Asymmetric phase-transfer catalysis of homo- and heterochiral quaternary ammonium salts: development and application of conformationally flexible chiral phase-transfer catalysts

Article abstract of DOI:10.1016/j.tet.2006.08.052

Inspired by the considerable difference of catalytic activity and stereocontrolling ability between the conformationally rigid, homo- and heterochiral quaternary ammonium bromides 1, conformationally flexible, N-spiro chiral quaternary ammonium bromides o

Full text of DOI:10.1016/j.tet.2006.08.052

Tetrahedron 62 (2006) 11425–11436
Asymmetric phase-transfer catalysis of homo- and heterochiral
quaternary ammonium salts: development and application of
conformationally flexible chiral phase-transfer catalysts
y
*
Takashi Ooi, Yukitaka Uematsu, Minoru Kameda and Keiji Maruoka
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Received 26 May 2006; revised 13 August 2006; accepted 14 August 2006
Available online 7 September 2006
Abstract—Inspired by the considerable difference of catalytic activity and stereocontrolling ability between the conformationally rigid,
homo- and heterochiral quaternary ammonium bromides 1, conformationally flexible, N-spiro chiral quaternary ammonium bromides of
type 4 have been designed and synthesized. Reliable procedures for the preparation of the appropriately substituted biphenyl subunits
have been established by the repeated use of ortho magnesiation–halogenation as a key synthetic tool. The relationship between the structure
of achiral biphenyl moiety and the reactivity and selectivity of 4 has been evaluated in the asymmetric alkylation of glycinate Schiff base 2
under typical phase-transfer conditions, leading to the identification of 4l as an optimal catalyst structure to exhibit an excellent enantiocontrol
in the reactions with various alkyl halides. The molecular structure of 4l was determined by X-ray crystallographic analysis and its unique
behavior in solution was examined by a variable-temperature 1H NMR study. These investigations uncovered that the observed high chiral
efficiency originated from the efficient asymmetric phase-transfer catalysis of homochiral-4l, which rapidly equilibrated with heterochiral-4l
of low catalytic activity and stereoselectivity.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
1 mol % of (S,S)-1 in 50% aqueous KOH/toluene (volume
ratio¼1:3) at 0 ꢀC for 3 h under argon atmosphere gave
rise to the corresponding benzylation product 3a, protected
phenylalanine, in 91% yield with 94% ee (R). The character-
istic feature of (S,S)-1 is the conformationally rigid, N-spiro
structure created by two chiral binaphthyl units. Since this
structure seemed essential for attaining sufficient reactivity
and enantioselectivity, we were intrigued by which bi-
naphthyl moiety would be more critically associated with
its chiral efficiency. This initial concern led us to prepare
the diastereomeric, heterochiral quaternary ammonium bro-
mide (R,S)-1 and to evaluate its reactivity and selectivity as
a chiral phase-transfer catalyst. Interestingly, the benzyl-
ation of 2 under similar conditions proceeded slowly, and,
after 60 h, furnished 3a in 47% yield with low enantiomeric
excess (11% ee, R). We also observed that the enantiomeric
(S,R)-1 exerted comparable catalytic activity in the benzyl-
ation with the opposite sense of asymmetric induction (51%,
11% ee, S). The significant rate retardation apparently indi-
cates that the parent homochiral ammonium bromide (S,S)-
or (R,R)-1 has substantially higher catalytic activity than
the heterochiral (R,S)- or (S,R)-1.4 Indeed, the benzylation
of 2 with each 0.5 mol % of (S,S)-1 and (R,S)-1 under other-
wise similar phase-transfer conditions at 0 ꢀC for 13 h
afforded 3a in 88% yield with 94% ee, and the use of each
0.5 mol % of (S,S)-1 and (S,R)-1 as catalyst, though a mis-
matched combination in terms of the enantioselectivity,
resulted in formation of 3a in 92% yield with 93% ee after
8.5 h at 0 ꢀC as shown in Scheme 1.
The use of chiral quaternary ammonium salts readily pre-
pared from naturally occurring cinchona alkaloids, cincho-
nine and cinchonidine as chiral phase-transfer catalysts has
provided a unique yet reliable tool for catalytic asymmetric
synthesis, and its utility has been well documented in the
number of valuable chemical transformations including
stereoselective functionalization of protected glycine deriv-
ative 2.1 Recent attractive emergence of a series of appropri-
ately modified cinchona alkaloid-based catalysts as well as
the elaboration of purely synthetic chiral quaternary ammo-
nium salts strongly suggest the significant importance and
usefulness of rational molecular design of chiral catalysts.1,2
Our own contribution to this rapidly growing area was the
design of chiral C2-symmetric quaternary ammonium bro-
mides of type 1, which efficiently catalyze the phase-transfer
alkylation of 2 with excellent enantioselectivities, providing
a practical method for the asymmetric synthesis of both nat-
ural and unnatural a-amino acids.3 For example, the reaction
of 2 with benzyl bromide (1.2 equiv) in the presence of
Keywords: Asymmetric phase-transfer alkylation; Atropinversion; Biphenyl
unit; Conformational flexibility; Molecular design.
* Corresponding author. Tel./fax: +81 75 753 4041; e-mail: maruoka@
kuchem.kyoto-u.ac.jp
Present address: Department of Applied Chemistry, Graduate School of
Engineering, Nagoya University, Chikusa, Nagoya 464-8603, Japan.
y
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.052

11426
T. Ooi et al. / Tetrahedron 62 (2006) 11425–11436
O
O
1, PhCH2Br (1.2 equiv)
N
N
Ph2C
Ph2C
t
t
OBu
OBu
toluene–50% KOH aq.
2
0 °C
H
3a
Ph
(S,S)-1 (1 mol%), 3 h
(R,S)-1 (1 mol%), 60 h
(S,R)-1 (1 mol%), 60 h
: 91%, 94% ee (R)
: 47%, 11% ee (R)
: 51%, 11% ee (S)
(S,S)-1 (0.5 mol%), (R,S)-1 (0,5 mol%), 13 h : 88%, 94% ee (R)
(S,S)-1 (0.5 mol%), (S,R)-1 (0,5 mol%), 8.5 h : 92%, 93% ee (R)
-Np
Br
-Np
N
Br
enantiomer
N
-Np
-Np
(S,S)-1 [(S,S)-β-Np-NAS-Br]
(R,R)-1
diastereomer
diastereomer
-Np
Br
-Np
N
Br
enantiomer
N
-Np
-Np
(R,S)-1
(S,R)-1
Scheme 1.
These results suggested that high levels of catalytic activity
and stereoselectivity could be retained even if one of the two
chiral binaphthyl subunits of 1 was racemic. On the basis of
the interesting findings, we sought to develop a new N-spiro
chiral C2-symmetric quaternary ammonium bromide 4 by
incorporating an achiral biphenyl structure. Our assumption
was that the conformationally flexible biphenyl subunits
could be atropisomerically biased by the simple chiral
binaphthyl unit through the central nitrogen atom so that 4
could exert chiral efficiency as high as the conformationally
rigid homochiral catalyst (S,S)-1. This approach, if success-
ful, should lead to simplification of the molecular design and
hence allows fruitful modification of the chiral catalysts. In
this article, we wish to describe the detailed procedure for
the facile synthesis of conformationally flexible 4, and its
reactivity and selectivity as chiral phase-transfer catalyst is
explored in relation to the unique behavior in solution, re-
vealing that 4 exhibits high chiral efficiency in the asymmet-
ric alkylation of 2 by taking advantage of the considerable
difference of activity between the two possible diastereo-
meric conformers through rapid interconversion.5,6
2. Results and discussion
2.1. Synthesis of conformationally flexible C2-symmetric
chiral quaternary ammonium bromide 4
Because the simple chiral element of the new catalyst 4 can
be served by previously known optically active secondary
amine 5,3c,7 we focused on the synthesis of appropriately
substituted achiral biphenyl moiety, which has been accom-
plished concisely in a five-step sequence starting from com-
mercially available diphenic acid as illustrated in Scheme 2.
Diphenic acid was first converted to the corresponding iso-
propyl ester 6 quantitatively. For the subsequent selective
bromination of the 3,30-position of 6, we fortunately found
that ortho magnesiation–bromination technique using mag-
nesium 2,2,6,6-tetramethylpiperamide and bromine was
quite effective, furnishing 7 in 90% yield.8 This success
allowed the preparation of 8 having a variety of 3,30-aromatic
substituents by Suzuki–Miyaura cross coupling reaction.
