2-Sulfoximidoyl acetic acids from multicomponent petasis reactions and their use as building blocks in syntheses of sulfoximine benzodiazepine analogues

Article abstract of DOI:10.1021/acs.orglett.1c00874

Upon application of a multicomponent Petasis reaction, a broad range of NH-sulfoximines and boronic acids react with glyoxalic acid to afford the corresponding 2-substituted acetic acids with N-bound sulfoximidoyl groups. The protocol features excellent y

Full text of DOI:10.1021/acs.orglett.1c00874

pubs.acs.org/OrgLett
Letter
2‑Sulfoximidoyl Acetic Acids from Multicomponent Petasis
Reactions and Their Use as Building Blocks in Syntheses of
Sulfoximine Benzodiazepine Analogues
̀
́
̃
ez Ponce, Khai-Nghi Truong, Kari Rissanen,
Rene Hommelsheim, Heliana Michaela Nun
and Carsten Bolm*
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ABSTRACT: Upon application of a multicomponent Petasis reaction, a
broad range of NH-sulfoximines and boronic acids react with glyoxalic
acid to afford the corresponding 2-substituted acetic acids with N-bound
sulfoximidoyl groups. The protocol features excellent yields under
ambient, metal-free conditions and short reaction times. Furthermore,
the applicability of 2-sulfoximidoyl acetic acids as building blocks for
synthesizing sulfoximine-based benzodiazepine analogues was demon-
strated.
Scheme 1. Bioactive Compounds with Sulfoximidoyl Motifs
ince the discovery of methionine sulfoximine (MSO) in
the late 1940s,1 sulfoximines have evolved from a chemical
S
rarity to a broadly applied and powerful tool in organic
chemistry.2 On the basis of their spatial structure and the
ability to form complexes with metals, sulfoximines have found
early applications as “chemical chameleons” in enantioselective
synthesis.3 In recent years, numerous publications and patents
have highlighted their potential in medicinal chemistry4 and
crop protection.5 As the sulfoximidoyl moiety is a small
hydrophilic group that can fine-tune the acid/base properties
by variation of the substituents attached to the nitrogen atom,
sulfoximines have become of great interest in the design of new
pharmacophores and bioisosteres for several chemical motifs.
The most prominent example of a bioactive compound with a
sulfoximidoyl motif is the commercial available insecticide
sulfoxaflor 1 (Scheme 1A, Isoclast), a nicotinic acetylcholine
receptor (nAChR) inhibitor.5 More recently, Bayer developed
and tested Roniciclib (2) as a pan-cyclin-dependent kinase
(pan-CDK) inhibitor in phase II studies.6
In light of our ongoing studies of the N-functionalization of
sulfoximines7 and bioactive compounds based on such
entities,8 we became interested in the synthesis of 2-
sulfoximidoyl acetic acids 4 as potential building blocks,
which could be useful in the construction of highly complex
sulfoximidoyl-containing scaffolds such as compound 3, a
candidate for an IRAK4 (interleukin-1 receptor-associated
kinase 4) inhibitor.9 Retrosynthetic analysis (Scheme 1B) of
the 2-sulfoximidoyl acetic acid scaffold 4 suggests a multi-
component Petasis reaction as an elegant way to access these
structures.
Received: March 13, 2021
Published: April 8, 2021
Discovered in the early 1990s by Petasis and co-workers,10
the Petasis reaction (borono-Mannich reaction) has become a
powerful synthetic tool in organic chemistry.11 Originally, this
https://doi.org/10.1021/acs.orglett.1c00874
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3415−3420
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a
multicomponent reaction referred to the synthesis of allyl-
amines from vinyl boronic acids, secondary amines, and
paraformaldehyde.10 In the following years, the concept was
expanded to the synthesis of amino acids12 and natural
products11a or the diversification of peptides.13 In addition to a
broad variety of amines, imines,14 enamines,14a and sulfona-
mides15 have also been investigated as the nitrogen
component. To the best of our knowledge, sulfoximines,
sulfilimines, or sulfonimidamides have not yet been inves-
tigated in this context.
