Catalytic asymmetric α-chlorination of 3-acyloxazolidin-2-one with a trinary catalytic system

Article abstract of DOI:10.1002/ejoc.201100453

Direct asymmetric α-chlorination of aryl acetic acid derivatives was achieved with a novel trinary activation system consisting of a catalytic amount of NiCl₂/(R)-BINAP, Et₃SiOTf, and a tertiary amine base. The reaction smoothly affo

Full text of DOI:10.1002/ejoc.201100453

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100453
Catalytic Asymmetric α-Chlorination of 3-Acyloxazolidin-2-one with a Trinary
Catalytic System
Yoshitaka Hamashima,[a][‡] Tatsuya Nagi,[a,b] Ryo Shimizu,[a,c] Teruhisa Tsuchimoto,[b] and
Mikiko Sodeoka*[a,c]
Keywords: Halogenation / Nickel / Enantioselectivity / Asymmetric catalysis
Direct asymmetric α-chlorination of aryl acetic acid deriva-
tives was achieved with a novel trinary activation system
consisting of a catalytic amount of NiCl2/(R)-BINAP, Et3Si-
OTf, and a tertiary amine base. The reaction smoothly af-
forded the chlorinated compound in good yield with up to
89%ee. Application of this reaction to a less acidic crotonic
acid derivative gave the β,γ-unsaturated α-chlorinated com-
pound through deprotonation at the γ-position.
cinchona alkaloid catalyzed chlorination/bromination of
acid chlorides through the formation of ketene intermedi-
Introduction
Because the chlorine atom is a good leaving group, substitu- ates.[2] Another example is chiral secondary amine catalyzed
tion reactions of alkyl chlorides with various nucleophiles chlorination/bromination of primary aldehydes.[3] In ad-
are routinely employed in organic synthesis. Such reactions dition to electrophilic halogenation reactions, MacMillan
occur through SN2-type displacement with (complete) in- and co-workers reported an oxidative nucleophilic α-chlori-
version of the stereochemistry. For this reason, optically nation of aldehydes by using LiCl in combination with Cu-
active chlorinated compounds can serve as versatile inter- (OCOCF3)2/Na2S2O8.[4] As for chiral Lewis acid catalyzed
mediates for further chemical modifications. Asymmetric α- reactions, active methine compounds such as α-substituted
halogenation reactions have progressed substantially in the β-keto esters and 3-substituted oxindole derivatives have
last decade.[1] One of the great achievements in this field is been chlorinated with excellent enantioselectivity.[5,6]
Scheme 1. α-Chlorination and potential chemical transformations.
[a] RIKEN Advanced Science Institute,
As a part of our continuing studies on transition metal
2-1 Hirosawa, Wako, Saitama 351-0198, Japan
enolate chemistry[7] and fluorine chemistry,[8] we previously
Fax: +81-48 462 4666
E-mail: sodeoka@riken.jp
developed a novel trinary catalytic system consisting of
NiCl2/(R)-BINAP (1a), a secondary Lewis acid (R3SiOTf),
and 2,6-lutidine for catalytic asymmetric α-monofluorin-
ation of aryl acetic acid derivatives.[9] On the basis of those
results, we hypothesized that a similar chlorination reaction
would also occur enantioselectively with the trinary catalyst
(Scheme 1). In principle, the obtained chlorinated com-
pounds can be converted into various useful com-
pounds.[1,3b] For example, reduction followed by basic treat-
[b] Department of Applied Chemistry,
School of Science and Technology, Meiji University,
Higashimita, Tama-ku, Kawasaki 214-8571, Japan
[c] Graduate School of Science and Engineering,
Saitama University,
255 Shimo-okubo, Sakura-ku, Saitama 338-8570, Japan
[‡] Current address: School of Pharmaceutical Sciences,
University of Shizuoka,
52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100453.
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Y. Hamashima, T. Nagi, R. Shimizu, T. Tsuchimoto, M. Sodeoka
SHORT COMMUNICATION
ment will give optically active terminal epoxides. Simple Table 1. Optimization of the reaction conditions.
substitution reaction with sodium azide may give precur-
sors to chiral aryl glycine derivatives. Furthermore, after
conversion of the products into the corresponding ketones,
the chlorine atom could be substituted by organozinc rea-
gents in the presence of a copper catalyst.[10] Because of
their synthetic utility, highly diastereoselective chlorination
reactions of chiral 3-acyl oxazoridin-2-ones have been de-
veloped.[11] However, the direct catalytic conversion of ester
equivalents has rarely been reported.[12] Here, we describe
