A base-free neutral phase-transfer reaction system

Article abstract of DOI:10.1002/asia.201402194

Although phase-transfer reactions catalyzed by using quaternary ammonium salts are generally believed to require base additives, we discovered that, even without any base additives, conjugate additions of 3-substituted oxindoles to nitroolefins proceeded smoothly in the presence of lipophilic quaternary ammonium bromide under water-organic biphasic conditions. The mechanism of this novel base-free neutral phase-transfer reaction system is investigated and the assumed catalytic cycle is presented together with interesting effects of water and lipophilicity of the phase-transfer catalyst. The base-free neutral phase-transfer reaction system can be applied to highly enantioselective conjugate addition and aldol reactions under the influence of chiral bifunctional ammonium bromides as key catalysts. The structure of the chiral ammonium enolate intermediate is discussed based on the single-crystal X-ray structures of relevant ammonium salts and the importance of bifunctional design of catalyst is clearly explained in the model of intermediate. In and out of phase: The mechanism of a novel base-free neutral phase-transfer reaction system was investigated (see scheme). The aqueous-organic biphasic reaction system with lipophilic tetraalkylammonium bromide was essential to promote the neutral phase-transfer reactions. The base-free reaction system could be applied to several asymmetric reactions.

Full text of DOI:10.1002/asia.201402194

FULL PAPER
DOI: 10.1002/asia.201402194
A Base-Free Neutral Phase-Transfer Reaction System
Seiji Shirakawa, Lijia Wang, Rongjun He, Satoru Arimitsu, and Keiji Maruoka*[a]
Abstract: Although phase-transfer re-
actions catalyzed by using quaternary
ammonium salts are generally believed
to require base additives, we discov-
ered that, even without any base addi-
tives, conjugate additions of 3-substitut-
ed oxindoles to nitroolefins proceeded
smoothly in the presence of lipophilic
quaternary ammonium bromide under
water–organic biphasic conditions. The
mechanism of this novel base-free neu-
tral phase-transfer reaction system is
investigated and the assumed catalytic
cycle is presented together with inter-
esting effects of water and lipophilicity
of the phase-transfer catalyst. The
base-free neutral phase-transfer reac-
tion system can be applied to highly
enantioselective conjugate addition and
aldol reactions under the influence of
chiral bifunctional ammonium bro-
mides as key catalysts. The structure of
the chiral ammonium enolate inter-
mediate is discussed based on the
single-crystal X-ray structures of rele-
vant ammonium salts and the impor-
tance of bifunctional design of catalyst
is clearly explained in the model of in-
termediate.
Keywords: asymmetric catalysis
·
asymmetric synthesis · organocatal-
ysis · phase-transfer catalysis · reac-
tion mechanisms
Introduction
Phase-transfer catalysis has long been recognized as a versa-
tile methodology for organic synthesis that features simple
experimental operation and mild reaction conditions.[1] In
particular, during the last two decades, asymmetric phase-
transfer catalysis based on the use of chiral quaternary am-
monium salts has become a topic of great scientific inter-
est.[2] Many studies have been undertaken to understand the
reaction mechanism of these reactions and it was believed
for a long period that base additives, such as alkali metals
(Na, K, Cs) hydroxide, or carbonate, were essential to pro-
mote the phase-transfer reactions.[1,2] Although phase-trans-
fer catalysis has made a significant contribution to practical
organic synthesis, the drawback of this method from the
point of view of atom economy[3] is that it often needs more
than stoichiometric amounts of base additives. As a solution
to this problem, we have recently developed a hitherto un-
known base-free neutral phase-transfer reaction system in
asymmetric conjugate addition reactions (Scheme 1).[4] The
reaction was efficiently promoted by a chiral bifunctional
phase-transfer catalyst of type (S)-1 under neutral condi-
tions with high enantioselectivity. Surprisingly, however, tet-
Scheme 1. Base-free neutral phase-transfer reaction.
rabutylammonium bromide as
a representative achiral
phase-transfer catalyst was less effective for the reaction
under the same base-free reaction conditions (Scheme 1).
Although some interesting observations have been reported
in our preliminary study on the novel base-free reaction sys-
tem,[4a] the mechanism for this very attractive and interest-
ing reaction system is totally unclear. To obtain mechanistic
insight into the base-free neutral phase-transfer reaction
system, we are interested in the effect of water and catalyst
structure on the efficiency of the reaction. Herein, we de-
scribe the full details of this base-free reaction system, in-
cluding mechanistic insight into the interesting effects of
water and lipophilicity of the catalyst.