Scheme 2. Investigation of the Substrate Scope
For a proof of concept, the reaction of S,S-diphenyl
sulfoximine (5a), glyoxylic acid (6), and phenylboronic acid
(7a) in nitromethane under previously reported conditions
was investigated (Table 1).15a To our delight, the correspond-
a
Table 1. Optimization of the Reaction Conditions
b
entry
equiv of 6/7a
volume (mL)
solvent
yield (%)
1
2
3
4
5
6
7
8
9
1.3/2.0
1.3/2.0
1.3/2.0
1.3/2.0
1.3/2.0
1.3/2.0
1.3/1.5
1.1/2.0
1.1/2.0
1.1/2.0
1.1/2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.0
1.0
MeNO2
EtOAc
THF
toluene
H2O
DCE
DCE
DCE
DCE
80
86
62
92
trace
98
30
99
99
99
c
10
11
DCE
DCE
c,d
99
a
Reaction conditions: 5a (0.25 mmol), 6 (0.33 mmol, 50% in H2O),
b
7a (0.50 mmol), solvent (1.5 mL), at 60 °C for 16 h. After column
a
c
Reaction conditions: 5 (0.40 mmol), 6 (0.44 mmol, 50% in H2O), 7
chromatography. Reaction performed on a 0.40 mmol scale.
b
d
(0.80 mmol), DCE (1.0 mL), at 60 °C for 3.5 h. With 4.60 mmol of
5a, at 60 °C for 6.5 h. After 16 h of reaction time.
Reaction finished after 3.5 h.
c
ing product 4aa was obtained in 80% yield after a reaction time
of 16 h.16 While the screening of different solvents revealed a
broad variety of solvents were well tolerated, 1,2-dichloro-
ethane (DCE) proved to be superior, affording the desired
product in 98% yield (entry 6). As shown in entry 5, water was
an unsuitable solvent, affording the product in only trace
amounts. Changing the ratio of 6 and 7a by decreasing the
amount of 7a led to a significantly lower yield of 30% (entry
7). On the contrary, the variation of the initial ratio of 1.3/2.0
to 1.1/2.0 did not diminish the yield (entry 8). Furthermore,
neither reducing the volume of the solvent (entry 9) nor
increasing the scale of the reaction (entry 10) impacted the
yield of 99%. Finally, the reaction time was decreased to 3.5 h
without a decrease in the yield (entry 11).17
With the optimal conditions in hand (Table 1, entry 11), the
substrate scope was investigated (Scheme 2). First, the aryl
boronic acid component was varied in reactions with S,S-
diphenyl sulfoximine (5a) and glyoxylic acid (6). In general, all
corresponding products 4aa−4ah were obtained in good to
excellent yields (65−99%). As shown by elemental analysis of
various compounds, the carboxylic acids were isolated as the
corresponding anhydrates in this series.18 Aryl boronic acids
with both electron-withdrawing and electron-donating groups
reacted well. An exception was strongly electron-deficient aryl
boronic acid 7f, which did not afford desired product 4af.
Rather unexpectedly, the lowest yield in this series was
observed with p-tolyl boronic acid (7b), giving 4ab in only
65% yield. The reactions with 2-naphthyl- and 3-benzo-
thiophthyl-substituted boronic acids 7g and 7h proceeded
smoothly to give 4ag and 4ah in 93% and 98% yields,
respectively. Upscaling the reaction to 1.0 g of NH-sulfoximine
5a proceeded well, affording the corresponding product 4aa in
98% yield after an extended reaction time of 6.5 h. The attempt
to use methylboronic acid (7i), representing a non-aromatic
coupling partner, in the reaction with 5a and 6 failed, and 4ai
remained undetected.19
Next, the sulfoximine structure was altered and products
4ba−4pa were targeted (Scheme 2). In combination with 6
and 7a, dibenzothiophene sulfoximine (5b) afforded the
corresponding product 4ba in 49% yield. The molecular
structure of 4ba, which crystallized as a monohydrate, was
confirmed by single-crystal X-ray analysis.20 Applying unsym-
metrically substituted S,S-diaryl sulfoximines led to the
corresponding products 4ca−4la in yields between 27% and
97%. While most products were formed as 1:1 mixtures of
diastereomers,21 the dr for 4ja was 1.0:3.3.22 Comparing the
results from the experiments with 4-, 3-, and 2-nitro-
substituted sulfoximines (5f, 5i, and 5k, respectively) revealed
that steric effects had an only weak influence on the yield of
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the corresponding carboxylic acid (4fa, 4ia, and 4ka,
respectively). Except for the strongly electron-deficient
trifluoromethyl-substituted sulfoximine 5g, which required an
extended reaction time of 16 h, electronic effects did not
influence the yield. Sulfoximines with alkyl-substituted S-aryl
groups (5c, 5d, and 5h) worked less efficiently, affording the
corresponding products 4ca (54%), 4da (80%), and 4ha
(27%), respectively, in significantly lower yields. Interestingly,
in this series, 4-tert-butyl-substituted sulfoximine 5d gave the
best result (80%). While the reaction of S-2-naphthyl-
substituted sulfoximine 5l resulted in an 87% yield of 4la, no
product was observed with 2-pyridyl-substituted sulfoximine
5m. To our surprise, carboxylic acids 4na and 4oa stemming
from the corresponding S-aryl sulfoximines with S-alkyl
substituents could not be obtained under these conditions.
