Palladium-catalyzed α-arylation of sulfoximines

Article abstract of DOI:10.1021/ol050176b

(Chemical Equation Presented). Palladium-catalyzed α-arylation of N-benzoyl sulfoximine ethyl ester with various aryl bromides leads to α-arylated products that can easily be hydrolyzed, giving the corresponding N-protected benzyl phenyl sulfoximines. In

Full text of DOI:10.1021/ol050176b

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1351-1354
Palladium-Catalyzed
Sulfoximines
r-Arylation of
Gae Young Cho and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen UniVersity, Landoltweg 1,
D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received January 27, 2005
ABSTRACT
Palladium-catalyzed
r
-arylation of N-benzoyl sulfoximine ethyl ester with various aryl bromides leads to
r
-arylated products that can easily
be hydrolyzed, giving the corresponding N-protected benzyl phenyl sulfoximines. In this manner, new sulfoximine derivatives are accessible
that have so far been difficult to prepare in enantiopure form.
Since the first independent reports by Hartwig,1 Buchwald,2
and Miura3 on palladium-catalyzed R-arylations of ketones
in 1997, this method has found numerous synthetic applica-
tions.4 Under similar conditions other substrates with acidic
hydrogens such as nitriles5 and sulfones6 react also leading
to the corresponding R-arylated products, which are often
synthetically highly valuable intermediates. We wondered
if this approach would also prove useful for the preparation
of novel sulfoximines.7 Recently, such sulfur-containing
compounds attracted significant attention due to their ap-
plicability as building blocks for chiral ligands8 and as
structural units in pseudopeptides.9 A number of approaches
have been developed for their synthesis, and several of them
allow the preparation of various enantiopure derivatives in
a relatively straightforward manner. Most of them, however,
rely on the use of a single starting material, S-methyl-S-
phenylsulfoximine (1a; R ) H, Ar ) Ph), since this particular
derivative can easily be prepared as a racemate in multigram
quantities and resolved with camphorsulfonic acid (CSA)
following well-established protocols introduced by Fusco10a
and improved by Johnson10b,c and Gais.10d Other sulfoximine
derivatives, in particular those bearing aryl groups in the R
position, such as 2, are either inaccessible by this route or
(8) For recent examples, see: (a) Bolm, C.; Simic, O. J. Am. Chem.
Soc. 2001, 123, 3830. (b) Harmata, M.; Ghosh, S. K. Org. Lett. 2001, 3,
3321. (c) Bolm, C.; Martin, M.; Simic, O.; Verrucci, M. Org. Lett. 2003,
5, 427. (d) Bolm, C.; Verrucci, M.; Simic, O.; Cozzi, P. G.; Raabe, G.;
Okamura, H. Chem. Commun. 2003, 2816. (e) Bolm, C.; Martin, M.;
Gescheidt, G.; Palivan, C.; Neshchadin, D.; Bertagnolli, H.; Feth, M. P.;
Schweiger, A.; Mitrikas, G.; Harmer, J. J. Am. Chem. Soc. 2003, 125, 6222.
(f) Langner, M.; Bolm, C. Angew. Chem., Int. Ed. 2004, 43, 5984.
(9) (a) Mock, W. L.; Tsay, J.-T. J. Am. Chem. Soc. 1989, 111, 4467. (b)
Mock, W. L.; Zhang, J. Z. J. Biol. Chem. 1991, 266, 6393. (c) Bolm, C.;
Kahmann, J. D.; Moll, G. Tetrahedron Lett. 1997, 38, 1169. (d) Bolm, C.;
Moll, G.; Kahmann, J. D. Chem. Eur. J. 2001, 7, 1118. (e) Tye, H.; Skinner,
C. L. HelV. Chim. Acta 2002, 85, 3272. (f) Bolm, C.; Mu¨ller, D.;
Hackenberger, C. P. R. Org. Lett. 2002, 4, 893. (g) Bolm, C.; Mu¨ller, D.;
Dalhoff, C.; Hackenberger, C. P. R.; Weinhold, E. Bioorg. Med. Chem.
Lett. 2003, 13, 3207.
(1) Hamann, B, C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382.
(2) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
(3) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem.,
Int. Ed. 1997, 36, 1740.
(4) For recent examples, see: (a) Muratake, H.; Natsume, M. Angew.
Chem., Int. Ed. 2004, 43, 4646. (b) Muratake, H.; Natsume, M.; Nakai, H.
Tetrahedron 2004, 60, 11783. (c) Chae, J.; Yun, J.; Buchwald, S. L. Org.
Lett. 2004, 6, 4809. (d) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew.
Chem., Int. Ed. 2005, 44, 403.
(5) For a review on palladium-catalyzed R-arylations of carbonyl
compounds and nitriles, see: Culkin, D. A.; Hartwig, J. K. Acc. Chem.
Soc. 2003, 36, 234.
(6) (a) Kashin, A. N.; Mitin, A. V.; Beleskaya, I. P.; Wife, R. Tetrahedron
Lett. 2002, 43, 2539. (b) Mitin, A. V.; Kashin, A. N.; Beleskaya, I. P. J.
Organomet. Chem. 2004, 689, 1085.
(7) Reviews on sulfoximines: (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, 1. (d) Harmata, M. Chemtracts 2003, 16, 660. (e) Okamura,
H.; Bolm, C. Chem. Lett. 2004, 33, 482.
(10) (a) Fusco, R.; Tericoni, F. Chem. Ind. (Milan) 1965, 47, 61. (b)
Johnson, C. R.; Schroeck, C. W. J. Am. Chem. Soc. 1973, 95, 7418. (c)
Johnson, C. R.; Schroeck, C. W.; Shanklin, J. R. J. Am. Chem. Soc. 1973,
95, 7424. (d) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8, 909.
10.1021/ol050176b CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/04/2005