the catalytic asymmetric α-chlorination of aryl acetic acid
derivatives by using our trinary activation system. We modi-
Entry
Base
[Cl+]
c
T
t
Yield[a]
[%]
ee[b]
[%]
fied the original conditions and found that tertiary amine
bases were more effective than 2,6-lutidine so that not only
aryl acetic acid derivatives but also an α,β-unsaturated com-
pound were chlorinated smoothly in an enantioselective
manner.
[m]
[°C]
[h]
1
2
3
4
5
6
7
8
2,6-lutidine
2,6-lutidine TfCl (3)
NCS
1.0
1.0
1.0
1.0
0.1
0.1
0.1
0.1
–20
–20
–20
–40
–40
–40
–60
–78
24
24
1
93
77
99
93
96
85
94
81
Ͻ10
30
43
64
79
85
87
89
Et3N
Et3N
3
3
3
3
3
3
1
Et3N
3
NMM
NMM
NMM
1
6
72
Results and Discussion
[a] Isolated yield. [b] Determined by chiral HPLC analysis. NMM
= N-methylmorpholine.
Initially, we examined several chlorinating reagents under
the optimized conditions for the fluorination reaction[9]
(Table 1). For these reactions, we utilized N-acyl oxazolidin-
2-one (2a) as a model substrate, as the corresponding N-
acyl thiazolidin-2-one, which was examined in our previous
study, gave an inseparable mixture of the product and the
starting material. Although the reaction with NCS, a com-
monly used chlorinating reagent, proceeded smoothly, neg-
ligible asymmetric induction was observed (Table 1, En-
try 1). Interestingly, trifluoromethanesulfonyl chloride
(TfCl, 3) was found to be suitable for use under our reac-
Scheme 2. Hydrolysis of 4a.
tion conditions,[13,14] and desired product 4a was obtained compounds in high yield with up to 88%ee. Interestingly,
with moderate enantioselectivity (Table 1, Entry 2). To ac- the dichlorinated compound was not isolated in any of
celerate the reaction, Et3N was tested in place of 2,6-lut- these reactions. Ether, thioether, and halogens were tolerant
idine. As we had hoped, the reaction was accelerated, reach- to the present conditions (Table 2, Entries 1–6). Bulkier
ing completion within only 1 h to afford 4a almost quanti- substrates such as 2h and 2i were also chlorinated smoothly
tatively with 43%ee (Table 1, Entry 3).[15] The reaction tem- (Table 2, Entries 7 and 8). When the amount of the catalyst
perature and the concentration of the reaction mixture in- was reduced to 5 mol-%, similar results were obtained
fluenced the selectivity (Table 1, Entries 4 and 5).[16] To our (Table 2, Entry 9). It is advantageous that a stable NiCl2/
delight, when less basic N-methylmorpholine (NMM) was BINAP complex can be used without the need to prepare
used, the ee was improved to 87% (Table 1, Entries 6 and the corresponding cationic Ni complex, such as the Ni-
7), and although a lower temperature gave a slightly im- (OTf)2/BINAP complex, which generally requires the use of
proved ee, the longer reaction time was unfavorable expensive silver triflate.
(Table 1, Entry 8).
In view of the strong activation ability of the modified
Obtained product 4a was hydrolyzed[17] to give corre- trinary system described above, we next examined the reac-
sponding carboxylic acid 5 quantitatively (Scheme 2). Neg- tions of less acidic substrates. No reaction was observed in
ligible loss of optical purity during the hydrolysis was con- the case of an aliphatic substrate derived from hexanoic
firmed after conversion into methyl ester 6. The absolute acid. In contrast, γ-deprotonation and α-chlorination of
configuration of 4a was determined to be R by comparing crotonic acid derivative 7 occurred (Scheme 3).[20] Though
the retention times of both enantiomers of 6 on a chiral 7 was recovered under the reaction conditions optimized
stationary phase with the reported data,[18,19] and this result for 4a, the reaction proceeded at –40 °C when Et3N was
is in accord with the sense of enantioselection observed in used in place of NMM. Monochlorinated product 8 was
the previous fluorination reaction.[9]
Under the optimized reaction conditions, we next exam- selectivity of 72%.
obtained in 62% yield with reasonably high enantio-
ined the generality of the reaction by using various aryl
Because product 4 is likely to be more acidic than the
acetic acid derivatives (Table 2). In most cases, the reaction starting material due to the presence of an electron-with-
proceeded smoothly to afford the desired monochlorinated drawing chlorine atom, we first considered that lower
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Eur. J. Org. Chem. 2011, 3675–3678

