Building Block Approach for the Synthesis of Sulfoximines

Article abstract of DOI:10.1021/acs.orglett.6b02678

A cross-coupling strategy for the preparation of novel sulfoximines via preformed sulfoximidoyl-containing building blocks has been developed. It allows obtaining a wide range of products in good yields under mild reaction conditions, and it can be applied in late-stage functionalizations, as demonstrated by the synthesis of a sulfoximine-based analogue of a recently reported potent valosine-containing protein inhibitor.

Full text of DOI:10.1021/acs.orglett.6b02678

Letter
pubs.acs.org/OrgLett
Building Block Approach for the Synthesis of Sulfoximines
Anne-Dorothee Steinkamp, Stefan Wiezorek, Felix Brosge, and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany
*
S Supporting Information
ABSTRACT: A cross-coupling strategy for the preparation of
novel sulfoximines via preformed sulfoximidoyl-containing
building blocks has been developed. It allows obtaining a
wide range of products in good yields under mild reaction
conditions, and it can be applied in late-stage functionaliza-
tions, as demonstrated by the synthesis of a sulfoximine-based
analogue of a recently reported potent valosine-containing
protein inhibitor.
1
he growing interest of applying sulfoximines in medicinal
integrated into a target structure at a late stage of a synthesis
could offer attractive solutions (Scheme 1, bottom).
2
3
T
chemistry and crop protection has prompted the
development of new strategies for the incorporation of
sulfoximidoyl moieties in functionalized molecules. The majority
of sulfoximine syntheses start from the corresponding sulfide,
Biaryl or heteroaryl units are important scaffolds in bioactive
compounds. In many cases, these motifs are introduced by
Suzuki−Miyaura couplings, which have proven to be robust and
4
8
which is oxidized and imidated in discretionary order. In most
cases, the resulting sulfoximines are N-protected, and an
additional step to reach the free NH-sulfoximine is required
industrially applicable. The success of these carbon−carbon
bond formations depends significantly on the type of boron
reagent and the reaction conditions, which have to be carefully
9
(Scheme 1, top). In addition to developing various protocols for
fine-tuned. With the vision of developing a building block
1
0
approach toward diaryl-containing sulfoximines, we felt
11
Scheme 1. Previous and Newly Developed Preparation of NH-
Sulfoximines
attracted to the work of Burke, who has established the use
of N-methyliminodiacetic acid (MIDA) boronates in such cross-
coupling reactions. Being stable to air, moisture, and silica gel,
these N-coordinated cyclic boronic esters appeared most
promising for our strategy. The first results of this study, which
involved the syntheses of novel MIDA boronates bearing
1
2
sulfoximidoyl substituents, are illustrated here.
The work by Burke
11f,g
suggested two routes toward thioanisyl
MIDA boronates 2, which we considered as key intermediates for
the syntheses of target structures 6 (Scheme 2). They differed in
the starting material. While route A made use of thioanisyl
bromoarenes 1, route B started from the corresponding boronic
acids 4. Both led to target compounds 6, but the overall efficiency
of route B was higher (considering the product yields and the
process practicability). For example, treatment of para-
substituted methyl sulfide 1a with triisopropylborate and
nBuLi in THF at −78 °C followed by transligation with MIDA
(3) in hot DMSO gave para-thioanisyl MIDA boronate 2a in
5
6
the synthesis and further functionalization of sulfoximines, we
have interest in the preparation of sulfoximidoyl-containing
3
0% yield (route A), whereas applying boronic acid 4a in the
7
reaction with 3 (route B) led to 2a in 88% yield. Analogously,
starting from meta-substituted 1b, meta-thioanisyl MIDA
boronate 2b was obtained in 68% yield (route A), while the
same product was isolated in 73% yield when boronic acid 4b was
applied following route B. The ortho-substituted 4c gave ortho-
thioanisyl MIDA boronate 2c in 81% yield. All three thioanisyl
MIDA boronates 2a−c could smoothly be oxidized to the
