Phase-transfer-catalyzed asymmetric synthesis of axially chiral anilides

Article abstract of DOI:10.1002/asia.201301036

Catalytic asymmetric synthesis of axially chiral o-iodoanilides and o-tert-butylanilides as useful chiral building blocks was achieved by means of binaphthyl-modified chiral quaternary ammonium-salt-catalyzed N-alkylations under phase-transfer conditions. The synthetic utility of axially chiral products was demonstrated in various transformations. For example, axially chiral N-allyl-o-iodoanilide was transformed to 3-methylindoline by means of radical cyclization with high chirality transfer from axial chirality to C-centered chirality. Furthermore, stereochemical information on axial chirality in o-tert-butylanilides could be used as a template to control the stereochemistry of subsequent transformations. The transition-state structure of the present phase-transfer reaction was discussed on the basis of the X-ray crystal structure of ammonium anilide, which was prepared from binaphthyl-modified chiral ammonium bromide and o-iodoanilide. The chiral tetraalkylammonium bromide as a phase-transfer catalyst recognized the steric difference between the ortho substituents on anilide to obtain high enantioselectivity. The size and structural effects of the ortho substituents on anilide were investigated, and a wide variety of axially chiral anilides that possess various functional groups could be synthesized with high enantioselectivities. This method is the only general way to access a variety of axially chiral anilides in a highly enantioselective fashion reported to date. Copyright

Full text of DOI:10.1002/asia.201301036

FULL PAPER
DOI: 10.1002/asia.201301036
Phase-Transfer-Catalyzed Asymmetric Synthesis of Axially Chiral Anilides
Kun Liu, Xiangfei Wu, S. B. Jennifer Kan, Seiji Shirakawa, and Keiji Maruoka*[a]
Abstract: Catalytic asymmetric synthe-
sis of axially chiral o-iodoanilides and
o-tert-butylanilides as useful chiral
building blocks was achieved by means
of binaphthyl-modified chiral quaterna-
ry ammonium-salt-catalyzed N-alkyla-
tions under phase-transfer conditions.
The synthetic utility of axially chiral
products was demonstrated in various
transformations. For example, axially
chiral N-allyl-o-iodoanilide was trans-
formed to 3-methylindoline by means
of radical cyclization with high chirality
transfer from axial chirality to C-cen-
tered chirality. Furthermore, stereo-
chemical information on axial chirality
in o-tert-butylanilides could be used as
a template to control the stereochemis-
try of subsequent transformations. The
transition-state structure of the present
phase-transfer reaction was discussed
on the basis of the X-ray crystal struc-
ture of ammonium anilide, which was
prepared from binaphthyl-modified
chiral ammonium bromide and o-io-
doanilide. The chiral tetraalkylammoni-
um bromide as a phase-transfer cata-
lyst recognized the steric difference be-
tween the ortho substituents on anilide
to obtain high enantioselectivity. The
size and structural effects of the ortho
substituents on anilide were investigat-
ed, and a wide variety of axially chiral
anilides that possess various functional
groups could be synthesized with high
enantioselectivities. This method is the
only general way to access a variety of
axially chiral anilides in a highly enan-
tioselective fashion reported to date.
Keywords: alkylation
· anilides ·
asymmetric synthesis
·
phase-
transfer
methods
catalysis
·
synthetic
Introduction
The importance of axially chiral compounds, such as biaryl
compounds, has been widely recognized in the chemical
community, and these compounds are indispensable for the
asymmetric synthesis of important chiral compounds.[1]
Among axially chiral compounds, axially chiral anilides have
received much attention in recent years as attractive atropi-
[2]
À
someric compounds that possess an N Ar chiral axis. In-
teresting properties and utility of axially chiral anilides have
been found not only in the research field of organic chemis-
try but also in biological chemistry,[3] and the structure of
ACHTUNGTRENNUNGaxially chiral anilides is actually observed in biologically
Figure 1. Axially chiral anilides.
active compounds such as metolachlor and methaqualone
(Figure 1).[4] The synthetic utility of axially chiral o-iodoani-
lides (1 and 2)[5] and o-tert-butylanilides (3)[6] as useful chiral
building blocks has also been reported in the field of organic
chemistry. However, efficient methods for the enantioselec-
tive synthesis of these axially chiral anilides are still very
limited,[7] and hence the development of catalytic asymmet-
ric methods for the synthesis of these anilides is an impor-
tant task for organic chemists. In this context, we have been
interested in the development of the catalytic asymmetric
synthesis of axially chiral anilides by means of phase-trans-
fer-catalyzed N-alkylations (Scheme 1).[8,9] Although several
examples of catalytic asymmetric methods for the synthesis
of axially chiral anilides have been reported, the structure of
the products is mainly limited to o-tert-butylanilides 3 that
possess a bulky tert-butyl group to obtain high enantioselec-
tivities.[10–12] Herein we report a valuable method for the cat-
alytic asymmetric synthesis of axially chiral anilides that
possess various functionalities, with insight into the transi-
tion-state structure for the present reaction on the basis of
the X-ray crystal structure of ammonium anilide. This cata-
lytic asymmetric method is the only general way to access
a variety of axially chiral anilides in a highly enantioselec-
tive fashion reported to date.
