Efficient copper-catalyzed N-arylation of sulfoximines with aryl iodides and aryl bromides

Article abstract of DOI:10.1021/jo051066l

Two simple and inexpensive systems for copper-catalyed N-arylations of sulfoximines with aryl bromides and aryl iodides have been developed. Using 10 mol % of a copper(I) salt in combination with 20 mol % of a 1,2-diamine and Cs₂CO₃ provides N-arylated sulfoximines in high yields. Various functional groups and heteroatoms are tolarated. The method is complementary to the known protocols for N-arylations of sulfoximines, which require stoichiometric quantities of copper salts or cost-intensive palladium/BINAP catalysts.

Full text of DOI:10.1021/jo051066l

Efficient Copper-Catalyzed N-Arylation of Sulfoximines with Aryl
Iodides and Aryl Bromides
Jo¨rg Sedelmeier and Carsten Bolm*
Institute of Organic Chemistry, RWTH-Aachen University, Landoltweg 1, D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received May 27, 2005
Two simple and inexpensive systems for copper-catalyed N-arylations of sulfoximines with aryl
bromides and aryl iodides have been developed. Using 10 mol % of a copper(I) salt in combination
with 20 mol % of a 1,2-diamine and Cs2CO3 provides N-arylated sulfoximines in high yields. Various
functional groups and heteroatoms are tolarated. The method is complementary to the known
protocols for N-arylations of sulfoximines, which require stoichiometric quantities of copper salts
or cost-intensive palladium/BINAP catalysts.
During the past decades, sulfoximines have attracted
significant attention due to their successful use as chiral
auxiliaries in asymmetric synthesis1 and ligands in
enantioselective metal catalysis.2 Furthermore, they
have been applied as structural units in pseudopeptides3
and other pharmaceutically interesting molecules.4
In general, the preparation of sulfoximines is well-
documented, and several approaches toward synthetically
useful derivatives have been established.1 For the N-
arylation of sulfoximines by cross-coupling with aryl
bromides, iodides, or triflates, we have recently intro-
duced two strategies utilizing either palladium catalysts5
or stoichiometric amounts of copper salts.6,7 Given the
metal and ligand cost in the first case and taking into
account the high metal loading in the second, we initiated
a search for other catalyst systems involving simple metal
salts and easy to perform reaction conditions. Here we
report on the development of highly efficient cross-
coupling reactions between NH-sulfoximines and aryl
iodides or bromides with catalytic quantities of copper(I)
salts.8,9
Results and Discussion
In the optimizing process, sulfoximine 1 and phenyl
iodide (2a) were used as starting materials, and the effect
of solvent, base, copper source, ligand, and temperature
(1) For reviews on sulfoximines and their use as chiral auxiliaries,
see: (a) Johnson, C. R. Acc. Chem. Res. 1973, 6, 341. (b) Pyne, S. Sulfur
Rep. 1992, 12, 57. (c) Reggelin, M.; Zur, C. Synthesis 2000, 1.
(2) For reviews on sulfoximines and their use as chiral ligands in
metal catalysis, see: (a) Harmata, M. Chemtracts 2003, 16, 660. (b)
Okamura, H.; Bolm, C. Chem. Lett. 2004, 32, 482.
(8) For reviews on copper-mediated carbon heteroatom bond forma-
tions, see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003,
42, 5400. (b) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev.
2004, 248, 2337.
(9) For selected contributions, in which applications of substoichio-
metric quantities of copper salts in cross-couplings have been described,
see: (a) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233. (b) Collman,
J. P.; Zhong, M., Zeng, L.; Costanzo, S. J. Org. Chem. 2001, 66, 1528.
(c) Collman, J. P.; Zhong, M.; Costanzo, S. J. Org. Chem. 2001, 66,
7892. (d) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077. (e)
Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K.
Tetrahedron Lett. 2001, 42, 3415. (f) Quach, T. D.; Batey, R. A. Org.
Lett. 2003, 5, 4397. (g) Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron
Lett. 2000, 41, 9053. (h) Sasaki, M.; Dalili, S.; Yudin, A. K. J. Org.
