Sodium Bicyclo[1.1.1]pentanesulfinate: A Bench-Stable Precursor for Bicyclo[1.1.1]pentylsulfones and Bicyclo- [1.1.1]pentanesulfonamides

Article abstract of DOI:10.1002/chem.202000097

Herein, we present the synthesis of the bench-stable sodium bicyclo[1.1.1]pentanesulfinate (BCP-SO₂Na) and its application in the synthesis of bicyclo[1.1.1]pentyl (BCP) sulfones and sulfonamides. The salt can be obtained in a four-step procedure from commercially available precursors in multigram scale without the need for column chromatography or crystallization. Sulfinates are known to be useful precursors in radical and nucleophilic reactions and are widely used in medicinal chemistry. This building block enables access to BCP sulfones and sulfonamides avoiding the volatile [1.1.1]propellane which is favorable for the extension of SAR studies. Further, BCP-SO₂Na enables the synthesis of products that were not available with previous methods. A chlorination of BCP-SO₂Na and subsequent reaction with a Grignard reagent provides a new route to BCP sulfoxides. Several products were analyzed by single-crystal X-ray diffraction.

Full text of DOI:10.1002/chem.202000097

A Journal of
Accepted Article
Title: Sodium Bicyclo[1.1.1]pentylsulfinate, a Bench-
stable Precursor for Bicyclo[1.1.1]pentylsulfones and
Bicyclo[1.1.1]pentylsulfonamides
Authors: Robin Bär, Patrick Groß, Martin Nieger, and Stefan Bräse
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.202000097
Link to VoR: http://dx.doi.org/10.1002/chem.202000097
Supported by

10.1002/chem.202000097
Chemistry - A European Journal
COMMUNICATION
Sodium Bicyclo[1.1.1]pentylsulfinate, a Bench-stable Precursor
for Bicyclo[1.1.1]pentylsulfones and
Bicyclo[1.1.1]pentylsulfonamides
Robin M. Bär,[a] Patrick J. Gross,[b] Martin Nieger[c] and Stefan Bräse*[a, d]
[a]
R. Bär, Prof. Dr. S. Bräse
Institute of Organic Chemistry
Karlsruhe Institute of Technology (KIT)
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
E-mail: braese@kit.edu
[b]
[c]
Dr. P. Gross
Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany
Dr. M. Nieger
Department of Chemistry
University of Helsinki
P.O. Box 55 (A. I. Virtasen aukio 1)
00014 Helsinki (Finland)
[d]
Prof. Dr. S. Bräse
Institute of Biological and Chemical Systems – FMS
Karlsruhe Institute of Technology (KIT)
Herman-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Supporting information for this article is given via a link at the end of the document.
Abstract: Herein we present the synthesis of the bench-stable
sodium bicyclo[1.1.1]pentylsulfinate (BCP-SO2Na) and its application
in the synthesis of bicyclo[1.1.1]pentyl (BCP) sulfones and
sulfonamides. The salt can be obtained in a four-step procedure from
commercially available precursors in multigram scale without the need
for column chromatography or crystallization. Sulfinates are known to
be useful precursors in radical and nucleophilic reactions and are
widely used in medicinal chemistry. This building block enables
access to BCP sulfones and sulfonamides avoiding the volatile
[1.1.1]propellane which is favorable for the extension of SAR studies.
Further, BCP-SO2Na enables the synthesis of products that were not
available with previous methods. A chlorination of BCP-SO2Na and
subsequent reaction with a Grignard reagent provides a new route to
BCP sulfoxides. Several products were analyzed by single crystal
X-ray diffraction.
However, all of these reactions require the handling of the volatile
precursor 5 and the necessity of Schlenk techniques in the
preparation. Bench-stable precursors facilitate the use of this
interesting group and a variety of BCP amines, acids and esters
are already commercially available. Recently Kanazawa,
Uchiyama et al. developed a gram scale synthesis of a silaborated
BCP.[15] The availability of sulfur-based BCP building blocks is still
limited and therefore the broad application of this bioisostere is
prevented.[16]
Sulfones and sulfonamides are, among other sulfur-containing
groups, common moieties in drug compounds,[1] with eletriptan (1),
a serotonin receptor agonist, and bosentan (2), an endothelin
receptor antagonist, being just two of many examples
(Figure 1 a).[2] ‘Escaping the flatland’ is a common trend in recent
years, where the bioisosteric replacement of planar aromatic
moieties
by
saturated
hydrocarbons
can
improve
pharmacological properties of drug candidates.[3] The rigid
bicyclo[1.1.1]pentanes (BCPs) have become famous target
structures in these approaches.[4] There have been studies that
have used BCPs successfully as a replacement of benzene
(Figure 1 b),[5] alkyne[6] and tert-butyl[7] groups.
Most BCPs are accessed by radical or anionic reactions with the
strained tricyclic compound [1.1.1]propellane (5).[8] The latter can
react with Grignard reagents,[6, 9] or alkyl iodides[9a, 10] to provide
aryl and alkyl substituted BCPs. BCP amines can be obtained by
the reaction of turbo-amides with 5.[11] Sulfur-based functional
groups allow the radical opening of 5 as well, as shown for
thiols,[12] disulfides[13] and xanthates.[14]
Figure 1. a) Examples for sulfone- and sulfonamide-containing drugs. b) The
replacement of a para-substituted fluorobenzene with BCP in the γ-secretase
inhibitor 3 led to improved pharmacological properties. c) Content of this work.
1
This article is protected by copyright. All rights reserved.