analogues of bioactive compounds. In general, the latter
molecules exhibit a high density of functional groups, and for
the synthetic efficiency, it is critical in which phase of the
synthesis the sulfoximidoyl moiety is introduced. For example, if
installed late, the chemical complexity of the molecular backbone
might hamper the aforementioned sulfur oxidation/imination
sequence. If introduced early, a sulfoximidoyl group can either
affect the subsequent synthetic steps or, in the worst case, be
degraded. In the light of this situation, preformed bench-stable
sulfoximidoyl-containing building blocks, which could be
Received: September 6, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02678
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Organic Letters
Letter
Scheme 2. Syntheses of Sulfoximidoylic Building Blocks 6a
and 6b
Scheme 3. Coupling between MIDA Boronate 6a and Various
Aryl and Heteroaryl Bromides
but the structural features played an important role, as revealed
by the very different results in the formation of 2-pyridinyl- and
2
-thiophenyl-substituted products 8k and 8l, which were
obtained in 20 and 80%, respectively. In several cases, the
crude product mixture contained significant amounts of the
corresponding N-trifluoroacetyl-substituted sulfoximine, reveal-
ing an incomplete cleavage of the protecting group during the
reaction and the subsequent workup. In those cases, the yield of
the desired NH-sulfoximine could be increased by stirring the
corresponding sulfoxides 5a−c using mCPBA in DCM at
ambient temperature (Scheme 2). For the final step, a rhodium-
catalyzed imination procedure developed in our group was
selected. The mild reaction conditions allow sulfoxide iminations
with readily available reagents and low catalyst loading (2.5 mol
13
crude reaction mixture in methanol in the presence of K CO for
2
3
2
h at room temperature. Most significantly, by following this
protocol, modification of the yield of 8g increased from 33 to
8
0% (Scheme 3).
Retaining the reaction conditions, couplings with meta-
%
) at room temperature, leading to N-trifluoroacetyl-protected
sulfoximines, which are synthetically privileged due to their
relative stability and ease of deprotection. While the imination of
sulfoximidoyl MIDA boronate 6b were studied next (Scheme
4
). This building block was also suitable, and products 9a−c were
2
a and 2b proceeded well, leading to para- and meta-
17
obtained in yields between 67 and 93%.
sulfoximidoyl MIDA boronates 6a and 6b in 71 and 79% yield,
respectively, only traces of ortho-substituted 6c were observed
Scheme 4. Couplings Involving MIDA Boronate 6b
(
by NMR spectroscopy) in the attempt to convert thioanisyl
14
MIDA boronate 2c. Presumably, the steric hindrance induced
by the bulky MIDA boronyl group ortho to the sulfoxide moiety
hampered the imination process.
With building blocks 6a and 6b in hand, Suzuki−Miyaura
coupling processes with aryl bromides were investigated to
validate the overall concept for the preparation of diaryl-
containing NH-sulfoximines. After several reaction parameters
were screened (temperature, catalyst, and base; for details, see
Supporting Information) with bromobenzene and para-sulfox-
imidoyl MIDA boronate 6a as representative starting materials,
the optimal reaction conditions involved the use of Pd(OAc) (5
Finally, we intended to demonstrate the synthetic value of the
newly devised building block approach by a late-stage
functionalization of a more complex molecule containing
multiple heteroatoms. Along these lines, we felt attracted by
sulfone 10, which was shown to be a potent and selective
valosine-containing protein (VCP) inhibitor with significant
2
mol %), XPhos (10 mol %), and K CO (aqueous solution) in
2
3
dioxane under an argon atmosphere at 40 °C for 26 h. Under
these conditions, coupling product 8a was obtained in 86% yield
1
5,16
(Scheme 3).
Other aryl/heteroaryl bromides reacted well
with MIDA boronate 6a, too, and in general, the target products
were isolated in good yields. Electronic factors appeared to have
only a minor effect on the coupling. Comparing the yields of 8b−
d indicated a negative influence of an ortho-substituent.