Chem. 2003, 68, 2045. (i) Lan, J.-B.; Chen, L.; Yu, X.-Q.; You, J.-S.;
Xie, R.-G. Chem. Commun. 2004, 188. (j) Lan, J.-B.; Zhang, G.-L.; You,
J.-S.; Chen, L.; Yan, M.; Xie, R.-G. Synlett 2004, 1095. (k) Cristau,
H.-J.; Cellier, P.; Spindler, J.-F.; Taillefer M. Chem.-Eur. J. 2004, 10,
5607. (l) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4120. (m) Lu, Z.; Twieg, R. J. Tetrahedron 2005,
903. (n) Kuil, M.; Bekedam, E. K.; Visser, G. M.; van den Hoogenband,
A.; Terpstra, J. W.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; van
Strijdonck, G. P. F. Tetrahedron Lett. 2005, 46, 2405. (o) Zhu, W.; Ma,
D. J. Org. Chem. 2005, 70, 2696.
(3) (a) Bolm, C.; Kahmann, J. D.; Moll, G. Tetrahedron Lett. 1997,
38, 1169. (b) Bolm, C.; Moll, G.; Kahmann, J. D. Chem.-Eur. J. 2001,
7, 1118. (c) Tye, H.; Skinner, C. L. Helv. Chim. Acta 2002, 85, 3272.
(d) Bolm, C.; Mu¨ller, D.; Hackenberger, C. P. R. Org. Lett. 2002, 4,
893. (e) Bolm, C.; Mu¨ller, D.; Dalhoff, C.; Hackenberger, C. P. R.;
Weinhold, E. Bioorg. Med. Chem. Lett. 2003, 13, 3207. For early work
in this field, see: (f) Mock, W. L.; Tsay, J.-T. J. Am. Chem. Soc. 1989,
111, 4467. (g) Mock, W. L.; Zhang, J. Z. J. Biol. Chem. 1991, 266, 6393.
(4) Kahraman, M.; Sinishtay, S.; Dolan, P. M.; Kensler, T. W.; Peleg,
S.; Saha, U.; Chuang, S. S.; Bernstein, G.; Korczak, B.; Posner, G. H.
J. Med. Chem. 2004, 47, 6854 and references therein.
(5) (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.
(6) Bolm, C.; Cho, G. Y.; Re´my, P.; Jansson, J.; Moessner, C. Org.
Lett. 2004, 6, 3293.
(7) Recently, we found that aryl boronic acids can also serve as aryl
sources in arylation reactions of NH-sulfoximines. For a first report,
see: Moessner, C.; Bolm, C. Org. Lett. 2005, 7, 2667.
10.1021/jo051066l CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/15/2005
6904
J. Org. Chem. 2005, 70, 6904-6906

Copper-Catalyzed N-Arylation of Sulfoximines
TABLE 1. Copper-Catalyzed N-Arylation Reactions of
Sulfoximine 1 with Aryl Halides
SCHEME 1
was investigated.10 The following observations were
made: (1) As solvent, toluene is superior to DMSO and
dioxane. (2) Cesium carbonate is a much more efficient
base than Cs(OAc)2, K2CO3, K3PO4, KOH, or NaH. (3)
Copper(I) iodide is a better copper source than Cu(OAc)2,
Cu(CF3SO3)2, Cu2O, [Cu(phen)(PPh3)2]NO3, and CuBr. (4)
As ligand, N,N′-dimethylethyldiamine (DMEDA) is su-
perior to TMEDA, proline, and 1,10-phenanthroline. (5)
The best conversions are achieved at 110 °C. From those
data a set of optimized parameters was deduced (method
A), and the best results were achieved using a combina-
tion of sulfoximine 1 (1.0 equiv), aryl iodide 2a (2.0 equiv),
Cs2CO3 (2.5 equiv), CuI (0.1 equiv), and DMEDA (0.2
equiv) in toluene at 110 °C (Scheme 1). With lower
amounts of base, ligand, or aryl halide, the yield of 3a
was reduced. Use of only 5 mol % of the copper salt
doubled the reaction time. As expected, no coupling took
place when the reaction was carried out in the absence
of the metal catalyst.
Under the optimized conditions, a variety of aryl
iodides reacted well, affording the corresponding N-
arylated sulfoximines in very good to excellent yield
(Table 1, entries 1-10). Electronic effects of the sub-
stituents on the arene were of minor importance as
revealed by the conversions of nitro- and methoxy-
substituted aryl iodides, which all led to products in
>92% yield. Steric hindrance appears to have an impact,
but even aryl iodide 2j having a rather bulky phosphorus
substituent in the ortho-position afforded the correspond-
ing sulfoximine with 86% yield (entry 10).