[a] Dr. K. Liu, X. Wu, Dr. S. B. J. Kan, Dr. S. Shirakawa,
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/asia.201301036.
1
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Keiji Maruoka et al.
Table 1. Optimization of the reaction conditions.[a]
Scheme 1. Catalytic asymmetric synthesis of axially chiral anilides by
phase-transfer-catalyzed alkylations.
Results and Discussion
Asymmetric Synthesis of Axially Chiral o-Iodoanilides
We were initially interested in the development of the cata-
lytic asymmetric synthesis of o-iodoacrylanilides 1 and N-
allyl-o-iodoanilides 2 (Figure 1).[12] Although the synthetic
utility of axially chiral o-iodoanilides 1 and 2 has been dem-
onstrated by Curran et al. in the chemistry of memory of
axial chirality,[13] either optical resolution or a stoichiometric
amount of chiral reagent is required to obtain these optical-
ly active anilides.[5] For this reason, the development of cata-
lytic asymmetric methods for the synthesis of o-iodoanilides
is highly desirable.
We first examined the asymmetric benzylation of o-iodoc-
rotonoylanilide 4a under the influence of chiral phase-trans-
fer catalysts of type (S)-5 as promising catalysts for asym-
metric alkylations (Table 1).[14] The reaction of 4a and
benzyl bromide with solid KOH in diisopropyl ether[15] cata-
lyzed by (S)-5a or 5b (2 mol%) at 08C for 24 h afforded
product 1a in high yields with moderate enantioselectivities
(34–52% ee; Table 1, entries 1 and 2). Switching the 3,3’-aro-
matic substituents (Ar) of the catalyst to radially extended
substituents ((S)-5c and 5d) resulted in improved enantiose-
lectivity (82–83% ee; Table 1, entries 3 and 4). The effect of
alkyl chain length (R) in catalyst (S)-5 was carefully exam-
ined (Table 1, entries 4–8), and the catalyst (S)-5 f, which
possessed hexyl groups, gave the highest enantioselectivity
(89% ee; Table 1, entry 6). The use of toluene and carbon
tetrachloride as solvent resulted in a slight decrease in enan-
tioselectivity (Table 1, entries 9 and 10); and other ethereal
solvents, such as diethyl ether, cyclopentyl methyl ether
(CPME), and tert-butyl methyl ether did not improve the
enantioselectivity (Table 1, entries 11–13). Conducting the
reaction at a lower temperature slightly increased the enan-
Entry
Catalyst
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
(S)-5a
(S)-5b
(S)-5c
(S)-5d
(S)-5e
(S)-5 f
(S)-5g
(S)-5h
(S)-5 f
(S)-5 f
(S)-5 f
(S)-5 f
(S)-5 f
(S)-5 f
iPr2O
iPr2O
iPr2O
iPr2O
iPr2O
iPr2O
iPr2O
iPr2O
toluene
CCl4
86
90
77
82
97
85
83
98
72
85
83
78
89
83
52
34
82
83
88
89
87
85
82
73
83
83
70
90
9
10
11
12
13
14[e]
Et2O
CPME[d]
tBuOMe
iPr2O
[a] Reaction conditions: 4a (0.050 mmol), benzyl bromide (0.060 mmol),
and solid KOH powder (0.10 mmol) in the presence of (S)-5 (2 mol%) in
solvent (1.0 mL) at 08C for 24 h. [b] Yield of isolated product. [c] Deter-
mined by chiral HPLC analysis. [d] CPME=cyclopentyl methyl ether.
[e] Reaction was performed at À208C.
tioselectivity, and the highest enantioselectivity was attained
at À208C when the reaction was carried out in diisopropyl
ether using (S)-5 f as catalyst (90% ee; Table 1, entry 14).
With optimal reaction conditions in hand, we further stud-
ied the generality of the asymmetric synthesis of axially
chiral o-iodoacrylanilides 1 by phase-transfer alkylation of
o-iodoacrylanilides 4 catalyzed by (S)-5 f (Scheme 2). Vari-
ous types of o-iodoacrylanilides 4 were found to be employ-
able for the reaction to give axially chiral anilides 1a–d in
good to high enantioselectivities (80–96% ee). Furthermore,
a series of alkyl halides with different steric and electronic
properties were tolerated in this reaction, thus allowing the
preparation of structurally diverse, enantioenriched axially
chiral o-iodoacrylanilides (1e–i, 80–92% ee). The introduc-
tion of different substituents at the ortho and para positions
(X and Y) of anilide 4 also worked well to give products 1j–
n in high enantioselectivities (92–95% ee). The absolute
configuration of axially chiral anilides 1 was determined by
X-ray diffraction analysis of 1a.[16,17]
Abstract in Japanese:
To further expand the utility of this synthetic method, we
were also interested in the asymmetric synthesis of N-allyl-
o-iodoanilides 2 by the asymmetric allylation of o-iodoani-
lides 6 (Scheme 3). Not only allyl bromide but also methallyl
&
&
2
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Keiji Maruoka et al.
