Exploiting amphiphilicity: Facile metal free access to thianthrenes and related sulphur heterocycles

Article abstract of DOI:10.1039/c5cc01757b

Benzodithioloimines are reacted with arynes or alkynes substituted with electron-withdrawing groups to afford the corresponding thianthrene or benzo[b][1,4]dithiine derivatives. The transformation takes place under mild reaction conditions without any transition metal. Furthermore, the reaction mode could be expanded to 2-thiocyanatopyrroles yielding pyrrolothiazoles.

Full text of DOI:10.1039/c5cc01757b

ChemComm
View Article Online
View Journal
COMMUNICATION
Exploiting amphiphilicity: facile metal free access
to thianthrenes and related sulphur heterocycles†
Cite this:DOI: 10.1039/c5cc01757b
Martin Pawliczek,ab Lennart K. B. Garvea and Daniel B. Werz*a
Received 28th February 2015,
Accepted 28th April 2015
DOI: 10.1039/c5cc01757b
www.rsc.org/chemcomm
Benzodithioloimines are reacted with arynes or alkynes substituted
with electron-withdrawing groups to afford the corresponding
thianthrene or benzo[b][1,4]dithiine derivatives. The transformation
takes place under mild reaction conditions without any transition
metal. Furthermore, the reaction mode could be expanded to
2-thiocyanatopyrroles yielding pyrrolothiazoles.
In the last decades sulphur-containing molecules have received
great attention because of their interesting biological proper-
ties1 and their unique application in material science.2 For that
purpose, the development of new methodologies dealing with
the formation of carbon–sulphur bonds has become a major
topic in modern organic synthesis.3 Traditional methods which
take advantage of the high nucleophilicity of sulphur require
harsh reaction conditions to form arene–sulphur bonds. There-
fore, elevated temperatures, strong bases or a specific substitu-
tion pattern at the arene are needed making them unattractive
for numerous target molecules.4 These drawbacks could be
Scheme 1 (a) Reaction mode of mononitrile-substituted 1,2-dithiophenol.
(b) Possible reaction partners and desired products.
bypassed utilising metal catalysed cross-coupling reactions for sulphur atom should act as nucleophile, the other one as
C–S bond formation.5 Nevertheless, applications in material electrophile. 2-Thiocyanatobenzenethiol (1a0) which exists in
science require highly pure compounds without any extraneous its closed form 1a was chosen as target substrate.8 Providing
metal impurities. Thus, transition metal free protocols for the the required abilities easily visualised by its open form 1a00,
formation of C–S bonds under mild reaction conditions are of compound 1a should be able to react with other easily polari-
considerable interest.6
sable or polarised substrates such as arynes9 or alkynes sub-
Regarding the reaction properties of thiophenols, sulphur stituted with electron-withdrawing (EWG) groups.10 As products,
reacts as a nucleophile. However, its philicity can be reversed by the corresponding dithiaheterocycles 3aa and 5, respectively,
converting thiophenol into the corresponding sulfenyl chloride should be formed (Scheme 1b).
or thiocyanate. In this shape, sulphur acts as electrophile
At the beginning of our investigations, we intended to
suitable for substitution by nucleophiles (e.g. lithium or Grignard establish a fast and efficient access to key compound 1a since
reagents).7 For the facile synthesis of heterocycles containing two the methods described in the literature proved to be tedious.8
sulphur atoms, 1,2-thiophenol derivatives equipped with both We discovered, when treating aromatic 1,2-dithiocyanato-
abilities are of utmost importance (Scheme 1a). This means one benzene 6a with PPh3 in the presence of base in acetonitrile,
1a is formed in up to 91% yield within 1 h at room temperature
(Scheme 2a). With compound 1a in hand, we proved the amphi-
a
¨
¨
Technische Universitat Braunschweig, Institut fur Organische Chemie, Hagenring 30,
philic behaviour of the two sulphur atoms. Based on our previous
considerations, we chose a common aryne precursor for the
desired metal free transformation which would provide a novel
38106 Braunschweig, Germany. E-mail: d.werz@tu-braunschweig.de
b
¨
¨
¨
Georg-August-Universitat Gottingen, Institut fur Organische und Biomolekulare
¨
Chemie, Tammannstraße 2, 37077 Gottingen, Germany
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5cc01757b entry to the thianthrene scaffold.11 To our delight, common
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun.