Then, simple reduction of 8 by LiAlH4 and, without any
purification, subsequent treatment with PBr3 afforded the
requisite bis-bromide 9. Finally, reaction of 9 with 5 under
basic conditions as previously reported3c afforded confor-
mationally flexible quaternary ammonium bromides 4b–h.
Ar1
4a : Ar1 = H
4b : Ar1 = Ph
Br
4c : Ar1 = 3,5-Me2-C6H3
4d : Ar1 = 3,5-(t-Bu)2-C6H3
4e : Ar1 = 3,4,5-F3-C6H2
4f : Ar1 = 3,5-(CF3)2-C6H3
N
Ar1
4g : Ar1
=
-Np
4h : Ar1= 3,5-Ph2-C6H3
Ar2
Ar2
Ar1
Br
Br
N
N
Ar2
Ar2
Ar1
4i : Ar2 = Ph
4j : Ar2
-Np
4k : Ar2 = 3,4,5-F3-C6H2
4l : Ar1 = 3,5-Ph2-C6H3, Ar2 = Ph
=

T. Ooi et al. / Tetrahedron 62 (2006) 11425–11436
11427
CO2H
CO2H
a
b
c
Br
OH
OH
4a
Br 91%
diphenic acid
96%
Ar1
d
quant.
Br
i
i
i
i
i
CO2Pr
CO2Pr
CO2Pr
CO2Pr
CO2Pr
f
a
e
90%
i
CO2Pr
Ar1 8b–h
91–95%
Br
7
6
Ar1
Ar1
OH
OH
c
b
Br
4b–h
Br 95–98%
Ar1
Ar1
9b–h
95–98%
Ar2
Ar2
Br
d,f
92–96%
h
76–84%
i
i
CO2H
CO2Pr
10a–c
CO2Pr
I
11a–c
Ar2
Ar2
i
i
CO2Pr
g,b
Br
Br
i
c
4i–k
82–90%
84–92%
68–78%
CO2Pr
Ar2
Ar2
12a–c
Ph
13a–c
Br
Ph
Ar1
i
i
i
CO2Pr
CO2Pr
CO2Pr
g,b
f
e
12a
93%
76%
92%
(Ar2 = Ph)
i
CO2Pr
Ar1
Ph
Ph
Br
14
15
Ph
Ar1
Br
Br
c
4l
HN
89%
Ph
Ar1
5
16
Scheme 2. Reagents and conditions: (a) LiAlH4, THF, reflux; (b) PBr3, THF, 0 ꢀC to rt; (c) 5, K2CO3, CH3CN, reflux; (d) SOCl2, 0 ꢀC to reflux, then i-PrOH,
pyridine; (e) (TMP)2Mg, THF, 0 ꢀC to rt, then Br2, ꢁ78 ꢀC to rt; (f) ArB(OH)2, Pd(OAc)2, PPh3, K2CO3, DMF, 90 ꢀC; (g) LiAlH4, THF, 0 ꢀC to rt;
(h) (TMP)2Mg, THF, 0 ꢀC to rt, then I2, ꢁ78 ꢀC to rt; (i) activated Cu, DMF, reflux.
In addition, the synthesis of the catalyst 4 having an aromatic
group at 5,50-positions of the biphenyl subunit has also been
executed by means of the ortho magnesiation–halogenation
procedure8 as included in Scheme 2. Commercially avail-
able 4-bromobenzoic acid was first transformed into its iso-
propyl ester and then coupled with an appropriate boronic
acid using the palladium catalyst to prepare 10. Treatment
of the ester 10 with (TMP)2Mg in THF followed by the re-
action with iodine resulted in the production of 11, a requisite
candidate for the next Ullmann coupling. Refluxing a
mixture of 11 with activated copper in DMF facilitated the
biphenyl formation to give 12, which was further derivatized
to 13 through the reduction and bromination sequences. The
subsequent use of 13 for the quaternization of 5 led to the

11428
T. Ooi et al. / Tetrahedron 62 (2006) 11425–11436
formation of catalysts 4i–k. In a meantime, installment of
3,30-(3,5-diphenylphenyl) groups on 12 and the generation
of bromomethyl functionality at 2,20-position could be con-
ducted in a manner as described. The final assembly of 16
thus obtained with 5 afforded 4l.
(R,S)-4b. Meanwhile, the installment of aromatic substitu-
ents at 5,50-position of the biphenyl moiety (Ar2) would not
deliver major influence on the stereodynamic of the chiral
ammonium cation, and thus only the beneficial effect of the
extended aromatic surface could be extracted. This interpre-
tation prompted us to further examine the impact of steric and
electronic properties of Ar2 particularly on the stereoselectiv-
ity, which consequently turned out to be marginal as included
in Table 1 (entries 4 and 5). In sharp contrast, however, ma-
nipulation of 3,30-aromatic substituents dramatically altered
both the reactivity and selectivity of the catalyst 4. On one
hand, the phase-transfer-catalyzed benzylation of 2 in the
presence of 3,5-dimethylphenyl-substituted 4c under other-
wise similar conditions afforded 3a in 90% yield with 80%
ee (entry 6), though use of sterically more demanding 4d as
catalyst cancelled the improvement (entry 7). On the other,
significant loss of the catalytic activity was observed when
electron-withdrawing substituent such as 3,4,5-trifluoro-
phenyl group was introduced and, to our surprise, no produc-
tion of 3a was detected under the influence of 4f having
3,5-bis(trifluoromethyl)phenyl unit (entries 8 and 9). Eventu-
ally, highest level of enantioselectivity was obtained with 4g
possessing b-naphthyl group (entry 10), and moreconjugated
meta-terphenyl group was identified as an ideal 3,30-substit-
uent of this type of catalyst for attaining sufficient reactivity
and selectivity (entry 11). These results clearly demonstrate
that appropriate choice of the 3,30-substituents allows the
2.2. Evaluation of the reactivity and selectivity of 4 in the
asymmetric alkylation of glycinate Schiff base 2
We then pursued the systematic evaluation of the reactivity
and selectivity of 4 in the phase-transfer-catalyzed benzyla-
tion of 2 starting from the use of 4a consisted of (S)-bi-
naphthyl and simple biphenyl subunits. Thus, treatment of
2 with benzyl bromide (1.2 equiv) in 50% aqueous KOH/
toluene (volume ratio¼1:3) in the presence of 1 mol % of
4a at 0 ꢀC for 36 h under argon atmosphere resulted in the
formation of 3a in 62% isolated yield. Its enantiomeric
excess was revealed to be appreciable (64% ee) and the ab-
solute configuration was assigned to be R, the same with that
of the major enantiomer in the reaction with (S,S)-1 (Table 1,
entry 1). This observation could be rationalized by the pre-
ferred nature of homochiral conformer (S,S)-4a in solution
on the basis of the elegant study of Lacour on the conforma-
tional preference of the simple spirobi[dibenzazepinium]
cation.9 It was of interest that introduction of phenyl substit-
uent to 3,30-position of the biphenyl subunit (4b) brought
a substantial decrease of the enantioselectivity (53% ee,
entry 2), while similar modification at 5,50-position (4i) led
to the enhancement of the selectivity (72% ee, entry 3). At
this stage, we assumed that the erosion of enantiocontrol
might stem from the intervention of heterochiral conformer
Table 2. Catalytic enantioselective phase-transfer alkylation of 2 with
conformationally flexible catalyst 4la
O
O
4l (1 mol%)
N
N
Ph2C
Ph2C
+
t
t
RX
OBu
OBu
toluene–CsOH aq.
Table 1. Evaluation of the reactivity and selectivity of 4 in the phase-
transfer-catalyzed asymmetric benzylation of 2a
H
R
2
3
–15 °C
4 (1 mol%)
PhCH2Br (1.2 equiv)
% Yieldb
% eec
O
O
Entry
RX
React.
time (h)
N
Ph2C
(config)d
N
Ph2C
t
t
OBu
OBu
toluene–50% KOH aq.
H
1
2
3
4-F-C6H4CH2Br
4-Me-C6H4CH2Br
2,6-Me2-C6H3CH2Br
36
29
64
83
83
90
95 (R)
96 (R)
90 (R)
2
3a
0 °C
Ph
Entry
4
React.
time (h)
% Yieldb % eec
(config)d
Br
Ph
4
5
6
18
18
19
91
92
91
94 (R)
92 (R)
93 (R)
1
2
3
4
5
6
7
8
4a [Ar1¼H]
4b [Ar1¼Ph]
4i [Ar2¼Ph]
36
18
4
32
48
14
2
22
29
18
27
62
87
96
73
90
90
70
25
n.r.
85
95
81
87
64 (R)
53 (R)
72 (R)
67 (R)
60 (R)
80 (R)
60 (R)
84 (R)
n.d.