As 4oa was identified by HRMS, we presume that those
products were formed but unstable, resulting in a rapid
degradation. S-Trifluoromethyl derivative 4pa was not formed
due to the low reactivity of the parent NH-sulfoximine.
To further investigate the substrate scope, the optimal
reaction conditions were applied to sulfilimine 9 and
sulfonimidamide 12 (Scheme 4). To our disappointment, the
a
Scheme 4. Applying Sulfilimines and Sulfonimidamides
a
Reaction conditions: 9 or 12 (0.40 mmol), 6 (0.44 mmol, 50% in
H2O) and 7a (0.80 mmol), DCE (1 mL), at 60 °C for 16 h.
Assuming that the free carboxyl groups of S-alkyl-substituted
products 4na and 4oa contributed to their aforementioned
instability, the corresponding methyl esters 8 were investigated
(Scheme 3). For the synthesis of 8, the optimal reaction
reaction of 9 did not yield the corresponding carboxylic acid.
Instead, the formation of diphenyl sulfide (11) was observed
(as confirmed by NMR spectroscopy and ESI MS), and a gas
that proved to be hydrogen cyanide evolved (as analyzed by
using an HCN test strip).23 In light of a report by Georg and
Haake,24 we assume that sulfilimine 9 reacts with glyoxylic acid
in a nucleophilic addition forming compound 10, which upon
thermal decomposition results in the formation of diphenyl
sulfide (11), carbon dioxide, water, and HCN. The reaction of
sulfonimidamide 12 led to trace amounts of 13 and 14 as
detected by ESI MS. However, neither of the two compounds
could be isolated.25
Scheme 3. Ester Formation of Products with S-Alkyl
a
Substituents
To demonstrate the usefulness of the developed protocol,
the synthesis of benzodiazepine analogue 16 was investigated
(Scheme 5). Early work by Beiersdorf AG and others
documented interest in such benzothiadiazepine scaffolds.26
For the synthesis of 16, acid 4ka was identified as a
promising starting material (Scheme 5). However, because the
Bechamp reduction28 of 4ka with elemental iron showed a low
́
a
Scheme 5. Gram-Scale Synthesis of Benzothiadiazepine 16
a
Reaction conditions: (i) 5 (0.40 mmol), 6 (0.44 mmol, 50% in H2O)
and 7a (0.8 mmol), DCE (1 mL), at 60 °C for 16 h, evaporated; (ii)
TMSCHN2 (0.80 mmol), MeOH (0.8 mL) and Et2O (2.4 mL), at rt
for 16 h.
conditions for the coupling reactions were applied, and without
workup, the acids 4 formed in situ were directly treated with
trimethylsilyl diazomethane (TMSCHN2).