View Article Online
Communication
ChemComm
Table 2 Scope of thianthrenes with respect to dithioloimine and arynea
Scheme 2 (a) Synthesis of 1a. (b) Reaction of 1a with aryne precursor 2a.
Table 1 Scope of thianthrenes with respect to arynea
a
Reaction conditions: 1 (50 mmol), 2 (75 mmol), KF (150 mmol), 18-C-6
(150 mmol), MeCN (2 mL), rt, 16 h.
reaction conditions yielding 3ba in 71%. Naphthyl-based 3be,
difluoro- 3bh and dimethyoxy-substituted systems 3bk were
obtained in yields ranging from 55 to 70%. Because of their
high electronegativity the latter two substituents render the
important in-plane p orbital of the aryne highly electron-
deficient. Further, benzodithioloimines containing pyrazine
or thiadiazole heterocyclic cores were also applied. Pyrazine
derivative 3ca could be obtained in 69% yield, whereas the
formation of 3ca stayed out.
a
Reaction conditions: 1a (50 mmol), 2 (75 mmol), KF (150 mmol), 18-C-6
Finally, 1b was exposed to unsymmetrical aryne precursors
substituted with a methyl or a methoxy group. As result, insepar-
able mixtures of 3bc/3bc0 (64%, ratio of 1 : 1) and 3bj/3bj0 (79%,
b
(150 mmol), MeCN (2 mL), rt, 16 h. 200 mmol of 2 were used.
conditions using KF and 18-crown-6 in acetonitrile at ambient ratio of 2 : 1) were obtained, respectively. This observation demon-
temperature yielded the desired thianthrene 3aa in excellent strates that even the methoxy-substituted aryne, known for its
95% yield (Scheme 2b).
Exposition of 1a to various aryne precursors under the above- chemistry, does not achieve a satisfying ratio of regioisomers.12
mentioned reaction conditions yielded the corresponding thi- In addition, we also tried a one-step procedure applying
high distortion and hence its high regioselectivity in aryne
anthrenes (Table 1). Alkyl-substituted arynes and such with 1,2-dithiocyanatobenzene 6a by addition of PPh3 to the aryne
extended p-systems were successfully converted to their thi- reaction. Unfortunately, the resulting yields were lower with
anthrene counterparts 3ab–3af in 58–87% yield. Chloro-, fluoro-, 65% as the best result. A further drawback was the separation
and bromo-substituted thianthrenes 3ag, 3ah, and 3ai were of PPh3 from the product by column chromatography where-
obtained in yields ranging from 44 to 74%. In the case of the fore the two-step procedure proved to be the method of choice.
dibromo derivative 3ai higher loadings of aryne precursor were
With this procedure for thianthrenes in hand, we tried to
required. Thianthrenes equipped with one or two methoxy expand the scope to other heterocyclic scaffolds. Therefore,
substituents 3aj and 3ak were accessed in 64% and 96% yield, alkynes 4 bearing an electron-withdrawing group were utilised
respectively. Furthermore, also a pyridine-based aryne precursor resulting in benzo[b][1,4]dithiines.13 Slight adjustments of the
was able to undergo the transformation to azathianthrene 3al in reaction conditions were necessary to obtain the desired products,
75% yield.
but in all cases much faster transformations were observed using
Similarly, variations with respect to the dithioloimine bearing these polarised alkynes.14
core are possible (Table 2). Methyl-substituted 1b in combination
Consequently, dimethylester 7aa and mono-methylester 7ab
with the unfunctionalised aryne precursor was exposed to the were reached in 75% and 57% yields, respectively (Table 3).
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2015

View Article Online
ChemComm
Communication
Table 3 Scope of dithioloimines with EWG-substituted alkynesa
Table 4 Reaction of 8 with EWG-substituted alkynes 4 to afford 10a
a
Reaction conditions: 8 (200 mmol), 4 (4.00 mmol), Cs2CO3 (300 mmol),
MeCN (3 mL), rt, 5 min.
a
Reaction conditions: 1a (200 mmol), 4 (300 mmol), KF (600 mmol), 18-C-6
b
(600 mmol), MeCN (2 mL), rt, 5 h. Reaction conditions: 1 (500 mmol), 4
(750 mmol), KF (1.50 mmol), 18-C-6 (1.50 mmol), MeCN (5 mL), rt, 5 h.
c
Cs2CO3 (600 mmol) instead of KF and 18-C-6.