87 (R)
92 (R)
95 (R)
94 (R)
O
4j [Ar2¼b-Np]
Br
Br
4k [Ar2¼3,4,5-F3-C6H2]
4c [Ar1¼3,5-Me2-C6H3]
4d [Ar1¼3,5-(t-Bu)2-C6H3]
4e [Ar1¼3,4,5-F3-C6H2]
4f [Ar1¼3,5-(CF3)2-C6H3]
4g [Ar1¼b-Np]
9
10
11
12
13e
4h [Ar1¼3,5-Ph2-C6H3]
S
4l [Ar1¼3,5-Ph2-C6H3, Ar2¼Ph] 48
4l [Ar1¼3,5-Ph2-C6H3, Ar2¼Ph] 16
7
CH2]CHCH2Br
CH2]C(Me)CH2Br
EtI
16
21
15
85
85
61
93 (R)
96 (R)
93 (R)
8
a
9e
Unless otherwise noted, the reaction was carried out with 2 (0.5 mmol)
and 1.2 equiv of benzyl bromide in the presence of 1 mol % of 4 in
50% aqueous KOH/toluene (volume ratio¼1:3) at 0 ꢀC for the given
reaction time under argon atmosphere.
Isolated yield.
Enantiopurity of 3a was determined by HPLC analysis using a chiral
column with hexane/2-propanol as solvent.
Absolute configuration of 3a was determined by comparison of the HPLC
retention time with the authentic sample independently synthesized by the
reported procedure.10
Use of CsOH$H2O (3 equiv) in water (29.2 mL) as a base and the reaction
was performed at ꢁ15 ꢀC.
a
Unless otherwise specified, the reaction was conducted with 2 (0.5 mmol)
and 1.2 equiv of RX in the presence of 1 mol % of 4l in aqueous CsOH/
toluene at ꢁ15 ꢀC for the given reaction time under argon atmosphere.
Isolated yield.
Enantiopurity of 3 was determined by HPLC analysis using a chiral
column with hexane/2-propanol as solvent.
Absolute configuration of 3 was determined by comparison of the HPLC
retention time with the literature value or the authentic sample indepen-
dently synthesized by the reported procedure.3c,10
b
c
b
c
d
e
d
e
With 5 equiv of alkyl halide.

T. Ooi et al. / Tetrahedron 62 (2006) 11425–11436
11429
homochiral (S,S)-4 to exert high catalytic and chiral effi-
ciency despite its conformational flexibility; this creates
a solid basis for further fine-tuning of 4 by making use of
the ample structural modularity of achiral biphenyl subunit.
For instance, the catalyst 4l having 3,30-bis(3,5-diphenyl-
phenyl)-5,50-diphenyl-1,10-biphenyl substructure can be
readily assembled and was found to provide even more rigor-
ous stereocontrol in the benzylation of 2 (entry 12). Although
the reactivity was sacrificed to certain extent, it was recov-
ered by the use of aqueous CsOH as a basic phase at a lower
reaction temperature without detrimental effect on the enan-
tioselectivity (entry 13).
with substituents of different steric and electronic properties
were employable, allowing the preparation of structurally
diverse phenylalanine analogues (entries 1–4). The effec-
tiveness of 4l was further demonstrated by using 1-bromo-
methylnaphthalene and 3-bromomethylbenzothiophene as
an electrophilic partner, respectively (entries 5 and 6). Enan-
tiomerically enriched allylglycine derivatives are also acces-
sible (entries 7 and 8), and the reaction with simple alkyl
halide such as ethyl iodide appeared feasible (entry 9).
2.3. Elucidation of structure of 4 and its behavior
in solution
As summarized in Table 2, the asymmetric phase-transfer
catalysis of 4l accommodates a variety of alkyl halides,
and the corresponding alkylation products 3 were obtained
in good to high chemical yields with excellent enantioselec-
tivities using 1 mol % of the catalyst with stirring for 15–
64 h at ꢁ15 ꢀC. In detail, a series of benzylic bromides
To analyze the dynamic structural behavior of 4h and 4l in
solution, a variable-temperature H NMR study was con-
ducted in dichloromethane-d2. The temperature dependence
of the 1H NMR signals of benzylic protons of 4h at low tem-
perature range is shown in Figure 1. The peak broadening
at 283–263 K and sharpening to two sets of four benzylic
1
298 K
283 K
273 K
263 K
253 K
243 K
233 K
223 K
213 K
203 K
193 K
PPM
4.5
4.0
3.5
3.0
2.5
5.0
Figure 1. The temperature dependence of the 1H NMR signals of the benzylic protons of homo- ( ) and heterochiral (B) conformers of 4h.11
*

11430
T. Ooi et al. / Tetrahedron 62 (2006) 11425–11436
298 K
283 K
273 K
263 K
253 K
243 K
233 K
223 K
213 K
PPM
5.0
4.5
4.0
3.5
3.0
2.5
Figure 2. The temperature dependence of the 1H NMR signals of the benzylic protons of homo- ( ) and heterochiral (B) conformers of 4l.11
*
signals (nearly 1:1 ratio) at 243 K clearly indicates that there
is a rapid equilibrium between two diastereomeric, homo-
chiral (S,S)-4h and heterochiral (R,S)-4h, and the composi-
tion of conformational structures depends on temperature.
On the basis of the initial studies with conformationally rigid
catalyst of type 1, the homochiral isomer is assumed to be cat-
alytically more active and, interestingly, the existence ratio
of (S,S)-4h was found to decrease as the temperature was
(Fig. 3).13 However, the ratio of (S,S)-4l/(R,S)-4l was re-
vealed to be 1:1.2 at 0 ꢀC and 1:0.68 at ꢁ15 ꢀC.12 The
increased existence ratio of homochiral (S,S)-4l around the
reaction temperature suggested that the introduction of
5,50-diphenyl substituents not only extended the attractive
aromatic surface but also affected the stereodynamic of 4l,
consequently imparting it with higher enantiocontrolling
ability than 4h.
Ar1
Ar2
Ar1
Ar2
Br
Br
atropinversion
N
N
diastereomer
Ar1
Ar1
Ar2
Ar2
(Ar1 = 3,5-Ph2-C6H3, Ar2 = H or Ph)
(Ar1 = 3,5-Ph2-C6H3, Ar2 = H or Ph)
heterochiral (R,S)-4
low activity and ee (R)
homochiral (S,S)-4
high activity and ee (R)
increased, being approximately 1:2.8 of (S,S)-4h/(R,S)-4h
at 0 ꢀC.12 Similar tendency was observed in the case of 4l
(Fig. 2), and thestereochemicalpreference toward the hetero-
chiral isomer at higher temperature (above 25 ꢀC) was also
supported by the single crystal X-ray diffraction analysis
of 4l after recrystallization from CH2Cl2/hexane at room
temperature, uncovering its heterochiral molecular structure
3. Summary
We have designed and prepared conformationally flexible,
N-spiro chiral quaternary ammonium bromides 4 incorporat-
ing a modular achiral biphenyl structure as a conceptually
new chiral phase-transfer catalyst. The concise synthetic
route to the appropriately substituted biphenyl subunit has

T. Ooi et al. / Tetrahedron 62 (2006) 11425–11436
11431
variable-temperature 1H NMR study, together with the
similar stereodynamic of structurally more simple 4h. This
provided a compelling evidence to support that the origin
of the high chiral efficiency laid on the considerable differ-
ence of catalytic activity between the rapidly equilibrated
homo- and heterochiral isomers, and homochiral-4l is pri-
marily responsible for the efficient asymmetric phase-trans-
fer catalysis to produce the corresponding alkylation product
3 with high enantiomeric excess, while heterochiral-4l
showed low reactivity and stereoselectivity. Our approach
parallels the successful utilization of flexible ligand to mag-
nify the effect of other chiral ligand through coordinative
interaction with metal center,6 and should offer a new yet
simple strategy for the molecular design of chiral phase-
transfer catalysts.
4. Experimental
4.1. General information
Infrared (IR) spectra were recorded on a Shimadzu IRPres-
tige-21 spectrometer. H NMR spectra were measured on
1
a JEOL JNM-FX400 (400 MHz) spectrometer. Chemical
shifts were reported in parts per million from tetramethyl-
silane as an internal standard. Data were reported as follows:
chemical shift, integration, multiplicity (s¼singlet, d¼
doublet, t¼triplet, q¼quartet, quint¼quintet, hept¼heptet,
sept¼septet, m¼multiplet, br¼broad), coupling constants
(hertz), and assignment. 13C NMR spectra were recorded
on a JEOL JNM-FX400 (100 MHz) spectrometer with com-
plete proton decoupling. Chemical shifts are reported in parts
per million from the residual solvent as an internal standard.
