C-H activation of methyl arenes in the MnO2-mediated aroylation of N-chlorosulfoximines

Article abstract of DOI:10.1021/ol5003016

An investigation into the reactivity profile of N-halogenated sulfoximines has led to the development of a new method for the synthesis of N-aroylated sulfoximines. This protocol involves the manganese oxide promoted C-H activation of methyl arenes to form an aroyl intermediate which then reacts readily with N-chlorosulfoximines to form a series of valuable aroyl sulfoximine derivatives in high yields.

Full text of DOI:10.1021/ol5003016

Letter
pubs.acs.org/OrgLett
C−H Activation of Methyl Arenes in the MnO2‑Mediated Aroylation
of N‑Chlorosulfoximines
Daniel L. Priebbenow and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: An investigation into the reactivity profile of N-
halogenated sulfoximines has led to the development of a new
method for the synthesis of N-aroylated sulfoximines. This
protocol involves the manganese oxide promoted C−H
activation of methyl arenes to form an aroyl intermediate which then reacts readily with N-chlorosulfoximines to form a
series of valuable aroyl sulfoximine derivatives in high yields.
n recent decades, sulfoximines have found extensive
The C−H activation and subsequent oxidative functionaliza-
Iapplication in asymmetric synthesis as both chiral auxiliaries tion of methyl arenes has recently emerged as an efficient
approach to access a range of valuable synthetic intermediates.9
This strategy for the formation of new carbon−heteroatom
bonds has been successfully applied to the oxidative cyanation,
esterification, and amidation of methyl arenes.9 Advantageously,
when the readily available methyl arenes are utilized as
precursors to the activated carbonyl coupling partner required
for amide bond formation, the use of more traditional carbonyl
coupling partners that require preactivation, including carbox-
ylic acids and acyl chlorides, is avoided.
Singh and co-workers recently disclosed a protocol for amide
bond formation through reaction of methyl arene derivatives
with N-chloroamines.9e After screening several plausible
oxidants, the in situ oxidation of the methyl arene to form an
activated carbonyl species was found to be best promoted by
manganese salts.10 In addition, the use of N-chloroamines
offered enhanced reactivity over the NH-amines trialed and
greatly increased the yields obtained for amide bond
formation.6,11 Inspired by these recent developments we then
turned our attention to exploring the N-aroylation of
sulfoximine derivatives using methyl arenes as the source of
the carbonyl coupling partner.
To initially explore this reaction process, N-choro-S-methyl-
S-phenylsulfoximine (1) was readily prepared by reaction of the
NH-sulfoximine with NCS in MeCN. Following isolation of the
N-chlorosulfoximine, it was subjected to the aroylation
conditions reported by Singh,9e using toluene as the methyl
arene in the presence of MnO2 and tert-butylhydroperoxide
(70% aqueous solution). To our delight, after 48 h of reaction
time at elevated temperatures, the N-benzoyl sulfoximine 3a
was formed in a yield of 81% (Scheme 1). To further
investigate this process, a range of methyl arenes were then
applied under the standard conditions (Scheme 1).
and ligands.1,2 More recently, the sulfoximidoyl moiety has
been successfully incorporated into molecules developed for
use in a clinical setting; however to date, there are no
commercially available pharmaceutical treatments containing
this fascinating functional group.3
Of particular interest, the exchange of a sulfonamide for a
sulfoximidoyl group in the optimization of the pan-CDK
inhibitor developed by Bayer (BAY 1000394 - now well into
clinical trials), had a significant impact on the success of this
medicinal chemistry program.4 More specifically, the sulfox-
imidoyl moiety incorporated into the drug candidate not only
facilitated retention of the high level of desired bioactivity but
also improved drug solubility and dramatically minimized off-
target activity against carbonic anhydrases (CAs), often
observed for other sulfonamide-based drugs.4
Following on from this exciting application of sulfoximine
derivatives in a medicinal chemistry setting, we envisage that
the sulfoximidoyl moiety will become a very important
functional group in drug discovery programs in years to
come. To facilitate this progress, our group, among others, has
undertaken an intensive research program to thoroughly
explore the properties of sulfoximines and to develop efficient
and practical methods for both the synthesis and derivatization
of sulfoximines.5
In recent years, N-chloroamines have been widely applied as
electrophilic amination reagents in numerous synthetic trans-
formations due to their enhanced reactivity when compared to
NH-amines.6 The analogous N-chlorosulfoximines were first
reported in 1968 by Cram and co-workers;7 however, since that
time few additional reports regarding either the synthesis or
application of N-halosulfoximines have appeared.8 As such, we
set out to further explore the synthetic potential of N-
halogenated sulfoximine derivatives as both reactants and chiral
reagents in numerous synthetic transformations. To this end,
we herein report the development of a new method to access
N-aroylated sulfoximines from N-chlorosulfoximines by the C−
H activation of methyl arenes.