Scheme 1
Figure 1.
at least difficult to prepare in enantiomerically pure form.11
Motivated by our previous work on intramolecular R-aryl-
ations of sulfoximines affording heterocycles,12 we wondered
if palladium-catalyzed intermolecular R-arylations would
offer a solution. If 1 (or an appropriate masked derivative
of it) could be efficiently arylated at the S-methyl group with
an appropriate aryl halide, structurally diverse aryl benzyl
sulfoximines 2, which we intend to apply as key elements
in chiral ligands and pseudopeptides, would result in a highly
flexible manner. Here, we report the successful implementa-
tion of this strategy by palladium-catalyzed R-arylation of
N-benzoyl sulfoximine ethyl ester 3 with aryl bromides,
followed by sequential hydrolytic decarboxylation and
deprotection.
Initial experiments revealed that the coupling reaction
required carefully selected starting materials and strictly
optimized reaction conditions. For example, simple N-
protected derivatives of 1 (with Ar ) Ph) having Boc, CF3-
CO, TBDMS, or tosyl groups at the sulfoximine nitrogen
did not undergo palladium-catalyzed R-arylations at all.
Either no reaction occurred or undesired products such as
sulfinamides 4 or olefinic NH-sulfoximine 5 were formed.13
Assuming that the pKa values of the S-methyl protons were
relevant for the coupling and that the acidity at this position
needed to be increased, further experiments were conducted
with N-protected sulfoximine esters. Supporting this hypo-
thesis, N-methoxylcarbonyl sulfoximine methyl ester (6),
which can be prepared from NH-free phenyl methyl sulfox-
imine (1a) with NaHMDS and dimethyl carbonate in a single
step, provided the first R-arylated product using phenyl
bromide as aryl source and Pd2(dba)3/PCy3 (in combination
with NaOt-Bu in dioxane at 70 °C) as catalyst in 27% yield.
Aiming to increase the efficiency of the catalysis and taking
into account the stability profile of N-aroylated sulfox-
imines,14 we next focused our attention on the synthesis and
use of N-benzoyl sulfoximine ethyl ester (3). The reaction
sequence, which led from 1a to 3 in high overall yield, is
depicted in Scheme 1.
Gratifyingly, protected sulfoximine ester 3 proved to be a
very suitable substrate for the R-arylation, and after an
intensive optimization of the reaction conditions using phenyl
bromide as coupling partner, a high yield (79%) of the
corresponding arylated product 8a was obtained (Table 1,
entry 1).15 In general, combinations of Pd2(dba)3 and BINAP
or Pd(OAc)2 and PCy3 gave the most active catalysts.16 The
catalyst loading could be as low as 1 mol %. Increasing it
to 9 mol % affected the reaction rate but had only a minor
influence on the yield of 8a (74% versus 79%, respectively).
Subsequently, most R-arylations of 3 were performed with
a catalyst consisting of 3 mol % of Pd(OAc)2 and 9 mol %
of PCy3. Several bases such as NaH, KHMDS, NaHMDS,