Attempts to utilize aryl bromides as aryl sources under
the conditions optimized for the coupling with aryl iodides
remained unsuccessful, and the conversions were low. A
solution of the problem was envisaged by making use of
Buchwald’s aromatic Finkelstein reaction.11 Conse-
quently, a (one-pot-two-steps) protocol was developed
that involved two sequential copper catalyses. First, the
bromide on the arene was substituted by an iodide, and
then, second, the NH-sulfoximine was N-arylated to give
3 as described above (Scheme 2).
Since the aromatic Finkelstein reaction did not tolerate
the presence of Cs2CO3 and the sulfoximine, the trans-
formation had to be performed sequentially (method B).
For the halide exchange reactions, the best results were
achieved by keeping mixtures of the aryl bromides, CuI
(10 mol %), DMEDA (20 mol %), and NaI (4 equiv) in
dioxane at 110 °C for 20 h. Then, the base and the
aryl
yield
entry halide
X
R
methoda product
(%)
1
2
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
I
H
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3a
3l
3m
3n
3e
3p
95
93
98
92
99
95
99
92
93
86
93
84
82
93
97
86
I
2-NO2
3-NO2
4-NO2
2-OMe
4-Me
3
I
4
I
5
I
6
I
7
I
3-CN
8
I
4-CO2Et
2,4,6-Cl3
2-P(O)Ph2
H
9
I
10
11
12
13
14
15
16
I
Br
Br 4-OMe
Br 3,5-Me2
Br 2-Me
Br 2-OMe
Br 2-F
a Method A: sulfoximine 1 (1.0 equiv), aryl iodide (2.0 equiv),
CuI (10 mol %), Cs2CO3 (2.5 equiv), and DMEDA (20 mol %) in
toluene at 110 °C for 18-22 h. Method B: aryl bromide (2.0 equiv),
CuI (10 mol %), DMEDA (20 mol %), and NaI (4.0 equiv) in dioxane
at 110 °C for 20 h, then addition of sulfoximine 1 (1.0 equiv) and
Cs2CO3 (2.5 equiv) followed by further stirring at 110 °C for 20 h.
SCHEME 2
sulfoximine were added, and stirring was continued at
110 °C for an additional 20 h. The results obtained in
couplings of sulfoximine 1 with various aryl bromides are
summarized in Table 1 (entries 11-16).
As evidenced by the data presented in Table 1, both
steps (the aromatic Finkelstein reaction as well as the
N-arylation) proceeded well, and independent of the
substitution pattern of the aryl bromides, the N-arylated
sulfoximines were obtained in high yields (82-97%).
Steric effects played no (or at least a very minor) role as
indicated by the excellent yields achieved in the couplings
of ortho-substituted aryl bromides 2n and 2o (entries 14
and 15). Compared to the reactions with the aryl iodides
(Table 1, entries 1-10), the yields in the transformations
of the aryl bromides (entries 11-16) appeared to be
slightly lower, which could be a result of two factors.
First, the latter process involved a two-step reaction
sequence, whereas the former only consisted of a single
step. Second, for the Finkelstein reaction the use of
dioxane as solvent was required, which was known to be
a less effective solvent for N-arylation reactions.
(10) In this study, only racemic 1 was used. For the preparation of
enantiomerically pure 1, see: (a) Fusco, R.; Tericoni, F. Chim. Ind.
(Milan) 1965, 47, 61. (b) Johnson, C. R.; Schroeck, C. W. J. Am. Chem.
Soc. 1973, 95, 7418. (c) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry
1997, 8, 909. For alternative approaches, see: (d) Okamura, H.; Bolm,
C. Org. Lett. 2004, 6, 1305 and references therein. Furthermore, there
is no indication that other sulfoximines behave differently, and thus,
we consider the copper-catalyzed protocol reported here to be a general
approach for the synthesis of N-arylated sulfoximines.
To expand the substrate scope, cross-couplings between
1 and heterocyclic aryl bromides were also briefly inves-
tigated. To our delight, we found that all transformations
proceeded well, giving the corresponding sulfoximines
3q-s with very high to excellent yields. Even potentially
coordinating 2-bromo pyridines 2r and 2s reacted well,
(11) Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
14844.
