Axial chirality in biaryl N,N-dialkylaminopyridine derivatives bearing an internal carboxy group

Article abstract of DOI:10.1002/chir.23207

Axial chirality in N,N-dimethylaminopyridines as well as N,N-dipropylaminopyridines bearing an internal carboxy group were evaluated based on their racemization barriers and circular dichroism spectra. The half-life of racemization of N,N-dipropylaminopyridine derivative 2 was estimated to be 19.7 days at 20°C. Its enantiomers isolated as optically active forms showed positive-negative and negative-positive Cotton effects for (+)-2 and (?)-2, respectively, from 310 to 210 nm. Furthermore, (?)-2 was applied as a chiral nucleophilic catalyst and exhibited asymmetric induction in acylative kinetic resolution of 1-(1-naphthyl)ethane-1-ol.

Full text of DOI:10.1002/chir.23207

Received: 15 January 2020
DOI: 10.1002/chir.23207
Revised: 25 January 2020
Accepted: 27 January 2020
S P E C I A L I S S U E A R T I C L E
Axial chirality in biaryl N,N-dialkylaminopyridine
derivatives bearing an internal carboxy group
Reiko Nishino1 | Shohei Hamada2
| Elghareeb E. Elboray2,3
|
Yoshihiro Ueda1 | Takeo Kawabata1 | Takumi Furuta2
1Institute for Chemical Research, Kyoto
Abstract
University, Uji, Japan
2Department of Pharmaceutical
Chemistry, Kyoto Pharmaceutical
University, Kyoto, Japan
3Chemistry Department, Faculty of
Science, South Valley University, Qena,
Egypt
Axial chirality in N,N-dimethylaminopyridines as well as N,N-
dipropylaminopyridines bearing an internal carboxy group were evaluated
based on their racemization barriers and circular dichroism spectra. The half-
life of racemization of N,N-dipropylaminopyridine derivative 2 was estimated
to be 19.7 days at 20ꢀC. Its enantiomers isolated as optically active forms
showed positive-negative and negative-positive Cotton effects for (+)-2 and
(−)-2, respectively, from 310 to 210 nm. Furthermore, (−)-2 was applied as a
chiral nucleophilic catalyst and exhibited asymmetric induction in acylative
kinetic resolution of 1-(1-naphthyl)ethane-1-ol.
Correspondence
Takumi Furuta, Department of
Pharmaceutical Chemistry, Kyoto
Pharmaceutical University, Yamashina-
ku, Kyoto 607-8414, Japan.
Email: furuta@mb.kyoto-phu.ac.jp
K E Y W O R D S
axial chirality, circular dichroism acylative kinetic resolution, DMAP derivative
Funding information
Ministry of Education, Culture, Sports,
Science and Technology, Japan
1 | INTRODUCTION
ring. This carboxylate ion was thought to work as a
general base in the transition state (TS-1) for accelerat-
Chiral N,N-dimethylaminopyridine (DMAP) derivatives
have attracted attention as asymmetric nucleophilic cata-
lysts for stereoselective acylations in kinetic resolution of
chiral alcohols and amines, as well as desymmetrization
of meso-diols.1-5 DMAP derivatives possessing central chi-
rality have been well developed6; however, only a few
DMAP derivatives bearing molecular asymmetry such as
axial chirality,7-22 planer chirality,23-25 and other miscel-
laneous chirality26-30 have been investigated.
We have previously prepared biaryl DMAP deriva-
tive 1a bearing an internal carboxy group modified at
the peri-position of the naphthyl moiety (Figure 1).31
Its corresponding carboxylate ion 1b prepared from 1a
showed high catalytic activity for acylation of an alco-
hol with acid anhydride by virtue of the internal car-
boxylate ion located in close proximity to the pyridine
ing the nucleophilic attack by the alcohol hydroxy
group to the carbonyl group of the acylpyridinium ion
generated from 1b and acid anhydride (Scheme 1).
