Copper-catalyzed direct sulfoximination of azoles and polyfluoroarenes under ambient conditions

Article abstract of DOI:10.1021/ol102844q

The direct dehydrogenative C-N coupling of azoles or polyfluoroarenes with N-H sulfoximines proceeds effectively in the presence of a copper catalyst at room temperature under air to afford the corresponding N-arylsulfoximines in good to high yields.

Full text of DOI:10.1021/ol102844q

ORGANIC
LETTERS
2011
Vol. 13, No. 3
359-361
Copper-Catalyzed Direct Sulfoximination
of Azoles and Polyfluoroarenes under
Ambient Conditions
Mitsuru Miyasaka,† Koji Hirano,† Tetsuya Satoh,† Rafal Kowalczyk,‡
Carsten Bolm,*,‡ and Masahiro Miura*,†
Department of Applied Chemistry, Faculty of Engineering, Osaka UniVersity, Suita,
Osaka 565-0871, Japan, and Institute of Organic Chemistry, RWTH Aachen
UniVersity, Landoltweg 1, D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de; miura@chem.eng.osaka-u.ac.jp
Received November 24, 2010
ABSTRACT
The direct dehydrogenative C-N coupling of azoles or polyfluoroarenes with N-H sulfoximines proceeds effectively in the presence of a
copper catalyst at room temperature under air to afford the corresponding N-arylsulfoximines in good to high yields.
Sulfoximines have attracted attention in organic chemistry
because of their successful use as chiral auxiliaries1 and
ligands2 in asymmetric synthesis as well as pivotal motifs
in biologically active compounds.3 In the latter context,
N-(hetero)arylsulfoximines are of particular interest due to
the fact that various derivatives showed anticancer activity4
or proved applicable as agrochemicals.5 Among the most
effective and convergent approaches to the target structures
are metal-catalyzed N-arylations of N-H sulfoximines
(Scheme 1). Various palladium, copper, and iron complexes
Scheme 1. Approaches to N-Arylsulfoximines
† Osaka University.
‡ RWTH Aachen University.
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Chem. 2004, 47, 6854. (b) Worch, C.; Mayer, A. C.; Bolm, C. In
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can be applied in catalytic reactions with aryl halides6 or
arylboronic acids7 (eqs 1 and 2). While useful, all protocols
have in common that a preactivation step such as halogena-
tion or stoichiometric metalation of original arenes is
(5) Tsukuda, K.; Yamada, S.; Yamaguchi, M. PCT Int. Appl. 2008, WO
2008/035737, A1 20080327 (CAN 148:403217).
10.1021/ol102844q  2011 American Chemical Society
Published on Web 12/21/2010

inevitable to prepare the coupling reagents. Ultimately, the
direct dehydrogenative C-N coupling between arenes and
N-H sulfoximines is ideal from the viewpoint of step
economy (eq 3). However, this type of coupling is, to the
best of our knowledge, unprecedented.
conversion, and other reaction systems using K2CO3, KOAc,
o-xylene, DMSO, THF, or CH2Cl2 largely diminished the yields
(0-54% GC yields). By using the copper-based catalyst, a
variety of 2-substituted 1,3,4-oxadiazoles efficiently coupled
with 2a. Electron-donating as well as electron-withdrawing
groups on the benzene ring were compatible toward the reaction
(entries 2-5). A bulky naphthalene substituent did not interfere
(entry 6). Moreover, alkyl-substituted 1g coupled (entry 7). The
generality of sulfoximines was also good (entries 8-11).
Noteworthy is the fact that the carbon bromide moiety of 2e
was left intact, which could be useful for further manipulation
by a conventional cross-coupling methodology (entry 11).
Among other azoles tested, benzoxazoles and benzothia-
zole were found to undergo direct coupling without any
difficulties (Figure 1).11 The corresponding 2-iminoazoles
Recently, synthetic options by metal-catalyzed direct C-H
functionalization have grown rapidly resulting in a large
impact on synthetic organic chemistry.8 In this context, a
few successful intermolecular C-N cross-couplings of arenes
and nitrogen nucleophiles involving alkylamines, anilines,
and amides have been developed.9,10 Herein, we report a
catalytic direct sulfoximination of azoles and polyfluoroare-
nes for the synthesis of N-(hetero)arylsulfoximines. The
reaction proceeds very smoothly under inexpensive copper
catalysis at room temperature.
In a typical experiment, treatment of 2-phenyl-1,3,4-oxadia-
zole (1a) with S-methyl-S-phenylsulfoximine (2a) in the pres-
ence of 10 mol % of Cu(OAc)2·OH2 and 3.0 equiv of K3PO4
in DMF under ambient conditions for 8 h afforded the directly
iminated product 3aa in 92% yield (96% GC) (Table 1, entry
Table 1. Copper-Catalyzed Direct Sulfoximination of
1,3,4-Oxadiazoles 1 with Sulfoximines 2a
Figure 1. Products of Copper-Catalyzed Direct Sulfoximination
of Azoles and Polyfluoroarenes.
entry
R1 1
Ph (1a)
4-MeC6H4 (1b)
4-MeOC6H4 (1c) 2a
4-CF3C6H4 (1d)
4-ClC6H4 (1e)
1-naphthyl (1f)
R2, R3 2
Ph, Me (2a)
3, yield (%)b
1
2
3
4
5
6
3aa, 92 (96)
3ba, 86
3ca, 95
3da, 89
3ea, 90
3fa, 92
4aa-ca and 5aa were obtained in good to high yields. Given
that (hetero)arenes containing a relatively acidic C-H bond
showed good efficiency, polyfluoroarenes were also antici-
2a
2a
2a
2a
(8) Recent reviews: (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
ReV. 2007, 107, 174. (b) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200.
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Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222. (f)
Lewis, L. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41,
1013. (g) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (h) Daugulis, O.;
Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (i) Kulkarni,
A. A.; Daugulis, O. Synthesis 2009, 4087. (j) Chen, X.; Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (k) Ackermann,
L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (l)
Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677. (m) Lyons,
T. W.; Sanford, M. S. Chem. ReV. 2010, 110, 1147. (n) Dudnik, A. S.;
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2010, 3395.
7
8
9
10
Ph(CH2)2 (1g)
2a
3ga, 85
3ab, 79
3ac, 60
1a
1a
1a
1a
Ph, Ph (2b)
Me, Me (2c)
2-naphthyl, Me (2d) 3ad, 87
11
4-BrC6H4, Me (2e) 3ae, 70
a A mixture of 1 (0.60 mmol), 2 (0.40 mmol), Cu(OAc)2·OH2 (0.040
mmol), and K3PO4 (1.2 mmol) was stirred in DMF (1.0 mL) for 8-24 h at
room temperature under air. b In parentheses, yield determined by GC
method.
1). Several observations concerning optimization studies are to
be noted: the use of other copper salts, Cu(OTf)2, CuI, and
CuCl2, resulted in comparable or somewhat lower yields of 93,
95, and 72% (GC), respectively; the addition of ligands such
as 1,10-phenanthroline, 2,2′-bipyridine, and N,N,N′,N′-tetram-
ethylethylenediamine decreased the yield of 3aa by ca. 30-40%;
a combination of K3PO4 and DMF was essential for full
(9) (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6790. (b) Uemura, T.; Imoto, S.; Chatani, N. Chem. Lett.
2006, 35, 842. (c) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A.
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S. L. J. Am. Chem. Soc. 2005, 127, 14560. (b) Thu, H.-Y.; Yu, W.-Y.;
Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048. (c) Wasa, M.; Yu, J.-Q.
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(b) Bolm, C.; Hildebrand, J. P. J. Org. Chem. 2000, 65, 169. (c) Bolm, C.;
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(11) Attempts to apply benzimidazole, benzothiophene, or benzofuran
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360
Org. Lett., Vol. 13, No. 3, 2011

