New neutral reaction system with crown ether-KCl complexes in aqueous solution

Article abstract of DOI:10.1002/chem.201201107

Chiral auxiliaries: A new neutral reaction system with lipophilic [18]crown-6 derivatives and with an aqueous KCl solution has been successfully utilized for several conjugate-addition reactions (see scheme). The ring size, lipophilicity of the crown ethe

Full text of DOI:10.1002/chem.201201107

COMMUNICATION
DOI: 10.1002/chem.201201107
New Neutral Reaction System with Crown Ether–KCl Complexes in
Aqueous Solution
Seiji Shirakawa, Lijia Wang, Atsuyuki Kasai, and Keiji Maruoka*[a]
Alkali metal chlorides, such as NaCl and KCl, are one of
the most abundant natural resources on the earth, and are
essential for life-supporting systems. The human body re-
quires an aqueous solution of NaCl and KCl, and many bio-
catalyzed reactions proceed under such aqueous neutral
conditions. Accordingly, development of organic reactions in
aqueous NaCl and KCl solutions, which are promoted by
utilizing the ionic nature of these salts, seems to be very at-
tractive for the development of green sustainable chemis-
try.[1] However, alkali metal chlorides are generally known
as less reactive neutral molecules for organic reactions, due
to the low solubility in organic solvents and the deactivation
Figure 1. Activation of a carbon nucleophile by a crown ether–KCl com-
plex.
of the ions through hydration in aqueous solution. To acti-
vate the neutral chloride salts for organic synthesis, we are
interested in the use of water and crown ethers as ligands
for alkali metal chlorides. Crown ethers have long been rec-
ognized as one of the most representative and important
host molecules in supramolecular chemistry.[2] The special
feature of crown ethers is their strong ability to bind alkali
metal cations, such as K+ and Na+, and the binding proper-
ty is recognized as an artificial model of ionophores in bio-
logical systems. Another feature of crown ethers is the ex-
traction ability of neutral alkali metal salts into organic sol-
vents by complexation with these salts. Furthermore, the
anion of the crown ether–neutral salt complex might exist as
an activated “naked anion” in organic solvents. Although
the activated chloride anion of crown ether–alkali metal
chloride complexes has been used as nucleophilic reagent,[3]
the catalytic ability of these complexes is still unexplored in
organic synthesis. In this context, we are interested in the
development of a new reaction system with crown ether–
alkali metal chloride complexes as neutral catalysts for the
activation of carbon nucleophiles.
that when the reaction is carried out under homogeneous
conditions in toluene, the reverse reaction becomes very fast
due to the facile protonation with in situ generated HCl,
thereby suppressing the formation of potassium enolate. On
the other hand, when the reaction is performed in H2O/tolu-
ene biphasic conditions, hydrophilic HCl would move to the
aqueous phase smoothly, thereby enhancing the lifetime of
enolate with crown ether–potassium complex to some
extent. Herein, we report the synthetic utility of such a new
neutral reaction system with [18]crown-6 derivatives and
aqueous KCl solution for conjugate-addition reactions
(Scheme 1), in which interesting effects of water and lipo-
philic crown ether are observed in the present reaction
system. The roles of water and lipophilic crown ether are
also discussed in the present report.
We first investigated the effect of crown ethers–neutral
alkali metal chloride complexes on the conjugate addition of
b-keto ester to b-nitrostyrene as shown in Table 1. The reac-
tion of b-keto ester 5 and b-nitrostyrene in saturated aque-
ous KCl/toluene (10:1) biphasic solution with dibenzo[18]-
crown-6 (1b) at room temperature (258C) for 2 h afforded
a conjugate adduct 6 in 52% yield (Table 1, entry 1). In con-
trast, almost no reaction was observed in the absence of
crown ether or KCl (entries 2 and 3), and hence both crown
ether and KCl are essential to promote the reaction. The ef-
fects of alkali metal chlorides and ring sizes of dibenzoc-
rown ethers were also examined (entries 4–7). The use of
aqueous NaCl and LiCl solutions with catalyst 1b gave
product 6 only in 10 and 5% yields, respectively (entries 4
and 5). Furthermore, the change of the ring size of crown
Our strategy for the activation of carbon nucleophiles by
KCl is that the reaction is performed in H2O/toluene bipha-
sic conditions with the crown ether (Figure 1). It is expected
[a] Dr. S. Shirakawa, Dr. L. Wang, A. Kasai, Prof. Dr. K. Maruoka
Laboratory of Synthetic Organic Chemistry and
Special Laboratory of Organocatalytic Chemistry
Department of Chemistry
Graduate School of Science, Kyoto University
Sakyo, Kyoto 606-8502 (Japan)
Fax : (+81)75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201107.