Michael acceptors based on ketones could be converted in yields
of 72% for 7ac and 77% for 7ad. Modifications regarding the
dithioloimine core were performed as well. Methyl-substituted
dimethylester derivative 7ba could be achieved in 72% yield. Also,
other heterocyclic systems could be introduced resulting in
pyrazine 7ca and thiadiazol 7da and in 75% and 66% yield. In
addition, the application of Michael acceptors based on double
bonds was unsuccessful. We assume that in such a case the
retro-Michael reaction in contrast to the ring closure is the
preferred mode of action.15
Scheme 4 Proposed mechanistic scenario: (a) for the reaction with
arynes; (b) for the reaction with Michael acceptors; (c) observed side
products.
Encouraged by these results, we investigated whether also
nitrogen might play the nucleophilic role. Changing the aromatic
core to 2-thiocyanatopyrrole the endocyclic nitrogen should be
prone to act as nucleophile. As result, the analogous transforma-
tion under modified reaction conditions yielded the desired benzodithioloimine favours the nucleophilic attack on the
benzo[d]pyrrolo[2,1-b]thiazole16 (9) in 45% yield (Scheme 3).
aryne leading to intermediate A (Scheme 4a). This species
Further, also Michael acceptors were shown to be suitable undergoes a concomitant nucleophilic substitution on sulphur,
substrates to afford the corresponding pyrrolo[2,1-b]thiazole17 whereby nitrile acts as leaving group to form product 3aa. The
derivatives 10ad, 10ba and 10bb in 50–63% yield (Table 4). pivotal reaction steps for alkynes substituted with electron-
Because of the high reactivity and amphiphilic character of 8, it withdrawing groups are similar (Scheme 4b). Nevertheless, in
rather tends to undergo a homocoupling than a 1,4-addition. this case the formation of the reactive triple bond is not
This problem was partially counteracted by applying higher necessary resulting in shorter reaction times in comparison
loadings of Michael acceptor.
with the previous transformation. The proposed reaction
We propose the following plausible reaction mechanisms mechanisms are supported by side products 12 and 13 which
being responsible for product formation (Scheme 4). Precursor are formed if ring-closure stays out because of protonation of
2a is transformed into the reactive aryne. Deprotonation of intermediate A or B (Scheme 4c).
In conclusion, we developed a broadly applicable transition
metal free method for the synthesis of thianthrenes and benzo-
dithiines. For this purpose, amphiphilic dithioloimines con-
taining negatively and positively polarised sulphur were reacted
with arynes and alkynes substituted with electron-withdrawing
groups. Additionally, the concept of two differently polarised
Scheme 3 Reaction of 8a with aryne precursor 2a.
heteroatoms was transferred to a nitrogen–sulphur combination.
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun.

View Article Online
Communication
ChemComm
Tian, Angew. Chem., Int. Ed., 2013, 52, 4929; (d) N. Umiersky and
G. Manolikakes, Org. Lett., 2013, 15, 188; (e) S. Liang, R. Zhang, L. Xi,
S. Chen and X. Yu, J. Org. Chem., 2013, 78, 11874; ( f ) S. A.
Amelichev, L. S. Konstantinova, N. V. Obruchnikova, O. A. Rakitin
and C. W. Rees, Org. Lett., 2006, 8, 4529.
7 (a) L. Melzig, C. B. Rauhut, N. Naredi-Rainer and P. Knochel,
Chem. – Eur. J., 2011, 17, 5362; (b) J. R. Fotsing and K. Banert,
Synthesis, 2006, 261; (c) D. B. Werz, R. Gleiter and F. Rominger,
J. Org. Chem., 2004, 69, 2945; (d) D. B. Werz and R. Gleiter, J. Org.
Chem., 2003, 68, 9400; (e) F. D. Toste and I. W. J. Still, Tetrahedron
Lett., 1995, 36, 4361; ( f ) H. Maruyama, M. Shiozaki, S. Oida and
T. Hiraoka, Tetrahedron Lett., 1985, 26, 4521.
The use of 2-thiocyanatopyrroles paves the way for a novel,
fast and efficient entry to benzo[d]pyrrolo[2,1-b]thiazoles and
pyrrolo[2,1-b]thiazoles, respectively. Further studies to expand
this methodology to other heterocyclic scaffolds are ongoing.
