; Jones, G.; Fatemeh, M.
Tetrahedron Lett. 1986, 27, 3543.
12. 3-Methyl-7-(toluene-4-sulfinyl)-[1,2,3]triazolo[1,5-a]pyri-
1
dine (1a): mp 145–147 ꢁC. H NMR (CDCl3, 300 MHz):
d = 7.89 (d, J = 8.2 Hz, 2H), 7.71 (dd, J = 6.9, 1.0 Hz,
1H), 7.65 (dd, J = 8.9, 1.0 Hz, 1H), 7.38 (dd, J = 8.9,
6.9 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 2.58 (s, 3H), 2.30 (s,
3H). 13C NMR (CDCl3, 75.5 MHz): d = 143.04 (C),
141.29 (C), 137.84 (C), 135.19 (C), 132.08 (CH), 129.92
(C), 126.28 (CH), 123.88 (CH), 118.88 (CH), 111.68 (CH),