Copper-catalyzed oxidative decarboxylative couplings of sulfoximines and aryl propiolic acids

Article abstract of DOI:10.1021/ol403106e

A method has been developed for the preparation of N-alkynylated sulfoximines involving the copper-catalyzed decarboxylative coupling of sulfoximines with aryl propiolic acids. A range of substituents on both the sulfoximidoyl moiety and the aryl group of the propiolic acid were compatible with this reaction process to afford a series of sulfoximidoyl-functionalized alkynes.

Full text of DOI:10.1021/ol403106e

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Copper-Catalyzed Oxidative
Decarboxylative Couplings of
Sulfoximines and Aryl Propiolic Acids
Daniel L. Priebbenow, Peter Becker, and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1,
D-52074 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received October 29, 2013
ABSTRACT
A method has been developed for the preparation of N-alkynylated sulfoximines involving the copper-catalyzed decarboxylative coupling of
sulfoximines with aryl propiolic acids. A range of substituents on both the sulfoximidoyl moiety and the aryl group of the propiolic acid were
compatible with this reaction process to afford a series of sulfoximidoyl-functionalized alkynes.
The recent development of numerous oxidative cross-
coupling processes [also referred to as cross-dehydrogena-
tive couplings (CDCs)] for carbonꢀcarbon and carbonꢀ
heteroatom bond formation is having a significant impact
on synthetic organic chemistry.1 Those protocols that allow
the utilization of molecular oxygen or air as an external
oxidant are particularly attractive as both reagent con-
sumption and waste generation are minimized.2
A subclass of the aforementioned oxidative coupling
processes that have attracted significant interest in recent
years are transition-metal-catalyzed decarboxylative cross-
coupling reactions based on metals including copper,
palladium, and silver.3 In particular, the transition-metal-
catalyzed decarboxylative coupling reactions employing
alkyne-derived carboxylic acids are particularly useful.4,5
The utilization of alkynyl carboxylic acids (or propiolic
acids) as coupling partners in such cross-coupling reac-
tions is highly advantageous, as (i) they are stable and
readily available or easily prepared6 and (ii) the approach
avoids the use of traditional coupling partners containing
unfavorable halide-leaving groups. To date, both alkyl-
and aryl-substituted propiolic acids have been applied in
cross-coupling reactions for the formation of new CꢀC,
CꢀN, CꢀS, and CꢀP bonds.7
N-Alkynylated sulfoximines possess enormous synthetic
potential, as when prepared using enantiopure sulfoxi-
mines they can be considered as chiral ynamide analogs.8,9
(6) (a) Das, J. P.; Roy, U. K.; Roy, S. Organometallics 2005, 64, 6136.
(b) Carey, J. S. J. Org. Chem. 2001, 66, 2526. (c) Hajbi, Y.; Neagoie, C.;
Biannic, B.; Chilloux, A.; Vedrenne, E.; Baldeyrou, B.; Bailly, C.;
Merour, J.-Y.; Rosca, S.; Routier, S.; Lansiaux, A. Eur. J. Med. Chem.
2010, 45, 5428. (d) Park, K.; You, J.-M.; Jeon, S.; Lee, S. Eur. J. Org.
Chem. 2013, 1973. (e) Park, K.; Palani, T.; Pyo, A.; Lee, S. Tetrahedron
Lett. 2012, 53, 733. (f) Arndt, M.; Risto, E.; Krause, T.; Goossen, L. J.
ChemCatChem 2012, 4, 484. (g) Yu, D.; Zhang, Y. Proc. Natl. Acad. Sci.
U.S.A. 2010, 107, 20184. (h) Ponpandian, T.; Muthusubramanian, S.
Tetrahedron Lett. 2012, 43, 4248.
(7) For selected examples, see: (a) Jia, W.; Jiao, N. Org. Lett. 2010, 12,
2000. (b) Hu, J.; Zhao, N.; Yang, B.; Wang, G.; Guo, L.-N.; Liang,
Y.-M.; Yang, S.-D. Chem.;Eur. J. 2011, 17, 5516. (c) Park, J.; Park, E.;
Kim, A.; Park, S.-A.; Lee, Y.; Chi, K.-W.; Jung, Y. H.; Kim, I. S. J. Org.