In this manner, several S-aryl-S-alkyl-substituted sulfoxi-
mines reacted well, providing the corresponding esters in good
to excellent yields (Scheme 3). In addition to linear aliphatic
substituted sulfoximines 5n and 5q, cyclopentyl- and benzyl-
substituted sulfoximines 5r and 5o, respectively, were
converted to the corresponding products. For those products,
the dr values varied from 1.0:1.3 (for 8a) to 1.0:4.0 (for 8c),
revealing a steric impact of the S-alkyl substituent in the
stereochemistry-determining step. Regardless, 2-pyridyl-sub-
stituted sulfoximine 5m proved to be incompatible even under
these reaction conditions, and thus, 8e was not obtained.
a
All reactions converting 4ka into 16 were performed on a 1.0 g scale,
and the optimization was done on a 0.2 mmol scale.
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selectivity for the targeted aniline derivative, the acid was first
treated with trimethylsilyl diazomethane to give methyl ester 8f
(91% yield). Subsequent nitro reduction of 8f proceeded well,
leading to ester 15 in 91% yield.29 Both of these reactions had
been performed on a gram scale. Finally, the ring closure to
provide benzothiadiazepine 16 was achieved by direct
amidation of 15 upon treatment with 1 equiv of lithium
hexamethyldisilazane (LiHMDS).30 Accordingly, the product
was obtained (on a gram scale) in 66% yield. Under these
conditions, the dr was 1.0:5.0. Interestingly, this ratio was
dependent on the amount of LiHDMS, and a careful
investigation (performed on a 0.2 mmol scale) revealed that
the dr changed from 1.0:5.4 to 1.0:6.1 and 1.0:2.0 when the
amount of the base was increased from 0.5 equiv to 1.0 and 2.0
equiv, respectively (Scheme 5). The yield of 16 remained
about the same under these conditions. Using more LiHDMS
(3.0 equiv) led to a decrease in both dr (1.0:1.1) and yield
(23%). Stirring of 16 with a dr of 1.0:5.0 in the presence of 2.0
equiv of LiHMDS overnight did not change the diastereomeric
ratio.31 The structure of thiadiazepine 16 was confirmed by
single-crystal X-ray analysis.
Kari Rissanen − University of Jyvaskyla, Department of
Chemistry, FI-40014 Jyväskylä, Finland; orcid.org/0000-
0002-7282-8419
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00874
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
R.H. thanks the Fonds der Chemischen Industrie e.V. for
financial support (Kekulé scholarship) and the Friedrich-Ebert-
Stiftung for ideational support (Promotionsförderung). The
authors are grateful to Susanne Grunebaum for her help in
synthetic work and to Christian Schumacher as well as Hannah
Fergen (all RWTH Aachen University) for stimulating
discussions. The Alexander von Humboldt Foundation is
acknowledged for the high recognition of K.R. (AvH research
award).
̈
In summary, we have developed a protocol for the synthesis
of 2-substituted acetic acids with N-bound sulfoximidoyl
groups using a multicomponent Petasis reaction. A broad range
of NH-sulfoximines and boronic acids is well tolerated,
affording the corresponding products in good to excellent
yields. We could further demonstrate the applicability of a 2-
sulfoximidoyl acetic acid as building block for the synthesis of a
sulfoximine-based benzodiazepine analogue.32
REFERENCES
■
(1) Bentley, H. R.; McDermott, E. E.; Whitehead, J. K. Action of
Nitrogen Trichloride on Proteins: a Synthesis of the Toxic Factor
from Methionine. Nature 1950, 165, 735.
(2) For general reviews of sulfoximines, see: (a) Ghosh, P.; Ganguly,
B.; Das, S. N−H and C−H Functionalization of Sulfoximine: Recent
Advancement and Prospects. Asian J. Org. Chem. 2020, 9, 2035−2082.
(b) Zheng, W.; Chen, X.; Chen, F.; He, Z.; Zeng, Q. Syntheses and
Transformations of Sulfoximines. Chem. Rec. 2021, 21, 396−416.
(c) Bull, J. A.; Degennaro, L.; Luisi, R. Straightforward Strategies for
the Preparation of NH-Sulfoximines: A Serendipitous Story. Synlett
2017, 28, 2525−2538. (d) Bizet, V.; Hendriks, C. M. M.; Bolm, C.
Sulfur imidations: access to sulfimides and sulfoximines. Chem. Soc.
Rev. 2015, 44, 3378−3390. (e) Bizet, V.; Kowalczyk, R.; Bolm, C.
