Mo-Based Oxidizers as Powerful Tools for the Synthesis of Thia- and Selenaheterocycles

Article abstract of DOI:10.1002/chem.201805938

A highly efficient synthetic protocol for the synthesis of thia- and selenaheterocycles has been developed. By employing a MoCl₅-mediated intramolecular dehydrogenative coupling reaction, a broad variety of structural motifs was isolated in yields up to 94 %. The electrophilic key transformation is tolerated by several labile moieties like halides and tertiary alkyl groups. Due to the use of disulfide or diselenide precursors, a high atom efficiency was achieved.

Full text of DOI:10.1002/chem.201805938

A Journal of
Accepted Article
Title: Mo-based Oxidizers as Powerful Tools for the Synthesis of Thia-
and Selenaheterocycles
Authors: Siegfried R Waldvogel, Peter Franzmann, Sebastian Beil, and
Dieter Schollmeyer
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201805938
Link to VoR: http://dx.doi.org/10.1002/chem.201805938
Supported by

10.1002/chem.201805938
Chemistry - A European Journal
COMMUNICATION
Mo-based Oxidizers as Powerful Tools for the Synthesis of Thia-
and Selenaheterocycles
P. Franzmann,[a] S. B. Beil,[a,b] D. Schollmeyer[a] and S. R. Waldvogel*[a,b]
Abstract: A highly efficient synthetic protocol for the synthesis of
thia- and selenaheterocycles has been developed. By employing
MoCl5-mediated intramolecular dehydrogenative coupling reaction, a
broad variety of structural motifs was isolated in yields up to 94%.
The electrophilic key transformation is tolerated by several labile
moieties like halides and tertiary alkyl groups. Due to the use of
disulfide or diselenide precursors, a high atom efficiency was
achieved.
Because of the high interest in those structures, a large variety
of syntheses have been reported throughout the last couple of
decades.[1,6] One of the most frequently used approaches
involves Friedel-Crafts type reactions and subsequent
reduction.[7] Due to the harsh reaction conditions, only few
functional groups are tolerated by this approach. Recently,
several methods for the formation of S- and Se- heterocycles
using transition-metal catalysis have been reported.[8] These
transformations are mostly conducted in high yields and a broad
product range. Nevertheless, they suffer from the necessity of
leaving group substituted precursor molecules. This results in
elaborate multi-step protocols for the synthesis of the starting
materials as well as a poor atom economy. Although various
examples for oxidative chalcogenation of arenes are known and
in particular, Braga et al. made significant advances,[9] only very
few oxidative approaches for the syntheses of thiaheterocycles
have been described in literature.[10] Although those direct C,H
activations improve the atom economy drastically, the use of
protected thiols as starting material still causes a significant
reagent waste. Furthermore, only a small number of tolerated
functional groups have been reported for those procedures.
Therefore, a new and versatile procedure for the syntheses of S-
and Se-heterocycles with an even more improved atom
economy would be highly desirable.
Sulfur and selenium containing heterocycles are compound
classes of paramount importance in medicinal chemistry as well
as in materials sciences.[1] Specifically, benzothiophene based
drugs like zileuton (1) or raloxifene (2) are essential in the
treatment of asthma and osteoporosis.[2] Dibenzothiepine
derivatives like clorotepine (3) and its analogues have been
used for the treatment of schizophrenia and other psychotic
diseases.[3] Furthermore, several selenaheterocycles have been
investigated as possible treatment for stroke, tinnitus (ebselen,
4) as well as leukemia (ethaselen, 5).[4] In addition, chalcogene
containing heterocycles are frequently used because of their
photophysical properties. For example, ITX (6) is used as a
photoinitiator in UV-offset printing techniques.[5]
Figure 1. Examples for applications of S-/Se-heterocycles.[2-5]
[a]
[b]
P. Franzmann, S. B. Beil, Dr. D. Schollmeyer,
Prof. Dr. S. R. Waldvogel
Institute of Organic Chemistry
Johannes Gutenberg University Mainz
Duesbergweg 10-14, 55128 Mainz (Germany)
E-mail: waldvogel@uni-mainz.de
URL: https://www.blogs.uni-mainz.de/fb09akwaldvogel/
S. B. Beil, Prof. Dr. S. R. Waldvogel