Cs2CO3, KOt-Bu, NaOMe, and Na2CO3 were examined, but
none of them were as effective as sodium tert-butoxide. To
achieve full conversion, at least 2 equiv of base was required,
with 3 equiv of NaOt-Bu being optimal. As solvent, dioxane
was superior to others such as THF, toluene, or DMF. An
excess of aryl halide was not essential for good yields, and
in most cases the reaction was complete within 1 h under
reflux.
To investigate the substrate scope, several other aryl
bromides were applied under the conditions optimized for
the coupling with phenyl bromide. The results are sum-
marized in Table 1.
(14) N-Aroylated sulfoximines are rather stable compounds with a
peculiar reactivity pattern (see Bolm, C.; Hackenberger, C. P. R.; Simic,
O.; Verrucci, M.; Mu¨ller, D.; Bienewald, F. Synthesis 2002, 879). Their
treatment with boran-based reducing agents does not lead to the expected
N-benzyl derivatives but results in either no conversion or the formation of
free NH-sulfoximines. This particular aspect was expected to be benefical
in the program described here, since it allowed a selective deprotecting of
the R-arylated products under reductive conditions.
(15) In this study mostly racemic sulfoximines were used, and generally,
the R-arylated products were isolated as a ca. 1:1 mixture of diastereomers
(for 8k ) 2:1). Based on previous results, we expect that a “chiral switch”
should simply lead to idential compounds in enantiomerically pure form.
(16) In this initial catalyst screening the following yields of 8a were
obtained with sulfoximine ethyl ester 3 (1.0 equiv), phenyl bromide (1.8
equiv), and sodium tert-butoxide (3 equiv) in dioxane (0.1 M with respect
to compound 3) under reflux. (a) Pd(OAc)2 (3 mol %) + PCy3 (9 mol %):
79%. (b) Pd(OAc)2 (3 mol %) + BINAP (5 mol %): 76%. (c) Pd2(dba)3 (3
mol %) + PCy3 (9 mol %): 68%. (d) Pd2(dba)3 (3 mol %) + BINAP (5
mol %): 76%. (e) Pd2(dba)3 (3 mol %) + BINAP (5 mol %). Use of only
1.1 equiv of PhBr: 79%.
(11) In principle, enantiopure aryl benzyl sulfoximines 2 should also
be accessible by sterospecific iminations of the corresponding sulfoxides,
which can be obtained by methods developed by Naso et al. (see Capozzi,
M. A. M.; Cardellicchio, C.; Naso, F.; Rosito, V. J. Org. Chem. 2002,
67, 7289). Then, however, each substrate would have to be prepared
individually starting from the corresponding sulfide, which would signifi-
cantly limit the flexibility and synthetic value of the overall approach
towards 2.
(12) (a) Bolm, C.; Martin, M.; Gibson, L. Synlett 2002, 832. (b) Bolm,
C.; Okamura, H.; Verrucci, M. J. Organomet. Chem. 2003, 687, 444.
(13) The formation of 5 in up to 80% yield starting from N-trifluoroacetyl
phenyl methyl sulfoximine in the presence of Pd(dba)2, dppf, and potassium
bis(trimethylsilyl)amide (KHMDS) in dioxane at room temperature was
rather surprising and will be the subject of further investigations.
1352
Org. Lett., Vol. 7, No. 7, 2005

