Cu(OAc)2-catalyzed N-arylations of sulfoximines with aryl boronic acids

Article abstract of DOI:10.1021/ol050816a

(Chemical Equation Presented) A simple and mild copper salt-catalyzed N-arylation of sulfoximines in high yields is reported. Cu(OAc)₂ activates aryl boronic acids for the reaction with NH-sulfoximines without additional base or heating. Furthe

Full text of DOI:10.1021/ol050816a

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2667-2669
Cu(OAc)2-Catalyzed N-Arylations of
Sulfoximines with Aryl Boronic Acids
Christian Moessner and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen UniVersity, Landoltweg 1,
D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received April 14, 2005
ABSTRACT
A simple and mild copper salt-catalyzed N-arylation of sulfoximines in high yields is reported. Cu(OAc)2 activates aryl boronic acids for the
reaction with NH-sulfoximines without additional base or heating. Furthermore, this new method allows the preparation of N-arylated sulfoximines,
which have previously been more difficult to access.
In 1998, Chan,1 Lam,2 and Evans3 reported on copper-
mediated carbon-heteroatom cross-coupling reactions of
boronic acids using a wide range of different nucleophiles
such as amines, anilides, amides, imines, ureas, carbamates,
and aromatic heterocycles. Very soon after, Collman and
Zhong described a copper-catalyzed system for the N-
arylation of imidazoles.4 Since then, several new applications
have been developed, which made this arylation method an
important tool for sp2-carbon-nitrogen bond formation.5 For
example, Lam recently showed that N-arylations of R-ami-
noesters with p-tolylboronic acid proceeded with almost
complete retention of configuration (94-99% ee),6 and Xie
demonstrated the use of stoichiometric amounts of boronic
acid for the N-arylation of imidazoles, amines, amides,
imides, and sulfonamides in refluxing methanol without the
need of an additional base.7
Our group has a long standing interest in N-arylation
reactions of sulfoximines, since the resulting compounds have
proven to be effective chiral ligands in various catalytic
asymmetric reactions.8 In particular for the synthesis of
sulfoximines containing a rigid backbone, N-arylation reac-
tions are often the key step to success.8,9 For this purpose,
two main methods based on palladium or copper catalysis
have been developed.10,11 Common characteristics of these
reactions are the use of aryl halides12 and the need for an
external base such as Cs2CO3 or KOt-Bu at elevated
(1) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933.
(2) 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.
(3) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937.
(4) (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.
(5) For reviews on copper-mediated carbon-heteroatom bond formations,
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.
For other selected contributions, see: (c) Antilla, J. C.; Buchwald, S. L.
Org. Lett. 2001, 3, 2077. (d) Lam, P. Y. S.; Vincent, G.; Clark, C. G.;
Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415. (e) Quach, T.
D.; Batey, R. A. Org. Lett. 2003, 5, 4397. (f) Chernick, E. T.; Ahrens, M.
J.; Scheidt, K. A.; Wasielewski, M. R. J. Org. Chem. 2005, 70, 1486. (g)
Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron Lett. 2000, 41, 9053. (h)
Rossiter, S.; Woo, C. K.; Hartzoulakis, B.; Wishart, G.; Stanyer, L.; Labadie,
J. W.; Selwood, D. L. J. Comb. Chem. 2004, 6, 385. (i) Sasaki, M.; Dalili,
S.; Yudin, A. K. J. Org. Chem. 2003, 68, 2045. (j) Mederski, W. W. K. R.;
Lefort, M.; Germann, M.; Kux, D. Tetrahedron 1999, 55, 12757.
(6) Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, C. G.; Combs, A. P.
Tetrahedron Lett. 2003, 44, 1691.
(7) (a) Lan, J.-B.; Chen, L.; Yu, X.-Q.; You, J.-S.; Xie, R.-G. Chem.
Commun. 2004, 188. (b) Lan, J.-B.; Zhang, G.-L.; You, J.-S.; Chen, L.;
Yan, M.; Xie, R.-G. Synlett 2004, 1095.
(8) For reviews on the use of sulfoximines as chiral ligands, see: (a)
Harmata, M. Chemtracts 2003, 16, 660. (b) Okamura, H.; Bolm, C. Chem.
Lett. 2004, 33, 482 and references therein.
(9) (a) Bolm, C.; Simic, O. J. Am. Chem. Soc. 2001, 123, 3830. (b) Bolm,
C.; Martin, M.; Simic, O.; Verrucci, M. Org. Lett. 2003, 5, 427. (c) Bolm,
C.; Verrucci, M.; Simic, O.; Cozzi, P. G.; Raabe, G.; Okamura, H. Chem.
Commun. 2003, 2816. (d) Bolm, C.; Langner, M. Angew. Chem., Int. Ed.
2004, 43, 5984. (e) Harmata, M.; Pavri, N. Angew. Chem., Int. Ed. Engl.
1999, 38, 2419. (f) Harmata, M.; Ghosh, S. K. Org. Lett. 2001, 3, 3321.
10.1021/ol050816a CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/20/2005