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crown ether is also important to promote the reaction under
the neutral conditions. Based on this observation, we next
employed lipophilic di-tert-butyldibenzo[18]crown-6 (4).
Pleasingly, lipophilic catalyst 4 efficiently promoted the re-
action, and conjugate adduct 6 was obtained in high yield
(entry 10). The yield of 6 was further enhanced with pro-
longed reaction time (entry 11). Notably, the reaction using
solid KCl instead of aqueous KCl solution does not proceed
at all (entry 12), and hence the presence of water is also es-
sential to promote the reaction under neutral conditions.
With these interesting observations in hand, the applica-
bility of the present neutral reaction system using crown
ether 4 with aqueous KCl solution was investigated, and se-
lected examples are listed in Scheme 2. Various types of
active methine compounds and conjugate acceptors were
employed for the neutral reaction system, and the desired
conjugate adducts 6–10 were obtained in high yields. Fur-
thermore, the reaction with azodicarboxylate gives the de-
sired amination product 11 in excellent yield.
Scheme 1. Neutral reaction system with crown ether and aqueous KCl so-
lution for conjugate additions; EWG=electron-withdrawing group.
Table 1. Effects of crown ethers and alkali metal chlorides on the conju-
gate addition of 5.[a]
Entry
Crown ether
MCl
d.r.[b]
Yield [%][c]
1
2
3
4
5
6
7
8
1b
none[d]
1b
1b
1b
1a
1c
2
3
4
4
4
KCl
KCl
1:1.2
–
–
52
trace
trace
10
5
4
none[e]
NaCl
LiCl
KCl
1:1
1:1
1:1
1:1
1:1.5
1:1
1:1.2
1:1.2
–
KCl
KCl
KCl
KCl
12
38
4
81
9
10
11[f]
12
Scheme 2. Conjugate-addition reactions of activated carbonyl substrates
under neutral conditions. Cbz=carboxybenzyl; Boc=tert-butoxycarbon-
yl; Bn=benzyl.
KCl
92[g]
trace
KCl[h]
[a] Reaction conditions: b-ketoester 5 (0.10 mmol) and b-nitrostyrene
(0.12 mmol) in the presence of crown ether (10 mol%) in saturated aque-
ous MCl solution (2.0 mL)/toluene (0.20 mL) at RT for 2 h. [b] Deter-
mined by 1H NMR analysis. [c] Determined by 1H NMR analysis based
on hexamethylbenzene as an internal standard. [d] In the absence of
crown ether. [e] In H2O (2.0 mL)/toluene (0.20 mL). [f] Reaction was per-
formed for 5 h. [g] Isolated yield. [h] Use of solid KCl (10 equiv) instead
of aqueous KCl solution.
This neutral reaction system was successfully applied to
asymmetric conjugate addition[5,6] with chiral oxazolidinone.
Thus, a-substituted nitroacetamide 12 with a chiral oxazoli-
dinone moiety[7] was treated with 1,1-bis(benzenesulfonyl)-
ethylene in saturated aqueous KCl/toluene solution (2:1) in
the presence of catalytic crown ether 4 (10 mol%) to give
the conjugate adduct 13 with excellent stereoselectivity
(Scheme 3). The reaction with only 1 mol% of crown ether
4 still worked well with prolonged reaction time. Notably,
the reaction in the absence of crown ether or KCl does not
proceed at all. Furthermore, the present reaction does not
work well under basic conditions using aqueous alkali metal
bases, such as KOH and K2CO3, which primarily caused the
decomposition of starting materials. Hence, the present
highly stereoselective reaction was only achieved under neu-
tral conditions using crown ether–KCl complexes.
ethers 1a–c caused a decrease in yields (entries 6 and 7 vs.