Material Science in Mainz (MAINZ)
Graduate School of Excellence
Scheme 1. Common approaches for the synthesis of thiaheterocycles.[7-10]
Staudingerweg 9, 55128 Mainz (Germany)
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201805938
Chemistry - A European Journal
COMMUNICATION
Table 1. Optimization of the reaction conditions for substrate 9a.
Here, we report an intramolecular oxidative cyclization of
ω-arylated dialkyldichalcogenides and diaryldichalcogenides
using molybdenum pentachloride as an oxidizer.
Molybdenum pentachloride is readily available molybdenum
commodity with a unique Lewis acid property and strong
oxidative power.[11] The combination of these attributes leads to
very fast transformations, which results in an outstanding
tolerance of labile functional groups such as halides, acetals or
amides.[12] By employing this reagent in oxidative C,C coupling
reactions, we were able to construct a variety of five-, six-,
seven- and eight-membered ring-systems.[13] Recently, we
described a procedure for the synthesis of non-symmetric diaryl-
and aryl-alkyl chalcogenides using a combination of MoCl5 and
TiCl4 as a performance enhancing additive.[14]
Beginning from these previously employed reaction
conditions, the reaction parameters for the cyclization of bis(2-
(3,4-dimethoxyphenyl)ethyl)disulfide (9a) were optimized. In
general, the disulfide precursors used in the intramolecular
cyclization reactions were synthesized starting from the
corresponding alcohols in a simple, high yielding two-step
protocol (scheme 2).
Entry
1
Reagent
Equivalents
Concentration
0.02 M
Yield
40%
10%
0%
MoCl5 & TiCl4
MoCl5
3
2
3
0.02 M
3
TiCl4
3
0.02 M
4
FeCl3
3
0.02 M
27%
traces[b]
42%
46%
41%
46%
52%
65%
58%
5
Mo-anode[a]
MoCl5 & TiCl4
MoCl5 & TiCl4
MoCl5 & TiCl4
MoCl5 & TiCl4
MoCl5 & TiCl4
MoCl5 & TiCl4
MoCl5 & TiCl4
3 F
2.5
2
0.02 M
6
0.02 M
7
0.02 M
8
1.5
2
0.02 M
9
0.01 M
10
11
12
2
0.005 M
0.0025 M
0.00125 M
2
2
Scheme 2. General procedure for the synthesis of the starting materials.
[a] electrolysis parameters: Mo || graphite; 0.1 M NBu4PF6 in HFIP. [b] detected
by GC/GC-MS.
Initially, we found that substrate 9a does not only undergo
cyclization towards the corresponding dihydrobenzothiophene,
but is further oxidized to form a 5,6-dimethoxybenzothiophene
(10a) in 40% yield. We were able to confirm the formation of this
domino-oxidized product by X-ray crystal structure analysis of a
suitable single crystal. Expectedly, the use of MoCl5 as a sole
reagent leads to a lower yield, since MoCl5 is only capable to
perform the cyclisation, but not the follow-up oxidation. This is in
complete accordance with our previously conducted mechanistic
studies that show that MoCl5 can only act as a two-electron
oxidizer in the presence of TiCl4.[15] The comparison of the
MoCl5/TiCl4 mixture to other common oxidizers like FeCl3 or our
recently reported Mo-Anode[16] shows, that these are not able to
perform this reaction in comparable yields. Variation of the
reagent equivalents shows that the theoretical minimum amount
of two equivalents of MoCl5 & TiCl4 gives the highest yields.
Since the formed product is prone to over-oxidation processes,
further addition of oxidizer leads to oligomerisation and therefore
lower yields. To supress these product decomposition processes
even more, the reaction was performed at lower concentrations.
The results show, that the reaction works best at low
concentrations of 2.5*10-3 M.
In a next step, the influence of the chain length and therefore on
the ring size of the newly formed cycle during the
dehydrogenative reaction was investigated. We were able to
synthesize
five-,
six-,
seven-
and
eight-membered
thiaheterocycles in yields up to 88% using this method (scheme
3). Since no domino oxidation was observed for any product
except substance 10a, all other C,S-coupling reactions were
conducted using two equivalents of MoCl5 and higher
concentrations of starting material. As expected, the six
membered ring is formed in the highest yield, whereas the yield
drops slightly for the seven membered derivative and
dramatically for the eight membered ring.
Scheme 3. Influence of the ring size on the cyclisation. [a]2 eq. MoCl5 & TiCl4,
0.0025 M solution.
This article is protected by copyright. All rights reserved.

