Thieme Chemistry Journals Awardees - Where Are They Now?Molybdenum(V)-Mediated Synthesis of Nonsymmetric Diaryl and Aryl Alkyl Chalcogenides

Article abstract of DOI:10.1055/s-0036-1588140

Oxidative chalcogenation reaction using molybdenum(V) reagents provides fast access to a wide range of nonsymmetric aryl sulfides and selenides. The established protocol is tolerated by a variety of labile functions, protecting groups, and aromatic heterocycles. In particular, when labile moieties are present, the use of molybdenum(V) reagents provides superior yields compared to other oxidants.

Full text of DOI:10.1055/s-0036-1588140

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
P. Franzmann et al.
Letter
Synlett
Thieme Chemistry Journals Awardees – Where Are They Now?
Molybdenum(V)-Mediated Synthesis of Nonsymmetric Diaryl and
Aryl Alkyl Chalcogenides
Peter Franzmanna
Sebastian B. Beila,b
Peter M. Winterscheidc
Dieter Schollmeyera
Siegfried R. Waldvogel*a,b
H
E
E
R
MoV
R
R'
R'
2
Y
Y
E = S, Se
Y = CH=CH, NR'', O
17 examples
a Johannes Gutenberg University Mainz, Institute of Organic Chemistry, Duesberg-
weg 10-14, 55128 Mainz, Germany
waldvogel@uni-mainz.de
b Graduate School Materials Science in Mainz, Staudingerweg 9, 55128 Mainz, Ger-
many
c Bonn University, Kekulé Institute of Organic Chemistry and Biochemistry, Ger-
hard-Domagk-Str. 1, 53121 Bonn, Germany
Received: 06.12.2016
Accepted after revision: 09.01.2017
Published online: 02.02.2017
DOI: 10.1055/s-0036-1588140; Art ID: st-2016-b0825-l
Abstract Oxidative chalcogenation reaction using molybdenum(V) re-
agents provides fast access to a wide range of nonsymmetric aryl sul-
fides and selenides. The established protocol is tolerated by a variety of
labile functions, protecting groups, and aromatic heterocycles. In par-
ticular, when labile moieties are present, the use of molybdenum(V) re-
agents provides superior yields compared to other oxidants.
Key words molybdenum pentachloride, oxidative coupling, C–S bond
formation, cross-coupling, disulfides
The formation of aryl–chalcogen bonds is a reaction of
significant importance in organic synthesis. In particular,
nonsymmetric diaryl chalcogenides are highly valuable
compounds for biological and pharmaceutical applications.1
They are part of numerous drugs for the potential treat-
ment of cancer, human immunodeficiency virus (HIV), in-
flammations, and Alzheimer’s disease (Figure 1).2 Further-
more, they serve as unique building blocks for functional
materials and as ligands in asymmetric catalysis.3
Siegfried R. Waldvogel was born in Konstanz, Germany, in 1969. He
obtained his diploma in chemistry from the University of Konstanz un-
der the supervision of Prof. W. Pfleiderer in 1994. He completed his
doctoral research with Prof. M. T. Reetz at the Max Planck Institute for
Coal Research in Mülheim in 1996. After a postdoctoral stay at the Scipps
Research Institute, La Jolla, California with Prof. J. Rebek, Jr. he started
his habilitation at the Westfälische Wilhelms University Münster in 1998.
In 2004, he was appointed as associate professor at the Kekulé Institute
at the University of Bonn, and in 2010 he was appointed as full profes-
sor for Organic Chemistry at the Johannes Gutenberg University Mainz.
His research interests include oxidative transformations of arenes with
molybdenum(V) reagents and electrochemical methods as well as su-
pramolecular receptor structures for the detection of drugs and explo-
sives. He received the following awards and fellowships throughout his
scientific career (selection): Fellowship of the German Scholarship foun-
dation (1990–1994), Kekulé Fellowship (1995–1996), Otto-Hahn-Med-
al of the Max-Planck-Society (1996), NATO stipend from the DAAD
(1997–1998), Liebig Fellowship (1998–2000), Thieme Chemistry Journals
Award (2000), Bennigsen-Foerder-Award of the state of North Rhine-
Westphalia (2001), Young researchers award of the Förderkreis der
Westfälischen Wilhelms Universität (2003), Inventors Award ‘Patente
Erfinder’ of the state of North Rhine-Westphalia (2008), Nicolaus-August-
Otto-Award of the city of Cologne (2008), and the Zukunftspreis Pfalz
Award (2013).