Indeed, the acylation kinetics of catalyst 1a were
greatly enhanced from the reaction with catalyst 1d
without a carboxylate ion as well as with catalyst 1c
possessing a methyl ester moiety instead of the carbox-
ylate ion (Scheme 1).31
On the other hand, biaryl compounds such as 3,
possessing the substituents at ortho- and peri-positions of
aryl and naphthyl moieties, respectively, are also known
as axially chiral compounds.32 We envisioned that the
carboxy group of 1a and 1b modified at the peri-position
of the naphthyl moiety play a role not only in the acceler-
ation of acylation but also in generating axial chirality in
these molecules. This hypothesis led us to investigate the
chiroptical properties of 1a and its derivative 2 bearing
an N,N-dipropylamino group and their potential as axi-
ally chiral compounds.
This paper is dedicated to the memory of Professor Koji Nakanishi, who
passed away on March 28, 2019.
Chirality. 2020;1–6.
wileyonlinelibrary.com/journal/chir
© 2020 Wiley Periodicals, Inc.
1

2
NISHINO ET AL.
(100-200 mesh). Thin-layer chromatography (TLC) analy-
sis was performed on commercial glass plates bearing a
0.25-mm layer and layer of Merck Kiesel-gel 60 F254
.
Analytical high-performance liquid chromatography
(HPLC) was performed with a JASCO PU-2089 Plus or
PU-4180 instrument, equipped with
a
Daicel
CHIRALPAK ID (4.6 mm × 250 mm) or CHIRALCEL
OD (4.6 mm × 250 mm), and a JASCO UV-2075 Plus or
UV-4075 UV/Vis detector (detection: 254 nm). Prepara-
tive HPLC was performed with a JASCO PU-2089 Plus or
PU-4180 instrument, equipped with
a
Daicel
CHIRALPAK ID (10 mm × 250 mm), and a JASCO UV-
2075 Plus or UV-4075 UV/Vis detector (detection:
254 nm).
FIGURE 1 Structure of biaryl compounds bearing the
substituents at ortho- and peri-positions
2.1 | Synthetic procedures
2.2 | 8-[4-(Dipropylamino)pyridine-3-yl]-
1-naphthonitrile (6)
A mixture of 4 (994 mg, 3.88 mmol), 5 (1.30 g, 4.66 mmol),
Pd (PPh3)4 (902 mg, 0.78 mmol), and K3PO4 (2.47 g,
11.6 mmol) in dimethylformamide (20 mL) was stirred
for 2 days at 120ꢀC under Ar atmosphere. The reaction
mixture was diluted with AcOEt and extracted with 1 N
aqueous HCl. The extract was basified with saturated
aqueous NaHCO3 and extracted with AcOEt. The organic
layer was washed with H2O, brine, dried over Na2SO4, fil-
tered, and evaporated. The residue was purified by silica
gel column chromatography (AcOEt to AcOEt/MeOH =
20/1) to give 6 (659 mg, 52%) as yellow amorphous.
1H NMR (400 MHz, CDCl3) δ 8.39 (1H, d, J = 6.0 Hz),
8.15 (1H, d, J = 6.8 Hz), 8.14 (1H, s), 8.05–7.90 (2H, m),
7.65 (1H, t, J = 7.2 Hz), 7.62–7.51 (2H, m), 6.79 (1H, d,
J = 6.0 Hz), 2.88–2.71 (4H, m), 1.38–1.20 (4H, m), 0.52
(6H, t, J = 7.6 Hz). 13C NMR (125 MHz, CDCl3) δ 155.8,
152.3, 149.7, 136.6, 136.4, 134.1, 134.0, 131.1, 130.4, 129.1,
127.0, 125.1, 124.3, 118.1, 111.8, 109.5, 52.7, 20.3, 11.1. IR
(neat) cm−1: 2963, 2872, 2216, 1585, 1502, 1369, 832, 774;
HRMS (FAB, m/z): [M+H]+ calcd for C22H24N3,
330.1970; found, 330.1968.
SCHEME 1 Acylation catalyzed by 1b through the transition
state (TS-1) involving an internal carboxylate ion
Herein, we report on the optical stability of 1a and 2,
as well as on initial investigations of 2 as an asymmetric
nucleophilic catalyst in acylative kinetic resolution.
2 | MATERIALS AND METHODS
Nuclear magnetic resonance (NMR) spectra were
obtained with a Bruker UltraShield 300 spectrometer, a
JEOL ECX-400 PKT Spectrometer, and a Bruker Ascend
500 Spectrometer, with chemical shift being given in
ppm units (1H NMR in CDCl3: CHCl3 as internal stan-
dards, indicating 7.26; tetramethylsilane as internal stan-
dards, indicating 0; and 13C NMR in CDCl3: CDCl3 as
internal standards, indicating 77.1; spin-spin coupling
constants were given in Hz units). Infrared (IR) spectra
were recorded with a JASCO FT-IR 4200 Spectrometer.