10.1002/chem.202000097
Chemistry - A European Journal
COMMUNICATION
Sulfinates seem to be ideal candidates for this purpose as they
are highly versatile reagents. They can be employed in
nucleophilic reactions, transition-metal catalysis or serve as
radical precursors.[17]
We
herein
report
the
synthesis
of
sodium
bicyclo[1.1.1]pentylsulfinate (BCP-SO2Na, 6) and the utilization of
this building block in different reactions to obtain BCP sulfones 7
and sulfonamides 8 (Figure 1 c).
The bench-stable salt could be obtained in good yield and purity
without the need of purification by column chromatography or
crystallization (Scheme 1). In the first step, [1.1.1]propellane (5)
was prepared from the commercially available precursor 9 with
phenyllithium as previously described and distilled together with
diethyl ether (see SI for details).[11a] The obtained solution was
used directly to perform a thiol addition with 10.[12] After one
washing step with NaOH-solution and removal of the solvent, pure
11 was obtained in 79% yield from 9. The sulfide 11 was oxidized
with 3-chloroperoxybenzoic acid (mCPBA), which led to formation
of 12 in 82% yield. The purity of 12 could be successfully
increased by changing the oxidant to oxone, yielding 72% after
extraction with dichloromethane. The sulfone 12 was converted to
the respective sulfinate in a retro-Michael reaction initiated by
sodium methoxide.[18] Without further purification, the product 6
was obtained in quantitative yield. The synthesis was performed
on a multigram-scale (9.4 g, 61 mmol) in an overall yield of 65%
(with mCPBA) or 57% (with oxone) over four steps.
Scheme 2. Syntheses of sulfones 7 through (a) SNAr, (b) copper(I) catalysis
and (c) alkylation. [a] Addition of 1.50 equiv. of K2CO3.
Numerous procedures can be found to convert sulfinates, isolated
or in situ, into sulfonamides. For a summary of recent methods
we refer the reader to review articles by Messaoudi, Alami and
Hamze et al.[17a] and Maulide et al.[17c] For the conversion of 6 into
N-alkyl sulfonamides 8a–b we chose the simple conditions by
Yuan et al. (Scheme 3a).[19] This reaction enables access to BCP
sulfonamides for the first time. Previous attempts with protected
BCP thiols (Bn- and TIPS-protected) were unsuccessful as the
BCP thiol seemed to rearrange during the deprotection step and
no desired product could be detected.
The primary BCP sulfonamide 8c could be obtained in very good
yield from 6 with hydroxylamine-O-sulfonic acid (Scheme 3b).
This compound provides easy access to N-acyl sulfonamides 16,
another medicinally relevant class of compounds.[20]
Scheme 1. Synthesis of sodium BCP-SO2Na (6) from commercially available
cyclopropane 9. The synthesis was performed on a multigram-scale (9.4 g,
61 mmol for method A). mCPBA: m-chloroperoxybenzoic acid; oxone:
2KHSO5·KHSO4·K2SO4.
With the novel building block 6 in hand, we performed several
reactions that prove its versatility. Nucleophilic aromatic
substitutions (SNAr) resulted in good to excellent yields with
electron-deficient aryl fluorides (7a–c), while poor to fair yields
were observed with heteroaryl chlorides (7d–e) (Scheme 2 a). It
should be noted that attempts to obtain heteroaryl-substituted
BCP sulfides through aromatic thiol addition to 5 were not
successful. This method is the first to provide access to
heteroaryl-containing structures, e.g. 7d and 7e, to our current
knowledge.
To access BCP sulfones with aryl substituents with higher
electron density such as 7f, a copper(I)-catalyzed reaction was
deployed successfully (Scheme 2 b).
Simple alkylation with methyl iodide (14) could be performed
without the addition of a base at low temperature (0 °C)
(Scheme 2 c).
Scheme 3. Syntheses of N-alkyl sulfonamides 8a–b (a) and primary
sulfonamide 8c (b).
To further extend the possible modifications of 6, a chlorination
was performed and the sulfinyl chloride 17 was reacted with
phenylmagnesium bromide in situ to obtain sulfoxide 18
(Scheme 4).
2
This article is protected by copyright. All rights reserved.