10.1002/chem.201805938
Chemistry - A European Journal
COMMUNICATION
For our next study, the size of the newly formed ring was kept
constant at six and the behaviour of different substituents on the
phenyl ring as well as the intramolecular C,S-coupling on
heteroarenes was investigated (scheme 4). We observed that
labile substituents like tert-butyl or halides are well tolerated.
Furthermore, we were also able to cyclize unsubstituted arenes
and heteroarenes in moderate to good yields up to 81%.
Additionally, a dibenzothiophene derivative as another five
membered ring system was synthesized without a possibility of a
domino oxidation process. Comparing the higher yielding
derivatives (10b, 10e, 10i) we came to the conclusion that the
yield is mostly determined by the possibility of follow-up
oligomerisation processes after the cyclization, since no leftover
starting material was observed for any of the derivatives. The
before mentioned derivatives are either blocked on the most
reactive sites of the molecule (10b, 10i) or have bulky
substituents in position ortho of the reactive site (10e).
successfully introduced as a completely new class of precursor
molecules, which underlines the variability of this method.
Finally, the protocol was adapted to several selenium analogues
of the above mentioned derivatives (scheme 6). We were able to
obtain these products in similar yields compared to the
corresponding thiaheterocycles. The dibenzoselenophene 12a
was obtained in
a
significantly higher yield as the
dibenzothiophene 10k. Most likely, because the larger selenium
atom results in a less planar product, which is less prone to be
over-oxidized. Interestingly, no indication for a domino-oxidation
step on product 12c was found. As for the dibenzoselenophene,
the larger selenium causes the five-membered ring to be more
crooked and therefore, less prone to be further oxidized. In
addition, an electrochemical protocol using an active Mo-anode
was successfully applied in the synthesis of 10e, 10i, 10l and
12a in excellent yields up to 85%, which gives rise to an even
more economic protocol for the cyclisation.
Scheme 6. Formation of selenaheterocycles. [a] Mo || graphite; 0.1 M NBu4PF6
in HFIP.
Scheme 4. Cyclization of differently substituted phenyl rings and heteroarenes.
[a] Mo || graphite; 0.1 M NBu4PF6 in HFIP.
To gain
a deeper understanding of the reaction, cyclic
voltammetry experiments with several precursors were
conducted (figure 2). Initially, the first oxidation takes place on
the arene should be conformed rather than on the disulfide
functionality. Therefore, the cyclic voltammogramms of bis(3-
(3,4-dimethoxyphenyl)propyl)disulfide
propylveratrole (blue) and a completely aliphatic disulfide (red)
were compared. For the cyclisation precursor, sharp
9b
(black),
4-
a
irreversible oxidation peak at ab out 0.86 V and a broad peak at
1.08 V was observed, which gives rise to two redox species with
similar redox-properties. The first oxidation peak of the veratrole
derivative is a similarly clear peak as the first oxidation of the
precursor 9b, whereas the alkyl disulfide shows a broader
oxidation wave at 1.03 V. We conclude that similarly to
observations by Chiba et al. the first oxidation occurs at the
activated arene.[17] A fast single electron transfer (SET) oxidises
the disulfide, which then forms the active trisulphide cation
(scheme 7). This cation is known from “cation pool” methods
and is then attacked intramolecularly by the arene.[18]
Scheme 5. Formation of thiaheterocycles containing multiple heteroatoms. [a]
Mo || graphite; 0.1 M NBu4PF6 in HFIP.
To achieve an even broader applicability of the MoCl5-mediated
cyclisation, we investigated if further heteroatoms in the newly
formed ring were also tolerated (scheme 5). Fortunately, we
were able to form heterocycles containing the most common
heteroatoms (oxygen, nitrogen, and sulphur) besides the sulphur
atom, which is involved in the C,S-coupling reaction. In addition,
for the formation of the benzothiazole 10n, thioamides were
This article is protected by copyright. All rights reserved.