Fluorinated sulfoximines: syntheses, properties and applications.
Chem. Soc. Rev. 2014, 43, 2426−2438. (f) Shen, X.; Hu, J. Fluorinated
Sulfoximines: Preparation, Reactions and Applications. Eur. J. Org.
Chem. 2014, 4437−4451. (g) Reggelin, M.; Zur, C. Sulfoximines:
Structures, Properties and Synthetic Applications. Synthesis 2000, 1−
64. (h) Johnson, C. R. Utilization of sulfoximines and derivatives as
reagents for organic synthesis. Acc. Chem. Res. 1973, 6, 341−347.
(3) (a) Trost, B. M.; Matsuoka, R. T. N-Nitrosulfoximines as
Chemical Chameleons for Asymmetric Synthesis. Synlett 1992, 27−
30. (b) Okamura, H.; Bolm, C. Sulfoximines: Synthesis and Catalytic
Applications. Chem. Lett. 2004, 33, 482−487. (c) Gais, H.-J.
Development of new methods for asymmetric synthesis based on
sulfoximines. Heteroat. Chem. 2007, 18, 472−481.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00874.
Experimental procedures, characterization data, X-ray
data, and NMR spectra for new compounds (PDF)
Accession Codes
CCDC 2069302−2069304 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(4) (a) Mäder, P.; Kattner, L. Sulfoximines as Rising Stars in
Modern Drug Discovery? Current Status and Perspective on an
Emerging Functional Group in Medicinal Chemistry. J. Med. Chem.
2020, 63, 14243−14275. (b) Han, Y.; Xing, K.; Zhang, J.; Tong, T.;
Shi, Y.; Cao, H.; Yu, H.; Zhang, Y.; Liu, D.; Zhao, L. Application of
sulfoximines in medicinal chemistry from 2013 to 2020. Eur. J. Med.
AUTHOR INFORMATION
■
Corresponding Author
Carsten Bolm − Institute of Organic Chemistry, RWTH
Aachen University, D-52074 Aachen, Germany;
orcid.org/0000-0001-9415-9917; Phone: (+49)-241-
8094675; Email: carsten.bolm@oc.rwth-aachen.de
Chem. 2021, 209, 112885. (c) Lucking, U. Neglected sulfur(VI)
̈
pharmacophores in drug discovery: exploration of novel chemical
space by the interplay of drug design and method development. Org.
Chem. Front. 2019, 6, 1319−1324. (d) Frings, M.; Bolm, C.; Blum, A.;
Gnamm, C. Sulfoximines from a Medicinal Chemist’s Perspective:
Physiochemical and in vitro Parameters Relevant for Drug Discovery.
Authors
̀
Rene Hommelsheim − Institute of Organic Chemistry,
Eur. J. Med. Chem. 2017, 126, 225−245. (e) Lucking, U. Sulfoximines:
̈
A Neglected Opportunity in Medicinal Chemistry. Angew. Chem., Int.
Ed. 2013, 52, 9399−9408.
(5) (a) Babcock, J. M.; Gerwick, C. B.; Huang, J. X.; Loso, M. R.;
Nakamura, G.; Nolting, S. P.; Rogers, R. B.; Sparks, T. C.; Thomas, J.;
Watson, G. B.; Zhu, Y. Biological characterization of sulfoxaflor, a
novel insecticide. Pest Manage. Sci. 2011, 67, 328−334. (b) Zhu, Y.;
RWTH Aachen University, D-52074 Aachen, Germany
́
̃
Heliana Michaela Nunez Ponce − Institute of Organic
Chemistry, RWTH Aachen University, D-52074 Aachen,
Germany
Khai-Nghi Truong − University of Jyvaskyla, Department of
Chemistry, FI-40014 Jyväskylä, Finland
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Letter
Loso, M. R.; Watson, G. B.; Sparks, T. C.; Rogers, R. B.; Huang, J. X.;
Gerwick, B. C.; Babcock, J. M.; Kelley, D.; Hegde, V. B.; Nugent, B.
M.; Renga, J. M.; Denholm, I.; Gorman, K.; DeBoer, G. J.; Hasler, J.;
Meade, T.; Thomas, J. D. Discovery and characterization of
sulfoxaflor, a novel insecticide targeting sap-feeding pests. J. Agric.