Chem. 2011, 76, 2214. (d) Shi, L.; Jia, W.; Li, X.; Jiao, N. Tetrahedron
Lett. 2013, 54, 1951. (e) Ranjit, S.; Duan, Z.; Zhang, P.; Liu, X. Org.
Lett. 2010, 12, 4134. (f) Zhao, D. B.; Gao, C.; Su, X. Y.; He, Y. Q.; You,
J. S.; Xue, Y. Chem. Commun. 2010, 46, 9049. (g) Zhang, W. W.; Zhang,
X. G.; Li, J. H. J. Org. Chem. 2010, 75, 5259.
(1) For recent reviews on oxidative cross-coupling reactions, see: (a)
Shi, W.; Liu, C.; Lei, A. Chem. Soc. Rev. 2011, 40, 2761. (b) Liu, C.; Jin,
L.; Lei, A. Synlett 2010, 17, 2527.
(2) Stahl, S. S. Angew. Chem. 2004, 116, 3480. Angew. Chem., Int. Ed.
2004, 43, 3400.
(3) For recent reviews, see: (a) Shang, R.; Liu, L. Sci. China Chem.
2011, 54, 1670. (b) Rodrıguez, N.; Goossen, L. J. Chem. Soc. Rev. 2011,
40, 5030.
(4) For selected examples, see: (a) Zhang, Y.; Patel, S.; Mainolfi, N.
Chem. Sci. 2012, 3, 3196. (b) Fu, Z.; Huang, S.; Su, W.; Hong, M. Org.
Lett. 2010, 12, 4992. (c) Myers, A. G.; Tanaka, D.; Mannion, M. R.
J. Am. Chem. Soc. 2002, 124, 11250. (d) Goossen, L. J.; Rodrıguez, N.;
Linder, C.; Lange, P. P. ChemCatChem 2010, 2, 430.
(5) For a comprehensive review on the decarboxylative coupling of
propiolic acids, see: Park, K.; Lee, S. RSC Advances 2013, 3, 14165.
r
10.1021/ol403106e
XXXX American Chemical Society

Scheme 1. Decarboxylative Oxidative Coupling of Sulfoximines with Aryl Propiolic Acidsa
a Reaction conditions: Sulfoximine (0.60 mmol), propiolic acid (0.40 mmol), CuBr (10 mol %), pyridine (20 mol %), K3PO4 (0.44 mmol), PhMe
(3.0 mL), 80 °C, 16 h.
As such, to allow rapid accesstothese valuablesulfoximine
derivatives, it is essential that efficient and reproducible
methodology for their preparation exist. To this end, we
herein disclose our recent efforts in the preparation of
N-alkynylated sulfoximines using a decarboxylative CꢀN
coupling reaction between sulfoximines and aryl propiolic
acids under oxidative conditions.
To explore the decarboxylative process for the prepara-
tion of N-alkynylated sulfoximines, initial reaction attempts
were performed with S-methyl-S-phenyl sulfoximine
(1 where R1 = Ph) and phenyl propiolic acid (2 where
R2 = Ph) using the conditions reported by Jiao for the
decarboxylative coupling of amides and propiolic acids.7a
Unfortunately however, under these conditions [CuCl2
(10 mol %), Na2CO3, PhMe, air, 100 °C] N-alkynylated
sulfoximine 3a was not formed. Subsequently, in toluene
using CuCl2 as the catalyst, a range of inorganic and
organic bases were screened (including K2CO3, Na2CO3,
and DBU). Interestingly, the desired reaction to yield 3a
only proceeded in synthetically useful levels when using
K3PO4 as the base.10
To further optimize the decarboxylative coupling of
sulfoximines with propiolic acids, a range of catalysts,
additives, solvents, and reaction temperatures were screened
(refer to Supporting Information for full reaction opti-
mization). The application of transition-metal catalysts
other than copper, such as silver or palladium complexes
previously shown to be effective in decarboxylative cou-
pling processes,5 failed to facilitate the desired sulfoxi-
mine alkynylation.
