Enantioselective halogenation of β-oxo esters catalyzed by a chiral sulfoximine-copper complex

Article abstract of DOI:10.1002/ejoc.200900467

A C₁-symmetric amino sulfoximine has been used as a chiral ligand in copper-catalyzed asymmetric halogenation reactions of β-oxo esters. Both the catalyst itself and the reaction conditions were optimized, and 26 fluorinated, chlorinated, and b

Full text of DOI:10.1002/ejoc.200900467

FULL PAPER
DOI: 10.1002/ejoc.200900467
Enantioselective Halogenation of β-Oxo Esters Catalyzed by a Chiral
Sulfoximine–Copper Complex
Marcus Frings[a] and Carsten Bolm*[a]
Keywords: Asymmetric catalysis / Copper / Halogenation / Sulfoximines / Enantioselectivity
A C1-symmetric amino sulfoximine has been used as a chiral
ligand in copper-catalyzed asymmetric halogenation reac-
tions of β-oxo esters. Both the catalyst itself and the reaction
conditions were optimized, and 26 fluorinated, chlorinated,
and brominated products were obtained with enantio-
selectivities of up to 91% ee in yields of up to 99%.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Sulfoximines, the monoaza analogues of sulfones, were
discovered in the mid 1940s, and since then they have
played an important role in various fields of chemistry. Ini-
tial research focused on their unusual structure and remark-
able biological activity.[1] Derivatives with a stereogenic cen-
ter at the sulfur atom have been used as chiral auxiliaries
in asymmetric synthesis.[2] In the early 1990s we were the
first to demonstrate the applicability of sulfoximines as chi-
ral ligands,[3] and since then a wide variety of compounds
with a sulfoximidoyl core have found application in asym-
metric metal catalysis (Figure 1).[4] For example, β-hydroxy
sulfoximines 1 have been used in nickel-catalyzed conjugate
addition to chalcones, asymmetric 1,2-addition of di-
organozinc reagents to aldehydes, enantioselective borane
reduction of ketones and imine derivatives, and in the syn-
thesis of asymmetric cyanohydrins.[3,5] C2-symmetric
bis(sulfoximines) 2 proved efficient ligands in highly enan-
tioselective (hetero-)Diels–Alder and allylic alkylation reac-
tions.[6] C1-symmetric monosulfoximines of the type 3 have
successfully been used in hetero-Diels–Alder reactions,[7]
and the related N,N ligands 4 gave products with excellent
stereoselectivities in Mukaiyama-type aldol reactions and
its vinylogous analogue.[8,9] Further modification of the li-
gand structure led to C1-symmetric oxazolinyl sulfoximines
5, which have been used in Mukaiyama aldol and Henry
reactions.[10] For iridium-catalyzed enantioselective hydro-
genation of imines and enones sulfoximine-derived P,N li-
gands such as 6 have been used.[11] We now wondered if
such sulfoximines could also be used in catalyzed asymmet-
ric carbon–halogen bond-forming reactions.
Figure 1. Sulfoximines 1–6 used as ligands in asymmetric metal ca-
talysis.
Surprisingly, reports on catalyzed asymmetric halogena-
tion reactions that provide products with high enantio-
selectivities in high yields are still comparatively rare despite
the fact that C–X (X = F, Cl, Br, I) bonds are both valuable
intermediates for further chemical transformations and im-
portant structural motifs in natural products.[12,13] Since the
first catalytic enantioselective fluorination was reported by
Togni and co-workers,[14] a number of related transforma-
tions have been described. Most of them rely on the use of
enolizable carbonyl compounds, and catalytic systems for
the asymmetric fluorination of nucleophiles such as β-oxo
esters,[14a,15] β-oxo phosphonates,[15e,16] oxindoles,[17] ma-
lonates,[18] cyanoacetates,[19] and other acid derivatives[20]
have been developed. Furthermore, aldehydes have recently
been enantioselectively fluorinated by organocatalysis.[21]
All the methods mentioned above have also been adopted
for organocatalytic and metal-catalyzed asymmetric bromi-
nation and chlorination reactions.[16b,17b,22]
[a] Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52056 Aachen, Germany
Fax: +49-241-809-2391
E-mail: carsten.bolm@oc.rwth-aachen.de
Herein we report on the general asymmetric carbon–
halogen bond formation of both cyclic and acyclic β-oxo
esters catalyzed by a sulfoximine–copper complex leading
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900467.