J. Org. Chem, Vol. 70, No. 17, 2005 6905

Sedelmeier and Bolm
SCHEME 3a
concentrated under reduced pressure. Purification by column
chromatography on silica gel afforded the N-arylated sulfox-
imines.
Method B. Under an argon atmosphere, a dry Schlenk tube
was charged with the aryl bromide (2.0 equiv), CuI (0.1 equiv),
DMEDA (0.2 equiv), and NaI (4.0 equiv). Then, degassed
dioxane (1 M) was added, and the resulting heterogeneous
mixture was heated to 110 °C for 18-22 h. Then, sulfoximine
1 (1.0 equiv) and Cs2CO3 (2.5 equiv) were added, and the
mixture was kept at 110 °C for an additional 20 h. Subse-
quently, the mixture was cooled to room temperature and
extracted sequentially with dichloromethane and an aqueous
ammonia solution. The combined organic extracts were dried
(MgSO4), filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel afforded
the N-arylated sulfoximines.
N-(Phenyl)-S-methyl-S-phenylsulfoximine (3a). Fol-
lowing method A using rac-S-methyl-S-phenylsulfoximine (1,
143 mg, 0.922 mmol) and iodobenzene (2a, 206 µL, 1.844
mmol) gave 200 mg (95%) of 3a as a light brown solid.
According to method B using rac-S-methyl-S-phenylsulfox-
imine (1, 83 mg, 0.538 mmol) and bromobenzene (2k, 105 µL,
1.00 mmol) 116 mg (93%) of 3a was obtained as a light brown
solid: mp 100-101 °C; 1H NMR (400 MHz, CDCl3): 7.95-
7.99 (m, 2H), 7.54-7.58 (m, 1H), 7.47-7.53 (m, 2H), 7.08-
7.14 (m, 2H), 6.99-7.03 (m, 2H), 6.83-6.88 (m, 1H), 3.22 (s,
3H); 13C NMR (100 MHz, CDCl3): 144.9 (C), 139.4 (C), 133.2
(CH), 129.5 (2 × CH), 129.0 (2 x CH), 128.6 (2 × CH), 123.3 (2
× CH), 121.7, (CH), 46.1 (CH3); MS [EI, m/z (relative intensity)]:
231 [M+ (100%)]. All spectral data correspond to those given
in the literature.6
a Coupling conditions: Ar-Br (1 equiv), CuI (10 mol %), DMEDA
(20 mol %), NaI (4 equiv), and dioxane, 110 °C, 20 h; then 1 (1
equiv), Cs2CO3 (2.5 equiv), 110 °C, 20 h.
affording 3r and 3s in 96 and 97% yield, respectively
(Scheme 3).
In summary, we have developed a copper-catalyzed
cross-coupling reaction for the synthesis of N-arylated
sulfoximines leading to products in excellent yields. In
comparison with the established copper-mediated and
palladium-catalyzed reactions reported by us earlier,5,6
this novel protocol requires a less cost-intensive ligand/
metal salt combination and provides the products in
higher yields.
Acknowledgment. This work was supported by the
Fonds der Chemischen Industrie and the Deutsche
Forschungsgemeinschaft (DFG) within the Collabora-
tive Research Center (SFB) 380 “Asymmetric Syn-
thesis by Chemical and Biological Methods” and the
“Graduiertenkolleg” (GRK) 440 “Methods in Asymmetric
Synthesis”.
Experimental Section
General Procedure for N-Arylations of Sulfoximines
(Method A). Under an argon atmosphere, a dry Schlenk tube
was charged with sulfoximine 1 (1.0 equiv), aryl iodide (2.0
equiv), CuI (0.1 equiv), DMEDA (0.2 equiv), Cs2CO3 (2.5 equiv),
and degassed toluene (1 M). After being heated to 110 °C for
18-22 h, the heterogeneous mixture was cooled to room
temperature and neutralized with aqueous HCl. The aqueous
layer was extracted three times with dichloromethane. The
combined organic extracts were dried (MgSO4), filtered, and
Supporting Information Available: General synthetic
procedures, characterization data of all products, and copies
of 1H and 13C NMR spectra of compounds 3a-s. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO051066L
6906 J. Org. Chem., Vol. 70, No. 17, 2005