Although a range of copper salts were effective in pro-
moting the cross-coupling reaction, the major focus of the
optimization process was centered on limiting formation
of the alkyne dimer. To this end, copper(I) halides such as
CuBr afforded the product in the highest yields, while
limiting homocoupling of the alkyne. High conversions to
the desired product were achieved, and the level of alkyne
homocoupling could be minimized when using up to 5.0
equiv of sulfoximine. This, however, was not deemed cost-
effective, and as such, the optimization process was per-
formed using 1.5 equiv of the sulfoximine substrate.
In the ynamide synthesis developed by Stahl and co-
workers,11 2 equiv of pyridine were employed to limit
formation of the GlaserꢀHay dimer; however, attempted
application of excess pyridine in this decarboxylative cou-
pling process inhibited the reaction. In subsequent trials,
enhanced yields were obtained when only a catalytic amount
of pyridine (20 mol %) was employed. Advantageously,
(8) (a) Wang, L.; Huang, H.; Priebbenow, D. L.; Pan, F.-F.; Bolm, C.
Angew. Chem. 2013, 125, 3562. Angew. Chem., Int. Ed. 2013, 52, 3478.
(b) Pirwerdjan, R.; Priebbenow, D. L.; Becker, P.; Lamers, P.; Bolm, C.
Org. Lett. 2013, 15, 5397. (c) The proposed first example of an
N-alkynylated sulfoximine ( Tanaka, R.; Yamabe, K. J. Chem. Soc.,
Chem. Commun. 1983, 329. ) was later revealed to be incorrect and our
recent report (see ref 8a) is the first to describe the preparation of
N-alkynylated sulfoximines. For further clarification, refer to: Banert,
K.; Hagedorn, M.; Wutke, J.; Ecorchard, P.; Schaarschmidt, D.; Lang,
H. Chem. Commun. 2010, 46, 4058.
(9) For reviews regarding ynamides, see: (a) DeKorver, K. A.; Li, H.;
Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev.
2010, 110, 5064. (b) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem.
2010, 122, 2902. Angew. Chem., Int. Ed. 2010, 49, 2840. (c) Wang, X.-N.;
Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.; Kedrowski, B. L.; Hsung,
R. P. Acc. Chem. Res. DOI: 10.1021/ar400193g.
(10) As the hydrogen initially abstracted from the carboxylic acid is
incorporated into a molecule of water during the oxidative coupling
process, utilization of only a catalytic amount of base was required for
this reaction process to proceed. However, greater yields were obtained
when a stoichiometric amount of K3PO4 was employed.
(11) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130,
833.
B
Org. Lett., Vol. XX, No. XX, XXXX

performing the reaction under air was sufficient, and
application of an oxygen atmosphere was not required.
It was determined that a CuBr/pyridine catalytic system
in the presence of K3PO4 in toluene at 80 °C under air was
effective in minimizing formation of the GlaserꢀHay
dimer and afforded the desired N-alkynylated sulfoxi-
mine 3a in a good yield of 81%.
obtained independent of the functional groups present in
the initial sulfoximine or aryl propiolic acid reagents.
Reaction attempts employing alkyl-substituted propiolic
acids, such as cyclopropyl propiolic acid, failed to afford
the corresponding N-alkynylated sulfoximine, proposedly
due to the inherent instability of the product.
With optimized reaction conditions in hand, a range of
sulfoximine derivatives 1 and aryl propiolic acids 2 were
investigated to afford a series of N-alkynlated sulfoximines
3 (Scheme 1). Initially, S-methyl-S-phenyl sulfoximine was
reacted with a range of aryl propiolic acids containing
halo- oralkyl functionalities atvariouspositionsof thearyl
ring attached to the alkyne (3aꢀh). In general, the aryl
propiolic acids containing alkyl or aryl groups performed
best in this reaction process to afford the corresponding
N-alkynylated sulfoximines in high yields (3aꢀc, 3h,
70ꢀ81%). The electron-deficient chloro- and fluoro-
substituted propiolic acids also reacted well, regardless of
the position of substitution on the aromatic ring (3dꢀg,
70ꢀ82% yield).
