Tetrahydrobenzo[c]thieno[2,1-e]isothiazole 4-Oxides: Three-Dimensional Heterocycles as Cross-Coupling Building Blocks

Article abstract of DOI:10.1021/acs.orglett.7b03475

Unprecedented three-dimensional heterocycles are introduced, and their scaffold functionalization is described. A robust synthetic method utilizing cheap commercially available starting materials leads to a wide range of products on gram scale. The product portfolio can be expanded by applying newly devised building blocks with relevance for automated parallel synthesis in cross-coupling reactions.

Full text of DOI:10.1021/acs.orglett.7b03475

Letter
pubs.acs.org/OrgLett
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Tetrahydrobenzo[c]thieno[2,1‑e]isothiazole 4‑Oxides: Three-
Dimensional Heterocycles as Cross-Coupling Building Blocks
Philip Lamers and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: Unprecedented three-dimensional heterocycles are
introduced, and their scaffold functionalization is described. A robust
synthetic method utilizing cheap commercially available starting
materials leads to a wide range of products on gram scale. The
product portfolio can be expanded by applying newly devised building
blocks with relevance for automated parallel synthesis in cross-
coupling reactions.
prepared, and subsequent skeleton modifications led to
functionalized building blocks for cross-coupling reactions.
The synthetic approach toward compounds 1 started by
treatment of the respective aniline 2 with tetrahydrothiophene
(3a), N-chlorosuccinimide (NCS), and triethylamine in
DCM.12 The resulting 2-(tetrahydrothiophen-2-yl)anilines 4
could generally be isolated in moderate to high yields ranging
between 50% and 87% (Scheme 2). Neither the substitution
pattern nor electronic effects of the aniline had a significant
effect on the yields of 4. Starting from m-iodoaniline, an almost
1:1 isomeric mixture of compounds 4l and 4m was obtained in
a combined yield of 87%. The isomers were separated by flash
column chromatography and were characterized individually. In
addition, anilines with nitrogen atoms in the aromatic core
reacted, providing 4o and 4p in 29% and 42% yield,
respectively. All syntheses were carried out on a 60 mmol
scale. Performing the reactions on a 250 mmol scale gave the
products with essentially identical yields.
With the intention of expanding the substrate scope, 6-
membered sulfur-containing heterocycles tetrahydro-2H-thio-
pyran (3b), tert-butyl thiomorpholine-4-carboxylate (3c), and
1,4-oxathiane (3d) were applied. To our delight, they reacted
equally well, affording aniline-derived products 5a−c in yields
of 74, 80, and 72% yield, respectively (Scheme 2).13
Next, the direct conversion of 2-(tetrahydrothiophen-2-
yl)anilines 4 into products 1 was targeted. Reacting 4 with
NCS and NaOH resulted in cyclizations affording 1,2,3,9b-
tetrahydro-4λ4-benzo[c]thieno[2,1-e]isothiazoles 6 (Scheme 3).
Without purification, products 6 were oxidized with m-CPBA
to give tetrahydrobenzo[c]thieno[2,1-e]isothiazole 4-oxides 1.
In this manner, a wide range of products 1 bearing various
functional groups was prepared. With the exception of naphthyl
and pyrimidyl derivates 4n and 4p, all 2-(tetrahydrothiophen-2-
yl)anilines 4 reacted well, affording the corresponding products
1 in yields ranging from 28% to 77% (Scheme 3). Also in this
n 2009, Pitt and co-workers generated a “virtual exploratory
Iheterocyclic library” (VEHICLe) containing 24847 mono-
and bicyclic ring systems.1 To their surprise, only 1701 of them
had ever been synthesized, and very few of them were routinely
used in approaches toward drug-like molecules. This very low
level of diversity could contribute to the low number of newly
approved drugs despite increasing investments in research and
development. For synthetic organic chemists, it provides
opportunities for exploring unconquered chemical space.2 As
illustrated by Lovering et al., in medicinal chemistry three-
dimensionality and saturation are important factors for a
successful transition from discovery through clinical trials to
drugs.3,4 In addition, the presence of stereogenic centers has
positive effects.5
In light of the aforementioned analysis, we initiated a
research program focusing on novel, three-dimensional
heterocyclic scaffolds6,7 with a high degree of complexity (as,
for example, expressed by their Fsp3).8 Molecular diversity
should result from substituents and the presence of suitable
functional groups, which could be utilized in cross-coupling
strategies.9 The latter render the new compounds as ready-to-
use building blocks applicable in automated parallel synthesis10
and continuous flow.11 Following this idea, we now introduce
tricyclic heterocycles 1 (1,2,3,9b-tetrahydrobenzo[c]thieno[2,1-
e]isothiazole 4-oxides), which to the best of our knowledge are
unprecedented (Scheme 1). The synthetic route is flexible
using readily available anilines 2 and tetrahydrothiophene (3a)
as starting materials. Accordingly, various products have been
Scheme 1. 1,2,3,9b-Tetrahydrobenzo[c]thieno[2,1-
e]isothiazole 4-Oxides 1 and the Respective Starting
Materials
Received: November 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03475
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Syntheses of 2-(Tetrahydrothiophen-2-yl)anilines
4a−p and Related Products 5a−c
Scheme 4. Functionalization of Compounds 1b and 1c Using
Cross-Coupling Strategies
Sonogashira cross-coupling14 and phenylated compound 10 in
89% yield from the Suzuki reaction.15 Generally speaking, these
modifications through cross-coupling reactions opened access
to libraries of such heterocycles. As the reaction conditions
were mild, sensitive coupling partners could be applied.