Nevertheless, using 2,6-dimethylbromobenzene led to sulfox-
imine 8i in 73% yield. Also, heteroaryl bromides could be applied,
1
8
antiproliferative activity (Scheme 5). Structurally, 10 is
characterized by its 1,2,4-triazole core, the 3-pyridinyl substituent
at the 3 position of the heterocycle, and the ether and thioether
linkages. Considering the potential of a bioisosteric replacement
2
of the sulfonyl group by a sulfoximidoyl moiety, we envisaged
B
DOI: 10.1021/acs.orglett.6b02678
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) For a recent reference on the synthesis of isoclast (sulfoxaflor),
Scheme 5. Synthesis of NH-Sulfoximine 12: Analogue of the
which is a relevant sulfoximidoyl-containing crop protection agent
commercialized by Dow AgroScience, see: Arndt, K. E.; Bland, D. C.;
Irvine, N. M.; Powers, S. L.; Martin, T. P.; McConnell, J. R.; Podhorez,
D. E.; Renga, J. M.; Ross, R.; Roth, G. A.; Scherzer, B. D.; Toyzan, T. W.
Org. Process Res. Dev. 2015, 19, 454.
VCP Inhibitor 10
(4) (a) For a review on sulfide imidation methods, see: Bizet, V.;
Hendriks, C. M. M.; Bolm, C. Chem. Soc. Rev. 2015, 44, 3378. (b) For a
recent methodological extension, see: Zenzola, M.; Doran, R.;
Degennaro, L.; Luisi, R.; Bull, J. A. Angew. Chem., Int. Ed. 2016, 55, 7203.
(5) For recent work, see: (a) Wen, J.; Cheng, H.; Dong, S.; Bolm, C.
Chem. - Eur. J. 2016, 22, 5547. (b) Dannenberg, C. A.; Bizet, V.; Bolm, C.
Synthesis 2015, 47, 1951. (c) Bizet, V.; Buglioni, L.; Bolm, C. Angew.
Chem., Int. Ed. 2014, 53, 5639.
(6) For recent examples, see: (a) Muneeswara, M.; Kotha, S. S.; Sekar,
G. Synthesis 2016, 48, 1541. (b) Cheng, H.; Bolm, C. Synlett 2016, 27,
7
2
2
69. (c) Bohmann, R. A.; Unoh, Y.; Miura, Y.; Bolm, C. Chem. - Eur. J.
016, 22, 6783. (d) Wang, H.; Frings, M.; Bolm, C. Org. Lett. 2016, 18,
431. (e) Pirwerdjan, R.; Becker, P.; Bolm, C. Org. Lett. 2016, 18, 3307.
the synthesis of sulfoximine 12 following the previously
introduced building block strategy. To our delight, the approach
proved successful, providing 12 by coupling of 6a with aryl
bromide 11. Although the yield of 12 was low (15%), we
considered the preparation of this compound a success as it
provided sufficient product quantities for potential biological
tests.
(f) Wang, H.; Cheng, Y.; Becker, P.; Raabe, G.; Bolm, C. Angew. Chem.,
Int. Ed. 2016, 55, 12655. (g) Aithagani, S. K.; Dara, S.; Munagala, G.;
Aruri, H.; Yadav, M.; Sharma, S.; Vishwakarma, R. A.; Singh, P. P. Org.
Lett. 2015, 17, 5547.
(
7) For selected examples, see: (a) Steinkamp, A.-D.; Seling, N.; Lee,
S.; Boedtkjer, E.; Bolm, C. MedChemComm 2015, 6, 2163. (b) Hendriks,
C. M. M.; Nurnberg, P.; Bolm, C. Synthesis 2015, 47, 1190. (c) Park, S. J.;
In summary, we developed sulfoximidoylic building blocks,
which can be used for synthesizing diaryl-containing NH-
sulfoximines by Suzuki−Miyaura-type cross-couplings and late-
stage functionalizations. Applying these air- and moisture-stable
molecular scaffolds in automated synthesis will rapidly expand
̈
Baars, H.; Mersmann, S.; Buschmann, H.; Baron, J. M.; Amann, P. M.;
Czaja, K.; Hollert, H.; Bluhm, K.; Redelstein, R.; Bolm, C.