Scheme 3. Asymmetric synthesis of axially chiral N-allyl-o-iodoanilides 2.
Table 2. Screening of chiral phase-transfer catalysts.[a]
Entry
Catalyst
Yield [%][b]
ee [%][c]
Scheme 2. Asymmetric synthesis of axially chiral o-iodoacrylanilides 1.
1
2
3
4
(S)-5c
(S)-5d
(S)-5 f
(S)-8a
(S)-8b
(S)-8b
73
89
98
90
80
97
62
70
76
69
90
95
bromide and crotyl bromide were employable for this reac-
tion to give axially chiral anilides 2a–e in high enantioselec-
tivities (88–90% ee). The allyl bromide that possesses a func-
tional group was also employable for the reaction (2 f,
93% ee). The absolute configuration of axially chiral ani-
lides 2 was confirmed by comparison of the optical rotation
of products 2a and 2b with the literature value.[5b]
5
6[d]
[a] Reaction conditions: 7a (0.050 mmol), benzyl bromide (0.060 mmol),
and solid KOH powder (0.10 mmol) in the presence of catalyst (S)-5 or 8
(2 mol%) in iPr2O (1.0 mL) at 08C for 24 h. [b] Yield of isolated product.
[c] Determined by chiral HPLC analysis. [d] Reaction was performed at
À208C.
(S)-5, which were effective for the alkylation of o-iodoani-
lides, afforded benzylation product 3a with moderate enan-
tioselectivities (62–76% ee; Table 2, entries 1–3). Although
switching the catalyst to (S)-8a, which possesses a morpho-
line skeleton, did not improve the enantioselectivity
(Table 2, entry 4), the use of piperidine-derived catalyst (S)-
8b proved to be effective (90% ee; Table 2, entry 5).[18] The
Asymmetric Synthesis of Axially Chiral o-tert-Butylanilides
Next, we were interested in the catalytic asymmetric synthe-
sis of axially chiral o-tert-butylanilides 3 as useful chiral
building blocks for organic synthesis (Table 2).[6] Attempted
reactions of o-tert-butylanilide 7a with benzyl bromide
under the influence of chiral phase-transfer catalysts of type
3
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Keiji Maruoka et al.
highest enantioselectivity was attained when the reaction
was conducted at À208C with catalyst (S)-8b (95% ee;
Table 2, entry 6).
With the optimal catalyst in hand, we studied the sub-
strate generality of asymmetric alkylation of o-tert-butylani-
lides 7 under the influence of chiral phase-transfer catalyst
(S)-8b (Scheme 4). Various types of o-tert-butylanilides 7
Scheme 5. Transformation of axially chiral o-iodoanilides.
Transformations of Axially Chiral Anilides
The synthetic utility of axially chiral anilides was demon-
strated in various transformations of the products
(Schemes 5 and 6). For example, o-iodoanilide 1a was trans-
formed into axially chiral phosphine oxide 9, which is an at-
Scheme 6. Transformation of axially chiral o-tert-butylanilides.
Scheme 4. Asymmetric synthesis of axially chiral o-tert-butylanilides 3.
and alkyl halides were found to be employable for this reac-
tion to give axially chiral anilides 3a–l in good to high enan-
tioselectivities (82–95% ee). The introduction of substituents
at the meta and para positions (X) of anilide 7 also works
well to give high enantioselectivities (3m and 3n, 85–
93% ee). The absolute configuration of axially chiral ani-
lides 3 was confirmed by comparison of the optical rotation
of products 3i, 3j, and 3k with the literature value.[7b,10a,b]
tractive precursor for the design of novel chiral ligands and
catalysts,[19] without any loss of stereoinformation
(Scheme 5).[5g] Furthermore, axially chiral N-allyl-o-iodoani-
lide 2c was transformed into 3-methyl indoline 10 by means
of radical cyclization with excellent axial to C-centered chir-
ality transfer (Scheme 5).[5b]
The stereochemical information of axial chirality in o-tert-
butylanilides 3 can be used as a template to control the ste-
&
&
4
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Keiji Maruoka et al.