10.1002/chem.202000097
Chemistry - A European Journal
COMMUNICATION
Subramanyam, I. V. Efremov, J. K. Dutra, T. J. O'Sullivan,
K. J. DiRico, W. S. McDonald, A. Won, P. H. Dorff, C. E.
Nolan, S. L. Becker, L. R. Pustilnik, D. R. Riddell, G. W.
Kauffman, B. L. Kormos, L. Zhang, Y. Lu, S. H. Capetta,
M. E. Green, K. Karki, E. Sibley, K. P. Atchison, A. J.
Hallgren, C. E. Oborski, A. E. Robshaw, B. Sneed, C. J.
O'Donnell, J. Med. Chem. 2012, 55, 3414–3424; c) K. C.
Nicolaou, D. Vourloumis, S. Totokotsopoulos, A.
Papakyriakou, H. Karsunky, H. Fernando, J. Gavrilyuk, D.
Webb, A. F. Stepan, ChemMedChem 2016, 11, 31–37; d)
Y. P. Auberson, C. Brocklehurst, M. Furegati, T. C.
Fessard, G. Koch, A. Decker, L. La Vecchia, E. Briard,
ChemMedChem 2017, 12, 590–598; e) Y. L. Goh, E. K.
Tam, P. H. Bernardo, C. B. Cheong, C. W. Johannes, A.
D. William, V. A. Adsool, Org. Lett. 2014, 16, 1884–1887;
f) N. D. Measom, K. D. Down, D. J. Hirst, C. Jamieson, E.
S. Manas, V. K. Patel, D. O. Somers, ACS Med. Chem.
Lett. 2017, 8, 43–48.
Scheme 4. Chlorination of 6 and subsequent reaction with phenylmagnesium
bromide to sulfoxide 18.
For several products, we were able to obtain single crystals and
determine the structure by X-Ray diffraction (SI). Three of those
structures (7a, 7g, 8b) are shown in Figure 2.
[6]
[7]
I. S. Makarov, C. E. Brocklehurst, K. Karaghiosoff, G.
Koch, P. Knochel, Angew. Chem. Int. Ed. 2017, 56,
12774–12777.
Figure 2. Molecular structures of 7a, 7g and 8b determined by X-Ray diffraction.
The displacement parameters are drawn at 50% probability level.
a) M. R. Barbachyn, D. K. Hutchinson, D. S. Toops, R. J.
Reid, G. E. Zurenko, B. H. Yagi, R. D. Schaadt, J. W.
Allison, Bioorg. Med. Chem. Lett. 1993, 3, 671–676; b) M.
V. Westphal, B. T. Wolfstädter, J.-M. Plancher, J. Gatfield,
E. M. Carreira, ChemMedChem 2015, 10, 461–469.
a) A. M. Dilmaç, E. Spuling, A. de Meijere, S. Bräse,
Angew. Chem. Int. Ed. 2017, 56, 5684–5718; b) J.
Kanazawa, M. Uchiyama, Synlett 2019, 30, 1–11.
a) M. Messner, Sergei I. Kozhushkov, A. de Meijere, Eur.
J. Org. Chem. 2000, 2000, 1137–1155; b) J. D. D. Rehm,
B. Ziemer, G. Szeimies, Eur. J. Org. Chem. 1999, 1999,
2079–2085.
a) J. Nugent, C. Arroniz, B. R. Shire, A. J. Sterling, H. D.
Pickford, M. L. J. Wong, S. J. Mansfield, D. F. J. Caputo,
B. Owen, J. J. Mousseau, F. Duarte, E. A. Anderson, ACS
Catal. 2019, 9, 9568–9574; b) D. F. J. Caputo, C. Arroniz,
A. B. Dürr, J. J. Mousseau, A. F. Stepan, S. J. Mansfield,
E. A. Anderson, Chem. Sci. 2018, 9, 5295–5300.
a) R. Gianatassio, J. M. Lopchuk, J. Wang, C.-M. Pan, L.
R. Malins, L. Prieto, T. A. Brandt, M. R. Collins, G. M.
Gallego, N. W. Sach, J. E. Spangler, H. Zhu, J. Zhu, P. S.
Baran, Science 2016, 351, 241–246; b) J. M. E. Hughes,
D. A. Scarlata, A. C. Y. Chen, J. D. Burch, J. L. Gleason,
Org. Lett. 2019, 21, 6800–6804.
R. M. Bär, S. Kirschner, M. Nieger, S. Bräse, Chem. Eur.
J. 2018, 24, 1373–1382.
R. M. Bär, G. Heinrich, M. Nieger, O. Fuhr, S. Bräse,
Beilstein J. Org. Chem. 2019, 15, 1172–1180.
S. K. Rout, G. Marghem, J. Lan, T. Leyssens, O. Riant,