entry 1). These results clearly indicate that the binding sta-
bility of the crown ether complex with the alkali metal chlo-
ride is crucial to promote the reaction efficiently.[4]
Other [18]crown-6 derivatives were also examined for the
reaction by using aqueous KCl solution (Table 1, entries 8–
10). Although dicyclohexano[18]crown-6 (2) promoted the
reaction to give adduct 6 in moderate yield (entry 8), the
use of simple [18]crown-6 (3) was found to be less effective
(entry 9). These results suggest that the lipophilicity of the
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Neutral Reaction System with Crown Ether–KCl Complexes
COMMUNICATION
and di-tert-butyldibenzo[18]crown-6 (4, 0.010 mmol, 10 mol%) in toluene
(0.20 mL) was added saturated aqueous KCl solution (2.0 mL), and the
mixture was vigorously stirred at RT for 5 h. The resulting mixture was
diluted with H2O (3.0 mL) and extracted with AcOEt (3ꢁ5.0 mL). The
combined organic extracts were dried over Na2SO4 and concentrated. Pu-
rification of the residue by column chromatography on silica gel (neutral)
with hexane/AcOEt as eluent gave the product.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific Re-
search from JSPS, MEXT (Japan), and The Association for the Progress
of New Chemistry.
Scheme 3. Asymmetric conjugate addition of chiral oxazolidinone 12.
Keywords: alkali metals
conjugation · crown compounds · synthetic methods
·
asymmetric synthesis
·
The absolute configuration of the conjugate adduct 13
was confirmed by X-ray diffraction analysis as shown in
Figure 2.[8]
[1] For reviews on green sustainable chemistry, see: a) S. L. Y. Tang,
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Angew. Chem. 1972, 84, 16; Angew. Chem. Int. Ed. Engl. 1972, 11,
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[3] For halogen-exchange reactions by using [18]crown-6 derivatives with
aqueous KCl solution, see: a) D. Landini, F. Montanari, F. M. Pirisi,
J. Chem. Soc. Chem. Commun. 1974, 879; b) J. W. Lee, H. Yan, H. B.
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Chem. 2009, 121, 7819; Angew. Chem. Int. Ed. 2009, 48, 7683.
[4] It is known that [18]crown-6 derivatives form most stable complex
with potassium cation; see Ref. [2].
[5] For reviews on asymmetric conjugate addition, see: a) B. E. Rossiter,
N. M. Swingle, Chem. Rev. 1992, 92, 771; b) J. Leonard, E. Dꢂez-
Barra, S. Merino, Eur. J. Org. Chem. 1998, 2051.
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Sogah, J. Chem. Soc. Chem. Commun. 1981, 625; b) P. Bakꢃ, T. Kiss,
L. Tçke, Tetrahedron Lett. 1997, 38, 7259; c) L. Tçke, P. Bakꢃ, G. M.
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M. Czugler, J. Tatai, T. Novꢅk, G. Parlagh, L. Tçke, Tetrahedron:
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2011, 52, 1473.
[7] a) D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981, 103,
2127; b) D. A. Evans, Aldrichimica Acta 1982, 15, 23; c) D. A. Evans,
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Synth. 1990, 68, 83.
Figure 2. X-ray crystal structure of the conjugate adduct 13.
In summary, we have successfully developed a new neu-
tral reaction system using lipophilic [18]crown-6 derivatives
with aqueous KCl solution. The ring size and lipophilicity of
the crown ether as well as the presence of water are crucial
to promote the reaction efficiently. The advantage of the
present neutral reaction system was clearly demonstrated
through the highly stereoselective conjugate addition of
chiral acyloxazolidinone. Further investigations on the neu-
tral reaction system including mechanistic studies are cur-
rently underway in our group and these studies will be re-
ported in due course.
[8] CCDC-832592 (13) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Experimental Section
General procedure for conjugate-addition reactions under neutral condi-
Received: April 1, 2012
tions: To a mixture of nucleophile (0.10 mmol), electrophile (0.12 mmol),
Published online: && &&, 0000
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K. Maruoka et al.
Crown Compounds
S. Shirakawa, L. Wang, A. Kasai,
K. Maruoka* .................. &&&& — &&&&
New Neutral Reaction System with
Crown Ether–KCl Complexes in
Aqueous Solution
Chiral auxiliaries: A new neutral reac-
tion system with lipophilic [18]crown-6
derivatives and with aqueous KCl solu-
tion has been successfully utilized for
several conjugate-addition reactions
(see scheme). The ring size, lipophilic-
ity of the crown ether, and the pres-
ence of water are crucial to promote
the reaction efficiently. The reaction
system can also be applied to asym-
metric conjugate addition of the chiral
acyloxazolidinone with excellent dia-
stereoselectivity.
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!