reochemistry of subsequent transformations. For example,
stereoselective cycloadditions of o-tert-butylanilide 3d with
nitrile oxides, which were generated in situ from the corre-
sponding hydroximoyl chloride, provided isoxazolines (11a
and 11b) as biologically interesting heterocycles[20] in high
stereoselectivities (Scheme 6).[6a,b,21] The configuration of
isoxazolines 11 was determined by X-ray diffraction analysis
of 11a.[22]
The conjugate addition and alkylation of o-tert-butylani-
lide 3 f were also examined in the presence of potassium
tert-butoxide, and the corresponding conjugate adduct 12
and alkylation product 13 were obtained with high stereose-
lectivities (Scheme 6).[6c,10c] The absolute configuration of
product 13 was confirmed after removal of the aniline
moiety by reduction to produce alcohol 14, which is
a known compound.[23]
the basis of the X-ray crystal structure of (S)-5i, plausible
transition-state models (A and B) are proposed to account
for the absolute configuration of products
1 and 2
(Figure 2). Transition-state A might be more favorable than
B to avoid steric repulsion between the aryl group (Ar) on
(S)-5 and the iodide on anilide. The binaphthyl unit of cata-
lyst (S)-5 completely shielded the backside of the anilide
anion, thereby allowing an alkyl halide to approach from
the front in transition-state A and leading to products 1 and
2 with the observed absolute configurations. This explana-
tion of the steric repulsion between the aryl group (Ar) on
catalyst (S)-5 and the iodide on anilide to obtain high enan-
tioselectivities is supported by results shown in Table 1,
wherein catalysts (S)-5, which possess radially extended
bulky aromatic substituents (5c and 5d), gave higher enan-
tioselectivities than catalyst (S)-5a and 5b (entries 3,4
versus 1,2 in Table 1).
The discussion on transition-state structure in Figure 2 in-
dicates that the catalyst (S)-5 recognizes the steric difference
between the iodide and methyl groups as ortho substituents
on anilide. On the basis of this hypothesis, the size effect of
ortho substituents on o-iodoanilide was investigated by in-
troducing different halogens to the ortho-position (X) of o-
iodoanilide 4 (Scheme 7). In this scenario, a clear trend was
observed, wherein smaller halogen-substituted o-iodoanilide
4 afforded benzylation product 1 in better enantioselectivi-
ties (F (1o, 80% ee)[25] >Cl (1p, 58% ee)>Br (1q,
31% ee)). A similar size effect of the ortho substituent was
observed when methoxy- and methylthio-group-substituted
Transition-State Model and Effect of ortho-Substituents on
Anilide
To obtain insight into the transition-state structure of the
present enantioselective N-alkylations of o-iodoanilides, we
carried out X-ray diffraction analysis of ammonium anilides
prepared from chiral ammonium bromides (S)-5 and o-io-
doanilides 6. Several kinds of ammonium anilides were pre-
pared to obtain crystals suitable for X-ray diffraction analy-
sis, and finally we succeeded in obtaining a single-crystal X-
ray structure of (S)-5i,[24] which was prepared from an am-
monium bromide (S)-5a and o-iodoanilide 6 (R1 =Ph). The
crystal structure of (S)-5i provides important structural in-
À
formation. The bond lengths of the amide moiety (O C:
À
1.348 ꢁ, N C: 1.351 ꢁ) indicate that the negative charge of
the anilide anion is delocalized as shown in Figure 2.[17] On
Figure 2. X-ray crystal structure of (S)-5i and plausible transition-state
models.
Scheme 7. Size effect of ortho substituents.
5
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Keiji Maruoka et al.
o-iodoanilides were used in the reaction (OMe (1m,
92% ee)>SMe (1r, 59% ee)). These results suggest that the
bromo group also behaves as a large substituent, similar to
an iodide substituent, in the present reaction. Actually, the
benzylation of o-bromoanilide 15a gave axially chiral prod-
uct 16a in high enantioselectivity (95% ee).
The effect of the ortho substituent was further examined
by introducing various functional groups to anilide 15
(Scheme 8). Although the ethyl group as a C2 unit worked
Scheme 9. Summary of the effect of ortho substituents.
Conclusion
In summary, we have successfully developed a method for
the catalytic asymmetric synthesis of axially chiral o-iodoa-
nilides and o-tert-butylanilides by phase-transfer-catalyzed
N-alkylations. The synthetic utility of these axially chiral
anilides was demonstrated in various transformations of the
products. The transition-state structure of the present reac-
tion has been discussed on the basis of the X-ray crystal
structure of ammonium anilide. The key to obtaining high
enantioselectivity relies on the ability of the chiral tetraalky-
lammonium bromide as a phase-transfer catalyst to recog-
nize the steric difference between the ortho substituents on
anilide. The size and structural effects of the ortho substitu-
ents on anilide were also investigated, and a wide variety of
axially chiral anilides that possess various functional groups
could be synthesized with high enantioselectivities. This
method is the only general way to access a variety of axially
chiral anilides in a highly enantioselective fashion reported
to date.