High-resolution mass spectrometry (HRMS) was recorded
with a JEOL JMS-DX 300 (for FAB) or JMS 700 mass
spectrometer. Specific rotation was measured with a
JASCO P-2200 Polarimeter. Circular dichroism
(CD) spectra were recorded with a JASCO J-720W Spec-
tropolarimeter. Silica gel column chromatography was
carried out by using Silica gel 60 N (spherical, neutral,
63-210 μm, Kanto Chemical Co., Inc.) or Wako gel C-200
2.2.1 | 8-[4-(Dipropylamino)pyridine-
3-yl]-1-naphthaldehyde (7)
DIBAL (5.2 mL, 5.3 mmol, 1.02 mol/L in toluene) was
added to a solution of 6 (184 mg, 0.59 mmol) in toluene
(2 mL) at −78ꢀC under Ar atmosphere. The mixture was
warmed to room temperature with stirring for 1 hour.

NISHINO ET AL.
3
AcOEt (2 mL), MeOH (2 mL), and 1 N aqueous HCl was
added to the mixture at −78ꢀC and stirred for 1 hour at
room temperature. The reaction was basified with satu-
rated aqueous NaHCO3, and 0.17 g/mL of aqueous
Rochelle's salt at 0ꢀC was added to the mixture and
stirred for 1 hour at room temperature. The mixture was
extracted with AcOEt, and the organic layer was washed
with brine, dried over anhydrous Na2SO4, filtered, and
evaporated. The crude residue was purified by silica gel
column chromatography (AcOEt to AcOEt/MeOH =
20/1) to afford 7 (71 mg, 55%) as a yellow amorphous.
1H NMR (500 MHz, CDCl3) δ 9.70 (1H, s), 8.34 (1H,
d, J = 6.0 Hz), 8.31 (1H, s), 8.10 (1H, dd, J = 8.1, 1.4 Hz),
7.97 (1H, dd, J = 7.9, 1.7 Hz), 7.89 (1H, dd, J = 7.1, 1.5
Hz), 7.66–7.56 (3H, m), 6.72 (1H, d, J = 6.0 Hz), 2.67–2.61
(4H, m), 1.30–1.18 (2H, m), 1.15–1.03 (2H, m), 0.52 (6H,
t, J = 7.4 Hz). 13C NMR (100 MHz, CDCl3) δ192.4, 154.2,
152.3, 149.6, 136.1, 135.8, 134.6, 134.5, 130.2, 130.1, 129.2,
129.1, 127.2, 126.6, 125.6, 111.7, 52.3, 20.3, 11.2. IR (neat)
cm−1: 2962, 2872, 1683, 1580, 1495, 1460, 984, 832,
811, 774; HRMS (FAB, m/z): [M+H]+ calcd for
C22H25N2O, 333.1967; found, 333.1965.
124.6, 122.9, 108.2, 53.4, 19.9, 10.8. IR (neat) cm−1: 2961,
2926, 1640, 1514, 1462, 1359, 777; HRMS (FAB, m/z): [M
+H]+ calcd for C22H25N2O2, 349.1916; found, 349.1921.
2.2.3 | Optical resolution of 2
A solution of racemic 2 (1.0 mg) in CHCl3 (0.1 mL) was
applied for one injection to a preparative HPLC with chi-
ral stationary phase (column: CHIRALPAK ID, 10 mm ×
250
mm;
eluent:
hexane/EtOH/TFA/Et3N
=
85/15/0.5/0.1, flow rate: 0.7 mL/min, detection: 254 nm).
The separation was repeated 12 times. Collected fractions
for each enantiomer were concentrated in vacuo to give a
residue. The residue was dissolved with saturated aque-
ous NaHCO3 (2 mL) and neutralized to pH 7.0 by 1 N
aqueous HCl. The H2O layer was saturated by NaCl and
extracted with CH2Cl2 (20 mL × 10). The organic layer
was dried over Na2SO4, filtered, and evaporated to give a
residue. The residue was purified by reverse phase col-
umn chromatography on Sep-Pak C18 Plus Short Car-
tridge (H2O to MeOH) to give (+)-2 and (−)-2.