Eur. J. Org. Chem. 2009, 4085–4090
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Frings, C. Bolm
FULL PAPER
to brominated, chlorinated, and fluorinated products in nation of oxo ester 7a with NCS (8) to give the product
high yields and with moderate to good enantioselectivi- 9a served as the test reaction. The results of this study are
ties.[23]
summarized in Table 2.
Table 2. Solvent effects in the copper-catalyzed asymmetric chlori-
nation of oxo ester 7a to give chlorinated product 9a.[a]
Results and Discussion
Entry
Solvent
Yield [%]
ee [%][b]
To identify the best ligand structure for the metal-cata-
lyzed asymmetric halogenation reactions ethyl 2-benzylace-
toacetate (7a) was chosen as the test substrate, and chlori-
nations with copper catalysts were investigated first. Ac-
cordingly, an ethereal solution of β-oxo ester 7a was treated
with N-chlorosuccinimide (NCS, 8) in the presence of a
catalytic amount of a 1:1 mixture of Cu(OTf)2 and a sulfox-
imine (10 mol-% each). After stirring at ambient tempera-
ture for 4 h, the product was isolated and analyzed spectro-
scopically. The enantiomer ratios were then determined by
HPLC using a chiral stationary phase (CSP). Various sulf-
oximines (at least three examples of each substrate class de-
picted in Figure 1) were tested and representative results are
shown in Table 1.
1
2
3
4
5
CH2Cl2
CHCl3
toluene
THF
1,4-dioxane
CH3CN
CH3OH
Et2O
98
98
96
99
94
50
99
99
16
0
31
19
23
0
6[c]
7[c]
8
0
41
[a] Reaction conditions: Cu(OTf)2 (10 mol-%), (S)-4a (10 mol-%),
NCS (8; 1.2 equiv.), solvent (0.1 ), room temp., 4 h. [b] Deter-
mined by CSP-HPLC. [c] Reaction time: 18 h.
With the exception of the catalysis performed in acetoni-
trile (Table 2, Entry 6), all the reactions led to very high
Chlorinated oxo ester 9a was obtained in excellent yield yields (94–99%) of the chlorinated oxo ester 9a irrespective
(94–99%) in almost all cases. Only when P,N-sulfoximine of the solvent. Very polar media (such as acetonitrile and
6a was employed was the yield of 9a moderate (66%), pre- methanol) hampered the catalysis, and the reaction time
sumably due to a competitive chlorination of the phos- had to be extended (from 4 to 18 h). Under these conditions
phanyl substituent of the ligand reducing its metal-binding 9a was obtained in 50 and 99% yields, respectively (En-
capability (Table 1, Entry 10). Most sulfoximine-based cata- tries 6 and 7). Presumably, these solvents competed with the
lysts provided racemic products. Noteworthy exceptions sulfoximine ligand in the coordination to the copper atom,
were those with bis(sulfoximine) 2b, which gave 9a with leading to catalysts of low activity. This hypothesis was sup-
16% ee (Entry 4), and C1-symmetric amino sulfoximines 4a ported by the fact that in these reactions only racemic prod-
and 4b, which led to the chlorinated product with 41 and ucts were formed. Catalysis in dichloromethane or chloro-
35% ee, respectively (Entries 6 and 7). Because monosulfox- form afforded 9a in 98% yield (Entries 1 and 2), but the
imine 4a gave the best result it was employed in the subse- ee was low (up to 16%). Aromatic or weakly coordinating
quent studies.[24]
solvents such as toluene, THF, or 1,4-dioxane gave the chlo-
Because the reaction medium can strongly influence a rinated oxo ester 9a with enantioselectivities in the range of
catalyst by altering important parameters such as solubility, 19–31% ee (Entries 3–5). The best result was obtained in
substrate/catalyst coordination, acidity, and polarity, the ef- the reaction performed in diethyl ether, which provided 9a
fect of the solvent was investigated next. Again, the chlori- with 41% ee (in 99% yield; Entry 8).
