N-arylations of sulfoximines with 2-arylpyridines by copper-mediated dual N-H/C-H activation

Article abstract of DOI:10.1021/ol500963p

A high-yielding method providing rapid access to new N-arylated sulfoximines has been developed. A stoichiometric amount of copper facilitates the C-H activation of 2-arylpyridines which then undergo oxidative C-N cross-couplings with various sulfoximine derivatives.

Full text of DOI:10.1021/ol500963p

Letter
pubs.acs.org/OrgLett
N‑Arylations of Sulfoximines with 2‑Arylpyridines by Copper-
Mediated Dual N−H/C−H Activation
Long Wang, Daniel L. Priebbenow, Wanrong Dong, and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056 Aachen, Germany
S
* Supporting Information
ABSTRACT: A high-yielding method providing rapid access
to new N-arylated sulfoximines has been developed. A
stoichiometric amount of copper facilitates the C−H activation
of 2-arylpyridines which then undergo oxidative C−N cross-
couplings with various sulfoximine derivatives.
ue to their unique properties sulfoximines have found a
reaction parameters including the metal, solvent, oxidant,
Dnumber of applications in medicinal and agricultural additive, and reaction temperature was explored. Using air as
chemistry.1 Since 1992, we have been involved in this area,2
oxidant and acetonitrile as solvent only Cu(OAc)2·H2O was
found to promote the coupling (at 130 °C) providing product
6a in 26% yield. Other metal salts such as CuBr2, CuCl2, and
Pd(OAc)2 proved inactive.12 A solvent screening revealed that
the use of an organonitrile was critical. (For further details, see
the Supporting Information.) Subsequently, the yield of 6a was
increased to 38% when dioxygen was used as oxidant instead of
air. Applying the higher boiling propionitrile as solvent and
increasing the reaction temperature to 130 °C led to an
additional improvement providing 6a in 55% yield. Finally, an
additive screening (see the Supporting Information) showed
that the presence of acetic acid (0.5 equiv) had a positive
effect,13 affording the N-arylated sulfoximine derivative 6a in
80% yield after 24 h (Scheme 1).14
mainly focusing on the use of sulfoximines as chiral ligands for
asymmetric metal catalysis.3 The most effective compounds of
this type identifed for this purpose were all arylated at the
sulfoximine nitrogen as exemplified by sulfoximines 1−3
(Figure 1), which all led to products with >90% ee in the
respective catalyses.4,5
Scheme 1. Optimized Conditions for the Coupling Reaction
Figure 1. Effective sulfoximine-based chiral ligands for asymmetric
metal catalysis.
For the preparation of N-arylated sulfoximines various
methods have been previously described, predominantly
involving the use of aryl halides, triflates, and boronic acids.
Those functionalized arenes are then coupled with NH-
sulfoximines by palladium or copper catalysis.6 More recently,
we found in collaboration with Miura and co-workers that N-
arylations could also be achieved by copper-catalyzed dual C−
H/N−H activation provided that the arene was sufficiently
activated to allow a base-assisted cupration.7,8 We herein report
that such couplings can now also be performed through
directed metalations of 2-arylpyridines leading to new N-
arylated sulfoximine derivatives which are difficult to prepare by
other means.9 It is also noteworthy that the substrate activation
was achieved with simple hydrated copper acetate and dioxygen
was applied as the terminal oxidant.10,11
Having established the optimized reaction conditions, an
investigation into the versatility and functional group tolerance
of this reaction process was performed (Figure 2).