High performance liquid chromatography (HPLC) was per-
formed on Shimadzu 10A instruments using 4.6 mmꢂ25 cm
Daicel Chiralcel OD or OD-H. The high-resolution mass
spectra (HRMS) were performed on Applied Biosystems
Mariner 8295 API-TOF workstation, Bruker microTOF,
and JMS-HX100. Optical rotations were measured on
a JASCO DIP-1000 digital polarimeter. Melting points
¨
were determined on a BUCHI Melting Point B-545 and are
uncorrected. For thin layer chromatography (TLC) analysis
throughout this work, Merck precoated TLC plates (silica
gel 60 GF254, 0.25 mm) were used. The products were puri-
fied by flash column chromatography on silica gel 60 (Merck
1.09386.9025, 230–400 mesh). In experiments requiring dry
solvents, ether, and tetrahydrofuran (THF) were purchased
from Kanto Chemical Co. Inc. as ‘dehydrated’. Toluene
was dried over sodium metal. Other simple chemicals were
purchased and used as such.
Figure 3. ORTEP diagram of (S)-4l [(a) top view; (b) side view].
been established by employing the selective ortho magnesia-
tion–halogenation as an essential technique. Systematic
evaluation of the structure–activity relationship of 4 in the
phase-transfer-catalyzed asymmetric benzylation of glyci-
nate Schiff base 2 revealed that 4l possessing 3,30-bis(3,5-
diphenylphenyl)-5,50-diphenyl-1,10-biphenyl substructure
displayed a prominent enantiocontrolling ability. Further,
the general applicability of the 4l-catalyzed enantioselec-
tive alkylation was demonstrated with representative alkyl
halides. The three-dimensional molecular structure of 4l
was unequivocally determined by X-ray crystallographic
analysis, and its behavior in solution was investigated by a
4.2. Representative procedure for catalytic asymmetric
alkylation of glycine tert-butyl ester benzophenone
Shiff base (2) under phase-transfer conditions (Table 1,
entry 13)
To a 10 mL two-neck flask containing a Teflon-coated mag-
netic stirring bar and CsOH$H2O (265 mg, 1.5 mmol) was
introduced water (29.2 mL) with stirring under argon atmo-
sphere. Then, (S)-4l (5.0 mg, 0.005 mmol) and a solution
of glycine tert-butyl ester benzophenone Schiff base (2;
148 mg, 0.5 mmol) in toluene (3 mL) were added and the
mixture was cooled to ꢁ15 ꢀC. After 10 min of gentle

11432
T. Ooi et al. / Tetrahedron 62 (2006) 11425–11436
stirring, benzyl bromide (73.6 mL, 0.6 mmol) was added
dropwise and the reaction mixture was stirred vigorously
for 16 h. The resulting mixture was poured into brine and
extracted with CH2Cl2. The organic layer was dried over
Na2SO4 and concentrated. The residual oil was purified by
column chromatography on silica gel (EtOAc/hexane¼1:12
to 1:6 as eluent) to give 3a10 (168 mg, 0.436 mmol; 87%
yield, 94% ee) as a colorless oil. The catalyst (S)-4l can be
recovered by further eluting with MeOH/CH2Cl2.14 The
enantiomeric excess of 3a was determined by chiral HPLC
analysis (Daicel Chiralcel OD, hexane/2-propanol¼100:1,
flow rate¼0.5 mL minꢁ1, retention time¼13.7 min (R) and
24.6 min (S)).
mixture was stirred for 3 h at room temperature. After being
cooled to ꢁ78 ꢀC, Br2 (264 mL, 5.0 mmol) was added and
stirring was continued for 1 h at room temperature. This
mixture was then poured into cooled 1 N HCl, washed with
saturated Na2SO3, and extracted with Et2O. The organic layer
was dried over Na2SO4 and concentrated. Purification of the
residue by column chromatography on silica gel (EtOAc/
hexane¼1:20 to 1:10 as eluent) furnished 7 (218 mg,
0.450 mmol, 90%) as a white powder; 1H NMR (400 MHz,
CDCl3) d 7.59 (2H, dd, J¼2.4, 6.7 Hz, ArH), 7.26–7.21
(4H, m, ArH), 4.97 (2H, sept, J¼6.3 Hz, CH(CH3)2), 1.18
(6H, s, CH3), 0.89 (6H, s, CH3) ppm; 13C NMR (100 MHz,
CDCl3) d 165.7, 138.1, 135.9, 132.1, 129.4, 128.7, 119.1,
69.2, 21.5, 20.9 ppm; IR (KBr) 2980, 1724, 1583, 1551,
4.3. Characterization of chiral quaternary ammonium
salt (R,S)-1 (Ar1¼2-naphthyl)
1439, 1375, 1286, 1101, 1059, 912, 858, 795, 766 cmꢁ1
;
HRMS (ESI-TOF) calcd for C20H20Br2O4Na ([M+Na]+):
504.9623, found: 504.9621.
1H NMR (400 MHz, CDCl3) d 8.18 (2H, s, ArH), 8.09 (2H,
d, J¼8.3 Hz, ArH), 7.85 (2H, br, ArH), 7.79–7.75 (4H, m,
ArH), 7.70–7.64 (6H, m, ArH), 7.59 (2H, d, J¼8.7 Hz,
ArH), 7.47–7.44 (6H, m, ArH), 7.36–7.30 (6H, m, ArH),
7.26–7.21 (4H, m, ArH), 7.06–7.02 (2H, m, ArH), 6.90
(2H, d, J¼8.7 Hz, ArH), 4.66 (4H, s, ArCH2), 4.40 (2H, d,
J¼12.7 Hz, ArCH2), 2.60 (2H, d, J¼12.3 Hz, ArCH2) ppm;
13C NMR (100 MHz, CDCl3) d 139.3, 138.4, 136.0, 135.8,
134.2, 133.7, 131.9, 131.1, 130.2, 129.5, 129.1, 128.8,
128.2, 128.0, 127.7, 127.6, 127.5, 127.2, 127.2, 126.9,
126.8, 126.6, 126.5, 126.4, 126.2, 125.9, 124.4, 63.6,
59.5 ppm; IR (KBr) 3647, 3400, 3047, 3008, 2989, 1624,
1589, 1506, 1456, 1351, 1028, 895, 877, 821, 777,
746 cmꢁ1; HRMS (ESI-TOF) calcd for C64H44N (M+):
826.3476, found: 826.3474; [a]2D8 146.6 (c 0.25, CHCl3).
4.4.3. 2,20-Bis(isopropoxycarbonyl)-3,30-bis(3,5-diphe-
nylphenyl)-1,10-biphenyl (8h). A mixture of 7 (484 mg,
1.0 mmol), 3,5-diphenylphenylboronic acid (658 mg,
2.4 mmol), Pd(OAc)2 (11.6 mg, 0.05 mmol), PPh3
(40.1 mg, 0.15 mmol), and K2CO3 (419 mg, 3.0 mmol) in
DMF (5 mL) was degassed and backfilled with argon. This
mixture was heated at 90 ꢀC for 8 h. After cooling to room
temperature, the resulting mixture was poured into 1 N HCl
and extracted with Et2O. The organic extracts were dried
over Na2SO4. Evaporation of solvents and purification of
the residue by column chromatography on silica gel
(EtOAc/hexane¼1:20 to 1:10 as eluent) afforded 8h
1
(744 mg, 0.95 mmol, 95%) as a white powder; H NMR
(400 MHz, CDCl3) d 7.80 (2H, t, J¼2.0 Hz, ArH), 7.68–
7.64 (12H, m, ArH), 7.51–7.34 (18H, m, ArH), 4.75 (2H,
sept, J¼6.3 Hz, CH(CH3)2), 0.86 (6H, d, J¼5.9 Hz, CH3),
0.67 (6H, d, J¼5.9 Hz, CH3) ppm; 13C NMR (100 MHz,
CDCl3) d 167.8, 141.7, 141.5, 140.7, 139.9, 138.3, 133.9,
129.1, 129.0, 128.9, 128.4, 127.4, 127.2, 126.3, 125.0,
68.4, 21.4, 21.0 ppm; IR (KBr) 2976, 1722, 1595, 1574,
1499, 1450, 1412, 1373, 1265, 1103, 1065, 883, 760,
700 cmꢁ1; HRMS (ESI-TOF) calcd for C56H46O4Na
([M+Na]+): 805.3273, found: 805.3288.