ChemMedChem 2013, 8, 217.
(
8) (a) Shimizu, M.; Hiyama, T. Eur. J. Org. Chem. 2013, 2013, 8069.
19
(b) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177. (c) Torborg,
C.; Beller, M. Adv. Synth. Catal. 2009, 351, 3027. (d) Naso, F.; Babudri,
F.; Farinola, G. M. Pure Appl. Chem. 1999, 71, 1485.
the sulfoximine portfolio and advance library synthesis.
ASSOCIATED CONTENT
Supporting Information
■
(
9) For very detailed mechanistic analyses of Suzuki−Miyaura
*
S
coupling reactions, see: (a) 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, DOI: 10.1038/nchem.2571.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02678.
(b) Cox, P. A.; Leach, A. G.; Campbell, A. D.; Lloyd-Jones, G. C. J. Am.
Experimental procedures, analytical data, and NMR
spectra of the presented products (PDF)
Chem. Soc. 2016, 138, 9145. (c) Lennox, A. J. J.; Lloyd-Jones, G. C.
Chem. Soc. Rev. 2014, 43, 412. (d) Lennox, A. J. J.; Lloyd-Jones, G. C.
Angew. Chem., Int. Ed. 2013, 52, 7362. (e) Lennox, A. J. J.; Lloyd-Jones,
G. C. J. Am. Chem. Soc. 2012, 134, 7431.
(10) For the coupling of a sulfoximidoyl-containing aryl bromide with
aryl boronic acids, see: Cho, G. Y.; Okamura, H.; Bolm, C. J. Org. Chem.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: carsten.bolm@oc.rwth-aachen.de.
2
(
005, 70, 2346.
11) (a) Li, J.; Grillo, A. S.; Burke, M. D. Acc. Chem. Res. 2015, 48, 2297.
(b) Woerly, E. M.; Miller, J. E.; Burke, M. D. Tetrahedron 2013, 69, 7732.
c) Dick, G. R.; Woerly, E. M.; Burke, M. D. Angew. Chem., Int. Ed. 2012,
51, 2667. (d) Li, J.; Burke, M. D. J. Am. Chem. Soc. 2011, 133, 13774.
Notes
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
The authors express their gratitude to Prof. Dr. P. Wipf
Department of Pharmacology & Chemical Biology, University
■
(
(
(
e) Struble, J. R.; Lee, S. J.; Burke, M. D. Tetrahedron 2010, 66, 4710.
f) Dick, G. R.; Knapp, D. M.; Gillis, E. P.; Burke, M. D. Org. Lett. 2010,
1
2, 2314. (g) Knapp, D. M.; Gillis, E. P. J. Am. Chem. Soc. 2009, 131,
of Pittsburgh) for stimulating discussions. Furthermore, we
thank Dr. C. Rauber (Institute of Organic Chemistry, RWTH
Aachen University) for special NMR experiments. A.-K. Roye
Institute of Organic Chemistry, RWTH Aachen University) is
6
961.
̈
(
12) Sulfoximidoylic boronic acids have recently been mentioned in
́
patent applications: (a) Wortmann, L.; Luecking, U.; Lefranc, J.; Briem,
H.; Koppitz, M.; Eis, K.; Nussbaum, V.; Bader, F.; Wengner, B.; Margret,
A.; Gerhard, S.; Bone, W.; Lienau, P.; Grudzinska-Goebel, J.;
Moosmayer, D.; Eberspaecher, U.; Schick, H. Patent Appl. WO
2016020320, 2016. (b) Alexander, R. P.; Calmiano, M. D.; Defays, S.;
Durieu, V.; Deligny, M.; Heer, J. P.; Jackson, V. E.; Keyaerts, J.;
Kroeplien, B.; Mac Coss, M.; Sabnis, Y. A.; Selby, M. D.; Swinnen, D. L.