This research was supported by the German Research Foun-
dation (DFG, Emmy Noether and Heisenberg Fellowships to
D.B.W.) and by the Fonds der Chemischen Industrie (PhD
Fellowship to M.P. and Dozentenstipendium to D.B.W.).
L.K.B.G. thanks the Studienstiftung des deutschen Volkes for
a PhD Fellowship.
8 (a) P. Stanetty, G. Hattinger, M. D. Mihovilovic and K. J. Mereiter,
J. Heterocycl. Chem., 2000, 37, 955; (b) J. Nakayama, A. Sakai,
S. Tokita and M. Hoshino, Heterocycles, 1984, 22, 27.
Notes and references
´
´
9 (a) J.-A. Garcıa-Lopez, M. Çetin and M. F. Greaney, Angew. Chem., Int.
Ed., 2015, 54, 2156; (b) D. Giallombardo, A. C. Nevin, W. Lewis,
C. C. Nawrat, R. R. A. Kitson and C. J. Moody, Tetrahedron, 2014,
70, 1283; (c) J. Zhao and R. C. Larock, J. Org. Chem., 2007, 72, 583;
(d) D. C. Rognessa and R. C. Larock, Tetrahedron Lett., 2009,
50, 4003; (e) J. Zhao and R. C. Larock, Org. Lett., 2005, 7, 4273;
( f ) D. Hong, Z. Chen, X. Lin and Y. Wang, Org. Lett., 2010, 12, 4608.
10 (a) C. Shao, Q. Zhang, G. Cheng, C. Cheng, X. Wang and Y. Hu, Eur.
J. Org. Chem., 2013, 6443; (b) K. Yoshimura, T. Oishi, K. Yamaguchi
and N. Mizuno, Chem. – Eur. J., 2011, 17, 3827; (c) E. B. Castillo-
Contreras and G. R. Dake, Org. Lett., 2014, 16, 1642; (d) M. Yoshida,
K. Saito, Y. Fujino and T. Doi, Chem. Commun., 2012, 48, 11796.
11 (a) D. Kundu, T. Chatterjee and B. C. Ranu, Adv. Synth. Catal., 2013,
355, 2285; (b) K. Radhakrishnan and C.-H. Lin, Synlett, 2005, 2179;
(c) P. Preedasuriyachai, P. Charoonniyomporn, O. Karoonnirun,
T. Thongpanchang and Y. Thebtaranonth, Tetrahedron Lett., 2004,
45, 1343.
1 (a) B. Stumpf, C. Eberle, M. Kaiser, R. Brun, R. L. Krauth-Siegel and
F. Diederich, Org. Biomol. Chem., 2008, 6, 3935; (b) A. Gangjee,
Y. Zeng, T. Talreja, J. J. McGuire, R. L. Kisliuk and S. F. Queener,
J. Med. Chem., 2007, 50, 3046; (c) S. F. Nielsen, E. Ø. Nielsen,
G. M. Olsen, T. Liljefors and D. Peters, J. Med. Chem., 2000, 43, 2217.
2 (a) P. Choto, K. Rasmussen and G. Grampp, Phys. Chem. Chem.
´
Phys., 2015, 17, 3415; (b) C. C. Ferron, M. Capdevila-Cortada,
R. Balster, F. Hartl, W. Niu, M. He, J. J. Novoa, J. N. L. Navarrete,
´
V. Hernandez and M. C. R. Delgado, Chem. – Eur. J., 2014, 20, 10351;
(c) A. M. Khenkin, G. Leitus and R. Neumann, J. Am. Chem. Soc.,
2010, 132, 11446; (d) C. Marti, J. Irurre, A. Alvarez-Larena,
J. F. Piniella, E. Brillas, L. Fajari, C. Aleman and L. Julia, J. Org.
Chem., 1994, 59, 6200; (e) T. Sarukawa and N. Oyama, J. Electrochem.
