Palladium-catalyzed heteroaryl thioethers synthesis overcoming palladium dithiolate resting states inertness: Practical road to sulfones and NH-sulfoximines

Article abstract of DOI:10.1016/j.catcom.2018.03.025

We provide efficient synthetic access to heteroaryl sulfones in two-steps using a simple palladium–1,1′-bis[(diphenyl)phosphanyl]ferrocene catalyst to form in high yields variously functionalized heteroaromatic thioethers. Pyridinyl-containing substrates can be subsequently selectively oxidized into sulfones and NH-sulfoximines by using very mild oxidation conditions with a high functional group tolerance. In the palladium-catalyzed C–S coupling of heteroaromatic thiols, reactivity limitation is attached with electron-deficient thiols. We show that this limitation can be resolved by the successful use of 2-bromoheteroarenes in the C–S coupling. We established herein that this choice of heteroaryl electrophilic reagent in palladium-catalyzed C–S bond formation allows overcoming palladium dithiolate out-of-cycle resting state inertness. This was illustrated in the stoichiometric reactivity study of the palladium dithiolate formed from 4-trifluoromethylbenzen-1-thiol –isolated and characterized by multinuclear NMR and XRD– with both 2-chloropyridine and 2-bromopyridine.

Full text of DOI:10.1016/j.catcom.2018.03.025

Accepted Manuscript
Palladium-catalyzed heteroaryl thioethers synthesis overcoming
palladium dithiolate resting states inertness: Practical road to
sulfones and NH-sulfoximines
Johan Guilbaud, Marine Labonde, Awatef Selmi, Majed
Kammoun, Hélène Cattey, Nadine Pirio, Julien Roger, Jean-
Cyrille Hierso
PII:
DOI:
Reference:
S1566-7367(18)30117-1
doi:10.1016/j.catcom.2018.03.025
CATCOM 5366
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
8 February 2018
19 March 2018
21 March 2018
Please cite this article as: Johan Guilbaud, Marine Labonde, Awatef Selmi, Majed
Kammoun, Hélène Cattey, Nadine Pirio, Julien Roger, Jean-Cyrille Hierso , Palladium-
catalyzed heteroaryl thioethers synthesis overcoming palladium dithiolate resting states
inertness: Practical road to sulfones and NH-sulfoximines. The address for the
corresponding author was captured as affiliation for all authors. Please check if
appropriate. Catcom(2018), doi:10.1016/j.catcom.2018.03.025
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ACCEPTED MANUSCRIPT
Palladium-catalyzed heteroaryl thioethers synthesis overcoming
palladium dithiolate resting states inertness: practical road to sulfones
and NH-sulfoximines
Johan Guilbauda, Marine Labondea, Awatef Selmia,b, Majed Kammounb, Hélène
Catteya, Nadine Pirioa, Julien Roger*a, Jean-Cyrille Hierso*a,c
a
Institut de Chimie Moléculaire de l’Université de Bourgogne, ICMUB-UMR CNRS 6302,
Université de Bourgogne Franche-Comté (UBFC), 9 Avenue Alain Savary, 21078 Dijon
Cedex, France.
b Unité de Recherche de Chimie Médicinale et Environnementale, (UR-17-ES-40), Université
de Sfax, Institut Supérieur de Biotechnologie, route Soukra Km 4 BP1175-3038, Sfax,
Tunisie
c
Institut Universitaire de France (IUF), 103 Boulevard Saint Michel, 75005 Paris Cedex,
France.
Corresponding authors:
julien.roger@u-bourgogne.fr
jean-cyrille.hierso@u-bourgogne.fr
Tel: (+33)3 80396107 – Fax: (+33)3 80393682
Date: 15/03/2018