4.4. Representative procedure for the preparation
of (S)-4a–h and their characterizations
4.4.1. 2,20-Bis(isopropoxycarbonyl)-1,10-biphenyl (6). Di-
phenic acid (1.26 g, 5.0 mmol) was placed in a dry two-neck
flask with a stirring bar under argon atmosphere and SOCl2
(5 mL) was introduced at 0 ꢀC. The mixture was refluxed for
4 h and excess SOCl2 was removed under reduced pressure.
Then, i-PrOH (5 mL) and pyridine (1 mL) were added and
the mixture was heated to reflux for 1 h. The resulting
solution was washed with H2O and extracted with EtOAc.
The organic layer was dried over Na2SO4 and concentrated.
The residue was purified by column chromatography on
silica gel (short-pass, EtOAc/hexane¼1:4 as eluent) to give
4.4.4. 2,20-Bis(bromomethyl)-3,30-bis(3,5-diphenyl-
phenyl)-1,10-biphenyl (9h). To a suspension of LiAlH4
(142 mg, 3.0 mmol) in THF (3 mL) was added 8h
(783 mg, 1.0 mmol) portionwise at 0 ꢀC and the reaction
mixture was stirred for 4 h at room temperature. Then, ether
(3 mL) was added and the reaction was quenched by the
sequential treatment with H2O (142 mL), 15% NaOH
(142 mL), and H2O (284 mL). After 1 h of additional stirring,
this mixture was filtered through a pad of Celite and the
filtrate was concentrated. This crude 3,30-bis(3,5-diphenyl-
phenyl)-2,20-bis(hydroxymethyl)-1,10-biphenyl was used
for the subsequent bromination without further purification.
A THF (ca. 3 mL) solution of 3,30-bis(3,5-diphenylphenyl)-
2,20-bis(hydroxymethyl)-1,10-biphenyl (1.0 mmol) was
cooled to 0 ꢀC and PBr3 (52.8 mL, 0.5 mmol) was added
dropwise. The reaction mixture was stirred at room temper-
ature for 1 h and poured into H2O. Extractive workup was
performed with EtOAc and the combined extracts were dried
over Na2SO4. Removal of volatiles and purification of the
residue by column chromatography on silica gel (CH2Cl2/
hexane¼1:10 as eluent) gave 9h (605 mg, 0.76 mmol, 76%
1
6 (1.63 g, quant.) as a white powder; H NMR (400 MHz,
CDCl3) d 8.10 (2H, dd, J¼1.2, 7.5 Hz, ArH), 7.49 (2H, dt,
J¼1.2, 7.5 Hz, ArH), 7.42 (2H, dt, J¼1.2, 7.5 Hz, ArH),
7.18 (2H, dd, J¼1.2, 7.5 Hz, ArH), 4.92 (2H, sept,
J¼6.3 Hz, CH(CH3)2), 0.99 (6H, d, J¼6.3 Hz, CH3), 0.89
(6H, d, J¼6.3 Hz, CH3) ppm; 13C NMR (100 MHz, CDCl3)
d 166.4, 143.1, 130.7, 130.1, 129.9, 129.6, 126.7, 67.8,
21.3, 21.2 ppm; IR (KBr) 2974, 1699, 1599, 1439, 1373,
1350, 1288, 1105, 1049, 916, 770, 710 cmꢁ1; HRMS (ESI-
TOF) calcd for C20H22O4Na ([M+Na]+): 349.1411, found:
349.1410.
4.4.2. 3,30-Dibromo-2,20-bis(isopropoxycarbonyl)-1,10-
biphenyl (7). To a THF solution of (TMP)2Mg (0.31 M,
2.25 mmol)8 was added 6 (126 mg, 0.5 mmol) in THF
(2 mL) dropwise at 0 ꢀC under argon atmosphere and the

T. Ooi et al. / Tetrahedron 62 (2006) 11425–11436
11433
in two steps) as a white powder; 1H NMR (400 MHz,
CDCl3) d 7.87 (2H, t, J¼1.6 Hz, ArH), 7.75–7.73 (12H, m,
ArH), 7.50–7.43 (14H, m, ArH), 7.40–7.36 (4H, m, ArH),
4.43 (2H, d, J¼9.7 Hz, ArCH2), 4.30 (2H, d, J¼9.7 Hz,
ArCH2) ppm; 13C NMR (100 MHz, CDCl3) d 143.4,
141.5, 141.3, 140.9, 140.6, 133.2, 130.4, 129.8, 128.8,
128.0, 127.5, 127.2, 126.8, 125.0, 31.3 ppm; IR (KBr)
3038, 1593, 1580, 1497, 1410, 1217, 1030, 885, 758, 700,
615, 538 cmꢁ1. Fragment peaks could be detected; MS
(APCI) m/z 867.787 (M+).
ArCH2), 2.82 (2H, br, ArCH2), 2.04 (12H, br, CH3) ppm;
13C NMR (100 MHz, CDCl3) d 143.8, 142.6, 138.8, 138.3,
136.4, 134.1, 131.0, 130.8, 129.5, 129.2, 128.9, 128.4,
127.4, 127.3, 127.2, 126.9, 126.2, 124.1, 63.2, 57.8 ppm;
IR (thin film) 3335, 3053, 3007, 2949, 2916, 2176, 1599,
1578, 1508, 1456, 1379, 1360, 1304, 1250, 1225, 1200,
1030, 922, 908, 854, 837, 822, 793, 748, 727 cmꢁ1
;
HRMS (ESI-TOF) calcd for C52H44N (M+): 682.3464,
found: 682.3468; [a]D24 190.0 (c 0.25, CHCl3); mp 280–
283 ꢀC (dec).
4.4.5. Chiral quaternary ammonium salt (S)-4h (Ar1¼
3,5-diphenylphenyl). A mixture of 9h (398 mg, 0.5 mmol),
chiral secondary amine 5 (147 mg, 0.5 mmol), K2CO3
(139 mg, 1.0 mmol) in CH3CN (3 mL) was refluxed for
6 h. This mixture was poured into H2O and extracted with
CH2Cl2. The organic extracts were dried over Na2SO4 and
concentrated. The residue was purified by column chromato-
graphy on silica gel (MeOH/CH2Cl2¼1:30 to 1:10 as eluent)
to give 4h (440 mg, 0.435 mmol, 87%) as a white powder;
1H NMR (400 MHz, CDCl3) d 7.80–7.08 (44H, br m,
ArH), 4.83 (4H, d, J¼13.1 Hz, ArCH2), 4.57 (2H, d,
J¼13.5 Hz, ArCH2), 2.78 (2H, br, ArCH2) ppm; 13C NMR
(100 MHz, CDCl3) d 143.3, 142.6, 139.8, 139.6, 136.2,
133.7, 131.0, 130.7, 130.5, 130.0, 129.7, 129.2, 128.6,
128.4, 127.6, 127.0, 127.0, 126.9, 126.8, 126.6, 126.2,
124.8, 124.6, 63.3, 58.1 ppm; IR (KBr) 3399, 3055, 2959,
1593, 1574, 1499, 1454, 1414, 1358, 883, 825, 760,
4.4.9. Chiral quaternary ammonium salt (S)-4d (Ar1¼
3,5-di-tert-butylphenyl). White powder; 1H NMR
(400 MHz, CDCl3) d 7.95–6.79 (24H, m, ArH), 4.68 (2H,
d, J¼12.8 Hz, ArCH2), 4.53 (2H, d, J¼13.2 Hz, ArCH2),
4.15 (2H, d, J¼12.4 Hz, ArCH2), 2.58 (2H, d, J¼12.8 Hz,
ArCH2), 0.98 (18H, s, CH3), 0.86 (18H, s, CH3) ppm; 13C
NMR (100 MHz, CDCl3) d 150.6, 144.3, 142.0, 137.8,
135.8, 133.6, 130.5, 130.3, 129.8, 128.3, 128.1, 127.0,
126.5, 126.3, 125.7, 124.6, 122.2, 120.6, 63.5, 58.5 ppm;
IR (thin film) 3337, 3055, 2961, 2903, 2868, 2174, 1707,
1593, 1578, 1464, 1427, 1395, 1362, 1250, 1223, 1200,
1032, 924, 907, 880, 839, 826, 787, 750, 723 cmꢁ1
;
HRMS (ESI-TOF) calcd for C64H68N (M+): 850.5345,
found: 850.5346; [a]D22 101.5 (c 0.25, CHCl3); mp 354–
356 ꢀC (dec).