Table 1. Effect of Various Copper Salts on the
Copper-Catalyzed Cross-Coupling Reaction of Sulfoximine 1a
and Phenyl Boronic Acid (2a)a
Table 2. Dependence of the Yield of 3aa on the Amounts of
Cu(OAc)2 and Phenyl Boronic Acid (2a) Used in the
N-Arylation of Sulfoximine 1aa
entry
Cu(OAc)2 (equiv)
2a (equiv)
yield of 3aa (%)
1
2
3
4
5
0.1
1
0.1
0.1
1
1
1
2
2.3
2.3
33 (83b)
58
86
93
93
entry
copper salt
CuI
CuCl
CuSO4
Cu(OAc)2‚H2O
Cu(OAc)2
yield of 3aa (%)
a Reaction conditions: sulfoximine (1 equiv), boronic acid and copper
salt in 0.3 M MeOH, rt, 24 h. b Based on recovered starting material.
1
2
3
4
5
85
55
91
87
93
times and incomplete conversions.15 Also the use of solvents
other than methanol (dried with 3 Å molecular sieves)
resulted in lower conversions as well as reduced reaction
rates.16 The reaction worked best with vigorous stirring under
anhydrous conditions.17 Consistent with reports by Xie,7 it
was not necessary to add an external base, and no homo-
coupling of the boronic acid was detected during the course
of the reaction. In some cases, the formation of small
quantities (<10%) of the corresponding arylmethyl ether was
observed.18
Table 2 shows that the amount of boronic acid was critical
to the reaction outcome. Less than 2 equiv of the aryl source
drastically reduced the yield of the N-arylated product. Even
with 1 equiv of the copper salt (entries 2 and 5), the reaction
of equimolar amounts of phenyl boronic acid and sulfoximine
led to only 33% yield (57% conversion).
To evaluate the substrate scope of this new approach
toward N-arylated sulfoximines, we investigated cross-
couplings of various commercially available aryl boronic
acids and a few other sulfoximines.19 In all cases, the
optimized conditions described above proved to be ap-
plicable. Good to excellent results were achieved with para-
substituted boronic acids (Table 3, entries 3, 5, 7 and 9),
irrespective of the electronic nature of the substituent of the
boronic acid. Thus, couplings of 2c, 2e, and 2h with
sulfoximine 1a gave almost identical yields of the corre-
sponding arylated products 3ac, 3ae, and 3ah, respectively.
The same observation was made in reactions with ortho-
substituted boronic acids 2b, 2f, and 2j, albeit in these cases,
the yields were slightly lower (Table 3, entries 2, 6, and 10).
The lower yields in most couplings of ortho-substituted
aryl boronic acids indicated the importance of steric effects,
and, indeed, whereas boronic acids with one ortho substituent
were very suitable substrates for the cross-coupling reaction
(entries 2, 4, 6 and 10), 2,4,6-trimethylphenyl boronic acid
(2k) failed to give the corresponding N-arylated product 3ak.
a Reaction conditions: sulfoximine (1.0 equiv), PhB(OH)2 (2.3 equiv),
copper salt (0.1 equiv), in 0.3 M MeOH (with respect to 1a) at room
temperature, moisture excluded by a CaCl2 drying tube.
temperatures.13 We wondered if the scope of this important
method could be extended by the application of other
(formally umgepolte) aryl sources such as boronic acids. In
this Letter, we present a simple and mild copper-catalyzed
N-arylation of sulfoximines that utilizes such boron reagents
under base free conditions.
Optimization experiments involved sulfoximine 1a and
phenyl boronic acid (2a) as test substrates and focused on
determining the effect of the copper salt, the solvent, and
the amount of boronic acid.14 Table 1 shows the influence
of various copper salts on this transformation.
Both copper(I) and copper(II) salts were catalytically active
in the coupling reaction even at room temperature. Among
the tested copper salts, anhydrous copper(II) acetate was
found to be the best catalyst, leading to 93% yield of 3aa
within 12 h at room temperature (Table 1, entry 4). Use of
the hydrated form of this copper(II) salt gave 3aa in 87%
yield (entry 3). Interestingly, copper(I) iodide, which is
known to promote the N-arylation of sulfoximines with aryl
halides,11 was also a good catalyst (entry 1), and the product
was obtained with only a slightly reduced yield (85%). The
best results were achieved with 10 mol % copper(II) acetate.
Increasing the catalyst amount had only a minor effect on
the product yield, and smaller quantities led to longer reaction
(10) (a) Bolm, C.; Hildebrand, J. P. J. Org. Chem. 2000, 65, 169. (b)
Bolm. C.; Hildebrand, J. P. Tetrahedron Lett. 1998, 39, 5731. (c) Bolm,
C.; Hildebrand, J. P.; Rudolph, J. Synthesis 2000, 911. (d) Harmata, M.;
Hong, X.; Ghosh, S. K. Tetrahedron Lett. 2004, 45, 5233.
(11) Cho, G. Y.; Re´my, P.; Jansson, J.; Moessner, C.; Bolm, C. Org.
Lett. 2004, 6, 3293.
(12) In Pd-catalyzed arylations, aryl triflates and aryl nonaflates can also
be applied. For details, see refs 10a-c.
(13) For intra- and intermolecular C-arylations of sulfoximines, see: (a)
Bolm, C.; Martin, M.; Gibson, L. Synlett 2002, 832. (b) Bolm, C.; Okamura,
H.; Verrucci, M. J. Organomet. Chem. 2003, 687, 444. (c) Cho, G. Y.;
Bolm, C. Org. Lett. 2005, 7, 1351.
(15) Use of 0.2 equiv of Cu(OAc)2 f 94% of 3aa after 10 h; 0.05 equiv
of Cu(OAc)2 f 86% of 3aa after 24 h; 0.01 equiv of Cu(OAc)2 f 52% of
3aa after 40 h.
(16) ) Yields of 3aa after 24 h: 72% in DCM, 74% in DMSO, 66% in
EtOH.
(14) Generally, racemic 1a was used in this study. However, it was also
demonstrated that the coupling of enantiopure (S)-1a with 2a to give 3aa
proceeded entirely stereospecifically. HPLC analysis of 3aa: Chiralcel OD-
H, 9:1 heptane-2-propanol, 0.5 mL/min; tR ) 53 min (S), tR ) 78 min
(R).
(17) Usually, the reactions were performed in 10 mL test tubes within a
250 mL flask under exclusion of atmospheric moisture.
(18) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 1381.
(19) No reaction was observed when methyl boronic acid was used
instead of phenyl boronic acid.
2668
Org. Lett., Vol. 7, No. 13, 2005