Here, a 1:1 mixture of mono- and dicoupled products (8j-A
and 8j-B, respectively) was obtained. Accordingly, use of
enantiopure 1a should afford the corresponding C2-symmetric
bissulfoximine 8j-B,15 which we then plan to apply in
analogy to Pincer-type ligands such as 9 (Figure 2).17
Table 1. Optimized Protocol for the Palladium-Catalyzed
R-Arylation of Sulfoximine Ethyl Ester 3 with Aryl Bromidesa
entry
R
product
yield (%)
1
2
3
4
5
6
7
8
9
H
8a
8b
8c
8d
8e
8f
8g
8h
8i
79
4-OCH3
4-CN
4-NO2
4-Cl
4-SCH3
4-Ph
3-OCH3
3-NO2
3-Br
87
90b
73
71b,c
85
86
79
Figure 2.
50b
82d
73
10
11
8j
8k
2-CH3
In order for the developed R-arylation process to be truly
valuable in synthesis, a selective deprotection strategy had
to be established. For this purpose, we first demonstrated
that arylated compound 8a could easily be hydrolyzed by
brief treatment with an aqueous methanolic solution of
NaOH, affording N-protected phenyl benzyl sulfoximine 10
in quantitative yield (Scheme 2).18
a Reagents and reaction conditions: N-benzoyl sulfoximine ethyl ester
3 (1 equiv), Ar-Br (1.2 equiv), Pd(OAc)2 (3 mol %), PCy3 (9 mol %), NaOt-
Bu (3 equiv), dioxane, reflux. b Pd2(dba)3 (3 mol %) was used instead of
Pd(OAc)2. c Only the 4-chlorobenzene derivative was formed. d Combined
yield of mono- (8j-A) and dicoupled (8j-B) products (in a ratio of 1:1).
As revealed by the data presented in Table 1, a large
variety of aryl bromides could be efficiently coupled with
N-benzoyl sulfoximine ethylester (3). Interestingly, in most
cases PCy3 proved more effective as a ligand than BINAP
(data not shown), and better yields were obtained in reactions
with the former. For some substrates the use of PCy3 was
even crucial for obtaining any of the desired arylated product.
For example, the coupling reaction of 3 with 4- or 3-nitro-
phenyl bromide did not give any of the corresponding
products with BINAP, whereas moderate to good yields of
8d and 8i were achieved using PCy3 as ligand (Table 1,
entries 4 and 9). This behavior was in contrast to that
observed during reaction with phenyl bromide, where both
phosphines worked equally well.
Generally, catalysts prepared from Pd(OAc)2 gave yields
better than those obtained from Pd2(dba)3. In reactions of
4-bromobenzonitrile, 4-bromochlorobenzene and 3-nitrophe-
nyl bromide, however, the latter palladium source proved
more effective (Table 1, entries 3, 5, and 9). The conversion
of 4-bromochlorobenzene afforded the corresponding 4-
chloro derivative exclusively, which revealed a high degree
of chemoselectivity of the coupling. Although the reaction
with 2-bromotoluene provided R-arylated 8k in good yield
(Table 1, entry 11), ortho-substituted aryl bromides were
generally unsuitable substrates. Thus, 2-bromoanisole gave
the coupled product in only 25% yield, and N,N-dimethyl-
2-bromoaniline, 2-bromobenzonitrile, and 2-bromobenzal-
dehyde did not afford the expected products at all. The use
of heterocyclic aryl halides such as 2-bromopyridine, 2-bro-
mothiophene, and 3-bromopyridine was also investigated,
but none of the reactions gave satisfying results.
Scheme 2
Since in most ligand and pseudopeptide syntheses the
“free” NH-sulfoximines are employed, the possibility of
cleaving the N-protective group had also to be realized. Much
to our surprise, N-benzoyl sulfoximine 10 proved rather
stable under basic conditions (K2CO3, NaOH, NaOMe, and
NH3-ethanol),19 and even after extended reaction times no
conversion was observed. Acidic conditions (1.2 N HCl,
reflux) led to decomposition of the starting material. Attempts
to reductively cleave the N-protective group by treatment
of 10 with DIBAL-H were also unsuccessful. Finally, we
utilized the BH3‚THF complex for the reductive N-benzoyl
cleavage, which afforded the desired “free” NH-phenyl
benzyl sulfoximine (11) in good yield (Scheme 2).
(17) Gerisch, M.; Krumper, J. R.; Bergman, R. G.; Tilley, T. D. J. Am.
Chem. Soc. 2001, 123, 5818.
(18) Rapid decarboxylations have also been observed in reaction
sequences involving other R-sulfoximidoyl carboxylates. Since some
ammonium salts proved rather stable at ambient temperature, they could
be applied in coupling reactions providing sulfoximine-containing pesudo-
peptides. For details, see refs 9c and 9d.
(19) For a detailed investigation of the nature of the N-C(O)-bond in
acylated sulfoximines, see: Hackenberger, C. P. R.; Raabe, G.; Bolm, C.
Chem. Eur. J. 2004, 10, 2942.
Of particular interest is entry 10 in Table 1, which
describes the R-arylation of 3 with 1,3-dibromobenzene.
Org. Lett., Vol. 7, No. 7, 2005
1353

In summary, various phenyl benzyl sulfoximines can be
readily prepared using palladium-catalyzed R-arylation. For
a successful coupling, the appropriate combination of pal-
ladium source, ligand, and base is crucial. N-Benzoyl-
protected sulfoximine ethyl ester (3) proved to be a particu-
larly suitable starting material for both the coupling and the
subsequent deprotection steps leading to the desired final
products. In further studies we plan to prepare and utilize
enantiopure derivatives of these products in the preparation
of new chiral ligands for asymmetric catalysis and building
blocks for pseudopeptides.
Acknowledgment. The Deutsche Forschungsgemein-
schaft within the SFB 380 and the Fonds der Chemischen
Industrie are gratefully acknowledged for financial support.
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.
OL050176B
1354
Org. Lett., Vol. 7, No. 7, 2005