Catalytic Asymmetric α-Chlorination of 3-Acyloxazolidin-2-one
Table 2. Scope of the reaction.
Entry Substrate
Ar
1a
[mol-%]
t
[h]
Yield[a]
[%]
ee[b]
[%]
1
2
3
4
5
6
7
8
9
2b
2c
2d
2e
2f
2g
2h
2i
p-MeC6H4
p-MeOC6H4
m-MeOC6H4
p-FC6H4
p-BrC6H4
p-MeSC6H4
1-naphthyl
2-naphthyl
Ph
10
10
10
10
10
10
10
10
5
24
24
24
24
6
86
86
89
89
87
93
94
96
99
83
83
80
86
75
76
88
78
84
Scheme 4. Control experiments.
6
to enhance its electrophilicity. The absolute configuration
observed in this reaction suggests that TfCl attacks the Ni
enolate from the Re face, which is sterically less hindered.
24
16
12
2a
[a] Isolated yield. [b] Determined by chiral HPLC analysis.
Scheme 3. Catalytic asymmetric α-chlorination of crotonyl deriva-
tive 8.
enantioselectivity observed in the case of Et3N might be
associated with in situ racemization of the product. Isolated
compound (R)-4a (79%ee) prepared with the NiCl2/(R)-
BINAP complex was therefore treated under identical con-
ditions with the two enantiomers of the NiCl2/BINAP com-
plex. As shown in Scheme 4, (R)-4a was recovered quantita-
tively without any loss of optical purity, which strongly in-
dicates that no racemization of the product occurred in the
reaction mixture (Scheme 4, Equation 1). Thus, we sus-
pected that the uncatalyzed reaction might proceed in the
presence of the silyl triflate and Et3N. Control experiments
revealed that TESOTf and Et3N alone could promote the
reaction even at –40 °C (Scheme 4, Equation 2). In contrast,
the reaction with NMM did not give 4a at all. These results
suggest that the occurrence of uncatalyzed reaction might
decrease the enantioselectivity.
The proposed reaction mechanism is outlined in
Scheme 5. On the basis of previous NMR spectroscopic ex-
periments, it seems likely that 1a is converted into active Ni
triflate complex 1b as a result of counteranion exchange
with Et3SiOTf.[9,21] Because the isolated Ni(OTf)2/BINAP
complex and Et3N alone did not promote the reaction, the
three activators are considered to act cooperatively to pro-
mote the reaction enantioselectively. Imide 2 coordinates to
the active Ni species, and Ni enolate 9 with the Z configura-
tion would be formed with the aid of the amine base. Even
though the exact role of Et3SiOTf is not clear at present,
Scheme 5. Proposed catalytic cycle.
Conclusions
In summary, the modified Ni-based trinary system was
found to promote the asymmetric α-chlorination of aryl
acetic acid derivatives. Notably, this powerful trinary system
allowed in situ activation of α,β-unsaturated compound 7,
and γ-deprotonation followed by α-chlorination occurred
enantioselectively. Although further improvement is re-
quired, our results demonstrate the great potential of our
cooperative activation method.
Experimental Section
Starting imide 4 (0.1 mmol) and Ni complex 1a (0.01 mmol,
7.5 mg, 10 mol-%) were suspended in toluene (1.0 mL, 0.1 m) under
an atmosphere of dry nitrogen. The resulting mixture was sonicated
we speculate that the secondary Lewis acid activates TfCl at ambient temperature for 2 min, and a dark purple solution was
Eur. J. Org. Chem. 2011, 3675–3678
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Y. Hamashima, T. Nagi, R. Shimizu, T. Tsuchimoto, M. Sodeoka
SHORT COMMUNICATION
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and the mixture was stirred for 10 min at the same temperature.
The solution was sonicated at ambient temperature for 2 min, af-
fording a red-brown solution. Trifluoromethanesulfonyl chloride
(TfCl, 0.15 mmol, 16 μL) was added at –60 °C. Next, N-methyl-
morpholine (NMM, 0.15 mmol, 20 μL) was added, and the reac-
tion mixture was stirred for the time given in Table 2. The reaction
was monitored by TLC (hexane/AcOEt) until completion, and then
the mixture was quenched with aqueous NaCl. Usual workup and
flash column chromatography were carried out for purification.
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data.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Research
on Priority Areas from the Ministry of Education, Culture, Sports,
Science and Technology of Japan (MEXT) (No. 19028065, “Chem-
istry of Concerto Catalysis”) and project funding from RIKEN.
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[21] The exact structure of 1b has not yet been determined.
Received: March 31, 2011
Published Online: May 17, 2011
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Eur. J. Org. Chem. 2011, 3675–3678