Food Chem. 2011, 59, 2950−2957.
(14) (a) Carrera, D. E. The acid promoted Petasis reaction of
organotrifluoroborates with imines and enamines. Chem. Commun.
2017, 53, 11185−11188. (b) Morin, M. S. T.; Lu, Y.; Black, D. A.;
Arndtsen, B. A. Copper-Catalyzed Petasis-Type Reaction: A General
Route to α-Substituted Amides From Imines, Acid Chlorides, and
Organoboron Reagents. J. Org. Chem. 2012, 77, 2013−2017.
(15) (a) Diehl, A. M.; Ouadoudi, O.; Andreadou, E.; Manolikakes,
G. Sulfonamides as Amine Component in the Petasis-Borono
Mannich Reaction: A Concise Synthesis of a-Aryl- and a-
Alkenylglycine Derivatives. Synthesis 2018, 50, 3936−3946. (b) Beisel,
T.; Diehl, A. M.; Manolikakes, G. Palladium-Catalyzed Enantiose-
lective Three-Component Synthesis of a-Arylglycines. Org. Lett. 2016,
18, 4116−4119. (c) Beisel, T.; Manolikakes, G. Palladium-Catalyzed
Enantioselective Three-Component Synthesis of a-Substituted
Amines. Org. Lett. 2015, 17, 3162−3165.
(6) (a) Siemeister, G.; Lucking, U.; Wengner, A. M.; Lienau, P.;
̈
Steinke, W.; Schatz, C.; Mumberg, D.; Ziegelbauer, K. BAY 1000394,
a novel cyclin-dependent kinase inhibitor, with potent antitumor
activity in mono- and in combination treatment upon oral application.
Mol. Cancer Ther. 2012, 11, 2265−2273. (b) Lu
̈
cking, U.; Jautelat, R.;
Kruger, M.; Brumby, T.; Lienau, P.; Schäfer, M.; Briem, H.; Schulze,
̈
J.; Hillisch, A.; Reichel, A.; Wengner, A. M.; Siemeister, G. The Lab
Oddity Prevails: Discovery of Pan-CDK (R)-S-Cyclopropyl-S-(4-{[4-
{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-(trifluoromethyl)-
pyrimidin-2-yl]amino}phenyl)sulfoximide (BAY 1000394) for the
Treatment of Cancer. ChemMedChem 2013, 8, 1067−1085. (c) Reck,
M.; Horn, L.; Novello, S.; Barlesi, F.; Albert, I.; Juhász, E.; Kowalski,
D.; Robinet, G.; Cadranel, J.; Bidoli, P.; Chung, J.; Fritsch, A.; Drews,
U.; Wagner, A.; Govindan, R. Phase II Study of Roniciclib in
Combination with Cisplatin/Etoposide or Carboplatin/Etoposide as
Frist-Line Therapy in Patients with Extensive-Disease Small Cell Lung
Cancer. J. Thorac. Oncol. 2019, 14, 701−711.
(16) Here, we describe the products as 2-sulfoximidoyl acetic acids.
In general, however, they are also α-amino acid derivatives.
(17) Substituting PhB(OH)2 with PhBpin and PhBF3K led to 4aa in
19% and 70% yields, respectively.
(18) For more details, see the Supporting Information.
(19) In the attempt to apply trans-phenylvinyl boronic acid in the
reaction with 5a and 6, the corresponding product was detected by
HRMS, but its isolation failed.
(20) Presumably, the water found in the crystal structure of 4ba
originated from the atmosphere during storage.
(7) For contributions from our group, see: (a) Ma, D.; Wang, C.;
Kong, D.; Tu, Y.; Shi, P.; Bolm, C. Palladium-Catalyzed Carbon-
ylation in the Synthesis of N-Ynonylsulfoximines. Adv. Synth. Catal.
2021, 363, 1330−1334. (b) Wang, C.; Wang, H.; Bolm, C.
Sulfoximines with α-Ketoester Functionalities at Nitrogen from
Cyanoacetates and Air. Adv. Synth. Catal. 2021, 363, 747−750.