It was observed that methyl arenes containing halide
substituents worked exceptionally well in this reaction process
Received: January 28, 2014
Published: March 3, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
the N-Cl bond,11a as recently proposed by Singh and co-
workers.9e
Scheme 1. Synthesis of N-Aroylated Sulfoximines by the C−
H Activation of Methyl Arenes
Traditionally, aroyl-functionalized sulfoximines have been
prepared by the reaction of aroyl chlorides with NH-
sulfoximines (Scheme 3, top).14 In addition, we recently
Scheme 3. Methodology Available for the N-Aroylation of
Sulfoximines
affording the corresponding sulfoximine derivatives in excellent
yield (82−92%, 3c,d,f−h,k,l). Other aryl substrates containing
methyl, nitro, or sulfonate groups also gave products in good
yields (61−75%, 3b,e,i,j,m). Methyl arenes containing two or
more methyl groups including mesitylene and halogenated
xylene derivatives also reacted well (3k−m), and none of the
polysulfoximine products that might arise for these substrates
were observed.
As reported for other reaction processes with the relatively
non-nucleophilic sulfoximines,5f electron-rich substrates includ-
ing 4-methyl anisole and 2-methyl furan failed to react under
the standard conditions. In regards to steric factors, substituents
at the 3- or 4-position of the aryl ring were well tolerated;
however, toluene derivatives containing a methyl or halo
substituent at the 2-position failed to afford synthetically useful
yields of the corresponding N-aroyl sulfoximine.
disclosed a new strategy for the preparation of aroylated
sulfoximines through the copper-catalyzed oxidative coupling of
NH-sulfoximines and aldehydes (Scheme 3, middle).5g The
novel method reported herein provides an alternative approach
to these syntheses of N-aroylated sulfoximine derivatives
through the reaction of N-chlorosulfoximines with methyl
arenes (Scheme 3, bottom). This protocol employs readily
available methyl arenes as substrates, instead of the more
commonly applied acyl chloride or carboxylic acid coupling
partners, and provides access to a range of functionalized N-
aroyl sulfoximines.
In summary, an investigation into the properties of N-
halosulfoximines has led to the development of a new method
for the N-aroylation of sulfoximines. Further exploration into
the potential of N-halosulfoximines as both reactants and
(chiral) reagents in chemical synthesis remain underway in our
laboratories.
To investigate variation in the sulfoximidoyl moiety, a one-
pot, two-step procedure was utilized. Initially, the nitrogen of
the sulfoximidoyl moiety was halogenated using NCS, and after
stirring for 2 h at room temperature, the additional reagents
were added and the reaction mixture was heated to 80 °C for
48 h (Scheme 2). Under these conditions, employing toluene
ASSOCIATED CONTENT
* Supporting Information
Experimental details and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
Scheme 2. Variation of the Sulfoximine Moiety in the
Aroylation of NH-Sulfoximines via NCl-Sulfoximines
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: carsten.bolm@oc.rwth-aachen.de.
Notes
The authors declare no competing financial interest.
as the methyl arene source, the S-methyl-S-arylsulfoximines
containing a chloro-, bromo-, methoxy-, or nitro-substituent
(4a−d) were all aroylated in good yield (73−88%, 3n−q).
Mechanistically, this process is proposed to proceed through
a radical intermediate, in analogy to previous reports on the
aroylation of both amines and sulfoximines.5g,9e,12 Following
the manganese promoted oxidation of the Ar−CH3 to the
corresponding aldehyde (Ar−CHO), in the presence of TBHP
an aroyl radical is generated.9e,12,13 This aroyl radical then
reacts with the sulfoximine to form the N-aroylated sulfoximine
adduct. Attempts to perform the same reaction using the NH-
sulfoximine only afforded trace amounts of the desired product.
