Copper-catalyzed oxidative cross-coupling of sulfoximines and alkynes

Article abstract of DOI:10.1002/anie.201209975

A 'Cu'te couple: A synthetically useful protocol for the preparation of N-alkynylated sulfoximines (yne sulfoximines) has been developed. The method involves a mild copper-catalyzed oxidative cross-coupling of NH-sulfoximines and terminal alkynes (see scheme). The corresponding N-acyl sulfoximines were also obtained selectively after acid-catalyzed hydrolysis of the yne sulfoximines.

Full text of DOI:10.1002/anie.201209975

Angewandte
Chemie
DOI: 10.1002/anie.201209975
Cross-Coupling
Copper-Catalyzed Oxidative Cross-Coupling of Sulfoximines and
Alkynes**
Long Wang, He Huang, Daniel L. Priebbenow, Fang-Fang Pan, and Carsten Bolm*
Until recently, the cross-coupling of two electron-rich nucleo-
philic substrates presented a significant challenge for syn-
thetic organic chemists.[1] In the past decade, however, several
breakthroughs have been reported for such processes, such as
employing transition-metal catalysts to facilitate the forma-
a copper(II) salt as catalyst. Furthermore, through a simple
modification in the purification procedure, the corresponding
N-acyl sulfoximines can also be obtained selectively in good
yields.
The sulfoximidoyl moiety is found in various bioactive
compounds currently examined in both medicinal and
agricultural chemistry.[5] In asymmetric metal catalysis, sul-
foximines have proven useful as chiral ligands for a range of
catalyzed processes.[6] Functionalization of the sulfoximine
À
À
tion of either a new C C or C N bond between two
nucleophiles.[2] Realizing that this approach could also open
access to N-alkynylated sulfoximines (2), which represent an
essentially unexplored substrate class, we considered oxida-
tive cross-coupling methods for the construction of the
À
N H bond enriches the diversity of sulfoximine libraries and
À
respective C N bonds (Scheme 1).
provides access to a plethora of potentially useful compounds.
By applying the currently available methods, alkyl, alkenyl,
and aryl groups can be introduced.[7] N-Alkynylations of
sulfoximines, however, are unknown. In this context it is also
noteworthy that the only reported representative of the
expected product class 2 is N-(phenylethynyl)-S,S-dimethyl-
sulfoximine (2a), which was obtained through nitrene addi-
tion to DMSO and isolated in only 1.5% yield (Scheme 1).[3]
In light of the rich chemistry of the structurally related
ynamides,[8] the scarcity of N-alkynylated sulfoximines is even
more surprising. The development of new synthetic protocols
for the preparation of stable and potentially chiral derivatives
of these ynamide-type products appears critical to allow
further progress to be made in this burgeoning field of
synthetic chemistry.
Scheme 1. a) The only previously reported preparation of an N-alkynyl
sulfoximine.[3] b) The approach reported herein. DMSO=dimethylsulf-
oxide.
Considering the advances in copper-catalyzed syntheses
of N-alkynylheterocycles and N-alkynylamides,[2,9] we
decided to apply those methods to the preparation of the
corresponding sulfoximine derivatives. In Table 1, the most
significant steps of this screening are summarized. In all cases,
racemic methyl phenyl sulfoximine (4a) served as the NH-
coupling partner and 2b was the expected product.