First, the sulfoximine component was varied, and couplings
with 2-phenylpyridine (4a) were investigated. To our delight,
all reactions proceeded well, and the resulting products (6a−g)
were obtained in good yields. Compared to the reaction of S-
methyl-containing sulfoximine 4a, the N-arylation of the
analogous S-ethyl derivative led to the corresponding product
in a slightly lower yield (80% for 6a versus 72% for 6b). This
was also comparable to the result observed for the formation of
S,S-diphenylsulfoximine 6c (69% yield). Other S-methyl-
During the reactivity search and the optimization process, 2-
phenylpyridine (4a) and S-methyl-S-phenylsulfoximine (5a)
were selected as starting materials. The latter substrate was used
in a 2-fold excess to maximize conversions. The role of several
Received: April 1, 2014
Published: April 30, 2014
© 2014 American Chemical Society
2661
dx.doi.org/10.1021/ol500963p | Org. Lett. 2014, 16, 2661−2663

Organic Letters
Letter
Figure 4. Major species identified by ESI-MS analysis of the reaction
mixture.
Figure 2. Substrate scope of the copper-mediated oxidative coupling.
*Use of 2-nitrobenzoic acid (0.5 equiv) instead of AcOH.
species as single crystals remained unsuccessful. The strength of
the metal coordination was indicated by the fact that liberation
of product 6a from the metal required treatment of the reaction
mixture with Na2S.16 If such metal−ligand coordination
complexes can lead to effective catalysts still requires additional
investigation.17
Based on all findings, we assume a mechanism that is
analogous to the one proposed by Yu and co-workers in related
C−H functionalizations of 2-phenylpyridine.11e In that
scenario, single-electron-transfer processes, coordinated copper
intermediates, and radical cations play significant roles (Scheme
2).
containing starting materials with substituted S-aryl groups
afforded the corresponding products (6d−f) in yields ranging
from 61% to 82%. In the reaction of S,S-dimethylsulfoximine, 2-
nitrobenzoic acid had to be used as additive instead of acetic
acid to avoid the acetylation of the sulfoximine, which occurred
as a side reaction. Accordingly, 6g was obtained in 55% yield.
Reactions of sulfoximine 5a with para-substituted 2-
arylpyridines led to products 6h−k in yields between 64%
and 85%. In this series, the halo-containing derivatives 6j and
6k were obtained with the highest yields (81% and 85%,
respectively). In addition, 2-(o-tolyl)pyridine reacted well with
5a (giving 6l in 57% yield) provided that 2-nitrobenzoic acid
was again used as additive in place of acetic acid to avoid
acetylation of the sulfoximine.
Scheme 2. Proposed Mechanism
Finally it was demonstrated that substituents on the pyridine
moiety were tolerated. Thus, compounds with methyl groups in
the 4 or 5 position reacted with 5a to give 6m and 6n in 72%
and 75% yield, respectively.
With a focus on the stereochemistry of the starting material,
2-phenylpyridine (4a) was reacted with enantiopure (S)-5a.
Analysis of the er of 6a by chiral HPLC confirmed our
assumption that the coupling was stereospecific.
Attempts to couple sulfoximine 5a under the optimized
conditions with benzaldehyde O-methyl oxime (7), N-
methoxybenzamide (8), or other aryl-substituted nitrogen-
containing heterocycles [phenyl pyrimide (9), 2-phenyl-1,3,4-
oxadiazole (10), and 7,8-benzoquinoline (11)] remained
unsuccessful (Figure 3).15
In conclusion, a new method for the N-arylations of
sulfoximines by dual C−H/N−H activation has been
discovered. Pyridine nitrogens serve as directing elements
allowing the remote positions of connected arenes to be
derivatized. The combined use of simple hydrated copper
diactetate as activator and dioxygen as oxidant are crucial for
the success of this reaction process. The resulting products are
capable of being N,N′-chelating ligands which might prove
useful for applications in catalysis, material sciences, and
biorelated areas. Studies along such lines are now ongoing in
our laboratories.
ASSOCIATED CONTENT
* Supporting Information
■
S
Figure 3. Potential reaction partners of 5a that did not react.