As such, it is proposed that this amidative reaction process also
involves a nitrogen-based radical formed following cleavage of
ACKNOWLEDGMENTS
D.L.P. is grateful to the Alexander von Humboldt Foundation
for a Postdoctoral Fellowship.
■
REFERENCES
■
(1) For reviews, see: (a) Johnson, C. R. Acc. Chem. Res. 1973, 6, 341.
(b) Reggelin, M.; Zur, C. Synthesis 2000, 1. (c) Harmata, M.
Chemtracts 2003, 16, 660. (d) Okamura, H.; Bolm, C. Chem. Lett.
2004, 33, 482. (e) Gais, H.-J. Heteroatom Chem. 2007, 18, 472.
(f) Bolm, C. Latv. J. Chem. 2012, 49. (g) Bizet, V.; Kowalczyk, R.;
Bolm, C. Chem. Soc. Rev., on-line, DOI:10.1039/C3CS60427F.
́
(2) For selected recent examples, see: Frings, M.; Thome, I.;
Schiffers, I.; Pan, F. F.; Bolm, C. Chem.Eur. J. 2014, 20, 1691 and
references therein.
1651
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Organic Letters
Letter
(3) For a summary of sulfoximine derivatives in medicinal chemistry,
see: Lucking, U. Angew. Chem., Int. Ed. 2013, 52, 9399.
̈
(4) Lucking, U.; Jautelat, R.; Kruger, M.; Brumby, T.; Lienau, P.;
̈
̈
Schafer, M.; Briem, H.; Schulze, J.; Hillisch, A.; Reichel, A.; Wengner,
A. M.; Siemeister, G. ChemMedChem 2013, 8, 1067.
̈
(5) For selected recent examples from our group, see: (a) Wang, J.;
Frings, M.; Bolm, C. Angew. Chem., Int. Ed. 2013, 52, 8661. (b) Wang,
J.; Frings, M.; Bolm, C. Chem.Eur. J. 2014, 20, 966. (c) Dong, W.;
Wang, L.; Parthasarathy, K.; Pan, F.; Bolm, C. Angew. Chem., Int. Ed.
2013, 52, 11573. (d) Wang, L.; Huang, H.; Priebbenow, D. L.; Pan, F.-
F.; Bolm, C. Angew. Chem., Int. Ed. 2013, 52, 3478. (e) Pirwerdjan, R.;
Priebbenow, D. L.; Becker, P.; Lamers, P.; Bolm, C. Org. Lett. 2013,
15, 5397. (f) Priebbenow, D. L.; Becker, P.; Bolm, C. Org. Lett. 2013,
15, 6155. (g) Wang, L.; Priebbenow, D. L.; Zou, L.-H.; Bolm, C. Adv.
Synth. Catal. 2013, 355, 1490.
(6) (a) Stella, L. Angew. Chem., Int. Ed. Engl. 1983, 22, 337. (b) Sinha,
P.; Knochel, P. Synlett 2006, 3304. (c) Hatakeyama, T.; Yoshimoto, Y.;
Ghorai, S. K.; Nakamura, M. Org. Lett. 2010, 12, 1516. (d) Kawano,
T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2010, 132, 6900.
(e) Ng, K.-H.; Zhou, Z.; Yu, W.-Y. Org. Lett. 2012, 14, 272.
(f) Grohmann, C.; Wang, H.; Glorius, F. Org. Lett. 2012, 14, 656.
(g) Miura, T.; Morimoto, M.; Murakami, M. Org. Lett. 2012, 14, 5214.
(h) Barker, T. J.; Jarvo, E. R. J. Am. Chem. Soc. 2009, 131, 15598.
(i) Barker, T. J.; Jarvo, E. R. Angew. Chem., Int. Ed. 2011, 50, 8325.
(7) Rayner, D. R.; Von Schriltz, D. M.; Day, J.; Cram, D. J. J. Am.
Chem. Soc. 1968, 90, 2721.
(8) (a) Yoshida, T.; Naruto, S.; Uno, H.; Nishimura, H. Chem.