Table 1. Screening of sulfoximines 1–6 in the asymmetric chlorination of 7a.[a]
Entry
Sulfoximine
R1
R2
R3
R4
Ph
Yield [%]
ee [%][b]
1
2
3
4
5
6
7
8
9
(S,S)-1a
(S)-1b
Ph
Ph
Ph
Ph
Me
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
iPr
99
99
97
0
0
0
16
–2
41
35
6
(CH2)6
(S,S)-2a[c]
(S,S)-2b[d]
(R)-3a
–
–
H
H
H
Me
tBu
–
–
–
–
Me
96
2-MeOC6H4
Me
99[e]
99
(S)-4a
(S)-4b
(S,1R,2S)-5a
(S,S)-5b
(S)-6a
2,4,6-iPr3C6H2
2,4,6-Me3C6H2
Me
Me
Me
Me
99
99
94
66
Ph
H
–
0
4
10
[a] Reaction conditions: Cu(OTf)2 (10 mol-%), sulfoximine 1–6 (10 mol-%), NCS (8; 1.2 equiv.), Et2O (0.1 ), room temp., 4 h. [b] Deter-
mined by CSP-HPLC. [c] Use of an ethylene-linked bis(sulfoximine). [d] Use of a bis(sulfoximine) with an ortho-disubstituted benzene
linker. [e] Reaction carried out in DCM.
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Eur. J. Org. Chem. 2009, 4085–4090

Enantioselective Halogenation of β-Oxo Esters
Besides Cu(OTf)2 several other metal triflates were found
to be catalytically active, affording 9a in good to excellent
yields (Table 3). Only the triflates of silver, tin, and bismuth
(Entries 1, 5, and 10) were inapplicable, and even after pro-
longed reaction times (18 h) the product was obtained in
low yields (27–39%). All the metal salts except iron and
copper formed the racemic oxo ester 9a. Interestingly, these
two salts gave opposite enantiomers (Entries 11 and 12)
with copper being superior in terms of enantioselectivity
(41% ee).
Table 3. Variation of the metal source in the catalyzed asymmetric
chlorination of 7a with NCS (8) to give β-oxo ester 9a.[a]
Figure 2. Chlorine donors used in the Cu(OTf)2-catalyzed asym-
metric halogenation of 7a to give 9a. Reaction conditions were as
described in footnote [a] of Table 3 with Cu(OTf)2 as MX2; the
numbers in parentheses refer to yields and ee values of 9a.
Entry
Metal source
Yield [%]
ee [%][b]
1[c]
2
3
AgOTf
LiOTf
27
86
99
98
39
99
99
80
80
29
99
99
67
69
99
71
79
93
96
0
0
0
3
0
0
0
0
0
Mg(OTf)2
Zn(OTf)2
Sn(OTf)2
Sc(OTf)3
Yb(OTf)3
In(OTf)3
Gd(OTf)3
Bi(OTf)3
Fe(OTf)2
Cu(OTf)2
CuSO4
4
5[c]
6
The fact that in successful reactions the yields were high
but the enantioselectivities low suggested that uncatalyzed
background reactions leading to racemic products were re-
sponsible for the reduced product ees. This hypothesis, how-
ever, was disproved by a control experiment. In the absence
of the sulfoximine–copper catalyst the chlorination reaction
of oxo ester 7a with 8 in Et2O showed only traces of 9a
after 24 h.
