Copper-Mediated Cross-Coupling Reactions of N-Unsubstituted Sulfoximines and Aryl Halides

Article abstract of DOI:10.1021/ol048806h

Copper-mediated cross-coupling reactions of sulfoximines with aryl iodides and aryl bromides provide N-arylated sulfoximines in high yields. The method is complementary to the known palladium-catalyzed N-arylation and allows the preparation of

Full text of DOI:10.1021/ol048806h

ORGANIC
LETTERS
2
004
Vol. 6, No. 19
293-3296
Copper-Mediated Cross-Coupling
Reactions of N-Unsubstituted
Sulfoximines and Aryl Halides
3
Gae Young Cho, Pauline R e´ my, Jenny Jansson, Christian Moessner, and
Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen UniVersity, Professor-Pirlet-Str. 1,
D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received June 23, 2004
ABSTRACT
Copper-mediated cross-coupling reactions of sulfoximines with aryl iodides and aryl bromides provide N-arylated sulfoximines in high yields.
The method is complementary to the known palladium-catalyzed N-arylation and allows the preparation of N-arylated sulfoximines, which have
previously been inaccessible.
1
Due to their applicability as chiral auxiliaries, ligands in
which aryl iodides, bromides, nonaflates, and triflates can
2
4
asymmetric catalysis, and building blocks in pseudo-
peptides, sulfoximines have attracted much attention. Their
preparation is well-established, and a number of synthetic
approaches have been developed, which give access to a
variety of derivatives in a relatively straightforward manner.
be used. This method has been extended by Harmata toward
3
5
couplings of aryl chlorides and was utilized in a number of
2
syntheses to give new sulfoximines as ligands for catalysis,
6
7
benzothiazines, and other cyclic derivatives. Despite this
success, some limitations of the palladium catalysis such as
long reaction times, restricted substrate scope, and high
metal/ligand (catalyst) cost motivated the search for an alter-
native cross-coupling protocol. Recently, copper-mediated
or -catalyzed carbon-heteroatom bond formations (C-O,
1
For N-arylations of sulfoximines we developed a stereo-
specific palladium-catalyzed cross-coupling reaction, in
(
1) Reviews: (a) Johnson, C. R. Acc. Chem. Res. 1973, 6, 341. (b) Pyne,
S. G. Sulfur Rep. 1999, 21, 281. (c) Reggelin, M.; Zur, C. Synthesis 2000,
8
,9
C-N, C-S) have been developed by several groups after
1
.
10
11
12
initial independent studies by Chan, Evans, and Lam.
(
2) For recent examples, see: (a) Bolm, C.; Simic, O. J. Am. Chem.
Soc. 2001, 123, 3830. (b) Bolm, C.; Simic, O.; Martin, M. Synlett 2001,
878. (c) Harmata, M.; Ghosh, S. K. Org. Lett. 2001, 3, 3321. (d) Bolm,
They can be used in transformations of a wide range of
1
C.; Martin, M.; Simic, O.; Verrucci, M. Org. Lett. 2003, 5, 427. (e) Bolm,
C.; Verrucci, M.; Simic, O.; Cozzi, P. G.; Raabe, G.; Okamura, H. Chem.
Commun. 2003, 2826. (f) Bolm, C.; Martin, M.; Gescheidt, G.; Palivan,
C.; Neshchadin, D.; Bertagnolli, H.; Feth, M.; Schweiger, A.; Mitrikas, G.;
Harmer, J. J. Am. Chem. Soc. 2003, 125, 6222. Reviews: (g) Harmata, M.
Chemtracts 2003, 16, 660. (h) Okamura, H.; Bolm, C. Chem. Lett. 2004,
(4) (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.
(5) Harmata, M.; Hong, X.; Ghosh, S. K. Tetrahedron Lett. 2004, 45,
5223.
(6) Harmata, M.; Pavri, N. Angew. Chem., Int. Ed. 1999, 38, 2419.
(7) (a) Bolm, C.; Martin, M.; Gibson, L. Synlett 2002, 832. (b) Bolm,
C.; Okamura, H.; Verrucci, M. J. Organomet. Chem. 2003, 687, 444.
(8) For a review, see: Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400.
(9) For recent examples of Cu-promoted C-N couplings, see: (a) Okano,
K.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2003, 5, 4987. (b) Xu, G.;
Wang, Y.-G. Org. Lett. 2004, 6, 985.
3
3, 482 and references therein.
3) (a) Bolm, C.; Kahmann, J. D.; Moll, G. Tetrahedron Lett. 1997, 38,
169. (b) Bolm, C.; Moll, G.; Kahmann, J. D. Chem. Eur. J. 2001, 7, 1118.
(
1
(
c) Tye, H.; Skinner, C. L. HelV. Chim. Acta 2002, 85, 3272. (d) Bolm, C.;
M u¨ ller, D.; Hackenberger, C. P. R. Org. Lett. 2002, 4, 893. (e) Bolm, C.;
M u¨ ller, D.; Dalhoff, C.; Hackenberger, C. P. R.; Weinhold, E. Bioorg. Med.
Chem. Lett. 2003, 13, 3207.
1
0.1021/ol048806h CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/18/2004