[a] Dr. S. Shirakawa, Dr. L. Wang, Dr. R. He, Dr. S. Arimitsu,
Prof. Dr. K. Maruoka
Laboratory of Synthetic Organic Chemistry and
Special Laboratory of Organocatalytic Chemistry
Department of Chemistry, Graduate School of Science
Kyoto University
Results and Discussion
Sakyo, Kyoto 606-8502 (Japan)
Fax : (+81)75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
Effect of Lipophilicity of the Phase-Transfer Catalyst
We first investigated the effect of the alkyl chain length in
tetraalkylammonium bromides in the conjugate addition of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201402194.
1
&
&
Chem. Asian J. 2014, 00, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Keiji Maruoka et al.
Table 1. Effect of alkyl chain-length of tetraalkylammonium bromides.[a]
tion system and the reactions using these catalysts gave
product 2a in almost quantitative yields even at 1 mol%
catalyst loading (Table 1, entries 5–7). These results clearly
indicate that high lipophilicity of the tetraalkylammonium
salt is important to promote the reaction efficiently under
neutral phase-transfer conditions. Tetraalkylammonium bro-
mide with longer alkyl chains, such as tetrahexadecylammo-
nium bromide, showed a decrease in catalytic efficiency that
is probably due to the steric bulkiness of the catalyst
(Table 1, entry 8).
Entry
R4N+BrÀ
Yield [%][b]
d.r.[c]
1
2
3
4
5
6
7
8
none
ꢀ0
–
–
–
Bu4N+BrÀ
Pen4N+BrÀ
Hex4N+BrÀ
Oct4N+BrÀ
Dec4N+BrÀ
trace
trace
84 (33)[d]
>95 (>95)[d]
>95 (>95)[d]
>95 (>95)[d]
49
79:21 (75:25)[d]
76:24 (80:20)[d]
81:19 (82:18)[d]
78:22 (81:19)[d]
81:19
Several chiral phase-transfer catalysts were employed in
the conjugate addition under base-free neutral phase-trans-
fer conditions (Scheme 2). Although binaphthyl-modified
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[a] Reaction conditions: 3-phenyloxindole (0.10 mmol) and b-nitrostyrene
(0.12 mmol) in the presence of tetraalkylammonium bromide (5 mol%)
in H2O (2.0 mL)/toluene (1.0 mL). [b] Yield was determined by using
1H NMR spectroscopy analysis based on 1,3,5-trimethoxybenzene as an
internal standard. [c] Determined by using 1H NMR spectroscopy analy-
sis. [d] Data in parenthesis were obtained by using 1 mol% of tetraalky-
lammonium bromide.
3-phenyloxindole to b-nitrostyrene[5] under base-free neutral
phase-transfer conditions (Table 1). In the absence of phase-
transfer catalyst, the reaction did not occur under the neu-
tral conditions (Table 1, entry 1). Tetrabutyl- and tetrapenty-
lammonium bromides were examined as phase-transfer cata-
lysts, and the reaction proceeded very sluggishly (Table 1,
entries 2 and 3). On the other hand, tetrahexylammonium
bromide promoted the reaction moderately and gave conju-
gate adduct 2a in 84% yield at a 5 mol% catalyst loading
(Table 1, entry 4) and in 33% yield at a 1 mol% catalyst
loading (Table 1, entry 4 in parenthesis). Tetraoctyl-, tetra-
ACHTUNGTRENNUNG(decyl)-, and tetradodecylammonium bromides worked as
more efficient phase-transfer catalysts for this neutral reac-
Scheme 2. Effect of chiral phase-transfer catalysts.
lipophilic catalysts (S)-1a, (S)-1b, and (S)-3[6] promote the
reaction efficiently, N-benzylcinchonidinium bromide 4,[2,7]
which is one of the most representative chiral phase-transfer
catalysts, is less effective under the neutral conditions likely
due to a lack of lipophilicity of the catalyst. It should be
noted that hydroxy-protected catalyst (S)-1b and catalyst
(S)-3 gave the product with only low enantioselectivities.
These results clearly indicate that the bifunctional design of
catalyst (S)-1a is essential to obtain high enantioselectivity
in this reaction.[8,9]
Abstract in Japanese:
Effect of Water
With important information about an effective catalyst in
hand, the solvent effect in this base-free neutral phase-trans-
fer reaction system was examined (Table 2). Tetra-
AHCTUNGTREG(NNNU decyl)ammonium bromide and chiral phase-transfer cata-
lyst (S)-1a were used in the reaction with various solvent
systems. The reactions in a biphasic solvent system (H2O/
toluene 2:1) were efficiently promoted by tetra-
&
&
2
Chem. Asian J. 2014, 00, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Keiji Maruoka et al.