(−)-2 (first eluting enantiomer on HPLC analysis):
20
[α]D –241 (c = 0.8, EtOH, 93% ee), CD λext (EtOH) nm
2.2.2 | 8-[4-(Dipropylamino)pyridine-
3-yl]-1-naphthoic acid (2)
(Δε): 334 (4.02), 327 (1.65), 322 (4.83), 281 (–25.4),
244 (21.1), 220 (31.7). UV λmax (EtOH) nm (log ε):
292 (4.13), 227 (4.53).
2-Methyl-2-butene (425 μL, 4.0 mmol) and aqueous
NaClO2 [109 mg, 1.20 mmol in H2O (1 mL)] was added
to a solution of 7 (134 mg, 0.40 mmol) in CH3CN (2.0
mL) at room temperature. After the mixture was cooled
to 0ꢀC, 10% (v/v) H2SO4 (640 μL, 0.30 mmol) was added
to the reaction mixture and stirred for 3 hours at 0ꢀC.
The mixture was quenched with 5% (w/v) aqueous
NaHCO3 (6.0 mL), and then concentrated in vacuo. The
solution was diluted with MeOH and filtered to remove
inorganic salts. The filtrate was evaporated to give a resi-
due. The residue was dissolved with H2O (20 mL) and
neutralized to pH 7.0 by 1 N aqueous HCl and saturated
aqueous NaHCO3. The H2O layer was saturated by
adding NaCl, extracted with CH2Cl2 (20 mL × 10), dried
over Na2SO4, filtered, and evaporated to give a residue.
The crude residue was purified by preparative TLC
(CHCl3/MeOH/H2O = 10/1/0 to 65/35/5) to afford
2 (108 mg, 78%) as a colorless amorphous.
(+)-2 (second eluting enantiomer on HPLC analysis):
[α]D +247 (c = 1.1, EtOH, 87% ee), CD λext (EtOH) nm
(Δε): 334 (–2.02), 326 (–0.12), 322 (–2.75), 283 (27.2),
243 (–19.9), 220 (–27.8).
20
2.2.4 | Acylative kinetic resolution of
8 in the presence of (−)-2
Et3N (260 μL, 0.052 mmol) and (−)-2 (149 μL, 0.58 μmol)
was added to a solution of racemic 8 (10 mg, 0.058 mmol)
in toluene (160 μL). The mixture was stirred for
10 minutes at −20ꢀC. Then, (i-PrCO)2O (7.3 μL,
0.44 mmol) was added to the mixture and stirred for
53 hours at −20ꢀC. The reaction was quenched with
MeOH, and the reaction mixture was evaporated to give
a residue. The residue was purified by preparative TLC
(n-hexane/AcOEt = 5/1) to give 8 (Rf 0.1) and 9 (Rf 0.6).
The enantiomeric excesses of 8 and 9 were determined by
HPLC analysis with the chiral stationary phase.
HPLC conditions for 8: column: CHIRALCEL OD
(4.6 mm × 250 mm), eluent: n-hexane/i-PrOH = 90/10,
flow rate: 1.0 mL/min, detection: 254 nm, retention time:
tR = 11.1 min (S), 15.6 min (R).23
HPLC conditions for 9: column: CHIRALCEL OD-H
(4.6 mm x 250 mm), eluent: n-hexane/i-PrOH = 98/2,
1H NMR (500 MHz, CDCl3) δ 8.15–8.10 (1H, m), 7.89
(1H, d, J = 8.0 Hz), 7.84 (1H, s), 7.81 (1H, d, J = 8.4 Hz),
7.60 (1H, d, J = 6.0 Hz), 7.49 (1H, t, J = 8.0 Hz), 7.44 (1H,
t, J = 7.2 Hz), 7.19 (1H, d, J = 6.4 Hz), 6.61 (1H, d, J = 7.2
Hz), 3.25–3.14 (2H, m), 3.11–2.98 (2H, m), 1.60–1.43 (2H,
m), 1.37–1.18 (2H, m), 0.51 (6H, t, J = 7.6 Hz). 13C NMR
(75 MHz, CDCl3/CD3OD) δ176.5, 157.6, 141.2, 139.9,
137.9, 134.4, 133.5, 129.8, 129.1, 128.1, 127.5, 126.2, 125.7,

4
NISHINO ET AL.
flow rate: 1.0 mL/min, detection: 254 nm, retention time:
be unsatisfactory as an asymmetric catalyst due to its rel-
atively short half-life. Therefore, we moved on to produce
tR = 5.0 min (R), 6.6 min (S).17
2
bearing the more sterically demanding N,N-
dipropylamino group, instead of the N,N-dimethylamino
group of 1a, for elongation of the half-life of
racemization.