Experimental procedures, analytical data, and NMR spectra for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
With the goal of gaining insight into the reaction details and
with the intention to detect relevant intermediates in the
conversion of 4a and 5a to give 6a, ESI-MS studies of the crude
reaction mixture were performed. This analysis revealed three
major species (Figure 4). In addition to protonated 6a, two
copper complexes {[6a·Cu(OAc)]+ and [(6a)2·Cu(OAc)]+}
were identified having one or two product molecules attached
to a cationic copper acetate fragment. Attempts to isolate such
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: carsten.bolm@oc.rwth-aachen.de.
Notes
The authors declare no competing financial interest.
2662
dx.doi.org/10.1021/ol500963p | Org. Lett. 2014, 16, 2661−2663

Organic Letters
Letter
Chem. 2011, 76, 4158. (d) Shuai, Q.; Deng, G.; Chua, Z.; Bohle, D. S.;
Li, C.-J. Adv. Synth. Catal. 2010, 352, 632. (e) Chen, X.; Hao, X. S.;
Goodhue, C. E.; Yu, J. Q. J. Am. Chem. Soc. 2006, 128, 6790.
(12) Combinations of Pd(OAc)2/K2S2O8 in dichloroethane and
CuBr/t-BuO-O-t-Bu in toluene (or neat) were unsuitable for
promoting the coupling
ACKNOWLEDGMENTS
■
D.L.P. is grateful to the Alexander von Humboldt Foundation
for a postdoctoral fellowship. W.D. thanks the China
Scholarship Council for a predoctoral stipend.
(13) (a) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
1932. (b) Wang, H.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. J. Am.
Chem. Soc. 2010, 132, 13217. (c) Mitchell, E. A.; Peschiulli, A.;
Lefevre, N.; Meerpoel, L.; Maes, B. U. Chem.Eur. J. 2012, 18, 10092.
(14) The attempt to reduce the metal salt loading from 1 equiv to 20
mol % significantly affected the yield of 6a (22%). That effect is
probably due to the chelating ability of the product to complex the
activating metal, which inhibits turnover.
REFERENCES
■
(1) For selected references regarding bioactive sulfoximines, see:
(a) Raza, A.; Sham, Y. Y.; Vince, R. Bioorg. Med. Chem. Lett. 2008, 18,
5406. (b) Yu, H.; Qin, Z.; Dai, H.; Zhang, X.; Qin, X.; Wang, T.; Fang,
J. J. Agric. Food. Chem. 2008, 56, 11356. (c) Zhu, Y.; 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. J. Agric. Food. Chem. 2011, 59, 2950. (d) Park, S. J.;
Buschmann, H.; Bolm, C. Bioorg. Med. Chem. Lett. 2011, 21, 4888.
(e) Chen, X. Y.; Buschmann, H.; Bolm, C. Synlett 2012, 23, 2808.
(15) In addition, biphenyl did not react with sulfoximine 5a (20 h
1
reaction time; analysis by TLC and H NMR).
(16) For details, see the Supporting Information
(17) In contrast to the copper complexes detected here, where the
metal and the N,N′-chelating ligand form 6-membered rings, most of
the successfully applied copper sulfoximine complexes appear to
involve 5-membered chelates. For relevant work on asymmetric
catalysis with such complexes, see ref 3 and articles cited therein. An
X-ray crystal structure of a related copper sulfoximine complex can be
found in: Bolm, C.; Verrucci, M.; Simic, O.; Cozzi, P. G.; Raabe, G.;
Okamura, H. Chem. Commun. 2003, 2816.
(f) Lucking, U. Angew. Chem., Int. Ed. 2013, 52, 9399.
̈
(2) Bolm, C.; Felder, M.; Muller, J. Synlett 1992, 439.
̈
(3) For the most recent work in this area from our group, see: Frings,
M.; Thome, I.; Schiffers, I.; Pan, F.; Bolm, C. Chem.Eur. J. 2014, 20,
́
1691.