(c) Wang, C.; Tu, Y.; Ma, D.; Bolm, C. Photocatalytic Fluoro
Sulfoximidations of Styrenes. Angew. Chem., Int. Ed. 2020, 59, 14134−
14137.
(8) For selected recent examples, see: (a) Strobbe, D.; Pecorari, R.;
Conte, O.; Minutolo, A.; Hendriks, C. M. M.; Wiezorek, S.; Faccenda,
D.; Abeti, R.; Montesano, C.; Bolm, C.; Campanella, M. NH-
sulfoximine: A novel pharmacological inhibitor of the mitochondrial
F1Fo-ATPase, which suppresses viability of cancerous cells. Br. J.
Pharmacol. 2021, 178, 298−311. (b) Horn, T.; Bettray, W.; Noll, U.;
Krauskopf, F.; Huang, M.-R.; Bolm, C.; Slusarenko, A. J.; Gruhlke, M.
C. H. The Sulfilimine Analogue of Allicin, S-Allyl-S-(S-allyl)-N-
Cyanosulfilimine, Is Antimicrobial and Reacts with Glutathione.
Antioxidants 2020, 9, 1086. (c) Altenburg, B.; Frings, M.; Schöbel, J.-
H.; Goßen, J.; Pannen, K.; Vanderliek, K.; Rossetti, G.; Koschmieder,
S.; Chatain, N.; Bolm, C. Chiral Analogues of PFI-1 as BET Inhibitors
and Their Functional Role in Myeloid Malignancies. ACS Med. Chem.
Lett. 2020, 11, 1928−1934.
(9) Ammann, S.; Bacon, E. M.; Brizgys, G.; Chin, E.; Chou, C.;
Cottell, J. J.; Ndukwe, M.; Shatskikh, M.; Taylor, J. G.; Wright, N. E.;
Yang, Z.-Y.; Zipfel, S. M. (Gilead Sciences, Inc.). WO 2020/036986,
2020.
(10) (a) Petasis, N. A.; Akritopoulou, I. The boronic acid Mannich
reaction: A new method for the synthesis of geometrically pure
allylamines. Tetrahedron Lett. 1993, 34, 583−586. (b) Petasis, N. A.;
Zavialov, I. A. Highly Stereocontrolled One-Step Synthesis of anti-b-
Amino Alcohols from Organoboronic Acids, Amines, and a-Hydroxy
Aldehydes. J. Am. Chem. Soc. 1998, 120, 11798−11799.
(21) The diastereomeric ratio was determined by 1H NMR
spectroscopy using the integral ratio of the corresponding signals
for the α-hydrogen atoms (4.8−5.3 ppm).
(22) In the attempt to apply the analogous sulfoximine to 5j with a
free phenolic OH in a reaction with benzaldehyde (instead of 5), no
reaction occurred under the standard conditions.
(23) Cyantesmo MACHEREY-NAGEL, containing N,N,N′,N′-
tetramethyl-4,4′-diaminodiphenylmethane (Michler’s base).
(24) Georg, G. I.; Haake, M. Novel Methods for the Synthesis of N-
Trichloroacetyl- and N-Formyl-S,S-diarylsulfilimines. Tetrahedron
Lett. 1984, 25, 47−48.
(25) Compounds such as 14 have been considered as carboxylic acid
bioisosteres: Pemberton, N.; Graden, H.; Evertsson, E.; Bratt, E.;
Lepistö, M.; Johannesson, P.; Svensson, P. H. Synthesis and
Functionalization of Cyclic Sulfonimidamides: A Novel Chiral
Heterocyclic Carboxylic Acid Bioisostere. ACS Med. Chem. Lett.
2012, 3, 574−578.
(26) In addition to the synthesis, the pharmacological properties of
benzothiadiazine derivatives were investigated. To some extent, they
were similar to those of diazepam, but with a lower potency. For
relevant work, see: (a) Cohnen, E.; Mahnke, J. 1.2.4-Benzothia(IV)-
diazine und 1.2.5-Benzothia(IV)diazepine, Ringerweiterung einiger
Chlormethyl-1.2.4-benzothia(IV)diazin-1-oxide. Chem. Ber. 1972,
105, 757−769. (b) Cohnen, E.; Mahnke, J. 1,2,4-Benzothia(IV)-
diazine und 1,2,5-Benzothia(IV)diazepine, 2. Darstellung und Ring-
erweiterung einiger 3-(Chlormethyl)-3,4-dihydro-1,2,4-benzothia-
(IV)diazin-1-oxide. Chem. Ber. 1973, 106, 3368−3375. (c) Cohnen,
E. (Beiersdorf AG). DE 2321786A1, 1974. (d) Jones, S. D.;
Kennewell, P. D.; Tulley, W. R.; Westwood, R.; Sammes, P. G.