Table 2. Effect of solvents.[a]
Table 3. Effect of pH value of the aqueous solution.[a]
Entry
pH of buffer
Yield [%][b]
d.r.[c]
ee [%][d]
Entry Catalyst
Solvent (ratio)
Dec4N+BrÀ H2O/toluene (2:1)
(S)-1a H2O/toluene (2:1)
Dec4N+BrÀ H2O/toluene (10:1)
Yield [%][b] d.r.[c] (ee [%])[d]
1
2
3
4
5
7.2
7.0
6.8
6.0
5.0
97
96
98
98
ꢀ0
92:8
92:8
92:8
92:8
–
91
91
91
90
–
1
2
3
>95
96[e]
>95
93[e]
98[e]
>95
39
82:18
91:9 (90)
79:21
93:7 (90)
94:6 (92)
75:25
78:22
4
5
6
7
(S)-1a
(S)-1a
H2O/toluene (10:1)
H2O/anisole (10:1)
[a] Reaction conditions: 3-phenyloxindole (0.05 mmol) and b-nitrostyrene
(0.06 mmol) in the presence of (S)-1a (1 mol%) in H2O buffer (2.0 mL)/
toluene (1.0 mL). [b] Yield of isolated product. [c] Determined by using
HPLC analysis. [d] Enantiomeric excess of the major diastereomer was
determined by using chiral HPLC analysis.
Dec4N+BrÀ H2O/toluene (100:1)
Dec4N+BrÀ H2O/toluene (1:10)
Dec4N+BrÀ toluene
8
trace
trace
trace
trace
trace
trace
–
–
–
–
–
–
9
(S)-1a
Dec4N+BrÀ THF
(S)-1a THF
Dec4N+BrÀ EtOH
(S)-1a EtOH
toluene
10
11
12
13
Reaction Mechanism
To obtain further information about the base-free neutral
phase-transfer reaction system, deuteration experiments of
3-phenyloxindole were performed (Scheme 3). To promote
this neutral reaction, ammonium enolate 6 should be
formed as an intermediate under base-free phase-transfer
conditions. Indeed, treatment of 3-phenyloxindole with (S)-
[a] Reaction conditions: 3-phenyloxindole (0.10 mmol) and b-nitrostyrene
(0.12 mmol) in the presence of catalyst (1 mol%). [b] Yield was deter-
mined by using 1H NMR spectroscopy analysis based on 1,3,5-trimethox-
1
ybenzene as an internal standard. [c] Determined by using H NMR spec-
troscopy or HPLC analysis. [d] Enantiomeric excess of the major diaste-
reomer was determined by using chiral HPLC analysis. [e] Yield of isolat-
ed product.
1a or tetraACHTNUGTRENUNG(decyl)ammonium bromide in D2O/toluene (2:1)
at 58C for 2 h gave rise to deuterated 3-phenyloxindole 5 in
yields of 89 and 55%, respectively, which indicates the for-
mation of ammonium enolate 6 with (S)-1a or tetra-
ACHTUNGTRENNUNG(decyl)ammonium bromide and (S)-1a (Table 2, entries 1
and 2). Even in the water-rich solvent system (H2O/toluene
10:1–100:1), which might be favorable from an environmen-
AHCTUNGTREG(NNNU decyl)ammonium bromide in the biphasic solvent system.
tal point of view,[10] tetra
N
However, in the presence of tetrabutylammonium bromide
or in the absence of catalyst, almost no deuteration product
5 was formed. These results completely agree with the re-
sults of conjugate addition in Table 1.
1a promoted the reaction efficiently to give conjugate
adduct 2a in high yields (Table 2, entries 3–6). The reaction
with (S)-1a under water-rich conditions gave high diastereo-
and enantioselectivity (90% ee; Table 2, entry 4), whereas
carrying out the reaction in H2O/anisole (10:1) slightly im-
proved the enantioselectivity (92% ee; Table 2, entry 5). Re-
duction of the amount of water (H2O/toluene 1:10) caused
a decrease in of the reaction rate (Table 2, entry 7). The ho-
mogeneous reactions in toluene in the absence of water
were also examined and very interestingly the reactions
were completely shut off (Table 2, entries 8 and 9). Further-
more, homogeneous reactions in polar and protic solvents,
such as THF and ethanol, were very sluggish (Table 2, en-
tries 10–13). These results indicate that water–organic bipha-
sic solvent systems, such as H2O/toluene, are essential for ef-
ficient promotion of the reaction under base-free neutral
conditions.
Based on these interesting observations for the neutral
phase-transfer reaction, the assumed catalytic cycle of the
present reaction system is proposed as shown in Scheme 4.
For the reaction to proceed, the combination of the H2O/tol-
uene biphasic solvent system with lipophilic phase-transfer
catalyst was indispensable. When the reaction is carried out
under homogeneous conditions in toluene only, the reversi-
ble reaction between 3-phenyloxindole and ammonium bro-
mide A does not favor the formation of ammonium enolate
B due to the facile protonation of ammonium enolate B
with in situ-generated HBr (Schemes 4 and 5). However,
The effect the pH of the aqueous solution in the enantio-
selective conjugate addition catalyzed by (S)-1a was careful-
ly examined (Table 3). The reaction was efficiently promot-
ed in buffer solutions at a nearly neutral pH range (pH 6.8–
7.2; Table 3, entries 1–3). Even in slightly acidic buffer solu-
tion (pH 6.0) the reaction was promoted efficiently with
high enantioselectivity (Table 3, entry 4). However, the reac-
tion was completely shut off by further lowering pH
(pH 5.0; Table 3, entry 5).