4.4.10. Chiral quaternary ammonium salt (S)-4e (Ar1¼
3,4,5-trifluorophenyl). White powder; 1H NMR (400 MHz,
CDCl3) d 8.01–7.99 (6H, m, ArH), 7.74–7.73 (4H, m, ArH),
7.60 (2H, t, J¼7.4 Hz, ArH), 7.41–7.29 (6H, m, ArH), 7.26
(2H, s, ArH), 7.01 (2H, br, ArH), 5.04 (2H, d, J¼11.8 Hz,
ArCH2), 4.85 (2H, d, J¼13.3 Hz, ArCH2), 4.32 (2H, d,
J¼13.3 Hz, ArCH2), 2.89 (2H, d, J¼12.6 Hz, ArCH2) ppm;
13C NMR (100 MHz, CDCl3) d 150.6 (d, JC–F¼257 Hz),
142.4, 140.5, 137.9, 136.7, 134.8 (m), 134.2, 131.4, 131.1,
130.7, 130.2, 129.9, 128.7, 127.8, 127.4, 127.0, 126.1,
124.3, 114.0, 63.7, 58.3 ppm; IR (thin film) 3055, 3011,
2955, 2926, 2893, 1614, 1526, 1422, 1362, 1281, 1246,
1209, 1146, 1043, 922, 908, 891, 866, 837, 822, 795, 764,
748, 731 cmꢁ1; HRMS (ESI-TOF) calcd for C48H30NF6
(M+): 734.2269, found: 734.2277; [a]2D4 147.3 (c 0.25,
CHCl3); mp 293–295 ꢀC (dec).
696 cmꢁ1
;
HRMS (FAB) calcd for C72H62N (M+):
930.4103, found: 930.4101; [a]2D4 55.0 (c 0.25, CHCl3);
mp 243–245 ꢀC (dec).
4.4.6. Chiral quaternary ammonium salt (S)-4a (Ar1¼H).
White powder; 1H NMR (400 MHz, CDCl3) d 8.28 (2H, d,
J¼8.3 Hz, ArH), 8.08–8.04 (4H, m, ArH), 7.88 (2H, br d,
J¼6.3 Hz, ArH), 7.74–7.68 (6H, m, ArH), 7.64–7.60 (2H,
m, ArH), 7.44 (2H, d, J¼8.7 Hz, ArH), 7.39–7.36 (2H, m,
ArH), 4.75 (2H, d, J¼13.1 Hz, ArCH2), 4.32 (2H, d,
J¼13.1 Hz, ArCH2), 3.99 (2H, d, J¼13.5 Hz, ArCH2),
3.93 (2H, d, J¼13.1 Hz, ArCH2) ppm; 13C NMR
(100 MHz, CDCl3) d 140.8, 136.7, 134.4, 132.0, 131.8,
131.3, 130.8, 129.7, 129.3, 128.6, 127.7, 127.6, 127.5,
127.3, 126.3, 125.5, 61.4, 60.9 ppm; IR (KBr) 3638, 3385,
3053, 2359, 1622, 1456, 1354, 1200, 1028, 878, 854, 818,
758 cmꢁ1
;
HRMS (FAB) calcd for C36H28N (M+):
4.4.11. Chiral quaternary ammonium salt (S)-4f [Ar1¼
1
474.2223, found: 474.2238; [a]2D8 ꢁ110.2 (c 0.25, CHCl3).
4.4.7. Chiral quaternary ammonium salt (S)-4b (Ar1¼
3,5-bis(trifluoromethyl)phenyl]. White powder; H NMR
(400 MHz, CDCl3) d 8.09–7.23 (24H, m, ArH), 5.27 (2H,
d, J¼12.3 Hz, ArCH2), 4.96 (2H, d, J¼13.5 Hz, ArCH2),
4.07 (2H, d, J¼13.5 Hz, ArCH2), 2.52 (2H, d, J¼12.3 Hz,
ArCH2) ppm; 13C NMR (100 MHz, CDCl3) d 142.6, 141.4,
140.3, 136.7, 134.1, 131.5, 131.0, 130.6, 130.6, 129.7,
128.4, 127.4, 127.0, 126.9, 126.7, 126.0, 124.5, 122.5 (q,
1JC–F¼273 Hz), 121.1 (m), 63.1, 58.0 ppm; IR (thin film)
3057, 3011, 2986, 2953, 2891, 1618, 1508, 1458, 1377,
1277, 1173, 1132, 1051, 1030, 922, 903, 870, 847, 835,
820, 791, 731, 714 cmꢁ1; HRMS (ESI-TOF) calcd for
C52H32NF12 (M+): 898.2303, found: 898.2338; [a]2D4 116.4
(c 0.25, CHCl3); mp 316–318 ꢀC (dec).
1
Ph). White powder; H NMR (400 MHz, CDCl3) d 7.93–
7.04 (28H, br, ArH), 4.61 (4H, br, ArCH2), 4.41 (2H, d,
J¼13.3 Hz, ArCH2), 2.71 (2H, br, ArCH2) ppm; 13C NMR
(100 MHz, CDCl3) d 143.4, 142.5, 138.8, 136.2, 133.9,
130.9, 130.6, 129.5, 129.1, 128.3, 127.5, 127.1, 127.0,
126.7, 126.0, 124.1, 63.1, 57.7 ppm; IR (thin film) 3356,
3055, 2955, 2891, 2178, 1595, 1508, 1464, 1360, 1250,
1196, 1030, 922, 870, 839, 826, 797, 760, 727, 706 cmꢁ1
;
HRMS (ESI-TOF) calcd for C48H36N (M+): 626.2842,
found: 626.2842; [a]D24 213.9 (c 0.25, CHCl3); mp 298–
299 ꢀC (dec).
4.4.12. Chiral quaternary ammonium salt (S)-4g (Ar1¼
4.4.8. Chiral quaternary ammonium salt (S)-4c (Ar1¼
2-naphthyl). White powder; H NMR (400 MHz, CDCl3)
d 8.10–7.20 (18H, br m, ArH), 7.79 (4H, t, J¼7.9 Hz,
1
1
3,5-dimethylphenyl). White powder; H NMR (400 MHz,
CDCl3) d 7.96–6.49 (24H, br, ArH), 4.56–4.45 (6H, m,
ArH), 7.34 (4H, t, J¼7.1 Hz, ArH), 7.05 (2H, t, J¼7.5 Hz,

11434
T. Ooi et al. / Tetrahedron 62 (2006) 11425–11436
ArH), 6.90 (2H, d, J¼8.7 Hz, ArH), 4.83 (2H, br, ArCH2),
4.56–7.52 (4H, br, ArCH2), 2.98 (2H, br, ArCH2) ppm;
13C NMR (100 MHz, CDCl3) d 143.4, 142.7, 136.2, 135.8,
133.5, 132.8, 132.2, 131.7, 130.9, 130.3, 129.3, 129.0,
128.8, 128.6, 127.9, 127.5, 127.2, 126.8, 126.8, 126.7,
126.5, 126.4, 126.3, 125.5, 124.0, 63.0, 57.6 ppm; IR (thin
film) 3383, 3051, 1622, 1595, 1504, 1456, 1357, 1197,
864, 821, 797, 752 cmꢁ1; HRMS (FAB) calcd for C56H40N
(M+): 726.3163, found: 726.3167; [a]2D2 174.2 (c 0.25,
CHCl3); mp 202–203 ꢀC (dec).
J¼7.9 Hz, ArH), 7.67 (2H, dd, J¼1.6, 7.9 Hz, ArH), 7.64–
7.61 (4H, m, ArH), 7.48 (2H, d, J¼1.6 Hz, ArH), 7.45–
7.42 (4H, m, ArH), 7.38–7.34 (2H, m, ArH), 4.95 (2H,
sept, J¼6.3 Hz, CH(CH3)2), 1.00 (6H, d, J¼2.4 Hz, CH3),
0.89 (6H, d, J¼2.4 Hz, CH3) ppm; 13C NMR (100 MHz,
CDCl3) d 166.3, 143.9, 143.7, 139.7, 130.6, 129.0, 128.8,
128.7, 127.9, 127.1, 125.4, 68.0, 21.5, 21.4 ppm; IR (KBr)
2982, 1695, 1604, 1452, 1383, 1288, 1148, 1105, 916,
851, 760, 698 cmꢁ1
; HRMS (ESI-TOF) calcd for
C32H30O4Na ([M+Na]+): 501.2037, found: 501.2036.