À
À
A necessity of such dual C H/N H activation cross-
coupling procedures is the inclusion of an oxidant, often in
stoichiometric amounts, to remove two electrons during the
bond-forming process. Molecular oxygen appears as an ideal
oxidant, thus avoiding the subsequent generation of addi-
tional waste.[4] Furthermore, it is desirable that the transition-
metal catalysts employed for the activation of the two
nucleophiles are cheap and readily available. To this end,
we herein report the development of a high-yielding oxidative
cross-coupling method for the preparation of N-alkynylated
sulfoximines. This protocol employs dioxygen as oxidant and
Initially, the N-alkynylation of the sulfoximine 4a was
tried with (bromoethynyl)benzene (1b)[9a–d] as an alkynyl-
ation reagent (Table 1, entries 1–3), but under these reaction
conditions, only the homocoupled diyne (not shown) was
identified in the reaction mixture. To our delight, however,
the application of the reaction conditions reported by Stahl
and co-workers for the oxidative amidation of terminal
alkynes[2a] (Table 1, entry 5), and Evano and co-workers for
the oxidative alkynylation of diaryl imines[2b] (Table 1,
entry 6) proved effective, thus leading to the yne sulfoximine
2b, with the former protocol being slightly higher yielding.
The use of copper(II) chloride as a catalyst and sodium
carbonate as a base in 1,4-dioxane proved optimal to afford
synthetically useful yields of 2b starting from 4a and phenyl-
acetylene (3a). With toluene as the solvent (Table 1, entry 6)
similar results to those obtained with 1,4-dioxane were
observed, however the starting materials were initially more
soluble in 1,4-dioxane, and as such, this was used as the
[*] L. Wang, H. Huang, Dr. D. L. Priebbenow, Prof. Dr. C. Bolm
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52056 Aachen (Germany)
E-mail: carsten.bolm@oc.rwth-aachen.de
F.-F. Pan
Institute of Inorganic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
[**] This work was supported by the German–Israeli Foundation (G.I.F.).
D.L.P. acknowledges support by the Alexander von Humboldt
foundation. We also thank Prof. Dr. Jiang Cheng (Changzhou
University, China) for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209975.
Angew. Chem. Int. Ed. 2013, 52, 1 – 4
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Table 1: Screening of the sulfoximine N-alkynylation conditions.
properties of the terminal alkyne coupling partner did not
significantly affect the yield. Substrates bearing a 3-pyridinyl
or a triethylsilyl group also reacted well, thus affording the
corresponding products 2i and 2j in 60 and 84% yield,
respectively. It is important to note that all the products were
obtained after purification by column chromatography using
triethylamine-deactivated silica gel.[11] In addition to (S,S)-4a,
reactions with S,S-dimethyl sulfoximine [(S,S)-4b] and S,S-
tetramethylene sulfoximine [(S,S)-4c] worked well, thus
affording the yne sulfoximines 2k and 2l in moderate yields.
Attempts to employ alkyl-substituted terminal alkynes (1-
hexyne and 1-octyne) under the previously optimized reac-
tion conditions remained unsuccessful.
During the investigation into the scope of the N-alkynyl-
ation of sulfoximines it was observed in some cases that the
yne sulfoximines were sensitive to hydrolysis, in particular on
silica gel. To further exploit this, reaction mixtures containing
newly formed yne sulfoximines were subjected to normal
silica gel chromatography, which led, to our delight, to the
corresponding N-acyl sulfoximines 6 in good overall yields
(Scheme 3).
Entry Alkynylation Reaction conditions[a]
reagent
Yield
[%]
1
1b
CuI (5 mol%), 2-acetylcyclohexanone
(20 mol%), Cs2CO3 (2 equiv),
–
1,4-dioxane, 4 ꢀ M.S., 508C
2
1b
CuSO4·5H2O (5 mol%),
–
1,10-phenanthroline (20 mol%),
K3PO4 (2 equiv), toluene, 608C
CuCN (5 mol%), DMEDA (20 mol%),
K3PO4 (2 equiv), toluene, 1108C
CuCl2 (10 mol%), Na2CO3 (2 equiv)
1,4-dioxane, 708C, O2
CuCl2 (10 mol%), pyridine (2 equiv),
Na2CO3 (2 equiv), 1,4-dioxane, 708C, O2
CuCl2 (10 mol%), pyridine (2 equiv),
Na2CO3 (2 equiv), toluene, 708C, O2
CuI (12 mol%), DMEDA (18 mol%),
Cs2CO3 (4 equiv), 1,4-dioxane, 708C
3
4
5
6
7
1b
3a
3a
3a
5
–
59
78
75
–
[a] Use of 2 equiv of sulfoximine to alkynylation reagent. O2 employed at
a pressure of 1 atm. DMEDA=N,N’-dimethylethylenediamine.
solvent for the remainder of the study. The use of molecular
oxygen was also essential for the reaction to proceed.