Preparation and chemistry of some 1,5-diphenyl-1l4,2,4-thiadiazine 1-
oxides. J. Chem. Soc., Perkin Trans. 1 1990, 447−455.
(27) The single-crystal X-ray structure analysis of product 16
depicted in Scheme 5 was performed with a crystal that was manually
separated from a 2:1 mixture of diastereomers. According to a
numerical analysis of the crystal mixture by vision, 16 is the major
diastereomer. The other diastereomer (dia-16) was also isolated in
this manner, and its single-crystal X-ray structure could also be
determined. For more details, see the Supporting Information.
(28) (a) Béchamp, A. De l’action des protosels de fer sur la
(11) (a) Wu, P.; Givskov, M.; Nielsen, T. E. Reactivity and Synthetic
Applications of Multicomponent Petasis Reactions. Chem. Rev. 2019,
119, 11245−11290. (b) Candeias, N. R.; Montalbano, F.; Cal, P. M.
S. D.; Gois, P. M. P. Boronic Acids and Esters in the Petasis-Borono
Mannich Multicomponent Reaction. Chem. Rev. 2010, 110, 6169−
6193.
(12) Petasis, N. A.; Zavialov, I. A. A New Practical Synthesis of α-
Amino Acids from Alkenyl Boronic Acids. J. Am. Chem. Soc. 1997,
119, 445−446.
́
nitronaphtaline et la nitrobenzine. Nouvelle methode de formation
(13) Ricardo, M. G.; Llanes, D.; Wessjohann, L. A.; Rivera, D. G.
Introducing the Petasis Reaction for Late-Stage Multicomponent
Diversification, Labeling, and Stapling of Peptides. Angew. Chem., Int.
Ed. 2019, 58, 2700−2704.
des bases organiques artificielles de Zinin. Ann. Chim. Phys. 1854,
186−196. (b) Frings, M.; Atodiresei, I.; Wang, Y.; Runsink, J.; Raabe,
G.; Bolm, C. C1-Symmetric Aminosulfoximines in Copper-Catalyzed
Asymmetric Vinylogous Mukaiyama Aldol Reactions. Chem. - Eur. J.
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Org. Lett. 2021, 23, 3415−3420

Organic Letters
pubs.acs.org/OrgLett
Letter
2010, 16, 4577−4587. (c) Langner, M.; Bolm, C. C1-Symmetric
Sulfoximines as Ligands in Copper-Catalyzed Asymmetric Mukaiya-
ma-Type Aldol Reactions. Angew. Chem., Int. Ed. 2004, 43, 5984−
5987. (d) Langner, M.; Rémy, P.; Bolm, C. Highly Modular Synthesis
of C1-Symmetric Aminosulfoximines and Their Use as Ligands in
Copper-Catalyzed Asymmetric Mukaiyama-Aldol Reactions. Chem. -
Eur. J. 2005, 11, 6254−6265.
(29) For optimization studies, see the Supporting Information.
(30) Li, G.; Ji, C.-L.; Hong, X.; Szostak, M. Highly Chemoselective,
Transition-Metal-Free Transamidation of Unactivated Amides and
Direct Amidation of Alkyl Esters by N−C/O−C Cleavage. J. Am.
Chem. Soc. 2019, 141, 11161−11172.
(31) Reaction conditions: 16 (0.1 mmol), LiHMDS (0.2 mmol),
THF (0.5 mL), at ambient temperature for 16 h. For more details, see
the Supporting Information.
(32) All chiral products shown here are racemates. As the rather
stable stereogenic center at sulfur is not involved in the reaction
process, enantiopure products should be accessible upon application
of the respective starting materials.
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