Soc., 2010, 157, F23; ( f ) G. Jones, B. Huang and S. F. Griffin, J. Org.
Chem., 1993, 58, 2035.
3 (a) J. Mao, T. Jia, G. Frensch and P. J. Walsh, Org. Lett., 2014,
16, 5304; (b) L. Wang, W. He and Z. Yu, Chem. Soc. Rev., 2013,
42, 599; (c) R. B. N. Baig and R. S. Varma, Chem. Commun., 2012,
48, 2582; (d) P. Bichler and J. A. Love, Top. Organomet. Chem., 2010,
31, 39; (e) C.-K. Chen, Y.-W. Chen, C.-H. Lin, H.-P. Lin and C.-F. Lee,
Chem. Commun., 2010, 46, 282.
4 (a) J. Ham, I. Yang and H. Kang, J. Org. Chem., 2004, 69, 3236;
(b) A. V. Bierbeek and M. Gingras, Tetrahedron Lett., 1998, 39, 6283;
(c) A. B. Pierini, M. T. Baumgartner and R. A. Rossi, J. Org. Chem.,
1987, 52, 1089; (d) J. Lindley, Tetrahedron, 1984, 40, 1433.
5 (a) I. P. Beletskaya and V. P. Ananikov, Chem. Rev., 2011, 111, 1569;
(b) H. Yang, Y. Li, M. Jiang, J. Wang and H. Fu, Chem. – Eur. J., 2011,
17, 5652; (c) P. Anbarasan, H. Neumann and M. Beller, Chem.
Commun., 2011, 47, 3233; (d) F. Ke, Y. Qu, Z. Jiang, Z. Li, D. Wu
12 (a) J. M. Medina, J. L. Mackey, N. K. Garg and K. N. Houk, J. Am.
Chem. Soc., 2014, 136, 15798; (b) F.-L. Liu, J.-R. Chen, Y.-Q. Zou,
Q. Wei and W.-J. Xiao, Org. Lett., 2014, 16, 3768; (c) S. S. Bhojgude,
T. Kaicharla and A. T. Biju, Org. Lett., 2013, 15, 5452.
13 (a) G. L. Morgans, E. L. Ngidi, L. G. Madeley, S. D. Khanye,
J. P. Michael, C. B. de Koning and W. A. L. van Otterlo, Tetrahedron,
2009, 65, 10650; (b) E. M. Engler, V. V. Patel and R. R. Schumaker,
Tetrahedron Lett., 1981, 22, 2035; (c) P. Blatcher, S. Warren, S. Ncube,
A. Pelter and K. Smith, Tetrahedron Lett., 1978, 26, 2349.
14 Different bases were tested (K2CO3, KOH, DABCO, KOAc, CsF,
Cs2CO3, KF/18-C-6). Cs2CO3 or KF/18-C-6 gave the best results in
the specific cases as stated in Table 3.
15 J. Evarts, E. Torres and P. L. Fuchs, J. Am. Chem. Soc., 2002, 124, 11093.
16 (a) P. Zhao, H. Yin, H. Gao and C. Xi, J. Org. Chem., 2013, 78, 5001;
(b) M. Kucukdisli and T. Opatz, Eur. J. Org. Chem., 2012, 4555.
17 (a) D. C. Rogness, N. A. Markina, J. P. Waldo and R. C. Larock, J. Org.
Chem., 2012, 77, 2743; (b) K. C. Majumdar and S. Nath, Synthesis,
2011, 1413; (c) Y. S. Song and K.-J. Lee, Synthesis, 2007, 3037.
´
´
and X. Zhou, Org. Lett., 2011, 13, 454; (e) M. A. Fernandez-Rodrıguez,
Q. Shen and J. F. Hartwig, Chem. – Eur. J., 2006, 12, 7782.
6 (a) Y. Yang, Z. Chen and Y. Rao, Chem. Commun., 2014, 50, 15037;
(b) J.-K. Qui, W.-J. Hao, D.-C. Wang, P. Wei, J. Sun, B. Jiang and
S.-J. Tu, Chem. Commun., 2014, 50, 14782; (c) F.-L. Yang and S.-K.
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2015