10.1002/chem.201805938
Chemistry - A European Journal
COMMUNICATION
Acknowledgements
The authors thank the German Research Foundation DFG (WA
1276/15-1) and the Center of Innovative and Emerging Materials
(CINEMA) for financial support. S.B.B. gratefully acknowledges
support by a Kekulé fellowship of the Fonds der Chemischen
Industrie (FCI).
Keywords: cyclization • sulfur heterocycles • C-H activation •
molybdenum • oxidation
[1]
a) K. C. Majumdar, S. Mondal in Heterocycles in natural product
synthesis (Eds.: K. C. Majumdar, S. K. Chattopadhyay) Wiley-VCH,
Weinheim, Germany, 2011, pp. 377-402. B) T. Eicher, S. Hauptmann,
A. Speicher, The chemistry of heterocycles. Structure, reactions,
synthesis, and applications, Wiley-VCH, Weinheim, 2012.
a) D. G. Patt in Progress in Medicinal Chemistry (Ed.: G. P. Ellis),
Elsevier, Amsterdam, 1992, pp. 1-64. b) T. A. Grese, J. A. Dodge in
Annual Reports in Medicinal Chemistry (Eds.: J. A. Bristol, W. K.
Hagmann), Elsevier, Amsterdam, 1996, pp 181-190.
[2]
Figure 2. Cyclic voltammogramms of several disulfide precursors. c(substrate)
= 10 mM, 100 mM NBu4PF6 in MeCN, WE/CE: glassy carbon, RE: Ag/AgNO3
in MeCN, scanrate = 50 mV s-1.
[3]
[4]
[5]
J. Schmutz, C. W. Picard in Psychotropic Agents. Part I: Antipsychotics
and Antidepressants (Eds.: F. Hoffmeister, G. Stille), Springer Berlin
Heidelberg, Berlin, Heidelberg, 1980, pp. 1-26.
a) M. Elsherbini, W. S. Hamama, H. H. Zoorob, Coord. Chem. Rev.
2016, 312, 149-177. b) B. Banerjee, M. Koketsu, Coord. Chem. Rev.
2017, 339, 104-127.
J. K. Fink, The chemistry of printing inks and their electronics and
medical applications, Scrivener Publishing, Beverly, MA, Hoboken, New
Jersey, 2015, pp 23-130.
[6]
[7]
M. D. McReynolds, J. M. Dougherty, P. R. Hanson, Chem. Rev. 2004,
104, 2239-2258.
a) B. Robillard, L. Hughes, M. Slaby, D. A. Lindsay, K. U. Ingold, J. Org.
Chem. 1986, 51, 1700-1704. b) W. E. Truce, J. P. Milionis, J. Am.
Chem. Soc. 1952, 74, 974-977. c) F. G. Bordwell, W. H. McKellin, J.
Am. Chem. Soc. 1951, 73, 2251-2253.
[8]
[9]
a) K. Nishino, Y. Ogiwara, N. Sakai, Chem. - Eur. J. 2018, 24, 10971-
10794. b) W. You, X. Yan, Q. Liao, C. Xi, Org. Lett. 2010, 12, 3930-
3933. c) Z. Qiao, H. Liu, X. Xiao, Y. Fu, J. Wei, Y. Li, X. Jiang, Org. Lett.
2013, 15, 2594-2597.
a) J. Rafique, S. Saba, M. S. Franco, L. Bettanin, A. R. Schneider, L. T.
Silva, A. L. Braga, Chem. - Eur. J. 2018, 24, 4173-4180. b) S. Saba, J.
Rafique, M. S. Franco, A. R. Schneider, L. Espíndola, D. O. Silva, A. L.
Braga, Org. Biomol. Chem. 2018, 16, 880-885. c) J. Rafique, S. Saba,
T. E. A. Frizon, A. L. Braga, ChemistrySelect 2018, 3, 328-334. d) J.
Rafique, S. Saba, A. R. Rosário, A. L. Braga, Chem. – Eur. J. 2016, 22,
11854-11862. e) L. D. Tran, I. Popov, O. Daugulis J. Am. Chem. Soc.
2012, 134, 18237-18240. f) C. Lin, D. Li, B. Wang, J. Yao, Y. Zhang,
Org. Lett. 2015, 17, 1328-1331.
Scheme 7. Proposed mechanism for the MoV-mediated cyclization of
disulfides.
[10] a) K. Nishino, Y. Ogiwara, N. Sakai, Eur. J. Org. Chem. 2017, 5892-
5895. b) N. E. Shevchenko, V. G. Nenajdenko, E. S. Balenkova,
Synthesis 2003, 1191-1200. c) Y. Kita, M. Egi, M. Ohtsubo, T. Saiki, T.
Takada, H. Tohma, Chem. Commun. 1996, 2225-2226. d) E.
Campaigne, B. G. Heaton, J. Org. Chem. 1964, 29, 2372–2378.
[11] a) M. Grzybowski, K. Skonieczny, H. Butenschön, D. T. Gryko, Angew.
Chem. 2013, 125, 10084-10115; Angew. Chem., Int. Ed. 2013, 52,
9900-9930. b) M. Bortoluzzi, E. Ferretti, M. Hayatifar, F. Marchetti, G.
Pampaloni, S. Zacchini, Eur. J. Inorg. Chem. 2016, 3838-3845. c) M.
Hayatifar, F. Marchetti, G. Pampaloni, C. Pinzino, S. Zacchini,
Polyhedron 2013, 61, 188-194. d) B. T. King, J. Kroulík, C. R.
Robertson, P. Rempala, C. L. Hilton, J. D. Korinek, L. M. Gortari, J. Org.
Chem. 2007, 72, 2279-2288.
In conclusion, we established a highly efficient protocol for the
synthesis of thia- and selenaheterocycles using disulfides or
diselenides as starting materials in the dehydrogenative coupling
reaction. By employing this reaction, five- to seven-membered
heterocycles with
a
broad tolerance towards different
substituents as well as biheterocyclic arenes were constructed.
The use of molybdenum pentachloride or in some cases an
active molybdenum anode as an oxidizer provided superior
yields compared to other reagents. Additionally, CV
measurements were conducted with several disulfides to provide
a consistent mechanistic picture.
[12] a) M. Schubert, S. R. Waldvogel, Eur. J. Org. Chem. 2016, 1921-1936.
b) S. R. Waldvogel, S. Trosien, Chem. Commun. 2012, 48, 9109-9119.
This article is protected by copyright. All rights reserved.