L.; Van Houtvin, N.; Zhu, Z. Patent Appl. WO 2015086525 A1, 2015.
(13) Okamura, H.; Bolm, C. Org. Lett. 2004, 6, 1305.
(14) In this study, only racemic products have been prepared. For
recent developments in preparing optically active sulfoximines by
asymmetric synthesis, see: (a) Dong, S.; Frings, M.; Cheng, H.; Wen, J.;
Zhang, D.; Raabe, G.; Bolm, C. J. Am. Chem. Soc. 2016, 138, 2166.
(b) Wang, J.; Frings, M.; Bolm, C. Angew. Chem., Int. Ed. 2013, 52, 8661.
(
thanked for practical assistance.
REFERENCES
■
(
1) For selected reviews demonstrating the relevance of sulfoximines in
organic synthesis, see: (a) Bizet, V.; Kowalczyk, R.; Bolm, C. Chem. Soc.
Rev. 2014, 43, 2426. (b) Shen, X.; Hu, J. Eur. J. Org. Chem. 2014, 4437.
(
c) Gais, H.-J. Heteroat. Chem. 2007, 18, 472. (d) Okamura, H.; Bolm, C.
Chem. Lett. 2004, 33, 482. (e) Harmata, M. Chemtracts 2003, 16, 660.
f) Reggelin, M.; Zur, C. Synthesis 2000, 1. (g) Johnson, C. R. Acc. Chem.
Res. 1973, 6, 341.
2) For an overview on the relevance of sulfoximines in medicinal
chemistry, see: Lucking, U. Angew. Chem., Int. Ed. 2013, 52, 9399.
(
(
̈
C
DOI: 10.1021/acs.orglett.6b02678
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Organic Letters
Letter
(
15) The attempt to apply a sulfoximidoyl-substituted pinacol boronic
acid ester analogous to 6a gave an unsatisfying result.
16) During the coupling process, partial protodeboronation occurred,
(
and the presence of the byproducts impeded the cleaning process by
column chromatography. Performing the coupling reactions at 40 °C
minimized this side reaction.
(
17) As meta-sulfoximidoyl MIDA boronate 6c remained inaccessible,
we investigated the cross-coupling of the corresponding sulfoxide 5c
with bromobenzene. The reaction proceeded well, providing 2-biphenyl
methyl sulfoxide in 87% yield. Attempts to iminate this product by the
aforementioned rhodium catalysis led to only trace quantities of the
1
expected sulfoximine (as proven by H NMR spectroscopy and mass
spectrometry).
(
18) Polucci, P.; Magnaghi, P.; Angiolini, M.; Asa, D.; Avanzi, N.;
Badari, A.; Bertrand, J.; Casale, E.; Cauteruccio, S.; Cirla, A.; Cozzi, L.;
Galvani, A.; Jackson, P. K.; Liu, Y.; Magnuson, S.; Malgesini, B.;
Nuvoloni, S.; Orrenius, C.; Sirtori, F. R.; Riceputi, L.; Rizzi, S.; Trucchi,
B.; O’Brien, T.; Isacchi, A.; Donati, D.; D’Alessio, R. J. Med. Chem. 2013,
56, 437.
(
19) For a recent (poster) publication along these lines, see: Knol, J.;
Cecchi, A.; Knol, J.; Pouwer, K. Polycyclic Sulfoximines as Scaffolds for
Library Production (P206), XXIV EFMC International Symposium on
Medicinal Chemistry, Manchester, UK; August 28−September 1, 2016.
D
DOI: 10.1021/acs.orglett.6b02678
Org. Lett. XXXX, XXX, XXX−XXX