substrates under very mild reaction conditions, and, for large-
scale applications, the low price of copper is a major
advantage compared to the palladium methodology. Fur-
thermore, differences in reactivity and regioselectivity be-
tween palladium and copper catalysts have been found that,
for example, proved to be useful for the selective arylation
of heterocycles such as 5-aryltetrazoles and 1,3-diaryl-
indazoles. In this Letter, we report the first copper-promoted
cross-couplings to give N-arylated sulfoximines. The protocol
starting from readily available educts is easy to perform; the
products are obtained in high yields, and several derivatives
can be prepared that were previously inaccessible.
2 3
Cs CO proved to be superior to other bases. Use of solvents
other than DMSO (such as DMF, THF, dichloroethane, or
toluene) as well as lower amounts of metal salt, base, or
1
5
aryl halide led to reduced yields of 3a. Exposure of the
reaction mixture to oxygen diminished the product yield. The
stereospecificity of the copper-promoted cross-coupling was
shown by the conversion of enantiopure 1a to give 3a as a
13
16
single enantiomer (HPLC analysis).
Next, we investigated the substrate scope using various
aryl iodides and bromides. The results are summarized in
Table 2.
As a test reaction, we chose the cross-coupling between
1
4
sulfoximine 1a and phenyl iodide (2a). To establish the
reaction conditions, the effect of base, solvent, and copper
salt was evaluated. The results of this initial screening are
summarized in Table 1.
Table 2. Copper-Mediated Cross-Coupling of Sulfoximine 1a
and Aryl Iodides (2a-n) or Aryl Bromides (2p-r) to Give
N-Arylated Sulfoximines 3a
Table 1. Effect of the Reaction Parameters on the
Copper-Mediated Cross-Coupling of Sulfoximine 1a and Phenyl
Iodide (2a) to Give N-Phenyl Sulfoximine 3aa
entry
2
X
R
methoda
3
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
4
5
b
I
I
I
I
I
I
I
I
I
I
I
I
2-Me
2-Br
2-NO2
2-OMe
2-P(O)Ph2
3-CN
4-Me
4-CHO
4-CO Et
4-NO2
A
A
A
A
B
A
A
C
A
A
B
B
B
B
B
C
C
b
84
68
83
72
71
94
93
85
88
82
95
80
60
78
83
65
48
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
entry
copper salt
base
yield (%)
1
2
3
4
5
6
CuI
CuI
CuI
CuI
CuBr
CuSO4
Cs2CO3
CsOAc
NaOt-Bu
K3PO3
Cs2CO3
Cs2CO3
94
78
91
39
85
46
2
2-NO ,4-F
2-NO ,4-OMe
2
2
I
2,4,6-Cl3
2-NO2
2-NO2,4-CF3
2-NHAc,5-NO2
2-NHAc, 3-NO2
1
1
Br
Br
Br
Br
a
Reaction conditions: sulfoximine (1.0 equiv), phenyl iodide (2.0 equiv),