Assuming that a decrease in temperature would have a
positive effect on the enantioselectivity, the standard reac-
tion of oxo ester 7a with NCS (8) in the presence of a cata-
lytic amount of Cu(OTf)2/(S)-4a was carried out in Et2O at
–78 °C (with warming to room temp. over 16 h). Chlori-
nated 9a was formed in excellent yield (99%) again, and the
ee increased to 54%. Under these conditions the addition
of 1 equiv. of hexafluoroisopropyl alcohol (HFIP) or 2,2,2-
trifluoroethanol reduced the enantioselectivity to 51 and
43% ee, respectively, whereas the yields remained almost
7
8
9
10[c]
11
0
–12
41
0
12
13[c]
14[c]
15
Cu(acac)2
Cu(ClO4)2·6H2O
Cu(BF4)2
Cu(PF6)2
Cu(SbF6)2
Cu(ClO4)2
4
21
23
0
6
15
16[d]
17[d]
18[d]
19[d]
[a] Reaction conditions: MXn (10 mol-%), (S)-4a (10 mol-%), NCS
(8; 1.2 equiv.), Et2O (0.1 ), room temp., 4 h. [b] Determined by
CSP-HPLC. [c] Reaction time: 18 h. [d] Prepared in situ from
CuCl2 (10 mol-%) and AgX (20 mol-%).
In previous studies it was shown that counterions are unaffected (99 and 96%). Both the yield and ee were lower
involved in the resulting sulfoximine–copper(II) complex,[25] when 1 equiv. of ethyldiisopropylamine (60% yield, 0% ee)
and consequently their effect on the given catalysis (yielding or 2,6-lutidine (42% yield, 6% ee) was added.
9a from 7a) was also studied in this work. Entries 12–19 of
The substrate scope of the enantioselective chlorination
Table 3 reveal that their influence on both yield and with NCS (8) was investigated next. Assuming analogous
enantioselectivity was significant with noncoordinating behavior in asymmetric bromination reactions with NBS
anions such as perchlorate, tetrafluoroborate, and triflate (14) both halogenation reactions were performed in parallel
being the best. This trend is similar to that observed in pre- (Table 4). In all cases Cu(OTf)2/(S)-4a served as the cata-
vious studies by our group.[8b] Interestingly, the commer- lyst, and the applicability of cyclic and acyclic β-oxo esters
cially available Cu(ClO4)2 hexahydrate gave better results 7 was examined.
(99% yield, 21% ee) than anhydrous Cu(ClO4)2 (96% yield,
In general, both the chlorinated and brominated prod-
15% ee), prepared in situ from CuCl2 and AgClO4 (En- ucts 9 and 15 were obtained in very high yields (88–99%),
try 15 vs. 19). Cu(OTf)2 proved superior to all other ion and the enantioselectivity reached a value of 91% ee (for
combinations in this metal-salt screening process.
chlorinated product 9f, Table 4, Entry 6). In the chlorina-
A brief screening of chlorine donors revealed that the tion reactions both the acyclic (Entries 1–4) and cyclic (En-
halogenation reactions with NCS (8) gave the best results tries 5–8) oxo esters 7 gave the corresponding products in
(Figure 2). The use of recrystallized 8 (from AcOH) had moderate to good enantioselectivities. Among the acyclic
no positive effect on the enantioselectivity of the reaction. substrates α-methyl-substituted oxo ester 9d had the highest
Although reagents 8, 10, and 12 bearing nitrogen–chlorine ee (73%), whereas 9b with a phenyl group at the α position
bonds gave rise to 9a in excellent yields (90–99%), halogen had only a 28% ee (Entries 4 and 2). For the cyclic oxo
donors 11 and 13 with carbon–chlorine bonds proved un- esters, six-membered-ring product 9f gave the best result
suitable.
(91% ee, Entry 6). Oxo esters with five- and eight-mem-
Eur. J. Org. Chem. 2009, 4085–4090
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M. Frings, C. Bolm
FULL PAPER
Table 4. Catalytic enantioselective chlorination and bromination reactions of β-oxo esters 7a–i.[a]
Entry
7
R1
R2
R3
9
Yield [%]
ee[b,c] [%]
15
Yield [%]
ee[b,c] [%]
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
Me
Me
Me
Me
Bn
Ph
Et
Et
Et
Et
Et
Et
Et
Et
Me
a
b
c
d
e
f
g
h
i
99
97
96
96
98
99
88
88
92
54
28 (R)
59
73 (R)
39 (R)
91 (R)
57
a
b
c
d
5e
f
g
–
h
98
99
97
95
99
99
91
–
48
39 (R)
73
Me
n.d.[d]
0
(CH2)3
(CH2)4
(CH2)6
(CH2)3
42 (R)
25
–
36
24
Me
(CH2)2
90
0
[a] Reaction conditions: Cu(OTf)2 (10 mol-%), (S)-4a (10 mol-%), NCS (8) or NBS (14) (1.2 equiv.), Et2O (0.1 ), –78 °C to room temp.