Scheme 3. Deuteration experiments.
3
&
&
Chem. Asian J. 2014, 00, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Keiji Maruoka et al.
Scheme 6. Formation of ammonium phenoxide under neutral condi-
tions.[11]
that of phenol, based on the pKa value of N-acetyloxindole
(pKa in DMSO=13.5).[13] These results suggest that lipophil-
ic tetraalkylammonium bromide can react with 3-phenylox-
indole to form ammonium enolate with release of HBr to
the aqueous phase under the neutral biphasic conditions, as
shown in Schemes 4 and 5.[14]
Scheme 4. Assumed catalytic cycle.
This hypothesis is further supported by the conjugate ad-
dition of thiophenol (pKa in DMSO=10.3)[15] to b-nitrostyr-
ene under neutral phase-transfer conditions (Scheme 7). Al-
Scheme 7. Conjugate addition of thiophenol.
Scheme 5. Formation of ammonium enolate.
when the reaction is performed in the H2O/toluene biphasic
solvent system, hydrophilic HBr moves smoothly into the
water phase, whereas lipophilic ammonium enolate B stays
in the toluene phase. Consequently, protonation by contact
of B and HBr was suppressed and the formation of ammoni-
um enolate B is promoted (Schemes 4 and 5). This allows
ammonium enolate B to react with b-nitrostyrene in the tol-
uene phase to give conjugate adduct C (Scheme 4).
This explanation for the formation of ammonium enolate
with release of HBr in the H2O/toluene biphasic system is
strongly supported by the experimental and theoretical stud-
ies of the formation of ammonium phenoxides under neutral
conditions by Ito, Odashima, Umezawa et al.[11] They found
that lipophilic tetraalkylammonium chlorides, such as trido-
decylmethylammonium chloride, react with phenols that
have various substituents to form ammonium phenoxides
under aqueous/organic biphasic conditions (Scheme 6). The
formation of ammonium phenoxide with the release of HCl
to the aqueous phase under neutral biphasic conditions was
proved by analytical methods. In this study, various phenols,
such as phenol and 4-nitrophenol, were examined for the
formation of ammonium phenoxides and it was found that
phenols with various pKa values (pKa in DMSO: phenol=
18.0, 4-nitrophenol=10.8)[12] could form ammonium phenox-
ides. Although the pKa value of N-tert-butoxycarbonyl-3-
phenyloxindole is unknown, it is expected to be lower than
though the reactions with phenols did not give the conjugate
adducts, probably due to the lack of nucleophilicity of am-
monium phenoxides, the reaction with thiophenol as a relat-
ed compound of phenols was efficiently promoted by tetra-
AHCTUNGTRENNUNG
(S)-1a in an enantioselective conjugate addition under neu-
tral conditions in a water-rich biphasic solvent (Scheme 8).
The reactions with ammonium trifluoromethanesulfonate
(X=OTf) and tetrafluoroborate (X=BF4) analogues of (S)-
1a gave product 2a in similar yields and stereoselectivities
to ammonium bromide (S)-1a (X=Br). The reaction with
Scheme 8. Effect of counterion of catalyst (S)-1a.
&
&
4
Chem. Asian J. 2014, 00, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Keiji Maruoka et al.
ammonium hydroxide (X=OH), which has a basic property
and could easily deprotonate an acidic hydrogen,[1] also gave
similar results. These results suggest that reactions with cata-
lysts that have different counterions proceed through the
same intermediate to produce conjugate adduct 2a in high
enantioselectivity. However, exchanging the counterion for
bulky hydrophobic anions, such as 3,5-bis(trifluoromethyl)-
phenyltrifluoroborate (X=BF3Ar) and tetrakisACHTNUTRGNE[NUG 3,5-bis(tri-
fluoromethyl)phenyl]borate (X=BAr4), caused a significant
decrease in reactivity. These results also support the pro-
posed reaction mechanism, which requires a hydrophilic HX
to move to the aqueous phase for efficient formation of an
ammonium enolate (Schemes 4 and 5).
Catalytic Enantioselective Conjugate Additions of
3-Substituted Oxindoles to Nitroolefins
With the assumed reaction mechanism in hand, we further
studied the generality of the asymmetric conjugate addition
of various 3-substituted oxindoles to b-nitrostyrene under
neutral conditions in water-rich biphasic solvent in the pres-
ence of chiral bifunctional phase-transfer catalyst (S)-1a
(Scheme 9). The introduction of electron-donating and elec-
tron-withdrawing substituents on both the oxindole core and
the 3-aryl group uniformly gave good diastereoselectivities
with high enantioselectivities (85–95% ee, 2a–j). 3-Hetero-
aryl-substituted oxindole could also be applied to this reac-
tion and gave conjugate adduct 2k with high enantioselec-
tivity (90% ee). Unfortunately, 3-alkyloxindoles, such as 3-
methyloxindole, gave low reactivity and selectivity (2l).