R'
N
O
S
S
HN
R
R''
2 HCl
N
H2N
N
H
1
2
antitumor agent (thymitaq)
tubulin polymerization inhibitors
BnO
S
OH
HCl
OH
3
Cl
NH2
immunomodulator (KRP-203)
Figure 1 Bioactive structures involving the diarylsulfide motif
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
P. Franzmann et al.
Letter
Synlett
The carbon–chalcogen bond is commonly accessible by
two strategies (Scheme 1): The route 1 involves a transi-
tion-metal-catalyzed cross-coupling of an aryl halogenide
and a reactive chalcogen intermediate.4,5 Secondly, the al-
ternative route 2 exploits oxidative chalcogenation of elec-
tron-rich arenes by direct C–H activation in the presence of
symmetrical dichalcogenides.5,6 Since the discovery by
Migita and co-workers, the transition-metal-catalyzed C–S
cross-coupling reactions have been further improved to ac-
cess a wide product range in excellent yields.7 Nevertheless,
the substrate scope of those transformations is limited to
precursor molecules equipped with leaving groups. In order
to overcome this disadvantage, several methods for direct
C–H sulfenylation have been recently reported.8 Those reac-
tions are either carried out employing a stoichiometric
amount of an oxidant or by transition-metal catalysis using
a co-oxidant. Although these recent developments signifi-
cantly increased the scope of accessible structures, the
number of tolerated functional groups is still highly limited
for these protocols. In particular, labile moieties like halides
or protecting groups are challenging at the harsh reaction
conditions involving high temperatures, long reaction
times, or strong oxidants.9 In contrast, a mild and versatile
protocol for oxidative chalcogenation, tolerating a broad
scope of functional groups, would be highly desirable.
OMe
OMe
MoCl5 (3 equiv)
TiCl4 (3.3 equiv)
E
R
E
R
2
CH2Cl2, 22 °C
30–60 min
MeO
OMe
MeO
OMe
4
5
6
OMe
OMe
S
S
MeO
OMe
MeO
OMe
6a
60%
6b
64%
OMe
OMe
S
S
MeO
OMe
MeO
MeO
OMe
6c
6d
51%
41%
OMe
OMe
S
S
MeO
MeO
OMe
I
OMe
F
6e
6f
55%
67%
OMe
Se
S
n-Octyl
OMe
6g
6h
45%a
26%
X
H
route 1
route 2
oxidant
MoCl3(HFIP)2: 45%
R
R
E
Scheme 2 Oxidative chalcogenation of 1,3,5-trimethoxybenzene with
different dichalcogenides. a Mesitylene was used instead of 4.
R'
Pd/Cu/Ni
catalysis
R
E
E
R'
Z
R'
E = S, Se
2
tion of 1,3,5-trimethoxybenzene (Scheme 2). The amounts
of reagents as well as the reaction times were elucidated by
GC-supported optimization. The dichalcogenides 5 were
synthesized by the oxidation of the corresponding thiols by
iodine.23 Our results reveal that the electron-withdrawing
or electron-releasing character of the substituent has no
major influence on the oxidative sulfenylation. As targeted,
we were able to obtain products including labile moieties
like iodo in 6e in good yields. Moreover, the synthetic pro-
tocol turned out to be suitable for aliphatic disulfides and
selenium derivatives (6g and 6h). Although full conversion
of the dichalcogenides was observed, we did not reach
quantitative yields due to the formation of nonidentified
byproducts (polymers, oligomers), which are easily separat-
ed during workup. The lower yields of product 6d and 6g
are attributed to the lower reactivity of the components
employed (5d and 5g), which results in prolonged reaction
times and the increased formation of byproducts. While di-
sulfide 5d can be transformed into a thianthrene species,
which has been described previously,23 the yield of 6g is di-
minished due to chlorination. Therefore, we performed this
synthesis using MoCl3(HFIP)2 as a more elaborated reagent.
The yield was almost doubled up to 45%. This demonstrates
the superior reactivity and selectivity of the second genera-
tion molybdenum(V) reagent.
Scheme 1 Reaction pathways towards nonsymmetric aryl chalco-
genides
Molybdenum pentachloride is a readily available bulk
chemical with a strong oxidative power.10 In combination
with its unique Lewis acidic characteristics this leads to
very fast substrate transformations.11 This results in a high-
ly valuable tolerance of acid-sensitive functional groups like
iodo,12 tert-butyl,13 ketals,14 or amides.15 In contrast to other
transition-metal-based oxidants, the molybdenum salts
formed during the reaction are considered as biocompati-
ble.16 The performance of MoCl5 can be further enhanced by
the addition of Lewis acids like TiCl4.17 The next generation
molybdenum(V) reagent was prepared by substitution of
two chlorido ligands by 1,1,1,3,3,3-hexafluoroisopropano-
late (HFIP), which significantly reduces the formation of
chlorinated byproducts.18 These molybdenum(V) reagents
have shown superior performance for the construction of
various five-,15,19 six-,20 seven-,21 and eight-membered22
ring systems compared to other oxidants.