10.1002/chem.201805938
Chemistry - A European Journal
COMMUNICATION
c) S. R. Waldvogel, E. Aits, C. Holst, R. Fröhlich, Chem. Commun.
2002, 1278-1279.
[13] a) P. Franzmann, S. Trosien, M. Schubert, S. R. Waldvogel, Org. Lett.
2016, 18, 1182-1185. b) M. Schubert, K. Wehming, A. Kehl, M. Nieger,
G. Schnakenburg, R. Fröhlich, D. Schollmeyer, S. R. Waldvogel, Eur. J.
Org. Chem. 2016, 60-63. c) K. Wehming, M. Schubert, G.
Schnakenburg, S. R. Waldvogel, Chem. - Eur. J. 2014, 20, 12463-
12469. d) S. Trosien, S. R. Waldvogel, Org. Lett. 2012, 14, 2976-2979.
e) B. Kramer, S. R. Waldvogel, Angew. Chem. 2004, 116, 2501-2503;
Angew. Chem., Int. Ed. 2004, 43, 2446-2449. f) B. Kramer, A. Averhoff,
S. R. Waldvogel, Angew. Chem. 2002, 114, 3103-3104; Angew. Chem.
Int. Ed. 2002, 41, 2981-2982.
[14] a) P. Franzmann, S. B. Beil, P. M. Winterscheid, D. Schollmeyer, S. R.
Waldvogel, Synlett 2017, 28, 957–961. b) B. Kramer, R. Fröhlich, S. R.
Waldvogel, Eur. J. Org. Chem. 2003, 18, 3549–3554.
[15] a) M. Schubert, P. Franzmann, A. Wünsche von Leupoldt, K.
Koszinowski, K. Heinze, S. R. Waldvogel, Angew. Chem. 2016, 128,
1168-1172; Angew. Chem., Int. Ed. 2016, 55, 1156-1159. b) J. Leppin,
M. Schubert, S. R. Waldvogel, K. Heinze, Chem. - Eur. J. 2015, 21,
4229-4232.
[16] a) S. B. Beil, T. Müller, S. B. Sillart, P. Franzmann, A. Bomm, M.
Holtkamp, U. Karst, W. Schade, S. R. Waldvogel, Angew. Chem. 2018,
130, 2475-2479; Angew. Chem., Int. Ed. 2018, 57, 2450-2454. Reviews
on electrochemical arylation and electrosynthesis: b) S. R. Waldvogel,
S. Lips, M. Selt, B. Riehl, C. J. Kampf, Chem. Rev. 2018, 118, 6706–
6765. c) S. Möhle, M. Zirbes, E. Rodrigo, T. Gieshoff, A. Wiebe, S. R.
Waldvogel, Angew. Chem. 2018, 130, 6124–6149; Angew. Chem. Int.
Ed. 2018, 57, 6018–6041. d) A. Wiebe, T. Gieshoff, S. Möhle, E.
Rodrigo, M. Zirbes, S. R. Waldvogel, Angew. Chem. 2018, 130, 5694–
5721; Angew. Chem. Int. Ed. 2018, 57, 5594–5619.
[17] Y. Okada, K. Chiba, Chem. Rev. 2018, 118, 4592-4630.
[18] J.-I. Yoshida, A. Shimizu, R. Hayashi, Chem. Rev. 2018, 118, 4702-
4730.
This article is protected by copyright. All rights reserved.

10.1002/chem.201805938
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
P. Franzmann, S. B. Beil, D.
Schollmeyer, S. R. Waldvogel*
Page No. – Page No.
Mo-based Oxidizers as Powerful
Tools for the Synthesis of Thia- and
Selenaheterocycles
Molybdenum opens the door as pentachloride or as an anode material to
synthezise a variety of thia- and selenaheterocycles in high yields up to 94%. The
dehdrogenative coupling of disulfides and diselenides leads to an excellent atom
economy for the key transformation.
This article is protected by copyright. All rights reserved.