ACCEPTED MANUSCRIPT
ABSTRACT
We provide efficient synthetic access to heteroaryl sulfones in two-steps using a simple
palladium–1,1'-bis[(diphenyl)phosphanyl)]ferrocene catalyst to form in high yields highly
functionalized heteroaromatic thioethers. Pyridinyl-containing substrates can be subsequently
selectively oxidized into sulfones and NH-sulfoximines by using very mild oxidation
conditions with a high functional tolerance. In the palladium-catalyzed C–S coupling of
heteroaromatic thiols reactivity limitation is attached with electron-deficient thiols. We show
that this limitation can be resolved by the successful use of 2-bromoheteroarenes in the C–S
coupling. We established herein that this choice of electrophilic reagent in palladium-
catalyzed C–S bond formation allows overcoming palladium dithiolate out-of-cycle resting
state inertness. This was illustrated in the stoichiometric reactivity study of the palladium
dithiolate formed from 4-trifluoromethylbenzen-1-thiol –isolated and characterized by
multinuclear NMR and XRD– with both 2-chloropyridine and 2-bromopyridine.
KEYWORDS: Thiolates; palladium; C–S coupling; resting state; sulfones; NH-
sulfoximines

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1. Introduction
Organosulfur derivatives have become attractive as bioactive compounds and in molecular
materials. Among them (2-pyridyl)sulfonyl derivatives are known as commercial or patented
drugs for animal and human health.[1] Recently, (pyridyl)sulfonyl groups have also been
demonstrated to be valuable directing groups for C–H activation,[2] in which they exert
complete and efficient C2 regiocontrol over the Pd(II)-catalyzed C–H alkenylation of
heteroarenes such as indoles and pyrroles.[3] C–H functionalization with acetate using (2-
pyridyl)sulfonyl directing group has also been reported.[4] Our group disclosed efficient C–X
bond formation (X = I, B, Cl, F) using (2-pyridyl)sulfonyl for C–H activation.[5] Despite the
valuable properties and topical applications of sulfonylated N-heteroaromatics their
preparation (Scheme 1) is limited to very few methods, which present shortcomings in terms
of reagents accessibility and waste disposal. A first approach is the coupling of arylsulfinic
acid salts with halopyridines and pseudohalides, either using palladium[6] or copper transition
metal (TM) assistance,[7] or metal-free conditions.[8] Alternatives exist using for examples
pyridyl boronic acids in presence of copper complexes.[9] Recently, diaryliodonium
derivatives have been used to react with sulfonate salt in metal-free condition.[10]
Scheme 1. N-heteroaromatic sulfones synthetic routes (TM = transition metal).
Synthetic access to highly functionalized sulfonate and diaryliodonium salts can be
delicate and they are not necessarily widely available commercially. Toxic polar solvents such
as DMSO, DMAc or DMF are also recurrently reported as media to achieve sulfones

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syntheses. On the other hand, facile access to a variety of functionalized thiols and progress in
palladium catalytic C–S bond formation has open the way to the formation of heteroaromatic
thioethers otherwise challenging to produce (Scheme 2).[11-13a,b] Synthetic progress was also
achieved for copper-based catalyst systems,13c-e and other less commonly used metals.13f-j
However, the latter systems remain generally less efficient in terms of substrate scope.
Scheme 2. N-heteroaromatic sulfones synthetic route from thiols and palladium catalytic
cycle of the C–S coupling.
Such thioethers are afterwards susceptible to undergo mild oxidation for efficiently providing
heteroaromatic sulfones, and other valuable derivatives as the frequently desired free-NH
derivative NH-sulfoximines.[14-17] We devised practical conditions for C–S coupling of
heteroaromatic thiols with a large variety of chloroheteroarenes. This by using the ubiquitous

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1,1'-bis[(diphenyl)phosphanyl)]ferrocene ligand (dppf), which combined with palladium,
produced heteroaromatic thioethers that can be selectively oxidized to sulfones by using meta-
chloroperoxybenzoic acid (mCPBA) at 0 °C. The resulting protocol gives access to heteroaryl
sulfones with an excellent functional group tolerance. From these thioethers the formation of
unprotected NH-sulfoximines was also achieved. In the course of these studies we observed
recurrent limitations in the coupling of electron-deficient thiols with 2-chloropyridine. This
limitation can be successfully overcome by using 2-bromopyridine in the coupling. Indeed,
we demonstrated herein that a palladium dithiolate resting state isolated from electron-
deficient thiol p-CF3C6H4SH is unreactive in the presence of 2-chloropyridine, while a
quantitative reaction of the dithiolate is obtained with 2-bromopyridine. We therefore showed
here that in the palladium-catalyzed C–S bond formation from thiols and halo(hetereo)arenes
the choice of an electrophile partner is a pertinent mean for overcoming dithiolate resting state
inertness.
2. Results and Discussion
2.1.Palladium-catalyzed heteroaromatic thioether formation
In order to provide a largely practicable access to heteroaromatic sulfones (without
sophisticated ligand/metal system) we investigated the use of palladium catalyst with the
ubiquitous commercially available ligand 1,1'-bis[(diphenyl)phosphanyl)]ferrocene (dppf) for
heteroaromatic thioether formation. The optimization of the protocol (see Supporting
Information) showed that combining 1.0 to 2.0 mol% of palladium with two equiv of dppf, in
the presence of tBuONa in toluene at 120 °C is convenient for the formation of a large scope
of pyridinyl-thioether in good yields from largely accessible thiols and chloroarenes (Fig. 1).
The use of less toxic toluene, compared to DMF,13b is an advantage here since moreover
cleaner reactions are obtained. In our case, in transition metal-free conditions (palladium or
nickel) we unsurprisingly observed quantitative formation of disulfide R–S–S–R. Thiophenol