pated to work well as arene coupling partners.12 As
hypothesized, pentafluorobenzene reacted with 2a under
identical conditions to provide 6aa in 82% yield. The
reactions with 2,3,5,6-tetrafluoro-substituted benzotrifluoride
and pyridine were also possible (6ba and 6ca). However,
1,2,4,5-tetrafluorobenzene itself coupled with 2a sluggishly
(not shown, ca. 20% GC yield).
Owing to the mildness of the reaction conditions, the
enantiopure sulfoximine (S)-2a could be transformed into
the N-benzoxazolylsulfoximine (S)-4aa without affecting the
enantiomeric excess (Scheme 2).
with sulfoximines at room temperature. The reaction enables
the rapid and concise construction of N-heteroaryl or
-polyfluoroarylsulfoximines of substantial interest in me-
dicinal and pharmaceutical chemistry.
Acknowledgment. This work was partly supported by
Grants-in-Aid from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan, Deutsche Fors-
chungsgemeinschaft (IRTG 1628), and the Fonds der Che-
mischen Industrie, Germany. M.M. acknowledges JSPS for
financial support. R.K. appreciates postdoctoral support by
Syngenta Crop Protection.
Supporting Information Available: Detailed experimen-
tal procedures and characterization data of compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 2
OL102844Q
(13) Base-assisted cupration of arenes :(a) Do, H.-Q.; Daugulis, O. J. Am.
Chem. Soc. 2007, 129, 12404. (b) Yoshizumi, T.; Tsurugi, H.; Satoh, T.;
Miura, M. Tetrahedron Lett. 2008, 49, 1598. (c) Do, H.-Q.; Daugulis, O.
J. Am. Chem. Soc. 2008, 130, 1128. (d) Zhao, D.; Wang, W.; Yang, F.;
Lan, J.; Yang, L.; Gao, G.; You, J. Angew. Chem., Int. Ed. 2009, 48, 3296.
(e) Kawano, T.; Yoshizumi, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2009, 11, 3072. (f) Besselie´vre, F.; Piguel, S. Angew. Chem., Int. Ed. 2009,
48, 9553. (g) Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem. 2010,
8, 4503. (h) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem.
Soc. 2010, 132, 6900, and references therein.
Although further efforts on the clarification of the reaction
mechanism are required, one possibility involves (i) the
sequential base-assisted cupration of sulfoximine and arene13
leading to the corresponding (aryl)(sulfoximidoyl)copper
intermediate [ArCuNdS(dO)R1R2] and (ii) oxygen-pro-
moted reductive elimination14 along with the regeneration
of a catalytically active copper species.15
(14) Even with 1.0 equiv of Cu(OAc)2·OH2, only a trace amount of 3aa
was detected under N2 conditions (vs Table 1, entry 1). The outcome
suggests that molecular oxygen may work as not only an oxidant to Cu but
also the crucial accelerator in the reaction.
In summary, we have described an effective copper
catalysis for the direct coupling of azoles or polyfluoroarenes
(15) Relevant reaction mechanism: (a) Hamada, T.; Ye, X.; Stahl, S. S.
J. Am. Chem. Soc. 2008, 130, 833. (b) Kitahara, M.; Hirano, K.; Tsurugi,
H.; Satoh, T.; Miura, M. Chem.sEur. J. 2010, 16, 1772. (c) Wei, Y.; Zhao,
H.; Kan, J.; Su, W.; Hong, M. J. Am. Chem. Soc. 2010, 132, 2522, and ref
9c,d, and 9g.
(12) Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron 2007,
63, 1568.
Org. Lett., Vol. 13, No. 3, 2011
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