Furthermore, it was determined that the presence of two
equivalents of pyridine provided higher yields (compare
entries 4 and 5), by preventing homocoupling of the alkyne to
form the Glaser–Hay dimer.[10] Attempts to employ (2,2-
dibromovinyl)benzene (5)[9e] as the alkynylation reagent
remained unsuccessful (Table 1, entry 7).
Following optimization of the reaction conditions, the
substrate scope of the alkynylation protocol was investigated
(Scheme 2). Initially, S,S-methylphenyl sulfoximine [(S,S)-4a]
was coupled with a range of terminal alkynes to afford the yne
sulfoximines 2b–j. In general, the products were obtained in
moderate to high yields. Various electron-donating and
electron-withdrawing moieties on the aryl alkynes were well
tolerated in this reaction process, and overall the electronic
Scheme 3. Products of sequential oxidative N-alkynylations and hydrol-
yses.
As confirmed by X-ray crystal structure analysis of 6b
(see the Supporting Information),[11,12] the hydrolysis of the
yne sulfoximines was regioselective, thereby providing access
to products which commonly involve reactions with highly
active acyl donors such as acyl halides.[13,14] This novel
oxidative coupling protocol, in contrast, is mild and utilizes
alternative starting materials (alkynes), which might prove
beneficial in many target-driven syntheses involving sensitive
substrates and products.
In conclusion, we have developed a synthetically useful
protocol for the preparation of yne sulfoximines through
copper-catalyzed oxidative couplings of sulfoximines and
terminal alkynes.[15] The mild reaction conditions involve
a cheap catalyst and molecular dioxygen as the oxidant.
Various yne sulfoximines can be generated from the corre-
sponding sulfoximines whereby both electron-rich and elec-
tron-deficient terminal alkynes are well tolerated. A modified
Scheme 2. Substrate scope of the oxidative N-alkynylation.
2
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 4
These are not the final page numbers!

Angewandte
Chemie
Renga, I. Denholm, K. Gorman, G. J. DeBoer, J. Hasler, T.
work-up (chromatography) opens up straightforward access
to the respective N-acyl sulfoximines by acid-mediated
hydrolysis of the yne sulfoximines during chromatography.
Various chemical transformations and applications of the
scarcely reported yne sulfoximines (which we consider
ynamide analogues accessible in enantiopure form) are
envisaged and these will be reported in due course.
Meade, J. D. Thomas, J. Agric. Food Chem. 2011, 59, 2950; c) S. J.
Park, H. Buschmann, C. Bolm, Bioorg. Med. Chem. Lett. 2011,
21, 4888; d) X. Y. Chen, S. J. Park, H. Buschmann, M. De Rosa,
C. Bolm, Bioorg. Med. Chem. Lett. 2012, 22, 4307; e) S. J. Park,
H. Baars, S. Mersmann, H. Buschmann, J. M. Baron, P. M.
Amann, K. Czaja, H. Hollert, K. Bluhm, R. Redelstein, C. Bolm,
ChemMedChem 2013, 8, 217.
[6] For selected recent examples published by our group, see: a) M.