Scheme 8. Structural effect of ortho substituents.
Experimental Section
as a small substituent (1n and 16b) in the present reaction,
an acetylene group as another C2 unit behaved as a large
substituent to give axially chiral product 16c in good enan-
tioselectivity (83% ee). These results indicate that the shape
of substituent is also important in the steric recognition by
catalyst (S)-5. On the basis of the structural effect of the
acetylene-substituted anilide, the effect of the cyano group,
which possesses a similar straight structure, was also exam-
ined, and axially chiral anilide 16d was obtained in high
enantioselectivity (93% ee).[25] The ester group also worked
as a large substituent to give axially chiral anilide 16e in
high enantioselectivity (93% ee). The effect of ortho sub-
stituents on anilide is summarized in Scheme 9.
General Procedure for Asymmetric Alkylation of Anilides
Alkyl halide (1.2–3 equiv) was added to a mixture of anilide 4, 6, 7, or 15
(0.050 mmol), catalyst (S)-5 f or 8b (2 mol%), and KOH (2–20 equiv) in
diisopropyl ether[15] (1.0 mL) at the reaction temperature (À408C–08C)
under an argon atmosphere. The reaction mixture was vigorously stirred
for 5–96 h at À408C–08C. The progress of the reaction was monitored by
TLC. The reaction mixture was quenched with saturated aqueous NH4Cl
and extracted with ethyl acetate (3ꢂ5 mL). The combined extracts were
dried over Na2SO4 and concentrated. The residue was purified by column
chromatography or preparative thin-layer chromatography on silica gel
to give the alkylation product.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific Re-
search from the JSPS and MEXT (Japan). We are grateful to Dr. Hiroya-
su Sato (Rigaku Corporation) for X-ray crystallographic analysis. S.B.J.K.
&
&
6
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Keiji Maruoka et al.
thanks the JSPS for a postdoctoral fellowship. X.W. thanks the China
Scholarship Council for a research fellowship.
[7] a) O. Kitagawa, H. Izawa, K. Sato, A. Dobashi, T. Taguchi, J. Org.
Chem. 1998, 63, 2634; b) O. Kitagawa, S.-i. Momose, Y. Fushimi, T.
Taguchi, Tetrahedron Lett. 1999, 40, 8827; c) A. Ates, D. P. Curran, J.
Am. Chem. Soc. 2001, 123, 5130; d) H. Koide, T. Hata, M. Uemura,
J. Org. Chem. 2002, 67, 1929.
[1] For reviews on axially chiral compounds, see: a) C. Rosini, L. Fran-
zini, A. Raffaelli, P. Salvadori, Synthesis 1992, 503; b) J. Clayden,
Angew. Chem. 1997, 109, 986; Angew. Chem. Int. Ed. Engl. 1997, 36,
949; c) G. Bringmann, A. J. P. Mortimer, P. A. Keller, M. J. Gresser,
J. Garner, M. Breuning, Angew. Chem. 2005, 117, 5518; Angew.
Chem. Int. Ed. 2005, 44, 5384; d) Y.-M. Li, F.-Y. Kwong, W.-Y. Yu,
A. S. C. Chan, Coord. Chem. Rev. 2007, 251, 2119; e) M. Ogasawara,
Tetrahedron: Asymmetry 2009, 20, 259; f) J. Clayden, W. J. Moran,
P. J. Edwards, S. R. LaPlante, Angew. Chem. 2009, 121, 6516; Angew.
Chem. Int. Ed. 2009, 48, 6398; g) G. Bringmann, T. Gulder, T. A. M.
Gulder, M. Breuning, Chem. Rev. 2011, 111, 563.
[8] For recent reviews on asymmetric phase-transfer catalysis, see:
a) M. J. OꢅDonnell, Aldrichimica Acta 2001, 34, 3; b) K. Maruoka,
T. Ooi, Chem. Rev. 2003, 103, 3013; c) M. J. O’Donnell, 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. 2007, 119, 4300; Angew. Chem. Int. Ed.
2007, 46, 4222; 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. 2013, 125,
4408; Angew. Chem. Int. Ed. 2013, 52, 4312.
[9] Phase-transfer-catalyzed asymmetric N-alkylation using alkyl halides
with modest enantioselectivities: a) S. Juliµ, A. Ginebreda, J.
Guixer, J. Chem. Soc. Chem. Commun. 1978, 742; b) S. Juliµ, A. Gi-
nebreda, J. Guixer, J. Masana, A. Tomµs, S. Colonna, J. Chem. Soc.
Perkin Trans. 1 1979, 574; c) S. Juliµ, A. Ginebreda, J. Guixer, A.
Tomµs, Tetrahedron Lett. 1980, 21, 3709; d) K. Tomooka, K. Uehara,
R. Nishikawa, M. Suzuki, K. Igawa, J. Am. Chem. Soc. 2010, 132,
9232.