Scheme 2. Derivatizations of N-Alkynylated Sulfoximines
Unfortunately, electron-rich aryl propiolic acids were
not well tolerated in this decarboxylative coupling reaction
process. For example, application of 4-methoxyphenyl-,
3,4-dimethoxyphenyl-, and 4-thiomethylphenylpropiolic
acids affordedthe GlaserꢀHay dimer asthe major product
and a less than 20% yield of the desired N-alkynlated
sulfoximine was isolated. In these cases, the alkynyl cou-
pling partner was not sufficiently electrophilic and dimer-
ized in preference to undergoing the desired cross-coupling
reaction with the sulfoximine.
To further explore this reaction process, a range of alkyl/
methyl and aryl/methyl sulfoximines containing halo-,
methoxy-, or nitro-phenyl groups were applied (Scheme 1,
3iꢀn). It was observed that the steric and electronic
properties of the sulfoximine moiety in this coupling
process did not play a significant role, with good yields
recorded for each reaction process (59ꢀ94% yield). Only
the 4-bromophenyl derivative 3l was isolated in a slightly
lower yield (59%) than in the case of the other examples.
Additional coupling reactions were then performed
using a range of alkynyl coupling partners including those
containing tolyl, thiophenyl, and (polyfluoro)aryl moieties
(Scheme 1, 3oꢀv). In each of these cases, good yields
(59ꢀ82%) of the desired N-alkynylated sulfoximines were
Derivatization of the N-alkynylated sulfoximines was
then explored (Scheme 2). An (Z)-alkenylated sulfoximine
4, of which very few previous acyclic examples exist,12 was
prepared by reduction of the alkyne using Pd/C (10 wt %),
under an atmosphere of H2, to almost selectively afford the
(Z)-alkene 4 in70% yield (ratioofZ/E = 21:1by1H NMR
analysis). The [2 þ 2]-cycloaddition of 3p with dimethyl
ketene was also accomplished to afford cyclobutenone
sulfoximine 5 in a yield of 81% by refluxing the alkyne
with isobutyryl chloride in the presence of triethylamine
(Scheme 2).8b,13
In summary, a new method has been developed that
facilitates the preparation of N-alkynylated sulfoximines
in good to excellent yields from aryl propiolic acids which
are stable, readily available, and easy to store and handle.
Advantageously, this protocol applies a cheap copper
catalytic system and allows air to be employed as the
oxidant, and as a result, the only byproducts from this
process are water and carbon dioxide. The properties and
reactivity profile of N-alkynylated sulfoximines remain
under investigation in our laboratories.
Acknowledgment. D.L.P. is grateful to the Alexander
von Humboldt Foundation for a postdoctoral fellowship.
(12) (a) Gao, X.; Gaddam, V.; Altenhofer, E.; Tata, R. R.; Cai, Z.;
Yongpruksa, N.; Garimallaprabhakaran, A. K.; Harmata, M. Angew.
Chem., Int. Ed. 2012, 51, 7016. (b) Reissig, H.-U.; Zimmer, R. Sci. Synth.
2006, 33, 391. (c) Bonacorso, H. G.; Bittencourt, S. R. T.; Lourega,
R. V.; Flores, A. F. C.; Zanatta, N.; Martins, M. A. P. Synthesis 2000, 10,
1431. (d) Tamura, Y.; Bayomi, S. M.; Tsunekawa, M.; Ikeda, M. Chem.
Pharm. Bull. 1979, 27, 2137.
Supporting Information Available. Experimental pro-
cedures, analytical data, and NMR spectra for all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Kohnen, A. L.; Mak, X. Y.; Lam, T. Y.; Dunetz, J. R.; Danheiser,
R. L. Tetrahedron 2006, 62, 3815.
The authors declare no competing financial interest.
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