Pharm. Bull. 1982, 30, 4346. (b) Akasaka, T.; Furukawa, N.; Oae, S. J.
Chem. Soc., Perkin Trans. 1 1980, 6, 1257. (c) Akasaka, T.; Furukawa,
N.; Oae, S. Chem. Lett. 1979, 529. (d) Morita, H.; Itoh, H.; Furukawa,
N.; Oae, S. Chem. Lett. 1978, 817. (e) Furukawa, N.; Akutagawa, K.;
Yoshimura, T.; Oae, S. Tetrahedron Lett. 1981, 22, 3989. (f) Akasaka,
T.; Furukawa, N.; Oae, S. Tetrahedron Lett. 1979, 22, 2035.
(g) Akasaka, T.; Furukawa, N.; Oae, S. Phosphorous Sulfur Relat.
Elem. 1985, 21, 277. (h) Akutagawa, K.; Furukawa, N. J. Org. Chem.
1984, 49, 2282. (i) Johnson, C. R.; Corkins, H. G. J. Org. Chem. 1978,
43, 4136.
(9) (a) Zhou, W.; Zhang, L.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48,
7094. (b) Rout, S. K.; Guin, S.; Ghara, K. K.; Banerjee, A.; Patel, B. K.
Org. Lett. 2012, 14, 3982. (c) Kamata, K.; Yamaura, T.; Mizuno, N.
Angew. Chem., Int. Ed. 2012, 51, 7250. (d) Guin, S.; Rout, S. K.;
Banerjee, A.; Nandi, S.; Patel, B. K. Org. Lett. 2012, 14, 5294.
(e) Vanjari, R.; Guntreddi, T.; Singh, K. N. Org. Lett. 2013, 15, 4908.
(f) Wang, Y.; Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2012,
51, 7250.
(10) (a) Firouzabadi, H.; Abbasi, M. Synth. Commun. 1999, 29, 1485.
(b) Kim, S. Y.; Park, K. H.; Chung, Y. K. Chem. Commun. 2005, 1321.
(c) Taylor, R. J. K.; Reid, M.; Foot, J.; Raw, S. A. Acc. Chem. Res. 2005,
38, 851. (d) Yu, X.; Liu, C.; Jiang, L.; Xu, Q. Org. Lett. 2011, 13, 6184.
(e) Wang, Y.; Kobayashi, H.; Yamaguchi, K.; Mizuno, N. Chem.
Commun. 2012, 48, 2642.
(11) (a) Kovacic, P.; Lowery, M. K.; Field, K. W. Chem. Rev. 1970,
70, 639. (b) Gassman, P. G.; Dygos, D. K.; Trent, J. E. J. Am. Chem.
Soc. 1970, 92, 2084. (c) Minakata, S. Acc. Chem. Res. 2009, 42, 1172.
(12) (a) Jiang, H.; Lin, A.; Zhu, C.; Cheng, Y. Chem. Commun. 2013,
49, 819. (b) Li, X.; Li, B.; You, J.; Lan, J. Org. Biomol. Chem. 2013, 11,
1925.
(13) Cadoni, R.; Porcheddu, A.; Giacomelli, G.; Luca, L. D. Org. Lett.
2012, 14, 5014.
(14) For previous examples of the synthesis of N-acyl sulfoximines,
see: (a) Bolm, C.; Okamura, H.; Verrucci, M. J. Organomet. Chem.
2003, 687, 444. (b) Huang, S.-L.; Swern, D. J. Org. Chem. 1979, 44,
2510. (c) Bolm, C.; Hackenberger, C. P. R.; Simic, O.; Verrucci, M.;
Muller, D.; Bienewald, F. Synthesis 2002, 879. (d) Cho, G. Y.; Bolm, C.
̈
Org. Lett. 2005, 7, 1351. (e) Yadav, M. R.; Rit, R. K.; Sahoo, A. K.
Chem.Eur. J. 2012, 18, 5541. (f) Hackenberger, C. P. R.; Raabe, G.;
Bolm, C. Chem.Eur. J. 2004, 10, 2942.
1652
dx.doi.org/10.1021/ol5003016 | Org. Lett. 2014, 16, 1650−1652