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and 4-methylthiophenol gave thioether compounds 1 and 2 with very good 83% yield of
isolated product, respectively. From 4-tertbutylthiophenol and 4-methoxythiophenol, the
corresponding thioethers 3 and 4 were obtained in 90% and 85% excellent yield of isolated
product.
Fig. 1. Palladium-catalyzed thioether formation from functionalized thiols and 2-
chloroheteroaromatics. Conditions: thiophenol derivative (1 equiv), 2-chloroarene (1 equiv),
[PdCl(ɲ3-C3H5)]2 / 4 dppf [1.0 mol% Pd], tBuONa (1.2 equiv), dry toluene (0.25 M), 120 °C,

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17 h. a ½ [PdCl(ɲ3-C3H5)]2 / 2 dppf [2.0 mol% Pd/4.0 mol% L]. GC/NMR yields are given
together with yields of isolated product in brackets.
4-Trifluoromethylthiophenol did not react with 2-chloropyridine and thioether 5 was not
obtained. Electron-withdrawing functions such as halides are tolerated in the para-position of
thiols and gave fluoro- and chloro-thioethers 6 and 7 in 82% and 87% yield of isolated
products, respectively. 4-Nitrothiophenol was reacted with 2-chloropyridine and was found
mostly unreactive. With methyl substituent in meta-position of thiophenol, thioether 9 was
obtained in a very good 86% yield from 2-chloropyridine. Conversely, compound 10 formed
with a moderate yield under the same conditions (46%). The polyaromatic naphthalene-2-
thiol formed thioether 11 in 80% yield of isolated product using 2.0 mol% of catalyst. 3-
Chlorothiophenol led to 12 in 73% yield in the presence of 1.0 mol% of palladium.
Pleasingly, functional groups in ortho-position of thiophenol ring are also tolerated. 2-
Methylthiophenol reacted with 2-chloropyridine to give 95% yield of isolated product 13.
ortho-Methoxy substituent gave 56% yield of congested thioether 14. The 2-halogenated
thioether 15 was obtained in 73% yield of isolated product. By using 2-chloropyridine as
coupling partner, 2-trifluoromethylthiophenol did not react, while methyl 2-mercaptobenzoate
gave only 18%. We extended the coupling procedure to various other N-heteroaryl halides
which efficiently coupled to thiophenol. The presence of 6-cyano and 4-methyl groups on 2-
chloropyridine partner is tolerated and coupling is achieved with very good to high yields to
the resulting thioethers 18 (78%) and 19 (87%). The 3-(thiophenyl)pyridine 20 formed in high
yield but was found difficult to purify and the yield of isolated product 20 was limited to 65%.
Coupling of the electron-poor 2-chloropyrimidine gave 28% of thioether 21. 2-
Chloropyrazine coupling to thiophenol formed thioether 22 in very good 86% yield. 3-Chloro-
6-methoxypyridazine successfully coupled to thiophenol giving 68% yield of isolated
thioether 23. By using p-dichloropyridazine with a large excess of thiophenol a mixture a