Various types of nitroolefins were found to be employable
for the reaction (Table 4). The reactions of nitroolefins that
have aromatic, heteroaromatic, and alkyl groups gave corre-
sponding products 2 in good-to-high enantioselectivities. In
Scheme 9. Enantioselective conjugate addition of 3-substituted oxindoles
to b-nitrostyrene.
Table 4. Enantioselective conjugate additions of 3-phenyloxindole to ni-
troolefins.[a]
the case of 1-nitro-1-pentene, high enantioselectivities were
observed for both diastereomers in spite of the low diaste-
reoselectivity (Table 4, entry 7). The reaction with nitroe-
thene gave product 2t in moderate enantioselectivity
(Table 4, entry 8).
To obtain insight into the enantiofacial recognition of 3-
substituted oxindoles by bifunctional catalysts of type (S)-1,
X-ray diffraction analysis of (S)-1c (Ar=Ph) was performed
(Figure 1, left).[16] Importantly, the hydrogen-bonding inter-
action between the hydroxy group and bromide anion is
clearly observed in the crystal structure of (S)-1c. Based on
the X-ray structure of (S)-1c, a plausible structure for the
ammonium enolate intermediate is proposed to account for
the absolute configuration of conjugate adducts 2 (Figure 1,
right). In the generation of ammonium enolate derived from
3-aryloxindole and catalyst (S)-1a under neutral conditions,
the enolate anion could be stabilized by both ionic interac-
tion with the ammonium cation and hydrogen bonding be-
tween the enolate oxygen and one hydroxy group in catalyst
(S)-1a. The binaphthyl unit of catalyst (S)-1a completely
Entry
R
Yield [%][b]
d.r.[c]
ee [%][d]
1
o-MeO-C6H4
m-MeO-C6H4
o-F-C6H4
2-thienyl
2-furyl
PhCH2CH2
CH3CH2CH2
H
91 (2m)
93 (2n)
99 (2o)
93 (2p)
91 (2q)
95 (2r)
98 (2s)
81 (2t)
65:35
92:8
91
85
94
90
80
91
94/84
51
2[e]
3[e]
4[e]
5
84:16
90:10
75:25
13:87
45:55
–
6[f]
7[f]
8[g]
[a] Reaction conditions: 3-phenyloxindole (0.05 mmol) and b-nitrostyrene
(0.06 mmol) in the presence of (S)-1a (1 mol%) in H2O (2.0 mL)/toluene
(0.2 mL). [b] Yield of isolated products. [c] Determined by using HPLC
analysis. [d] Enantiomeric excess of the major diastereomer was deter-
mined by using chiral HPLC analysis. [e] Reaction was performed in
H2O (2.0 mL)/anisole (0.2 mL). [f] Reaction was performed for 12 h.
[g] Nitroethene was added over 7 h.
5
&
&
Chem. Asian J. 2014, 00, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Keiji Maruoka et al.
(S)-1.[4b,c] Furthermore, the neutral reaction system could be
applied to the hitherto difficult direct aldol reaction[19] of a-
substituted nitroacetates with aqueous formaldehyde to
obtain a-alkyl serine derivatives in high enantioselectivi-
ty.[4d,20] It should be noted that these reactions do not work
well under ordinary phase-transfer conditions with aqueous
base solutions, such as aqueous KOH, K2CO3, and PhCO2K,
and under homogeneous reaction conditions without aque-
ous solution.[4b–d] Thus, these highly enantioselective reac-
tions were only achieved when the reaction was performed
under base-free neutral phase-transfer conditions.
Herein, we attempted X-ray diffraction analysis of ammo-
nium nitronate and ammonium amide to gain insight into
the structure of intermediate and succeeded in obtaining
single-crystal X-ray structures of ammonium nitronate (S)-
1 f and ammonium amide (S)-1g (Figure 2).[21] Very impor-
Figure 1. X-ray crystal structure of (S)-1c and plausible structure of
ammonium enolate intermediate. Ellipsoids were drawn at the 50%
probability level.
shields the lower face of the enolate, which allows the nitro-
olefin to approach from the upper face and leads to conju-
gate adduct 2 with the observed absolute configuration.[17]
Other Asymmetric Reactions under Base-Free Neutral
Phase-Transfer Conditions
This attractive base-free neutral phase-transfer reaction
system was applied to other asymmetric conjugate additions
by using carbon and heteroatom nucleophiles (Scheme 10).