With the vision to incorporate three-dimensional hetero-
cyclic scaffold 1 into bench stable, ready-to-use boron-based
building blocks, pinacol boronic acid esters 11 and potassium
aryltrifluoroborates 12 (Schemes 5 and 6) were targeted. Both
Scheme 5. Syntheses of Pinacol-Protected Boronic Acids
11a−c
Scheme 3. Syntheses of Tetrahydrobenzo[c]thieno[2,1-
e]isothiazole 4-Oxides 1
Scheme 6. Syntheses of Potassium Aryltrifluoroborates 12a
and 12b
case, the reactions could be up-scaled, allowing the cyclization/
oxidation sequence to be performed with up to 150 mmol of 4.
Attempts to apply 5a−c under the same conditions remained
unsuccessful.
In order to ensure that the heterocyclic core of products 1
allowed the application of metal-catalyzed cross-coupling
strategies, compounds 1b and 1c were reacted with phenyl-
acetylene (7) and phenylboronic acid (9), respectively, under
palladium catalysis (Scheme 4). Both transformations pro-
ceeded well, giving alkynylated product 8 in 94% yield from the
B
DOI: 10.1021/acs.orglett.7b03475
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(4) See also: (a) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011,
54, 3451. (b) Walters, W. P.; Green, J.; Weiss, J. R.; Murcko, M. A. J.
Med. Chem. 2011, 54, 6405.
(5) For a review on the design of building blocks with attractive
features for medicinal chemistry, see: Goldberg, F. W.; Kettle, J. G.;
Kogej, T.; Perry, M. W. D.; Tomkinson, N. P. Drug Discovery Today
2015, 20, 11.
reagent classes have proven highly valuable for Suzuki-type
cross-coupling reactions.15,16 Following a protocol described by
Miyaura and co-workers, which involved the use of bis-
(pinacolato)diboron (B2pin2), PdCl2(dppf) (10 mol %), and
potassium acetate in DMSO at 50 °C for 16 h,17 pinacol
boronic acid esters 11a−c were readily prepared from the
corresponding iodides (Scheme 5). Substitution at the C-6
position (with the intention to convert 1k into 11d) did not
occur, either due to steric interactions of the heterocyclic
backbone with the methyl groups of the pinacol fragment or
chelating effects after palladium insertion into the aryl iodine
bond.
Using a procedure introduced by Lloyd-Jones and co-
workers,18 potassium aryltrifluoroborates 12a and 12b were
synthesized by treatment of pinacol boronic acid esters 11a and
11b, respectively, with KHF2 in a methanol/water mixture for
16 h at room temperature (Scheme 6). Because of the high
polarity of all compounds, the standard workup procedures
could not be applied. Finally, the products were isolated and
purified by washing with diethyl ether followed by repeated hot
filtrations. In this manner, potassium aryltrifluoroborates 12a
and 12b were obtained in yields of 84% and 72%. Attempts to
prepare 12c from 11c failed. Although the product was
detected by NMR spectroscopy, its isolation was hampered by
its high polarity.
(6) Aldeghi, M.; Malhotra, S.; Selwood, D. L.; Chan, A. W. E. Chem.
Biol. Drug Des. 2014, 83, 450.
(7) (a) Ritchie, T. J.; Macdonald, S. J. F. Drug Discovery Today 2009,
14, 1011. (b) Ritchie, T. J.; Macdonald, S. J. F.; Young, R. J.; Pickett, S.
D. Drug Discovery Today 2011, 16, 164.
(8) Fsp3 stands for “Fraction sp3” (being the number of sp3
hybridized carbons/total carbon count); see ref 3 and: Yan, A.;
Gasteiger, J. QSAR Comb. Sci. 2003, 22, 821.