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mono- and di-functionalized pyridazine formed that was found to be very difficult to purify at
this stage. We directly oxidized it to the corresponding sulfones for easier separation. We
experienced troubles to achieve satisfactory yields of thioethers 5, 8, 16 and 17 from the
coupling of electron-deficient thiols with 2-chloropyridine. In the related coupling of aryl
chlorides
with
thiols
(non-heteroaromatic)
by
using
kinetic
chelating
[2-
(dicyclohexylphosphano)ferrocenyl]ethyl-di-tert-butylphosphane
measurements
concluded that thiolate resting states with strong Pd–S bonds determine the readiness of the
active catalyst system to re-enter the catalytic cycle (Scheme 2).[12e] In order to clarify the lack
of reactivity in our system we isolated the dithiolate complex {dppf-Pd[S(4-CF3C6H4)]2}. The
reaction was achieved using [dppf-PdCl2] in THF, in the presence of excess NEt3 and 4-
methylbenzene-1-thiol. The reaction proceeds in few minutes at room temperature, which
evidences the facile formation of thiolate resting states already documented by DFT.[11] 31
P
NMR confirmed that the reaction is quantitative, giving the expected dithiolates characterized
31
19
by singlets at 26.4 ppm in P NMR, and –62.0 ppm in F NMR (vs –62.9 ppm for the
starting thiol). From single crystals grown in dichloromethane we achieved the XRD analysis
of {dppf-Pd[S(4-CF3C6H4)]2} (ORTEP in Fig. 2).

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Fig. 2. Molecular structure of {dppf-Pd[S(4-CF3C6H4)]2}(left, hydrogen atoms and three
dichloromethane solvent molecules were omitted for clarity) and 31P and 19F NMR (right).
We monitored by 31P NMR and 19F the reactivity of {dppf-Pd[S(4-CF3C6H4)]2 with
haloarenes (Fig. 3). The complex was found fully unreactive in the presence of 2-
chloropyridine in toluene at 120 °C for 20 h (Fig. 3, d). Conversely, under these conditions
the dithiolate dppf-Pd[S(4-CF3C6H4)]2 was found to be partly reacting with 2-bromopyridine,
and accordingly we experienced forcing conditions to achieve full conversion (Fig.3, e). The
reactivity (or inertness) of the thiolate-containing resting state {dppf-Pd[S(4-CF3C6H4)]2 was
19
also confirmed by F NMR. Thus, by using 2-bromopyridine at high temperature in long
reaction time, the resting state dithiolate was totally consumed to give the complex [dppf-
PdBr2] (31P NMR, δ= 31 ppm) together with the expected thioether.
Fig. 3. 31P NMR spectrum of (a) dppf, (b) [dppf-PdCl2], (c) {dppf-Pd[S(4-CF3C6H4)]2}
resting state and the monitoring of stoichiometric reaction of {dppf-Pd[S(4-CF3C6H4)]2} with
(d) 2-chloropyridine and (e) 2-bromopyridine.

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Based on these results we successfully achieved the synthesis of thioethers 5, 8, 16 and 17 by
using 2-bromopyridine (Fig. 4) which met in general excellent success, except for 8 in which
disulfide formation was dominant. We employed iodide for the formation of 8. Indeed, in the
catalytic cycle (Scheme 2) we assume that the oxidative addition of haloarenes to Pd0 is
kinetically competent to avoid dithiolate formation, and we showed that even in the case of
dithiolate formation the presence of 2-bromopyridine overcome the inertness of this out-of-
cycle resting state. These observations point to the same direction than those initially reported
for palladium-catalyzed C–S coupling with arenes.[12e]
Fig.
4
Palladium-catalyzed thioether formation from thiophenols and 2-
bromoheteroaromatics. Conditions: thiophenol (1 equiv), heteroaryl bromide (1 equiv),
½[PdCl(ɲ3-C3H5)]2 / 2 dppf [1.0 mol% Pd/2.0 mol% L], tBuONa (1.2 equiv), dry toluene (0.3
M), 120 °C, 17 h. a heteroaryl iodide instead of bromide.
2.2. Heteroaromatic sulfones and NH-sulfoximines formation
We optimized efficient conditions for the oxidation of this set of thioethers towards
heteroaromatic sulfones (see optimization details in SI). The addition of mCPBA at 0 °C to
the thioether 1 in a dichloromethane solution led to pure sulfone 25 with an excellent 86%
yield (Table 1). This oxidation reaction was found general and we applied it to the full set of
thioethers, eventually at gram scale. Thioethers bearing electron-donating groups in para-
position of the arene such as tertio-butyl, methyl and methoxy allowed the formation of the