Highly enantioselective conjugate additions[18] were ach-
ieved by using bifunctional phase-transfer catalysts of type
Figure 2. X-ray crystal structures of ammonium nitronate (S)-1 f and am-
monium amide (S)-1g.
tantly, the hydrogen-bonding interactions between the hy-
droxy group in the binaphthyl unit and the anionic oxygen
are clearly observed in the crystal structures. These X-ray
structures of (S)-1 f and (S)-1g strongly support the plausi-
ble structure of the ammonium enolate intermediate in
Figure 1.
Conclusion
In summary, a mechanism for the novel base-free neutral
phase-transfer reaction system based on some interesting
observations was presented in this study. The aqueous–or-
ganic biphasic reaction system with lipophilic tetraalkylam-
monium bromide was essential to promote neutral phase-
transfer reactions. The base-free neutral phase-transfer reac-
tion system could be applied to several asymmetric reactions
under the influence of chiral bifunctional tetraalkylammoni-
Scheme 10. Asymmetric reactions under base-free neutral phase-transfer
conditions.
&
&
6
Chem. Asian J. 2014, 00, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Keiji Maruoka et al.
naga, M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 9168; c) X. Li, B.
Zhang, Z.-G. Xi, S. Luo, J.-P. Cheng, Adv. Synth. Catal. 2010, 352,
416; d) M. Ding, F. Zhou, Z.-Q. Qian, J. Zhou, Org. Biomol. Chem.
2010, 8, 2912; e) X.-L. Liu, Z.-J. Wu, X.-L. Du, X.-M. Zhang, W.-C.
Yuan, J. Org. Chem. 2011, 76, 4008; f) Y.-Y. Han, Z.-J. Wu, W.-B.
Chen, X.-L. Du, X.-M. Zhang, W.-C. Yuan, Org. Lett. 2011, 13,
5064; g) M. Ding, F. Zhou, Y.-L. Liu, C.-H. Wang, X.-L. Zhao, J.
Zhou, Chem. Sci. 2011, 2, 2035; h) C. Wang, X. Yang, D. Enders,
Chem. Eur. J. 2012, 18, 4832.
um bromides. The role of hydroxy groups in the bifunctional
catalysts was clearly shown based on the single-crystal X-ray
structures of ammonium salts. Further application of the
base-free neutral phase-transfer reaction system to other
asymmetric reactions by using a chiral bifunctional ammoni-
um salt is currently underway in our group.
[6] a) M. Kitamura, S. Shirakawa, K. Maruoka, Angew. Chem. Int. Ed.
2005, 44, 1549; Angew. Chem. 2005, 117, 1573; b) M. Kitamura, Y.
Arimura, S. Shirakawa, K. Maruoka, Tetrahedron Lett. 2008, 49,
2026; c) M. Kitamura, S. Shirakawa, Y. Arimura, X. Wang, K. Mar-
uoka, Chem. Asian J. 2008, 3, 1702.
Experimental Section
Typical Procedure for Enantioselective Conjugate Addition of 3-
Aryloxindoles to Nitroolefins
[7] a) S. Colonna, R. Fornasier, J. Chem. Soc. Perkin Trans. 1 1978, 371;
b) S. Juliꢃ, A. Ginebreda, J. Guixer, A. Tomꢃs, Tetrahedron Lett.
1980, 21, 3709; c) U.-H. Dolling, P. Davis, E. J. J. Grabowski, J. Am.
Chem. Soc. 1984, 106, 446; d) M. Masui, A. Ando, T. Shioiri, Tetra-
hedron Lett. 1988, 29, 2835; e) M. J. OꢂDonnell, W. D. Bennett, S.
Wu, J. Am. Chem. Soc. 1989, 111, 2353; f) B. Lygo, P. G. Wainwright,
Tetrahedron Lett. 1997, 38, 8595; g) E. J. Corey, F. Xu, M. C. Noe, J.
Am. Chem. Soc. 1997, 119, 12414.
Water (2.0 mL) was added to
(0.050 mmol), trans-b-nitrostyrene
a
mixture of 3-phenyloxindole
(0.060 mmol), and (S)-1a
(0.00050 mmol, 1 mol%) in toluene (0.20 mL) at 08C, and the mixture
was vigorously stirred at 08C for 2 h. The resulting mixture was diluted
with water (3.0 mL) and extracted with Et2O (5.0 mLꢁ3). The combined
organic extracts were dried over Na2SO4 and concentrated. Purification
of the residue by using column chromatography on silica gel (neutral)
with hexane/EtOAc (10:1) as the eluent gave 2a. The diastereomeric and
enantiomeric ratios of the product were determined by using chiral
HPLC analysis.
[8] For a review of chiral bifunctional quaternary ammonium salts, see:
J. Novacek, M. Waser, Eur. J. Org. Chem. 2013, 637.
[9] For examples of chiral bifunctional phase-transfer catalysts possess-
ing hydroxy groups, see: a) A. Loupy, A. Zaparucha, Tetrahedron
Lett. 1993, 34, 473; b) T. Ooi, D. Ohara, M. Tamura, K. Maruoka, J.