base (2.5 equiv), copper salt (1.0 equiv), in DMSO (1 M with respect to
1
a) at 90 °C.
16
7
1
a
Method A: sulfoximine (1.0 equiv), aryl halide (2.0 equiv), CuI (1.0
equiv), Cs2CO3 (2.5 equiv) in DMSO at 90 °C. Method B: same as A
except CsOAc (2.5 equiv) was used instead of Cs2CO3. Method C:
sulfoximine (2.0 equiv), aryl halide (1.0 equiv), CuI (1.0 equiv), CsOAc
(2.5 equiv) in DMSO at 90 °C. b Enantiopure (S)-1a was used.
To our delight, several copper salts were found to promote
the N-arylation giving N-phenyl sulfoximine 3a in good to
excellent yields. The best result was achieved with a
2 3
combination of copper(I) iodide (1.0 equiv) and Cs CO (2.5
equiv) in DMSO at 90 °C (Table 1, entry 1). Other copper
salts such as copper(I) bromide or copper(II) sulfate also
promoted the reaction; however, the yields were lower.
For most substrates the conditions optimized for the cross-
coupling of 1a with phenyl iodide (2a) (method A) proved
to be applicable, and generally the corresponding arylated
sulfoximines 3 were obtained in high yields. In some cases,
the use of CsOAc instead of Cs CO (method B) or the
2 3
application of an excess of sulfoximine (method C) led to
an improved yield. For example, when 4-iodobenzaldehyde
(
10) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933.
11) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
937.
12) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M.
P.; Chan. D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941.
13) (a) Beletskaya, I. P.; Davydov, D. V.; Gorovoy, M. S. Tetrahedron
(
2
(
2 3
(2i) was applied in the coupling using Cs CO as a base,
(
Lett. 2002, 43, 6221. (b) Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron
Lett. 2000, 41, 9053.
many byproducts were detected. In contrast, with CsOAc a
very smooth conversion led to the corresponding arylated
(14) In this study, racemic 1a was mostly used. For the preparation of
enantiomerically pure 1a, see: (a) Fusco, R.; Tericoni, F. Chim. Ind. (Milan)
1
965, 47, 61. (b) Johnson, C. R.; Schroeck, C. W. J. Am. Chem. Soc. 1973,
5, 7418. (c) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8, 909.
(15) For example, with 1.0 equiv of Cs2CO3 and 1.2 equiv of phenyl
iodide the yield of 2 was only 24%.
9
(
6
d) For alternative approaches, see: Okamura, H.; Bolm, C. Org. Lett. 2004,
, 1305 and references therein.
(16) HPLC analysis of 3a: Chiralcel OD-H, 9:1 heptane/2-propanol, 0.5
mL/min; tR ) 30 min (S), tR ) 44 min (R).
3294
Org. Lett., Vol. 6, No. 19, 2004