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corresponding sulfones 26, 27 and 28 with excellent yields (Table 1, 87%, 92% and 87%,
respectively). The presence of electron-withdrawing functions on the thioether, such as
trifluoromethyl, fluoride, chloride and nitro, gave lower yield of sulfones 29, 30, 31 and 32
with 57%, 79%, 76% and 78%, respectively.
Thioethers bearing electron-donating and electron-withdrawing functions in meta-position
equally tolerate oxidation. These formed chlorinated 36 in 78% yield, methylated 33 in 68%
yield, and methoxylated 34 in 66% yield. Bulkiest aryl thioethers were also successfully
converted to the corresponding sulfones with moderate to high yield (35, 37-41, 46-95%).
This procedure is not limited to 2-pyridine thioethers and was extended to more challenging
heteroarenes (Table 1, 42-47). Thus, comparatively electron-poor heteroarenes furnished in
general a moderate yield of isolated product (ca. 55%). Nevertheless, the sulfone 42 was
obtained in a higher 73% yield. Finally, we were glad to achieve oxidation of original dimeric
1,6-diphenylpyridazine thioether with the high yield of 81% (48).

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Table 1. Heteroaromatic thioethers oxidation to sulfones.a
Entry Reagent
R1
R2 or HetAr
Product Yield of
isolated
product
1
H
H
86%
87%
92%
87%
57%
79%
76%
78%
68%
66%
95%
78%
61%
80%
73%
46%
72%
73%
56%
57%
55%
58%
68%
1
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
2
4-tBu
4-Me
4-OMe
4-CF3
4-F
H
2
3
H
3
4
H
4
5
H
5
6
H
6
7
4-Cl
4-NO2
3-Me
3-OMe
2-naphthyl
3-Cl
2-Me
2-OMe
2-Cl
2-CF3
2-CO2Me
H
H
7
8
H
8
9
H
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
H
H
H
H
H
H
H
6-CN
H
4-Me
H
3-pyridine
2-pyrimidine
2-pyrazine
6-methoxy-3-
pyridazine
6-(phenylsulfonyl)-
3pyridazine
H
H
H
24
H
81%
24
48
a thioether (1 equiv), mCPBA (2.5 equiv at 0.1 M in CH2Cl2), CH2Cl2 (1.5 M), 0 °C to RT, 20
h. Yield of isolated product.
We also successfully applied the recently reported conditions from Luisi group[16] to access
NH-sulfoximine in one step from our heteroaromatic thioethers. These conditions nicely apply

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to 2-pyridine thioethers giving satisfactory yield of isolated products (see SI compounds 49,
74% and 50, 65%).
3. Conclusions
We reported a convenient two-steps method for synthesizing heteroaromatic sulfones and NH-
sulfoximines using broadly available thiols and haloheteroarenes in palladium-catalyzed
heteroaromatic thioether formation. The synthesis of sulfonated pyridines is possible at gram
scale. The palladium catalytic system insured a large tolerance of functional groups over both
aromatic and heteroaromatic moieties of the formed thioethers and corresponding sulfones.
Electron-deficient thiols because of quickly formed highly stable palladium dithiolate resting
state do not couple with 2-chloropyridines. The use of 2-bromopyridine allows C–S coupling
with good efficiency by destabilizing these thiolates resting state more efficiently than
chloroheteroarenes.
Acknowledgments
This work was by supported by the CNRS, Université de Bourgogne, Conseil Régional de
Bourgogne (JCE PhD grant for JG) through the plan d’actions régional pour l’innovation
(PARI, program CDEA, 3MIM) and the fonds européen de développement regional (FEDER)
programs. Support from ANR-PRC 2016 program (ALCATRAS) is also acknowledged. We
are thankful for fruitful discussions with INVENTIVA Pharma.
Supplementary data
Experimental details. C–S coupling catalytic conditions screening. Optimization of thioether
1
19
13
oxidation step. Full characterization of products 1-23, 25-46 with copy of H, F and C
NMR spectra. CCDC contains the supplementary crystallographic.
The authors have no competing interests to declare

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 Practical synthetic access to heteroaryl thioethers, sulfones and sulfoximines
 X-Ray and reactivity of palladium dithiolate towards haloarenes
 Electron-deficient thiols C–S coupling