Chem. Commun. 2019, 55, 14976–14979.
M. Kondo, J. Kanazawa, T. Ichikawa, T. Shimokawa, Y.
Nagashima, K. Miyamoto, M. Uchiyama, Angew. Chem.
Int. Ed., doi:10.1002/anie.201909655.
To the best of our knowledge there are only few sulfur-
containing BCPs available from Enamine Ltd. BCP thiol
costs ~2000 $/g
In conclusion, we have developed a four-step synthesis of
BCP-SO2Na (6) from commercially available precursors. The
synthesis is scalable and requires no chromatography or
crystallization to purify the product. We have shown the
application of this building block in the syntheses of several
sulfones and sulfonamides. The synthesis of sulfoxides was
shown for one example as a proof-of-concept.
This building block will be a useful tool in novel structure-activity-
relationship studies and will expand the application of BCPs in
medicinal chemistry.
[8]
[9]
[10]
[11]
Experimental Section
Full experimental details and analytical data (1H NMR, 13C NMR, X-ray
analysis) are provided in the Supporting Information (SI).
CCDC 1959595 (7a), 1959596 (7b), 1959597 (7c), 1959598 (7g), and
1959599 (8b) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[12]
[13]
[14]
[15]
Acknowledgements
R.M.B. acknowledges the SFB 1176 funded by the German
Research Foundation (DFG) in the context of projects A4 & B3 for
funding.
[16]
[17]
a) J. Aziz, S. Messaoudi, M. Alami, A. Hamze, Org.
Biomol. Chem. 2014, 12, 9743–9759; b) J. M. Smith, J. A.
Dixon, J. N. deGruyter, P. S. Baran, J. Med. Chem. 2019,
62, 2256–2264; c) D. Kaiser, I. Klose, R. Oost, J.
Neuhaus, N. Maulide, Chem. Rev. 2019, 119, 8701–8780.
J. M. Baskin, Z. Wang, Tetrahedron Lett. 2002, 43, 8479–
8483.
X. Pan, J. Gao, J. Liu, J. Lai, H. Jiang, G. Yuan, Green
Chem. 2015, 17, 1400–1403.
A. Ammazzalorso, B. De Filippis, L. Giampietro, R.
Amoroso, Chem. Biol. Drug Des. 2017, 90, 1094–1105.
Keywords: bioisosteres • sulfonamides • sulfur • propellanes •
bicyclo[1.1.1]pentane
[18]
[19]
[20]
[1]
[2]
[3]
[4]
[5]
M. Feng, B. Tang, S. H. Liang, X. Jiang, Curr. Top. Med.
Chem. 2016, 16, 1200–1216.
K. A. Scott, J. T. Njardarson, Top. Curr. Chem. 2018, 376,
1–34.
F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009,
52, 6752–6756.
G. M. Locke, S. S. R. Bernhard, M. O. Senge, Chem. Eur.
J. 2019, 25, 4590–4647.
a) R. Pellicciari, R. Filosa, M. C. Fulco, M. Marinozzi, A.
Macchiarulo, C. Novak, B. Natalini, M. B. Hermit, S.
Nielsen, T. N. Sager, T. B. Stensbøl, C. Thomsen,
ChemMedChem 2006, 1, 358–365; b) A. F. Stepan, C.
3
This article is protected by copyright. All rights reserved.

10.1002/chem.202000097
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
We present a scalable synthesis of the bench-stable sodium bicyclo[1.1.1]pentane sulfinate (BCP-SO2Na) in four steps without the
need of chromatography or crystallization. Further its application in the synthesis of BCP sulfones and sulfonamides is shown.
Institute and/or researcher Twitter usernames: @braeselab, @BraseStefan, @Propellanes, @KITKarlsruhe
4
This article is protected by copyright. All rights reserved.