sulfoximine 3i in 85% yield (Table 1, entry 8). In general,
electronic effects played a minor role and high conversions
were achieved no matter if the substituents were electron
withdrawing or donating. Ortho substituents did not hamper
the coupling reactions. Both aryl iodides as well as aryl
bromides (Table 1, entries 1-13 and 14-17, respectively)
could be used. A direct comparison using aryl iodide 2d and
aryl bromide 2o in the coupling with 1a to give 3d in each
case (Table 1, entries 3 and 14) revealed that both aryl halides
react equally well. A reactivity difference, however, was
indicated in the conversion of 2-bromophenyl iodide (2c),
which selectively gave N-2-bromoaryl sulfoximine 3c in 68%
yield (Table 2, entry 2). Interestingly, the chemoselectivity
Scheme 1
pure 3f in 71% yield after simple purification by column
chromatography.
The most interesting difference between the palladium-
and copper-mediated routes is shown in Scheme 2. Recently,
(iodide preferred over bromide) was base dependent, and
switching from Cs CO to CsOAc gave a mixture of both
2
3
possible monocoupled products.
N-Arylations of sulfoximines 1b and 1c17 with phenyl
iodide (2a) as an aryl source and Cs
s and 3t in 63 and 53% yield, respectively, confirmed that
the protocol was not limited to conversions of 1a (Figure
). Particularly noteworthy are the results that highlight the
2
CO
3
as a base to give
Scheme 2a
3
1
Figure 1.
a
2
Key: Palladium route: Pd(OAc) , BINAP, NaOt-Bu, toluene,
reflux, 48 h. Copper route: CuI, CsOAc, DMSO, 90 °C, 12 h.
differences between the copper- and the palladium-promoted
cross-coupling. For example, we previously reported, that
transformations of aryl iodides under palladium catalysis
were difficult, even in the presence of additives such as
we have reported that the palladium-catalyzed coupling of
dibromoarenes and sulfoximines affords six- to eight-
4
lithium and silver salts. In the copper-mediated reactions
7
a
membered heterocycles in excellent yields. For example,
,8-dibromonaphthalene (4) gives 5 in 90% yield by a
described here, those substrates behave perfectly well, giving
products in high yields. Furthermore, we found that in several
cases even for aryl bromides the copper-based protocol was
superior to the palladium-based one. For example, attempts
to cross-couple multiply substituted aryl bromide 2q under
palladium catalysis for 2 days gave 3q in only 10% yield.
In contrast, the novel copper-mediated transformation af-
forded the desired product in 65% yield after only 12 h
1
sequence of intermolecular N-arylation followed by intra-
molecular ring closure. Interestingly, the copper-mediated
reaction of the same substrates gives an entirely different
product. Thus, C
56% yield), which results from a double cross-coupling
reaction lacking the intramolecular cyclization through C-C
2
-symmetric bissulfoximine 6 is formed
(
1
8
bond formation. In this context, it should be noted that
related C -symmetric bissulfoximines have been successfully
applied as ligands in asymmetric catalysis, leading to
(Table 1, entry 16). Moreover, N-arylated sulfoximine 3r
2
could only be obtained by the copper-mediated route,
whereas no product was observed under palladium catalysis.
The synthesis of 3f was improved by using copper for a
different reason. There, the N-arylated sulfoximine was
formed (albeit in low quantities) in the palladium-catalyzed
coupling, but isolation of the product proved to be cumber-
some due to the presence of inseparable impurities. Fortu-
nately, the copper methodology allowed the preparation of
the desired product in a very straightforward manner, giving
2
a
excellent enantioselectivities in hetero-Diels-Alder reactions,
2c,d
2b
other cycloadditions, and nucleophilic allylic substitutions.
In summary, we have developed ligand-free copper-
mediated cross-coupling reactions for the synthesis of various
N-arylated sulfoximines in high yields. The novel protocol
has been proven to be a powerful complement to the
previously described palladium catalysis. Shorter reaction
(
18) As indicated in Scheme 2, the coupling was performed with
(17) For the preparation and synthetic application of 1c, see: Cho, G.-
enantiopure sulfoximine 1a. Only a single diastereomer of 6 was obtained
Y.; Okamura, H.; Bolm, C. Manuscript in preparation.
(after column chromatography).
Org. Lett., Vol. 6, No. 19, 2004
3295

times, higher reactivity, and economical practicality are
advantages of the copper methodology. We are currently
searching for catalytic versions of copper-mediated cross-
coupling reactions, investigating the use of the new bis-
sulfoximines as ligands in asymmetric catalysis, and studying
copper-catalyzed C-arylation reactions.
for financial support. J.J. thanks Uppsala University for
supporting her stay as an exchange student at RWTH Aachen
University.
Supporting Information Available: Experimental pro-
1
13
31
cedures and full characterization ( H, C, and P NMR data
and spectra and MS, IR, and CHN analyses) for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. The Deutsche Forschungsgemein-
schaft within the SFB 380 and the GRK 440 as well as the
Fonds der Chemischen Industrie are gratefully acknowledged
OL048806H
3296
Org. Lett., Vol. 6, No. 19, 2004