(9) For the introduction and use of this strategy with respect to
sulfoximine chemistry, see: (a) Steinkamp, A.-D.; Wiezorek, S.; Brosge,
F.; Bolm, C. Org. Lett. 2016, 18, 5348. (b) Hendriks, C. M. M.;
Hartkamp, J.; Wiezorek, S.; Steinkamp, A.-D.; Rossetti, G.; Luscher, B.;
̈
Bolm, C. Bioorg. Med. Chem. Lett. 2017, 27, 2659. (c) Bachon, A.-K.;
Steinkamp, A.-D.; Bolm, C. Submitted for publication..
(10) Reizman, B. J.; Wang, Y.-M.; Buchwald, S. L.; Jensen, K. F.
React. Chem. Eng. 2016, 1, 658.
(11) Len, C.; Bruniaux, S.; Delbecq, F.; Parmar, V. S. Catalysts 2017,
7, 146.
(12) The general synthetic strategy has previously been applied in
accessing 2-methyl-3H-2λ4-benzo[c]isothiazole 2-oxides. For details,
see: (a) Claus, P. K.; Hofbauer, P.; Rieder, W. Tetrahedron Lett. 1974,
15, 3319. (b) Lamers, P.; Buglioni, L.; Koschmieder, S.; Chatain, N.;
Bolm, C. Adv. Synth. Catal. 2016, 358, 3649 and references cited
therein.
In summary, we developed a robust method for synthesizing
three-dimensional heterocycles 1. Sonogashira and Suzuki
cross-couplings of halo derivatives allow straightforward
structural modifications. Pinacol boronic acid esters and
potassium aryltrifluoroborates with scaffolds derived from 1
represent bench stable, ready-to-use boron-based building
blocks.
(13) Thiomorpholine, thiethane, 1,3-oxathiolane, and tert-butyl
thiazolidine-3-carboxylate proved unreactive.
(14) For the initial reports, see: (a) Sonogashira, K.; Tohda, Y.;
Hagihara, N. Tetrahedron Lett. 1975, 16, 4467. (b) Tohda, Y.;
Sonogashira, K.; Hagihara, N. J. Chem. Soc., Chem. Commun. 1975, 54.
For overviews, see: (c) Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed.
2007, 46, 834. (d) Plenio, H. Angew. Chem., Int. Ed. 2008, 47, 6954.
(e) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874.
(15) (a) For the “Nobel Review”, see: Suzuki, A. Angew. Chem., Int.
Ed. 2011, 50, 6722. For recent mechanistic studies, see: (b) Gonzalez,
J. A.; Ogba, O. M.; Morehouse, G. F.; Rosson, N.; Houk, K. N.; Leach,
A. G.; Cheong, P. H. Y.; Burke, M. D.; Lloyd-Jones, G. C. Nat. Chem.
2016, 8, 1067. (c) Cox, P. A.; Leach, A. G.; Campbell, A. D.; Lloyd-
Jones, G. C. J. Am. Chem. Soc. 2016, 138, 9145. (d) Lennox, A. J. J.
Chem. Soc. Rev. 2014, 43, 412.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03475.
General experimental procedure and characterization
details (PDF)
(16) For overviews, see: (a) Molander, G. A.; Ellis, N. Acc. Chem. Res.
2007, 40, 275. (b) Molander, G. A.; Sandrock, D. L. Curr. Opin. Drug
Discovery Devel. 2009, 12, 811. (c) Darses, S.; Genet, J.-P. Chem. Rev.
2008, 108, 288.
(17) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508.
(18) (a) Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.; Lloyd-
Jones, G. C.; Murray, P. M. Angew. Chem., Int. Ed. 2010, 49, 5156.
(b) Lennox, A. J. J.; Lloyd-Jones, G. C. Isr. J. Chem. 2010, 50, 664.
(c) Lennox, A. J. J.; Lloyd-Jones, G. C. J. Am. Chem. Soc. 2012, 134,
7431. (d) Lennox, A. J. J.; Lloyd-Jones, G. C. Angew. Chem., Int. Ed.
2012, 51, 9385.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: carsten.bolm@oc.rwth-aachen.de.
ORCID
Carsten Bolm: 0000-0001-9415-9917
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Laura Buglioni (formerly RWTH Aachen
University, now ICIQ Tarragona), Stefan Wiezorek, and Dr.
Christian Bohnen (both RWTH Aachen University) for helpful
discussions during the project.
REFERENCES
■
(1) Pitt, W. R.; Parry, D. M.; Perry, B. G.; Groom, C. R. J. Med. Chem.
2009, 52, 2952.
(2) Tsukamoto, T. ACS Med. Chem. Lett. 2013, 4, 369.
(3) (a) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52,
6752. (b) Lovering, F. MedChemComm 2013, 4, 515.
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DOI: 10.1021/acs.orglett.7b03475
Org. Lett. XXXX, XXX, XXX−XXX