4.5. Typical procedure for the synthesis of (S)-4i–k and
their characterizations
4.5.4. 2,20-Bis(bromomethyl)-5,50-diphenyl-1,10-biphenyl
(13a). The title compound was obtained as described for
the synthesis of 9h; H NMR (400 MHz, CDCl3) d 7.69–
1
4.5.1. 4-Phenylbenzoic acid isopropyl ester (10a). The title
compound was prepared from 4-phenylbenzoic acid, and the
esterification was conducted as described for the synthesis
of 6 [chromatography on silica gel (short-pass, EtOAc/
hexane¼1:4 as eluent), colorless oil, quant.]; 1H NMR
(400 MHz, CDCl3) d 8.10 (2H, d, J¼8.3 Hz, ArH), 7.64
(2H, d, J¼7.9 Hz, ArH), 7.60 (2H, d, J¼7.5 Hz, ArH), 7.46–
7.43 (2H, m, ArH), 7.39–7.35 (1H, m, ArH), 5.28 (1H, sept,
J¼6.3 Hz, CH(CH3)2), 1.38 (6H, d, J¼6.3 Hz, CH3) ppm;
13C NMR (100 MHz, CDCl3) d 165.7, 145.2, 139.9, 129.9,
129.5, 128.7, 127.9, 127.1, 126.8, 68.3, 22.0 ppm; IR (neat)
2980, 1713, 1611, 1478, 1404, 1279, 1178, 1101, 1009, 920,
7.63 (8H, m, ArH), 7.59 (2H, d, J¼1.7 Hz, ArH), 7.44
(4H, t, J¼7.5 Hz, ArH), 7.36 (2H, t, J¼7.5 Hz, ArH), 4.46
(2H, d, J¼10.2 Hz, CH2), 4.30 (2H, d, J¼9.9 Hz, CH2) ppm;
13C NMR (100 MHz, CDCl3) d 141.2, 139.9, 139.8, 131.2,
128.9, 128.8, 127.8, 127.3, 127.2, 31.9 ppm; IR (thin film)
3057, 3028, 2972, 2924, 2853, 1601, 1564, 1477, 1437,
1379, 1223, 1204, 903, 864, 837, 820, 756, 733 cmꢁ1
.
Fragment peaks could only be detected; MS (APCI) m/z
411.331 (M+).
4.5.5. Chiral quaternary ammonium salt (S)-4i (Ar2¼
phenyl). White powder; 1H NMR (400 MHz, CDCl3)
d 8.32 (2H, d, J¼8.5 Hz, ArH), 8.10 (2H, d, J¼8.5 Hz,
ArH), 8.09 (2H, d, J¼8.2 Hz, ArH), 8.03–7.92 (4H, m,
ArH), 7.94 (2H, s, ArH), 7.71–7.69 (4H, m, ArH), 7.65–
7.61 (2H, m, ArH), 7.52–7.37 (10H, m, ArH), 4.77 (2H, d,
J¼13.3 Hz, ArCH2), 4.43 (2H, d, J¼13.3 Hz, ArCH2), 4.04
(4H, t, d, J¼13.9 Hz, ArCH2) ppm; 13C NMR (100 MHz,
CDCl3) d 145.0, 141.4, 139.4, 136.9, 134.6, 132.8, 131.5,
131.0, 129.1, 128.8, 128.5, 128.4, 128.1, 127.9, 127.7,
127.5, 127.4, 125.7, 125.4, 61.4, 60.6 ppm; IR (thin film)
3055, 3030, 2955, 2924, 2853, 2158, 1730, 1597, 1558,
1508, 1485, 1454, 1356, 1261, 1157, 1028, 1016, 923, 889,
864, 824, 799, 760, 725 cmꢁ1; HRMS (ESI-TOF) calcd for
C48H36N (M+): 626.2855, found: 626.2842; [a]2D6 ꢁ208.0
(c 0.25, CHCl3); mp 323–326 ꢀC (dec).
858, 748, 698 cmꢁ1
; HRMS (ESI-TOF) calcd for
C16H16O2Na ([M+Na]+): 263.1041, found: 263.1043.
4.5.2. 2-Iodo-4-phenylbenzoic acid isopropyl ester (11a).
To a THF solution of (TMP)2Mg (0.31 M, 12.5 mmol)8
was added 10a (1.20 g, 5.0 mmol) in THF (20 mL) dropwise
at 0 ꢀC under argon atmosphere and the mixture was stirred
for 3 h at room temperature. After being cooled to ꢁ78 ꢀC,
a THF (5 mL) solution of I2 (7.63 g, 30.0 mmol) was added
and stirring was continued for 1 h at room temperature. This
mixture was then poured into cooled 1 N HCl, washed with
saturated Na2SO3, and extracted with Et2O. The organic
layer was dried over Na2SO4 and concentrated. Purification
of the residue by column chromatography on silica gel
(EtOAc/hexane¼1:20 to 1:10 as eluent) afforded 11a
(1.54 g, 4.20 mmol, 84%) as an yellow oil; 1H NMR
(400 MHz, CDCl3) d 8.21 (1H, d, J¼2.0 Hz, ArH), 7.85
(1H, d, J¼7.9 Hz, ArH), 7.60 (1H, dd, J¼2.0, 7.9 Hz,
ArH), 7.58–7.55 (2H, m, ArH), 7.48–7.44 (2H, m, ArH),
7.42–7.38 (1H, m, ArH), 5.29 (1H, sept, J¼6.3 Hz,
CH(CH3)2), 1.42 (6H, d, J¼6.3 Hz, CH3) ppm; 13C NMR
(100 MHz, CDCl3) d 165.6, 145.1, 139.6, 138.2, 133.8,
130.9, 128.8, 128.3, 127.0, 126.3, 94.5, 69.4, 21.9 ppm; IR
(neat) 2980, 1720, 1593, 1468, 1373, 1285, 1250, 1103,
4.5.6. Chiral quaternary ammonium salt (S)-4j (Ar2¼
1
2-naphthyl). White powder; H NMR (400 MHz, CDCl3)
d 8.33 (2H, d, J¼8.2 Hz, ArH), 8.19 (2H, s, ArH), 8.14–
8.07 (10H, m, ArH), 7.98 (2H, d, J¼8.7 Hz, ArH), 7.96–
7.93 (2H, m, ArH), 7.91–7.88 (2H, m, ArH), 7.84 (2H, dd,
J¼1.7, 8.5 Hz, ArH), 7.64 (2H, t, J¼7.0 Hz, ArH), 7.56–
7.52 (4H, m, ArH), 7.48 (2H, d, J¼8.5 Hz, ArH), 7.40
(2H, t, J¼7.6 Hz, ArH), 4.83 (2H, d, J¼13.1 Hz, ArCH2),
4.47 (2H, d, J¼13.5 Hz, ArCH2), 4.16 (2H, d, J¼13.1 Hz,
ArCH2), 4.05 (2H, d, J¼12.1 Hz, ArCH2) ppm; 13C NMR
(100 MHz, CDCl3) d 145.0, 141.6, 136.9, 136.7, 134.6,
133.6, 133.1, 132.9, 131.5, 131.0, 128.9, 128.8, 128.8,
128.4, 127.9, 127.7, 127.7, 127.5, 126.7, 126.6, 126.6,
125.7, 125.4, 125.3, 61.5, 60.6 ppm; IR (thin film) 3313,
3196, 3053, 2172, 1609, 1597, 1558, 1506, 1497, 1456,
1395, 1348, 1192, 1028, 1018, 924, 908, 872, 816, 750,
727 cmꢁ1; HRMS (ESI-TOF) calcd for C56H40N (M+):
726.3155, found: 726.3155; [a]2D6 ꢁ127.9 (c 0.25, CHCl3);
mp 329–330 ꢀC (dec).
1015, 756, 693 cmꢁ1
; HRMS (ESI-TOF) calcd for
C16H15O2INa ([M+Na]+): 389.0006, found: 389.0009.