Am. Chem. Soc. 2004, 126, 6844; c) X. Wang, Q. Lan, S. Shirakawa,
K. Maruoka, Chem. Commun. 2010, 46, 321; d) B. A. Provencher,
K. J. Bartelson, Y. Liu, B. M. Foxman, L. Deng, Angew. Chem. Int.
Ed. 2011, 50, 10565; Angew. Chem. 2011, 123, 10753; e) E. Yamamo-
to, D. Gokuden, A. Nagai, T. Kamachi, K. Yoshizawa, A. Hamasaki,
T. Ishida, M. Tokunaga, Org. Lett. 2012, 14, 6178; f) Y. Liu, S. Shira-
kawa, K. Maruoka, Org. Lett. 2013, 15, 1230; g) H. Kawai, Z. Yuan,
T. Kitayama, E. Tokunaga, N. Shibata, Angew. Chem. Int. Ed. 2013,
52, 5575; Angew. Chem. 2013, 125, 5685.
[10] For reviews on organic reactions in aqueous media, see: a) C.-J. Li,
T.-H. Chan, Organic Reactions in Aqueous Media, Wiley, New York,
1997; b) P. A. Grieco, Organic Synthesis in Water, Blackie Academic
and Professional, London, 1998; c) S. Kobayashi, K. Manabe, Acc.
Chem. Res. 2002, 35, 209; d) S. Otto, J. B. F. Engberts, Org. Biomol.
Chem. 2003, 1, 2809; e) C. J. Li, Chem. Rev. 2005, 105, 3095; f) U. M.
Lindstrçm, F. Andersson, Angew. Chem. Int. Ed. 2006, 45, 548;
Angew. Chem. 2006, 118, 562.
[11] a) T. Ito, H. Radecka, K. Tohda, K. Odashima, Y. Umezawa, J. Am.
Chem. Soc. 1998, 120, 3049; see also: b) P. Mukerjee, K. Banerjee, J.
Phys. Chem. 1964, 68, 3567.
[12] F. G. Bordwell, R. J. McCallum, W. N. Olmstead, J. Org. Chem.
1984, 49, 1424.
[13] F. G. Bordwell, H. E. Fried, J. Org. Chem. 1991, 56, 4218.
[14] Although we have tried to check the pH of the water phase, the
measurement is difficult with the ordinary methods because only
catalytic amounts of HBr are generated for this reaction and vigo-
rous stirring of the H2O/toluene biphasic solvent is required for effi-
cient release of HBr to the aqueous phase.
[15] F. G. Bordwell, D. L. Hughes, J. Org. Chem. 1982, 47, 3224.
[16] CCDC-875850 ((S)-1c) 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.a-
c.uk/data_request/cif.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific Re-
search from JSPS and MEXT (Japan). We are grateful to Dr. Hiroyasu
Sato (Rigaku Corporation) for X-ray crystallographic analysis.
[1] For reviews on phase-transfer catalysis, see: a) E. V. Dehmlow, S. S.
Dehmlow, Phase Transfer Catalysis, 3rd ed., VCH, Weinheim, 1993;
b) C. M. Starks, C. L. Liotta, M. Halpern, Phase-Transfer Catalysis,
Chapman&Hall, New York, 1994; c) Handbook of Phase-Transfer
Catalysis (Eds.: Y. Sasson, R. Neumann), Blackie Academic&Pro-
fessional, London, 1997; d) Phase-Transfer Catalysis (ACS Symposi-
um Series 659) (Ed.: M. E. Halpern), American Chemical Society,
Washington DC, 1997.
[2] For recent reviews on asymmetric phase-transfer catalysis, see:
a) M. J. OꢂDonnell, Aldrichimica Acta 2001, 34, 3; b) K. Maruoka,
T. Ooi, Chem. Rev. 2003, 103, 3013; c) M. J. OꢂDonnell, Acc. Chem.
Res. 2004, 37, 506; d) B. Lygo, B. I. Andrews, Acc. Chem. Res. 2004,
37, 518; e) J. Vachon, J. Lacour, Chimia 2006, 60, 266; f) T. Ooi, K.
Maruoka, Angew. Chem. Int. Ed. 2007, 46, 4222; Angew. Chem.
2007, 119, 4300; g) T. Ooi, K. Maruoka, Aldrichimica Acta 2007, 40,
77; h) T. Hashimoto, K. Maruoka, Chem. Rev. 2007, 107, 5656; i) K.
Maruoka, Org. Process Res. Dev. 2008, 12, 679; j) S.-s. Jew, H.-g.