[10] a) O. Kitagawa, M. Kohriyama, T. Taguchi, J. Org. Chem. 2002, 67,
8682; b) J. Terauchi, D. P. Curran, Tetrahedron: Asymmetry 2003, 14,
587; c) O. Kitagawa, M. Yoshikawa, H. Tanabe, T. Morita, M. Taka-
hashi, Y. Dobashi, T. Taguchi, J. Am. Chem. Soc. 2006, 128, 12923;
d) W.-L. Duan, Y. Imazaki, R. Shintani, T. Hayashi, Tetrahedron
2007, 63, 8529; e) S. Lin, D. Leow, K.-W. Huang, C.-H. Tan, Chem.
Asian J. 2009, 4, 1741; f) J. Clayden, H. Turner, Tetrahedron Lett.
2009, 50, 3216; g) H. Liu, W. Feng, C. W. Kee, D. Leow, W.-T. Loh,
C.-H. Tan, Adv. Synth. Catal. 2010, 352, 3373.
[11] a) K. Tanaka, K. Takeishi, K. Noguchi, J. Am. Chem. Soc. 2006, 128,
4586; b) S. Brandes, B. Niess, M. Bella, A. Prieto, J. Overgaard,
K. A. Jørgensen, Chem. Eur. J. 2006, 12, 6039; c) K. Tanaka, Y. Ta-
kahashi, T. Suda, M. Hirano, Synlett 2008, 1724; d) J. Oppenheimer,
W. L. Johnson, R. Figueroa, R. Hayashi, R. P. Hsung, Tetrahedron
2009, 65, 5001; e) G. Onodera, M. Suto, R. Takeuchi, J. Org. Chem.
2012, 77, 908; f) M. Augꢄ, M. Barbazanges, A. T. Tran, A. Simon-
neau, P. Elley, H. Amouri, C. Aubert, L. Fensterbank, V. Gandon,
M. Malacria, J. Moussa, C. Ollivier, Chem. Commun. 2013, 49, 7833.
[12] Preliminary communication for the synthesis of axially chiral o-io-
doanilides: S. Shirakawa, K. Liu, K. Maruoka, J. Am. Chem. Soc.
2012, 134, 916.
[2] For reviews on axially chiral anilides, see: a) O. Kitagawa, T. Tagu-
chi, J. Synth. Org. Chem. Jpn. 2001, 59, 680; b) M. Takahashi, O. Ki-
tagawa, J. Synth. Org. Chem. Jpn. 2011, 69, 985.
[3] a) C. Kashima, A. Katoh, J. Chem. Soc. Perkin Trans. 1 1980, 1599;
b) C. Roussel, M. Adjimi, A. Chemlal, A. Djafri, J. Org. Chem.
1988, 53, 5076; c) A. Ohno, J. Kunitomo, Y. Kawai, T. Kawamoto,
M. Tomishima, F. Yoneda, J. Org. Chem. 1996, 61, 9344; d) K. D.
Shimizu, H. O. Freyer, R. D. Adams, Tetrahedron Lett. 2000, 41,
5431; e) K. Kondo, T. Iida, H. Fujita, T. Suzuki, K. Yamaguchi, Y.
Murakami, Tetrahedron 2000, 56, 8883; f) M. Sakamoto, N. Utsumi,
M. Ando, M. Saeki, T. Mino, T. Fujita, A. Katoh, T. Nishio, C. Ka-
shima, Angew. Chem. 2003, 115, 4496; Angew. Chem. Int. Ed. 2003,
42, 4360; g) R. J. Brown, G. Annis, A. Casalnuovo, D. Chan, R. Sha-
piro, W. J. Marshall, Tetrahedron 2004, 60, 4361; h) T. Adler, J. Bon-
joch, J. Clayden, M. Font-Bardꢃa, M. Pickworth, X. Solans, D. Solꢄ,
L. Vallverdffl, Org. Biomol. Chem. 2005, 3, 3173; i) D. B. Guthrie,
S. J. Geib, D. P. Curran, J. Am. Chem. Soc. 2009, 131, 15492; j) B.
Paul, G. L. Butterfoss, M. G. Boswell, P. D. Renfrew, F. G. Yeung,
N. H. Shah, C. Wolf, R. Bonneau, K. Kirshenbaum, J. Am. Chem.
Soc. 2011, 133, 10910; k) B. Paul, G. L. Butterfoss, M. G. Boswell,
M. L. Huang, R. Bonneau, C. Wolf, K. Kirshenbaum, Org. Lett.
2012, 14, 926; l) A. Nakazaki, A. Mori, S. Kobayashi, T. Nishikawa,
Tetrahedron Lett. 2012, 53, 7131; m) J. Mandel, X. Pan, E. B. Hay,
S. J. Geib, C. S. Wilcox, D. P. Curran, J. Org. Chem. 2013, 78, 4083.
[4] a) A. Mannschreck, H. Koller, G. Stühler, M. A. Davies, J. Traber,
Eur. J. Med. Chem. 1984, 19, 381; b) H.-U. Blaser, Adv. Synth. Catal.