Frings, I. Atodiresei, Y. Wang, J. Runsink, G. Raabe, C. Bolm,
Chem. Eur. J. 2010, 16, 4577; b) M. Frings, D. Goedert, C. Bolm,
Chem. Commun. 2010, 46, 5497; c) E. B. Benetskiy, C. Bolm,
Tetrahedron: Asymmetry 2011, 22, 373; d) M. Frings, I. Thomꢀ,
C. Bolm, Beilstein J. Org. Chem. 2012, 8, 1443; e) For a summary,
see: C. Worch, A. C. Mayer, C. Bolm, Organosulfur Chemistry in
Asymmetric Synthesis (Eds.: T. Toru, C. Bolm), Wiley-VCH,
Weinheim, 2008, p. 209.
[7] a) B. Raguse, D. D. Ridley, Aust. J. Chem. 1986, 39, 1655;
b) C. R. Johnson, O. M. Lavergne, J. Org. Chem. 1993, 58, 1922;
c) C. Bolm, J. P. Hildebrand, J. Org. Chem. 2000, 65, 169; d) C.
Moessner, C. Bolm, Org. Lett. 2005, 7, 2667; e) J. Sedelmeier, C.
Bolm, J. Org. Chem. 2005, 70, 6904; f) J. R. Dehli, C. Bolm, Adv.
Synth. Catal. 2005, 347, 239; g) G. Y. Cho, P. Remy, J. Jansson, C.
Moessner, C. Bolm, Org. Lett. 2004, 6, 3293; h) M. Harmata, X.
Hong, S. K. Ghosh, Tetrahedron Lett. 2004, 45, 5233; i) M.
Harmata, W. Ying, C. L. Barnes, Tetrahedron Lett. 2009, 50,
2326; j) M. Miyasaka, K. Hirano, T. Satoh, R. Kowalczyk, C.
Bolm, M. Miura, Org. Lett. 2011, 13, 359; k) B. Vaddula, J.
Leazer, R. S. Varma, Adv. Synth. Catal. 2012, 354, 986.
[8] a) K. A. DeKorver, H. Li, A. G. Lohse, R. Hayashi, Z. Lu, Y.
Zhang, R. P. Hsung, Chem. Rev. 2010, 110, 5064; b) G. Evano, A.
Coste, K. Jouvin, Angew. Chem. 2010, 122, 2902; Angew. Chem.
Int. Ed. 2010, 49, 2840.
[9] a) C. Laroche, J. Li, M. W. Freyer, S. M. Kerwin, J. Org. Chem.
2008, 73, 6462; b) Y. Zhang, R. P. Hsung, M. R. Tracey, K. C.
Kurtz, E. L. Vera, Org. Lett. 2004, 6, 1151; c) M. O. Frederick,
J. A. Mulder, M. R. Tracey, R. P. Hsung, J. Huang, K. C. Kurtz, L.
Shen, C. J. Douglas, J. Am. Chem. Soc. 2003, 125, 2368; d) X.
Zhang, Y. Zhang, J. Huang, R. P. Hsung, K. C. Kurtz, J.
Oppenheimer, M. E. Petersen, I. K. Sagamanova, L. Shen,
M. R. Tracey, J. Org. Chem. 2006, 71, 4170; e) A. Coste, G.
Karthikeyan, F. Couty, G. Evano, Angew. Chem. 2009, 121, 4445;
Angew. Chem. Int. Ed. 2009, 48, 4381.
[10] a) C. Glaser, Ber. Dtsch. Chem. Ges. 1869, 2, 422; b) C. Glaser,
Ann. Chem. Pharm. 1870, 154, 137.
[11] See the Supporting Information for details.
[12] CCDC 915210 (6b) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[13] C. Bolm, C. P. R. Hackenberger, O. Simic, M. Verrucci, D.
Mꢁller, F. Bienewald, Synthesis 2002, 879.