Park, Chem. Commun. 2009, 7090; k) K. Maruoka, Chem. Rec. 2010,
10, 254; l) S. Shirakawa, K. Maruoka, Angew. Chem. Int. Ed. 2013,
52, 4312; Angew. Chem. 2013, 125, 4408.
[3] For reviews on atom economy, see: a) B. M. Trost, Science 1991, 254,
1471; b) B. M. Trost, Angew. Chem. Int. Ed. Engl. 1995, 34, 259;
Angew. Chem. 1995, 107, 285; c) P. Anastas, N. Eghbali, Chem. Soc.
Rev. 2010, 39, 301.
[4] a) R. He, S. Shirakawa, K. Maruoka, J. Am. Chem. Soc. 2009, 131,
16620; b) L. Wang, S. Shirakawa, K. Maruoka, Angew. Chem. Int.
Ed. 2011, 50, 5327; Angew. Chem. 2011, 123, 5439; c) S. Shirakawa,
S. J. Terao, R. He, K. Maruoka, Chem. Commun. 2011, 47, 10557;
d) S. Shirakawa, K. Ota, S. J. Terao, K. Maruoka, Org. Biomol.
Chem. 2012, 10, 5753; e) S. Shirakawa, A. Kasai, T. Tokuda, K. Mar-
uoka, Chem. Sci. 2013, 4, 2248; f) S. Shirakawa, T. Tokuda, A. Kasai,
K. Maruoka, Org. Lett. 2013, 15, 3350; see also, g) S. Shirakawa, L.
Wang, A. Kasai, K. Maruoka, Chem. Eur. J. 2012, 18, 8588.
[17] For the stereochemical determination of 2, see the Supporting Infor-
mation.
[18] For representative reviews on asymmetric conjugate addition, see:
a) B. E. Rossiter, N. M. Swingle, Chem. Rev. 1992, 92, 771; b) J. Leo-
nard, E. Dꢄez-Barra, S. Merino, Eur. J. Org. Chem. 1998, 2051; c) L.-
W. Xu, C.-G. Xia, Eur. J. Org. Chem. 2005, 633; d) S. B. Tsogoeva,
Eur. J. Org. Chem. 2007, 1701; e) D. Almas¸i, D. A. Alonso, C.
Nꢃjera, Tetrahedron: Asymmetry 2007, 18, 299; f) P. R. Krishna, A.
Sreeshailam, R. Srinivas, Tetrahedron 2009, 65, 9657; g) D. Enders,
[5] a) T. Bui, S. Syed, C. F. Barbas III, J. Am. Chem. Soc. 2009, 131,
8758; b) Y. Kato, M. Furutachi, Z. Chen, H. Mitsunuma, S. Matsu-
7
&
&
Chem. Asian J. 2014, 00, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Keiji Maruoka et al.
C. Wang, J. X. Liebich, Chem. Eur. J. 2009, 15, 11058; h) Y. Zhang,
W. Wang, Catal. Sci. Technol. 2012, 2, 42.
[20] C. B. Ji, Y.-L. Liu, Z.-Y. Cao, Y.-Y. Zhang, J. Zhou, Tetrahedron
Lett. 2011, 52, 6118.
[19] For representative reviews on the enantioselective direct aldol reac-
tion, see: a) B. Alcaide, P. Almendros, Eur. J. Org. Chem. 2002,
1595; b) M. Shibasaki, S. Matsunaga, N. Kumagai in Modern Aldol
Reactions, Vol. 2 (Ed.: R. Mahrwald), Wiley-VCH, Weinheim, 2004,
Chap. 6, p. 197; c) W. Notz, F. Tanaka, C. F. Barbas III, Acc. Chem.
Res. 2004, 37, 580; d) S. Mukherjee, J. W. Yang, S. Hoffmann, B.
List, Chem. Rev. 2007, 107, 5471; e) B. M. Trost, C. S. Brindle, Chem.
Soc. Rev. 2010, 39, 1600.
[21] The crystal structures of (S)-1 f and (S)-1g have been deposited at
the Cambridge Crystallographic Data Centre: CCDC-805745 ((S)-
1 f) and -792748 ((S)-1g) contain 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.a-
c.uk/data_request/cif.
Received: March 6, 2014
Published online: && &&, 0000
&
&
8
Chem. Asian J. 2014, 00, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

FULL PAPER
Phase-Transfer Catalysis
Seiji Shirakawa, Lijia Wang,
Rongjun He, Satoru Arimitsu,
Keiji Maruoka*
&&&& — &&&&
A Base-Free Neutral Phase-Transfer
Reaction System
In and out of phase: The mechanism
of a novel base-free neutral phase-
transfer reaction system was investi-
gated (see scheme). The aqueous–
organic biphasic reaction system with
lipophilic tetraalkylammonium bro-
mide was essential to promote the neu-
tral phase-transfer reactions. The base-
free reaction system could be applied
to several asymmetric reactions.
9
&
&
Chem. Asian J. 2014, 00, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