3 | RESULTS AND DISCUSSION
We initially performed HPLC analysis of 1a with the chi-
ral stationary phase to observe the enantiomers at room
temperature. It was suggested that apparent peak separa-
tion of 1a indicated the existence of relatively stable
enantiomers bearing enough of a racemization barrier to
separate distinct peaks in HPLC analysis (see the
Supporting Information). Upon separation of the enantio-
mers by preparative HPLC, the racemization barrier was
estimated at 60ꢀC by tracing the time-dependent decrease
of optical purity of 1a (Figure 2). This experiment rev-
ealed that the racemization barrier was determined to be
107.1 kJ/mol (60ꢀC). The half-life of racemization at 20ꢀC
was estimated to be 201 hours (8.4 days). Although the
racemization barrier is enough for separation of the
enantiomers at room temperature, 1a was still found to
The synthetic route of 2 is depicted in Scheme 2.
Suzuki-Miyaura cross-coupling between pyridyl bromide
433 and boronate ester 531 afforded 6 in 52% yield. Succes-
sive reduction of the cyano group of 6 gave aldehyde 7 in
55% yield. Kraus-Pinnick oxidation of 7 yielded 2. Both
enantiomers of 2 were subsequently isolated by prepara-
tive HPLC with the chiral stationary phase.
Time-dependent racemization of the separated enan-
tiomer was traced by HPLC analysis under the same con-
ditions employed for 1a (Figure 3). As we expected, the
half-life of racemization was increased compared with
that of 1a, with t1/2 = 201 hours at 20ꢀC, to t1/2
=
472 hours (19.7 days) at 20ꢀC [racemization barrier: 109.2
kJ/mol (60 ꢀC)].
The CD spectra of each enantiomer exhibited a Cot-
ton effect in a mirror image pattern (Figure 4). The enan-
tiomer showed positive optical rotation exhibited a
positive (283 nm)-negative (220 nm) Cotton effect, and
the enantiomer showing negative optical rotation
exhibited a mirror image pattern of the (+)-enantiomer.
In order to evaluate the utility of 2 as an asymmetric
nucleophilic catalyst, we examined the acylative kinetic
resolution of a racemic secondary alcohol (Scheme 3).
Upon treatment of 0.75 equivalent of isobutyric anhy-
dride with racemic 1-(1-naphthyl)ethane-1-ol (8) in the
presence of 1 mol% of optically active (−)-2 (93% ee) and
Et3N, the acylation proceeded to give ester (R)-9 and the
recovered alcohol (S)-8 with 35% and 28% ee, respec-
tively, in a 45% conversion [kR/kS (s) = 2.6].34 This pre-
liminary result indicates that axially chiral DMAP
derivatives possessing a carboxy group may have the
potential for asymmetric acylation, although this prelimi-
nary investigation did not show satisfactory asymmetric
induction.
FIGURE 2 Time-dependent decrease of the enantiomeric
purity of 1a at 60ꢀC in EtOH
SCHEME 2 Preparation of optically active 2

NISHINO ET AL.
5
4 | CONCLUSION
The axial chirality of DMAP derivatives 1a and 2 bearing
a carboxy group was investigated, and their racemization
barriers were evaluated. Furthermore, the acylative
kinetic resolution of 8 was examined by (−)-2. This pre-
liminary result suggested the usefulness of axially chiral
DMAP derivatives as asymmetric nucleophilic catalysts.
Design and preparation of new catalysts based on 2 are
under investigation in our laboratory.
ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid for Scientific
Research (C) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
FIGURE 3 Time-dependent decrease of the enantiomeric
purity of 2 at 60ꢀC in EtOH
ORCID
Shohei Hamada https://orcid.org/0000-0003-4352-0017
Takumi Furuta https://orcid.org/0000-0003-1037-9715
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