Here, we report a highly versatile and valuable molyb-
denum(V)-mediated oxidative chalcogenation of highly
functionalized arenes as substrates. Initially, we studied the
influence of different dichalcogenides onto the sulfenyla-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
P. Franzmann et al.
Letter
Synlett
Secondly, the sulfenylation reaction was performed
with di(p-tolyl)disulfide (5b). A scope of ten different diar-
ylsulfides with sophisticated substitution patterns was ob-
tained in moderate to good yields (Scheme 3). The molyb-
denum(V)-mediated sulfenylation tolerates different pro-
tecting groups for phenols or amines as well as labile
moieties such as tert-butyl or iodo groups. Furthermore, we
have shown that the synthetic protocol is suitable for het-
erocyclic substrates such as indoles or benzofuranes.
not successful, which reveals that MoCl5 acts as the oxidant
in the reaction, while TiCl4 only serves as an additive to de-
crease chlorination. This is in complete accordance to previ-
ous mechanistic studies.24
Table 1 Comparison of Different Oxidants
I
I
S
S
oxidant
MeO
2
MeO
MoCl5 (3 equiv)
TiCl4 (3.3 equiv)
S
S
Br
Br
2
R
R
7f
5b
8f
CH2Cl2, 22 °C
10–30 min
7
5b
8
Entry
Reagent8,9,25
MoCl5/TiCl4
Temp (°C)
Time
Yield (%)
OMe
1
2
3
4
5
6
22
22
22
22
80
22
15 min
52
43
37
17
0
S
S
DDQ/MeSO3H
FeCl3
15 min
15 min
16 h
MeO
MeO
OMe
6b
8a
K2S2O8/TFA
I2/DMSO
TiCl4
64%
67%
3 h
p/o = 4.3/1
15 min
0
S
S
Previous studies by Yoshida and co-workers indicate
that the initial step in the oxidative sulfenylation reaction is
the formation of an (RS)3 species (Scheme 4).26 This inter-
+
8b
8c
62%
30%
mediate can be attacked by an activated arene as nucleo-
phile to form the desired product after subsequent proton
extrusion and re-aromatization. According to the oxidation
potentials of similar substrates described in the literature,
an initial oxidation of the aromatic substrate is also plausi-
ble.27 Since we only observed the formation of thianthrenes
as byproducts, but no biaryl species, it is more likely that
the reaction occurs according the mechanism described by
Yoshida and co-workers.
OMe
S
TIPSO
MeO
S
8d
8e
44%
36%
I
S
S
O
MeO
Ph
Br
8f
8g
R'
S
S
R
R
MoV
R
S
52%
30%
R
S
S
R'
R
– H+
2
MeO
– RSSR
S
S
Scheme 4 Plausible mechanistic rationale for the molybdenum(V)-me-
diated sulfenylation
N
N
Ts
Ms
8h
8i
In conclusion, we established a novel protocol for mo-
lybdenum(V)-mediated oxidative sulfenylation reactions.28–
The synthesis is reliable, easy to perform, and provides
39%
20%
Scheme 3 Oxidative aryl-sulfenylation of different aromatic substrates
31
moderate to good yields. Various labile moieties like iodo
groups or protecting groups are tolerated in the oxidative
coupling reaction. The use of molybdenum(V) as an oxidant
provides superior yields compared to other reagents in the
presence of labile functional groups. The method is highly
complementary to other reagents described. Furthermore,
we were able to obtain several molecular structures by X-
ray analysis of suitable single crystals.
In order to verify the superior performance compared to
other oxidants we studied the oxidative sulfenylation of 2-
bromo-5-iodoanisole (Table 1). Other oxidants result in an
increased formation of byproducts and therefore lower
yields. These byproducts are mostly formed by protodeha-
logenation of the labile iodo moiety. A milder oxidant like
I2/DMSO is not capable to form the desired product. The ox-
idative sulfenylation with TiCl4 as a sole reagent was also
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
P. Franzmann et al.
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Acknowledgment
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1328. (b) Prasad, C. D.; Balkrishna, S. J.; Kumar, A.; Bhakuni, B.
S.; Shrimali, K.; Biswas, S.; Kumar, S. J. Org. Chem. 2013, 78,
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Angew. Chem. Int. Ed. 2013, 52, 10084. (b) Schubert, M.;
Franzmann, P.; Wünsche von Leupoldt, A.; Koszinowski, K.;
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(c) Rempala, P.; Kroulik, J.; King, B. T. J. Org. Chem. 2006, 71,
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Zacchini, S. Polyhedron 2013, 61, 188. (e) King, B. T.; Kroulík, J.;
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L. M. J. Org. Chem. 2007, 72, 2279. (f) Bortoluzzi, M.; Feretti, E.;
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(b) Waldvogel, S. R.; Trosien, S. Chem. Commun. 2012, 48, 9109.