Table 3. Cu(OAc)2-Catalyzed N-Arylation of Sulfoximine 1a
with Aryl Boronic Acids 2a-ka
entry ArB(OH)2
Ar
product yield (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
C6H5-
2-Me-C6H4-
4-Me-C6H4-
2-Cl-C6H4-
4-Cl-C6H4-
2-MeO-C6H4-
4-Br-C6H4-
4-(t-BuMe2Si)O-C6H4-
4-Ph-C6H4-
2-naphthyl-
2,4,6-Me3-C6H2-
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
93
75
92
90
93
73
71
88
74
62
Figure 1.
tolerated, which further extends the scope of potential
applications of the coupling process. In conclusion, we
reported a novel copper-catalyzed N-arylation of sulfox-
imines using boronic acids as arylating agents. The cross-
couplings proceed under mild reaction conditions at room
temperature without additional external base. Considering
the structural diversity and the huge number of boronic acid
derivatives, we forsee that this new method will find broad
application for the synthesis of a wide variety of sulfoximines
with so far unknown properties.
10
11
2j
2k
3aj
3ak
a Reaction conditions: sulfoximine 1a (1 equiv), aryl boronic acid 2a-k
(2.3 equiv), Cu(Oac)2 (0.1 equiv), 0.3 M MeOH, 12 h.
Sulfoximines 1b and 1c also reacted well with phenyl
boronic acid (2a), and the corresponding N-phenylated
products 3ba and 3ca were obtained with 86 and 81% yield,
respectively (Figure 1). The chemoselective coupling of S-(4-
bromo)-phenyl-S-methylsulfoximine (1b) is interesting for
several reasons. First, it reveals that the N-coupling process
is favorable over possible C-arylations (at both the aryl as
well as the methyl group of the sulfoximine),20 and second,
it allows further functionalizations of the resulting N-arylated
product, since the sulfoximine aryl group still bears a
p-bromo substituent, which is accessible for further modi-
fications.21 The high yield in the coupling of 1c demonstrates
that steric bulk at the R-carbon of the sulfoximine moiety is
Acknowledgment. The Deutsche Forschungsgemein-
schaft within the SFB 380 and the GRK 440, as well as the
Fonds der chemischen Industrie, are gratefully acknowledged
for financial support. We thank Gae Young Cho for
providing a sample of sulfoximine 1b.
Supporting Information Available: Experimental pro-
cedures and full characterization (1H and 13C NMR data and
spectra, MS, IR, and CHN analyses) for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) For interesting selectivities observed in metal-catalyzed N- and
C-arylations of indazole derivatives with aryl boronic acids, see ref 5g.
(21) Cho, G. Y.; Okamura, H.; Bolm, C. J. Org. Chem. 2005, 70, 2346.
OL050816A
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2669