(4) For the initial reports on compounds 1−3, see: (a) Bolm, C.;
Simic, O. J. Am. Chem. Soc. 2001, 123, 3830. (b) Langner, M.; Bolm,
C. Angew. Chem., Int. Ed. 2004, 43, 5984. (c) Moessner, C.; Bolm, C.
Angew. Chem., Int. Ed. 2005, 44, 7564.
(5) Harmata and co-workers used N-arylated sulfoximines as key
intermediates in total syntheses. For representative examples, see:
(a) Harmata, M.; Pavri, N. Angew. Chem., Int. Ed. 1999, 38, 2419.
(b) Yongpruksa, N.; Pandey, S.; Baker, G. A.; Baker; Harmata, M. Org.
Biomol. Chem. 2011, 9, 7979. (c) Yongpruksa, N.; Calkins, N. L.;
Harmata, M. Chem. Commun. 2011, 7665.
(6) (a) Bolm, C.; Hildebrand, J. P. Tetrahedron Lett. 1998, 39, 5731.
(b) Bolm, C.; Hildebrand, J. P. J. Org. Chem. 2000, 65, 169. (c) Bolm,
C.; Hildebrand, J. P.; Rudolph, J. Synthesis 2000, 911. (d) Cho, G. Y.;
Remy, P.; Jansson, J.; Moessner, C.; Bolm, C. Org. Lett. 2004, 6, 3293.
(d) Sedelmeier, J.; Bolm, C. J. Org. Chem. 2005, 70, 6904.
(e) Moessner, C.; Bolm, C. Org. Lett. 2005, 7, 2667. (f) Harmata,
M.; Hong, X.; Ghosh, S. K. Tetrahedron Lett. 2004, 45, 5233.
(g) Harmata, M.; Hong, X. Synlett 2007, 969. (h) Yongpruksa, N.;
Calkins, N. L.; Harmata, M. Chem. Commun. 2011, 47, 7665.
(7) Miyasaka, M.; Hirano, K.; Satoh, T.; Kowalczyk, R.; Bolm, C.;
Miura, M. Org. Lett. 2011, 13, 359.
(8) For extensions of this approach to other N-functionalizations of
sulfoximines, see: (a) Wang, L.; Huang, H.; Priebbenow, D. L.; Pan, F.
F.; Bolm, C. Angew. Chem., Int. Ed. 2013, 52, 3478. (b) Priebbenow, D.
L.; Becker, P. Org. Lett. 2013, 15, 6155. (c) Wang, L.; Priebbenow, D.
L.; Zou, L.-H.; Bolm, C. Adv. Synth. Catal. 2013, 355, 1490.
(9) For selected reviews regarding C−H bond functionalization, see:
(a) Bergman, R. G. Nature 2007, 446, 391. (b) Mkhalid, I. A.; Barnard,
J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010,
110, 890. (c) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698.
(d) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J. Q. Angew. Chem., Int.
Ed. 2009, 48, 5094. (e) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius,
F. Chem. Soc. Rev. 2011, 40, 4740. (f) Yeung, C. S.; Dong, V. M. Chem.
Rev. 2011, 111, 1215. (g) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S.
Chem. Soc. Rev. 2011, 40, 5068. (h) Ackermann, L. Chem. Rev. 2011,
111, 1315. (i) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
1147. (j) Satoh, T.; Miura, M. Chem.Eur. J. 2010, 16, 11212. (k) Liu,
C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780.
(l) Kakiuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077.
(m) Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41,
3381. (n) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464.
(10) For a most stimulating review on metal catalysis involving
dioxygen, see: Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400.
(11) For other selected examples of intermolecular C−H/N−H
oxidative cross-couplings, see: (a) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J.
Am. Chem. Soc. 2006, 128, 9048. (b) Uemura, T.; Imoto, S.; Chatani,
N. Chem. Lett. 2006, 35, 842. (c) John, A.; Nicholas, K. M. J. Org.
2663
dx.doi.org/10.1021/ol500963p | Org. Lett. 2014, 16, 2661−2663