(c) Kramer, B.; Fröhlich, R.; Bergander, K.; Waldvogel, S. R. Syn-
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(12) (a) Waldvogel, S. R.; Aits, E.; Holst, C.; Fröhlich, R. Chem.
Commun. 2002, 1278. (b) Mirk, D.; Kataeva, O.; Fröhlich, R.;
Waldvogel, S. R. Synthesis 2003, 2410.
The authors thank the German Research Foundation DFG (WA
1276/15-1) for financial support. S.B.B. gratefully acknowledges sup-
port by a Kekulé fellowship of the Fonds der Chemischen Industrie
(FCI).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588140.
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u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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(28) General Protocol of the Disulfide Synthesis (A)
A solution of the given thiol (1.0 equiv) in pyridine was treated
with iodine (0.66 equiv) and stirred for the given time (15–30
min) at r.t. at argon atmosphere. Subsequently, water was
added, and the mixture was extracted with EtOAc. The com-
bined organic layers were washed with brine, dried over MgSO4,
and the solvent was evaporated. The crude product was puri-
fied as described below.
was filtered through a pad of silica (eluent: cyclohexane–EtOAc,
9:1) to yield compound 5e as a colorless solid (0.44 g, 88%). H
NMR (400 MHz, CD2Cl2): δ = 7.65–7.62 (m, 4 H), 7.25–7.21 (m, 4
H). 13C NMR (101 MHz, CD2Cl2): δ = 138.7, 137.2, 129.9, 93.0.
HRMS (APCI+): m/z calcd for C12H8I2S2 [M]•+: 469.8151; found:
469.8160.
1
(31) 4-Methylphenyl-5′-bromo-2′-iodo-4′-methoxyphenylsulfide
(8f)
(29) General Protocol of the Oxidative Coupling Reaction Using
Mo(V) Reagents (B)
According to the protocol for the oxidative coupling reaction
(B), bis(4-methylphenyl)disulfide (5b, 0.20 g, 0.81 mmol) was
treated with TiCl4 (0.51 g, 2.68 mmol) and MoCl5 (0.66 g, 2.44
mmol) in anhydrous CH2Cl2 (20 mL). Subsequently, 2-bromo-5-
iodoanisole (7f, 1.27 g, 4.06 mmol) in anhydrous CH2Cl2 (10 mL)
was added dropwise, and the reaction mixture was stirred for
15 min. After the described workup, the crude product was
purified by flash column chromatography (eluent: cyclohex-
ane–EtOAc, 99:1) and recrystallized from MeOH (approx. 15
mL, 65 → 4 °C) to yield compound 8f as a colorless solid (0.37 g,
A solution of the disulfide 5 (1.0 equiv) in anhydrous CH2Cl2
was treated with TiCl4 (3.3 equiv) and subsequently MoCl5 (3.0
equiv) or with MoCl3(HFIP)2 (3.0 equiv). Subsequently, a solu-
tion of the aromatic compound (5.0 equiv) in anhydrous CH2Cl2
was added dropwise,e and the mixture was stirred for the given
time (10–60 min) at r.t. at argon atmosphere. After completion
of the reaction, a sat. aq solution of NaHCO3 was added and it
was stirred for additional 5 min. The mixture was extracted
with CH2Cl2, washed with brine, dried over MgSO4, and the
solvent was evaporated. The crude product was purified as
described below.
1
52%); mp 135.2–136.7 °C. H NMR (400 MHz, CD2Cl2): δ = 7.38
(s, 1 H), 7.32 (s, 1 H), 7.32–7.20 (m, 2 H), 7.18–7.16 (m, 2 H),
3.87 (s, 3 H), 2.34 (s, 3 H). 13C NMR (101 MHz, CD2Cl2): δ = 155.8,
138.7, 135.5, 134.5, 131.9, 131.9, 130.9, 123.5, 113.1, 101.4,
57.3, 21.4. HRMS (ESI+): m/z calcd for C14H12OS79BrI [M + H]+:
434.8915; found: 434.8924.
(30) Bis(4-iodophenyl)disulfide (5e)
According to the protocol for the disulfide synthesis (A), 4-iodo-
thiophenol (0.50 g, 2.12 mmol) was treated with iodine (0.36 g,
1.40 mmol) in pyridine (20 mL) for 15 min. The crude product
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E