2002, 344, 17; c) H.-U. Blaser, B. Pugin, F. Spindler, M. Thommen,
Acc. Chem. Res. 2007, 40, 1240.
[5] a) D. P. Curran, W. Liu, C. H.-T. Chen, J. Am. Chem. Soc. 1999, 121,
11012; b) D. P. Curran, C. H.-T. Chen, S. J. Geib, A. J. B. Lapierre,
Tetrahedron 2004, 60, 4413; c) M. Petit, S. J. Geib, D. P. Curran, Tet-
rahedron 2004, 60, 7543; d) M. Petit, A. J. B. Lapierre, D. P. Curran,
J. Am. Chem. Soc. 2005, 127, 14994; e) A. J. B. Lapierre, S. J. Geib,
D. P. Curran, J. Am. Chem. Soc. 2007, 129, 494; f) D. B. Guthrie,
D. P. Curran, Org. Lett. 2009, 11, 249; g) A. Bruch, A. Ambrosius,
R. Frçhlich, A. Studer, D. Guthrie, B. H. Zhang, D. P. Curran, J.
Am. Chem. Soc. 2010, 132, 11452; h) D. B. Guthrie, S. J. Geib, D. P.
Curran, J. Am. Chem. Soc. 2011, 133, 115; i) A. Bruch, R. Frçhlich,
S. Grimme, A. Studer, D. P. Curran, J. Am. Chem. Soc. 2011, 133,
16270.
[13] For reviews on the memory of chirality, see: a) T. Kawabata, K.
Fuji, J. Synth. Org. Chem. Jpn. 1994, 52, 589; b) T. Kawabata, K.
Fuji, Top. Stereochem. 2003, 23, 175; c) H. Zhao, D. C. Hsu, P. R.
Carlier, Synthesis 2005, 1; d) T. Kawabata, ACS Symp. Ser. 2009,
1009, 31.
[14] a) M. Kitamura, S. Shirakawa, K. Maruoka, Angew. Chem. 2005,
117, 1573; Angew. Chem. Int. Ed. 2005, 44, 1549; 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.
[15] Diisopropyl ether might contain peroxides, which are formed by
contact with air, and requires care during treatment.
[16] CCDC-845829 (1a) 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.
[6] a) D. P. Curran, H. Qi, S. J. Geib, N. C. DeMello, J. Am. Chem. Soc.
1994, 116, 3131; b) D. P. Curran, G. R. Hale, S. J. Geib, A. Balog,
Q. B. Cass, A. L. G. Degani, M. Z. Hernandes, L. C. G. Freitas, Tet-
rahedron: Asymmetry 1997, 8, 3955; c) A. D. Hughes, D. A. Price,
N. S. Simpkins, J. Chem. Soc. Perkin Trans. 1 1999, 1295; d) M.
Fujita, O. Kitagawa, Y. Yamada, H. Izawa, H. Hasegawa, T. Taguchi,
J. Org. Chem. 2000, 65, 1108; e) D. J. Bennett, A. J. Blake, P. A.
Cooke, C. R. A. Godfrey, P. L. Pickering, N. S. Simpkins, M. D.
Walker, C. Wilson, Tetrahedron 2004, 60, 4491; f) J. Clayden, H.
Turner, M. Helliwell, E. Moir, J. Org. Chem. 2008, 73, 4415; g) A. J.-
L. Ayitou, J. Sivaguru, J. Am. Chem. Soc. 2009, 131, 5036; h) A. J.-L.
Ayitou, J. L. Jesuraj, N. Barooah, A. Ugrinov, J. Sivaguru, J. Am.
Chem. Soc. 2009, 131, 11314; i) A. J.-L. Ayitou, J. Sivaguru, Chem.
Commun. 2011, 47, 2568.
À
[17] The bond lengths of the amide moiety in product 1a (O C: 1.223 ꢁ,
À
N C: 1.379 ꢁ). See also Ref. [5].
[18] a) X. Wang, M. Kitamura, K. Maruoka, J. Am. Chem. Soc. 2007,
129, 1038; b) Q. Lan, X. Wang, R. He, C. Ding, K. Maruoka, Tetra-
hedron Lett. 2009, 50, 3280; c) Y.-G. Wang, T. Kumano, T. Kano, K.
Maruoka, Org. Lett. 2009, 11, 2027; d) Y. Liu, A. Usui, S. Shirakawa,
K. Maruoka, Asian J. Org. Chem. 2012, 1, 180.
7
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Keiji Maruoka et al.