16 h. [b] Determined by CSP-HPLC or GC. [c] The absolute configurations given in parentheses were determined by comparison of the
optical rotation values with those reported in the literature. [d] Not determined; no separation conditions could be found on HPLC or
GC.
bered rings gave products with considerably lower ee (39% ution.[26] These, however, are inadequate due to their high
for 9e and 57% for 9g, Entries 5 and 7). Changing from an boiling points, which prevents a clean separation from vola-
ethyl to a methyl ester had no significant influence on the tile products (for details see the Experimental Section).
stereoselectivity (39% for 9e vs. 36% for 9h), but led to Table 5 summarizes the results obtained from the fluorina-
a lower yield (98% vs. 88%, Entries 5 and 8). The ester tion of oxo esters 7a–i with NFSI (21).
functionality could also be located inside the ring (Entry 9);
Table 5. Catalytic enantioselective fluorination of β-oxo esters 7a–i.[a]
acetyl butyrolactone (7i) afforded chlorinated product 9i in
a very good yield (92%), albeit with a low ee (24%).
The enantioselective bromination reactions also gave the
corresponding products 15 in high yields, but in most cases,
the enantioselectivities were lower than in the analogous
chlorination reactions. The only exceptions were observed
for the halogenation reactions of 7b and 7c, which gave the
corresponding brominated oxo esters 15b and 15c, respec-
tively, with higher ees (Entries 2 and 3). In the bromination
reactions of cyclic oxo esters 7e and 7h the products 15e
and 15h were obtained as racemates, albeit in high yields
(Entries 5 and 9).
To extend the scope of the reaction further, enantioselec-
tive fluorination reactions catalyzed by Cu(OTf)2/(S)-4a
were investigated. As the optimization of the chlorination
reactions had revealed that the enantioselectivity strongly
depended on the halogen source, the five commercially
available electrophilic fluorination agents 17–21 were exam-
ined. Again, oxo ester 7a served as the initial test substrate.
Only N-fluorobenzenesulfonimide (NFSI, 21) could suc-
cessfully be used under the previously optimized reaction
conditions, affording fluorinated product 16a with 58% ee
in 83% yield (Table 5, Entry 1). All the other electrophilic
fluorine donors 17–20 showed no conversion, and unhalo-
genated oxo ester 7a was fully recovered. These results can
be rationalized by the poor solubility of the fluorinating
agents of the type R3N+F– (17–20) in most organic solvents.
Whereas “neutral” NFSI (21) is fairly soluble in Et2O,
mono- or dicationic species, 17–20 require aprotic, dipolar
Entry β-Oxo ester R1
R2
R3 Product Yield [%] ee[b,c] [%]
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
7i
Me
Me
Me
Me Me
(CH2)3
(CH2)4
(CH2)6
(CH2)3
Me
Bn
Ph
Et
Et
Et
Et
Et
Et
Et
Et
Me
16a
16b
16c
16d
16e
16f
16g
16h
16i
83
88
66
49
99
92
96
99
99
58
42
68
63 (S)
74 (S)
71
73
74
(CH2)2
39
[a] Reaction conditions: Cu(OTf)2 (10 mol-%), (S)-4a (10 mol-%),
NFSI (21) (1.2 equiv.), Et2O (0.1 ), –78 °C to room temp., 16 h.
[b] Determined by CSP-HPLC or GC. [c] The absolute configura-
tions given in parentheses were determined by comparison of the
solvents such as CH3CN, DMF, or CH3NO2 for dissol- optical rotation values with those reported in the literature.