Experimental Section
Typical procedure for the N-alkynylation of sulfoximines: A 100 mL
three-necked flask equipped with a stirring bar was loaded with CuCl2
(6 mg, 10 mol%), sulfoximine (1.0 mmol) and Na2CO3 (106 mg,
1.0 mmol). Under an oxygen atmosphere (1 atm), a solution of
pyridine (1.0 mmol) in 1,4-dioxane (5 mL) was added. After heating
to 708C, a solution of the terminal alkyne (0.5 mmol) in 1,4-dioxane
(3 mL) was added slowly to the reaction mixture using a syringe pump
over 4 h. After the addition, the reaction mixture was stirred at 708C
for an additional 2 h, and then cooled to room temperature. The
reaction mixture was filtered over a plug of triethylamine-deactivated
silica gel and washed with dichloromethane and concentrated.
Purification by triethylamine-deactivated silica gel column chroma-
tography afforded the yne sulfoximine.
Typical Procedure for the N-alkynylation of sulfoximines: As
above, however, the crude reaction mixture was subjected to normal
silica gel column chromatography to afford the corresponding N-acyl-
sulfoximines.
Received: December 13, 2012
Published online: && &&, &&&&
À
Keywords: alkynes · C H activation · cross-coupling ·
sulfoximines · synthetic methods
.
[1] For a discussion on oxidative cross-coupling reactions, see: a) W.
Shi, C. Liu, A. Lei, Chem. Soc. Rev. 2011, 40, 2761; b) C. Liu, L.
Jin, A. Lei, Synlett 2010, 2527.
À
[2] For selected examples of oxidative C N bond-forming reactions,
see: a) T. Hamada, X. Ye, S. S. Stahl, J. Am. Chem. Soc. 2008,
130, 833; b) A. Laouiti, M. M. Rammah, M. B. Rammah, J.
Marrot, F. Couty, G. Evano, Org. Lett. 2012, 14, 6; c) S. H. Cho, J.
Yoon, S. Chang, J. Am. Chem. Soc. 2011, 133, 5996; d) D.
Monguchi, T. Fujiwara, H. Furukawa, A. Mori, Org. Lett. 2009,
11, 1607.
[3] R. Tanaka, K. Yamabe, J. Chem. Soc. Chem. Commun. 1983, 329.
[4] S. S. Stahl, Angew. Chem. 2004, 116, 3480; Angew. Chem. Int. Ed.
2004, 43, 3400.
[5] For selected recent examples of bioactive sulfoximines, see:
a) D. P. Walker, M. P. Zawistoski, M. A. McGlynn, J. C. Li, D. W.
Kung, P. C. Bonnette, A. Baumann, L. Buckbinder, J. A. Houser,
J. Boer, A. Mistry, S. Han, L. Xing, A. Guzman-Perez, Bioorg.
Med. Chem. Lett. 2009, 19, 3253; b) Y. Zhu, M. R. Loso, G. B.
Watson, T. C. Sparks, R. B. Rogers, J. X. Huang, B. C. Gerwick,
J. M. Babcock, D. Kelley, V. B. Hegde, B. M. Nugent, J. M.
[14] For an analogous regioselectivity observed in a copper-catalyzed
hydrative amide synthesis, see: S. H. Cho, E. J. Yoo, I. Bae, S.
Chang, J. Am. Chem. Soc. 2005, 127, 16046.
[15] For a mechanistic description of the related oxidative cross-
coupling reaction between alkynes and amides, see Ref. [2a].
Angew. Chem. Int. Ed. 2013, 52, 1 – 4
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
Communications
Cross-Coupling
L. Wang, H. Huang, D. L. Priebbenow,
F.-F. Pan, C. Bolm*
&&&& — &&&&
A ’Cu’te couple: A synthetically useful
protocol for the preparation of N-alkyny-
lated sulfoximines (yne sulfoximines) has
been developed. The method involves
a mild copper-catalyzed oxidative cross-
coupling of NH-sulfoximines and termi-
nal alkynes (see scheme). The corre-
sponding N-acyl sulfoximines were also
obtained selectively after acid-catalyzed
hydrolysis of the yne sulfoximines.
Copper-Catalyzed Oxidative Cross-
Coupling of Sulfoximines and Alkynes
4
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 4
These are not the final page numbers!