[19] a) X. Dai, A. Wong, S. C. Virgil, J. Org. Chem. 1998, 63, 2597; b) Y.
Chen, M. D. Smith, K. D. Shimizu, Tetrahedron Lett. 2001, 42, 7185;
c) T. Mino, H. Yamada, S. Komatsu, M. Kasai, M. Sakamoto, T.
Fujita, Eur. J. Org. Chem. 2011, 4540.
[21] a) S. Kanemasa, K. Onimura, Tetrahedron 1992, 48, 8645; b) H. Ya-
mamoto, S. Hayashi, M. Kubo, M. Harada, M. Hasegawa, M. Nogu-
chi, M. Sumimoto, K. Hori, Eur. J. Org. Chem. 2007, 2859; c) H.
Suga, Y. Adachi, K. Fujimoto, Y. Furihata, T. Tsuchida, A. Kakehi,
T. Baba, J. Org. Chem. 2009, 74, 1099.
[20] a) M. L. Quan, J. R. Pruitt, C. D. Ellis, A. Y. Liauw, R. A. Galem-
mo, Jr., P. F. W. Stouten, J. Wityak, R. M. Knabb, M. J. Thoolen,
P. C. Wong, R. R. Wexler, Bioorg. Med. Chem. Lett. 1997, 7, 2813;
b) J. Wityak, T. M. Sielecki, D. J. Pinto, G. Emmett, J. Y. Sze, J. Liu,
A. E. Tobin, S. Wang, B. Jiang, P. Ma, S. A. Mousa, R. R. Wexler,
R. E. Olson, J. Med. Chem. 1997, 40, 50; c) M. C. Pirrung, L. N.
Tumey, C. R. H. Raetz, J. E. Jackman, K. Snehalatha, A. L. McCler-
ren, C. A. Fierke, S. L. Gantt, K. M. Rusche, J. Med. Chem. 2002,
45, 4359; d) P. Y. S. Lam, J. J. Adams, C. G. Clark, W. J. Calhoun,
J. M. Luettgen, R. M. Knabb, R. R. Wexler, Bioorg. Med. Chem.
Lett. 2003, 13, 1795; e) M. A. Weidner-Wells, H. M. Werblood, R.
Goldschmidt, K. Bush, B. D. Foleno, J. J. Hilliard, J. Melton, E.
Wira, M. J. Macielag, Bioorg. Med. Chem. Lett. 2004, 14, 3069;
f) C. M. Salisbury, J. A. Ellman, ChemBioChem 2006, 7, 1034; g) V.
Varshney, N. N. Mishra, P. K. Shukla, D. P. Sahu, Bioorg. Med.
Chem. Lett. 2009, 19, 3573; h) M. Gucma, W. M. Gołe˛biewski, Mon-
atsh. Chem. 2010, 141, 461; i) A. Alam, C. Pal, M. Goyal, M. K.
Kundu, R. Kumar, M. S. Iqbal, S. Dey, S. Bindu, S. Sarkar, U. Pal,
N. C. Maiti, S. Adhikari, U. Bandyopadhyay, Bioorg. Med. Chem.
2011, 19, 7365.
[22] CCDC-914810 (11a) 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.
[23] a) F. Tanaka, M. Node, K. Tanaka, M. Mizuchi, S. Hosoi, M. Na-
kayama, T. Taga, K. Fuji, J. Am. Chem. Soc. 1995, 117, 12159; b) M.
Mizuno, M. Kanai, A. Iida, K. Tomioka, Tetrahedron 1997, 53,
10699; c) K. Sasaki, T. Hayashi, Angew. Chem. 2010, 122, 8321;
Angew. Chem. Int. Ed. 2010, 49, 8145; d) A. E. Allen, D. W. C. Mac-
Millan, J. Am. Chem. Soc. 2011, 133, 4260.
[24] CCDC 845830 ((S)-5i) 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.
[25] Products 1o and 16d gradually racemized at room temperature (1o:
t1/2 ꢀ3.5 days at 258C, DGꢀ25.6 kcalmolÀ1; 16d: t1/2 ꢀ27 h at 258C,
DGꢀ24.9 kcalmolÀ1).
Received: August 3, 2013
Published online: && &&, 0000
&
&
8
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

FULL PAPER
A salty solution: Catalytic asymmetric
synthesis of axially chiral anilides that
possess various functionalities was ach-
ieved by means of chiral quaternary
ammonium-salt-catalyzed N-alkyla-
tions under phase-transfer conditions
(see scheme). The transition-state
structure for the present reaction is
discussed on the basis of the X-ray
crystal structure of ammonium anilide.
Asymmetric Synthesis
Kun Liu, Xiangfei Wu, S. B.
Jennifer Kan, Seiji Shirakawa,
Keiji Maruoka*
&&&& — &&&&
Phase-Transfer-Catalyzed Asymmetric
Synthesis of Axially Chiral Anilides
9
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