4.5.3. 2,20-Bis(isopropoxycarbonyl)-5,50-diphenyl-1,10-bi-
phenyl (12a). The solution of 11a (1.46 g, 4.0 mmol) in dry
DMF (4 mL) was added activated Cu (2.0 g) and the mixture
was refluxed for 3 days. After cooling to room temperature,
the resulting mixture was filtered through a pad of Celite to
remove Cu. This filtrate was washed with 1 N HCl and brine,
and concentrated. Purification of the crude product by col-
umn chromatography on silica gel (EtOAc/hexane¼1:20
as eluent) furnished 12a (746 mg, 1.56 mmol, 78%) as a
4.5.7. Chiral quaternary ammonium salt (S)-4k (Ar2¼
3,4,5-trifluorophenyl). White powder; 1H NMR (400 MHz,
1
white powder; H NMR (400 MHz, CDCl3) d 8.13 (2H, d,

T. Ooi et al. / Tetrahedron 62 (2006) 11425–11436
11435
CDCl3) d 8.29 (2H, d, J¼8.0 Hz, ArH), 8.10–8.06 (4H, m,
ArH), 8.00 (2H, br, ArH), 7.87–7.82 (4H, m, ArH), 7.64
(2H, t, J¼7.3 Hz, ArH), 7.47–7.38 (4H, m, ArH), 7.33 (3H,
t, J¼7.1 Hz, ArH), 7.23 (1H, d, J¼6.5 Hz, ArH), 4.92–4.85
(2H, m, ArCH2), 4.42 (2H, br, ArCH2), 4.32–4.16 (2H, m,
ArCH2), 4.00 (2H, br, ArCH2) ppm; 13C NMR (100 MHz,
CDCl3) d 152.9, 152.8, 152.8, 152.7, 151.5 (ddd, JC–F¼4.1,
9.8, 51.6 Hz), 150.3, 150.3, 150.2, 150.2, 142.0, 141.4,
139.9 (dt, JC–F¼15.5, 15.5, 254 Hz), 136.9, 135.6 (dd,
JC–F¼7.4, 12.3 Hz), 134.6, 133.2, 131.5, 131.0, 128.8,
128.6, 128.0, 127.9, 127.7, 127.7, 127.6, 126.6, 125.5,
111.7 (m), 61.4, 60.1 ppm; IR (thin film) 3352, 3049, 2986,
2932, 2178, 1618, 1595, 1568, 1499, 1443, 1393, 1360,
4.6.4. Chiral quaternary ammonium salt (S)-4l (Ar1¼3,5-
diphenylphenyl, Ar2¼Ph). White powder; 1H NMR
(400 MHz, CDCl3) d 8.02–7.10 (52H, br m, ArH), 4.96
(2H, d, J¼13.5 Hz, ArCH2), 4.85 (2H, br, ArCH2), 4.65
(2H, d, J¼13.1 Hz, ArCH2), 2.77 (2H, br, ArCH2) ppm;
13C NMR (100 MHz, CDCl3) d 143.9, 143.6, 139.5, 136.1,
133.6, 130.4, 129.6, 128.8, 128.5, 128.2, 128.1, 127.8,
127.6, 127.4, 126.9, 126.7, 126.5, 63.3, 58.0 ppm; IR
(KBr) 3370, 3057, 3033, 1593, 1497, 1456, 1383, 1354,
1028, 881, 819, 760, 698 cmꢁ1; HRMS (FAB) calcd for
C84H60N: 1082.4729 (M+), found: 1082.4713 (M+); [a]2D5
41.2 (c 0.25, CHCl3); mp 303–306 ꢀC (dec).
1296, 1242, 1119, 989, 908, 874, 822, 764, 752, 727 cmꢁ1
;
4.7. X-ray structure determination of chiral quaternary
ammonium salt (S)-4l
HRMS (ESI-TOF) calcd for C48H30NF6: 734.2274 (M+),
found: 734.2277 (M+); [a]D22 ꢁ210.3 (c 0.25, CHCl3); mp
308–310 ꢀC (dec).
The single crystal of (S)-4l (colorless needle) was obtained
by recrystallization from CH2Cl2/hexane solvent system
and was mounted on a CryoLoop (Hampton Research Co.
Ltd). Data of X-ray diffraction were collected by a Rigaku
RAXIS-RAPID Imaging Plate two-dimensional area detec-
tor using graphite-monochromated Mo Ka radiation (l¼
4.6. Synthesis of (S)-4l
Chiral quaternary ammonium salt (S)-4l was prepared from
12a in a manner similar to the preparation of (S)-4b–h from
6. Characterizations of each intermediate and (S)-4l are as
follows.
ꢀ
˚
0.71069 A) to a maximum 2q value of 55 . All of the crys-
tallographic calculations were performed using teXsan soft-
ware package of the Molecular Structure Corp. The crystal
structure was solved by the direct methods and refined by
the full-matrix least squares using SIR-97. All non-hydrogen
atoms and hydrogen atoms were refined anisotropically and
isotropically, respectively. The crystallographic data were
summarized in the following table.
4.6.1. 3,30-Dibromo-2,20-bis(isopropoxycarbonyl)-5,50-
1
diphenyl-1,10-biphenyl (14). H NMR (400 MHz, CDCl3)
d 7.84 (2H, d, J¼1.6 Hz, ArH), 7.58–7.54 (6H, m, ArH),
7.46–7.44 (4H, m, ArH), 7.41–7.37 (2H, m, ArH), 5.00
(2H, sept, J¼6.3 Hz, CH(CH3)2), 1.12 (6H, d, J¼1.6 Hz,
CH3), 0.89 (6H, d, J¼1.6 Hz, CH3) ppm; 13C NMR
(100 MHz, CDCl3) d 165.8, 142.7, 138.7, 138.0, 134.3,
130.4, 128.8, 128.3, 127.4, 126.9, 119.7, 69.3, 21.5,
21.0 ppm; IR (KBr) 2980, 1722, 1595, 1537, 1499, 1373,
Experimental details
Empirical formula C87H66BrNCl6 T, ꢀC
ꢁ150.0
Formula weight
Crystal system
Space group
1418.11
m (Mo Ka), cmꢁ1
No. of reflns measrd 30,354
8.75
1281, 1177, 1141, 1101, 1043, 916, 883, 758, 696 cmꢁ1
;
Monoclinic
P21 (#4)
12.8560 (6)
18.0233 (8)
15.0569 (9)
3463.9 (3)
2
HRMS (ESI-TOF) calcd for C32H28O4Br2Na ([M+Na]+):
657.0264, found: 657.0247.
No. of reflns obsd
No. of variable
R1
8194
856
0.048
0.123
1.20
˚
a, A
˚
b, A
˚
4.6.2. 2,20-Bis(isopropoxycarbonyl)-3,30-bis(3,5-diphe-
nylphenyl)-5,50-diphenyl-1,10-biphenyl (15). 1H NMR
(400 MHz, CDCl3) d 7.83 (2H, s, ArH), 7.75 (2H, s, ArH),
7.71–7.65 (18H, m, ArH), 7.48–7.33 (18H, m, ArH), 4.76
(2H, sept, J¼6.3 Hz, CH(CH3)2), 0.82 (6H, d, J¼6.3 Hz,
CH3), 0.68 (6H, d, J¼6.3 Hz, CH3) ppm; 13C NMR
(100 MHz, CDCl3) d 167.8, 141.6, 141.4, 141.3, 140.6,
140.6, 139.4, 138.9, 132.5, 128.7, 128.6, 127.7, 127.7,
127.6, 127.5, 127.3, 127.1, 127.0, 126.2, 125.1, 68.4, 21.2,
20.9 ppm; IR (KBr) 2983, 1720, 1593, 1497, 1450, 1387,
1277, 1101, 1078, 881, 760, 698 cmꢁ1; HRMS (ESI-TOF)
calcd for C68H54O4Na ([M+Na]+): 957.3948, found:
957.3914.
c, A
wR
3
˚
V, A
Goodness of fit
Max shift/error
in final cycle
Z
0.002
Dcalcd, g cmꢁ3
1.360
Acknowledgements
This work was partially supported by a Grant-in-Aid for Sci-
entific Research on Priority Areas ‘Advanced Molecular
Transformation of Carbon Resources’ from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
M.K. is grateful to the Japan Society for the Promotion of
Science for Young Scientists for a research fellowship.
4.6.3. 2,20-Bis(bromomethyl)-3,30-bis(3,5-diphenyl-
phenyl)-5,50-diphenyl-1,10-biphenyl (16). 1H NMR
(400 MHz, CDCl3) d 7.90 (2H, s, ArH), 7.83 (4H, s, ArH),
7.79–7.71 (16H, m, ArH), 7.50–7.34 (18H, m, ArH), 4.54
(2H, d, J¼9.7 Hz, ArCH2), 4.40 (2H, d, J¼9.7 Hz,
ArCH2) ppm; 13C NMR (100 MHz, CDCl3) d 144.0, 141.6,
141.4, 141.3, 140.6, 139.5, 132.1, 129.0, 128.8, 128.8,
128.4, 127.8, 127.5, 127.3, 127.1, 126.8, 125.2, 31.3 ppm;
IR (KBr) 3058, 3032, 1592, 1496, 1448, 1411, 1389, 1217,
1075, 1028, 881, 759, 696 cmꢁ1. Fragment peaks could
only be detected; MS (APCI) m/z 867.787 (M+).
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T. Ooi et al. / Tetrahedron 62 (2006) 11425–11436
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