4088 Eur. J. Org. Chem. 2009, 4085–4090
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Enantioselective Halogenation of β-Oxo Esters
samples of 1a, 1b, 5a and 5b. Dr. C. Moessner is kindly acknowl-
edged for the donation of 6a, and we thank Annika Lödden and
Christoph Ariaans for preparative work.
Most of the fluorinated oxo esters 16 were obtained in
excellent yields ranging from 83 to 99% (Entries 1, 2, and
5–9). Only the acyclic substrates 7c and 7d, bearing an ethyl
and a methyl substituent at the α position, respectively (En-
tries 3 and 4), gave the corresponding products in lower
yields (66 and 49%, respectively). Compared with the chlo-
rination and bromination reactions, in which such a de-
crease in yield did not occur, this observation was surpris-
ing. Note that the enantioselectivities were generally higher
in the fluorination reactions (39–74% ee) than in the analo-
gous chlorination and bromination reactions. Overall, the
trend with respect to the product ee was fluorination Ͼ
chlorination Ͼ bromination.
Recently, Shibatomi et al. reported that the slow addition
of a solution of 21 to a mixture of β-oxo esters and an
Ni(ClO4)2/N,N,N-tridentate ligand complex (instead of
simultaneously mixing all the reagents) resulted in a signifi-
cantly improved enantioselectivity.[15h] When this protocol
was applied in this work and 21 was slowly added (by sy-
ringe pump over 5 h) to a mixture of 7a and Cu(OTf)2/(S)-
4a the ee of the resulting product 9a remained unaffected.
[1] For reviews on sulfoximines, see: a) C. R. Johnson, Acc. Chem.
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[3] C. Bolm, M. Felder, J. Müller, Synlett 1992, 439.
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Conclusions
We have developed a general protocol for the enantiose-
lective halogenation of β-oxo esters. All three chlorination,
bromination, and fluorination reactions proceeded well
with the latter giving the best results. Starting from both
cyclic and acyclic substrates the corresponding products
were formed with moderate to good enantioselectivities (up
to 91% ee) in excellent yields.[27] The catalyst was prepared
in situ from Cu(OTf)2 and a commercially available amino
sulfoximine [(S)-4a]. An extension of the method to the use
of other nucleophiles is now envisaged.
[7] C. Bolm, M. Verrucci, O. Simic, P. G. Cozzi, G. Raabe, H. Oka-
mura, Chem. Commun. 2003, 2826.
[8] a) M. Langner, C. Bolm, Angew. Chem. 2004, 116, 6110; An-
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Experimental Section
General Procedure for the Copper-Catalyzed Bromination, Chlorina-
tion, or Fluorination Reactions of β-Oxo Esters: A dry Schlenk tube
was charged with Cu(OTf)2 (0.020 mmol, 0.10 equiv.) and sulfoxi-
mine (S)-4a (0.020 mmol, 0.10 equiv.) under Ar. Dry Et2O (2.0 mL,
0.1 ) was added, and the green solution was stirred at room temp.
for 30 min. Subsequently, oxo ester 7 (0.20 mmol) was added and
stirring of the reaction mixture was continued at room temp. for
an additional 5 min. The solution was then cooled to –78 °C, and
halogen donor 8, 14, or 21 (0.24 mmol, 1.2 equiv.) was added. Stir-
ring was continued for 16 h while the suspension warmed to room
temp. Direct column chromatography of the now brownish reaction
mixture afforded pure products. Depending on their volatility the
products were dried at ambient temperature under high vacuum or
at 40 °C in a rotary evaporator under reduced pressure.
Supporting Information (see footnote on the first page of this arti-
cle): General Procedures for the halogenation reaction and charac-
terization data for compounds 9a–i, 15a–h, and 16a–i.
Acknowledgments
The authors are grateful to the Fonds der Chemischen Industrie
for financial support. We also thank Dr. J. Sedelmeier for providing
Eur. J. Org. Chem. 2009, 4085–4090
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4089

M. Frings, C. Bolm
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Received: April 29, 2009
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Published Online: July 13, 2009
4090
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Eur. J. Org. Chem. 2009, 4085–4090