N?C Axially Chiral Anilines: Electronic Effect on Barrier to Rotation and A Remote Proton Brake

Article abstract of DOI:10.1002/chem.201706115

N-Aryl-N-methyl-2-tert-butyl-6-methylaniline derivatives exhibit a rotationally stable N?C axially chiral structure and the rotational barriers around an N?C chiral axis increased with the increase in electron-withdrawing character of para-substituent on the aryl group. X-ray crystal structural analysis and the DFT calculation suggested that the considerable change of the rotational barriers by the electron effect of para-substituents is due to the disappearance of resonance stabilization energy caused by the twisting of para-substituted phenyl group in the transition state. This structural property of the N?C axially chiral anilines was employed to reveal a new acid-decelerated molecular rotor caused by the protonation at the remote position (remote proton brake).

Full text of DOI:10.1002/chem.201706115

A Journal of
Accepted Article
Title: N-C Axially Chiral Anilines: Electronic Effect on Barrier to
Rotation and A Remote Proton Brake
Authors: Yumiko Iwasaki, Ryuichi Morisawa, Satoshi Yokojima, Hiroshi
Hasegawa, Christian Roussel, Nicolas Vanthuyne, Elsa
Caytan, and Osamu Kitagawa
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To be cited as: Chem. Eur. J. 10.1002/chem.201706115
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Supported by

10.1002/chem.201706115
Chemistry - A European Journal
FULL PAPER
N-C Axially Chiral Anilines: Electronic Effect on Barrier to Rotation and
A Remote Proton Brake
Yumiko Iwasaki[a], Ryuichi Morisawa[a], Satoshi Yokojima[b], Hiroshi Hasegawa[b], Christian Roussel[c],
Nicolas Vanthuyne[c], Elsa Caytan[d] and Osamu Kitagawa*[a]
Abstract: N-Aryl-N-methyl-2-tert-butyl-6-methylaniline derivatives
exhibit rotationally stable N-C axially chiral structure, and the
rotational barriers around an N-C chiral axis increased with the
increase in electron-withdrawing character of para-substituent on the
aryl group. X-Ray crystal structural analysis and the DFT calculation
suggested that the considerable change of the rotational barriers by
the electron effect of para-substituents is due to the disappearance
of resonance stabilization energy caused by the twisting of para-
substituted phenyl group in the transition state. This structural
property of the N-C axially chiral anilines was employed to reveal a
new acid-decelerated molecular rotor caused by the protonation at
remote position (remote proton brake).
developments are expected.
(Shimizu et al)
H
O
H+
H+
N
N
O
Me
Me
N
N
O
O
Me
Me
I-H+ (!G‡ = 12.9 kcal/mol)
I (!G‡ = 22.2 kcal/mol)
H
‡
‡
O
N
O
N
N
Me
Me
N
O
Me
O
Me
(Our group)
H+
Introduction
N
N
H
tBu
tBu
quick
rotation
rotational
restriction
Chiral compounds owing to rotational restriction around an
N-C bond have received remarkable attention in the area of
synthetic organic chemistry.[1] Syntheses of various N-C axially
chiral compounds and their applications to asymmetric reactions
have been investigated by many groups.[1-3]
tBu
II-H+ (!G‡ = 16.3 kcal/mol)
tBu
II (!G‡ = 25.1 kcal/mol)
Figure 1. Acid-accelerated molecular rotors based on the rotation around
N-C bond.
Meanwhile, the application of N-C axially chiral compounds
to molecular devices (molecular rotors) was recently reported.[4]
Molecular rotors, which can control the rate of a bond rotation by
external stimuli, are one of the most fascinating classes of
molecular devices.[5] Shimizu and our groups found acid-
accelerated molecular rotor based on the rotation around N-C
bond (Figure 1). Shimizu et al revealed that N-C bond rotation
of N-(quinolin-8-yl)succinimide I is significantly accelerated (the
rotational barrier of I is significantly lowered) by the addition of
protic acid.[4b] The acid-mediated significant acceleration is
caused by the stabilization of the planar transition state by the
formation of an intramolecular hydrogen bond (proton grease).
In our molecular rotor (N-C axially chiral cyclic amine II), the
addition of protic acid led to the remarkable acceleration of N-C
bond rotation through change upon hybridization of nitrogen
atom due to the formation of protonated amine II-H+.[4c] Acid
catalyzed acceleration of rotation about a N-C bond added a
new facet to N-C axially chiral chemistry and further
We report herein the atropisomerism of new N-C axially
chiral amines in the almost unexplored N-aryl-N-methyl-2-tert-
butyl-6-methylaniline series. The considerable change of the
rotational barriers according to the electronic effect of the para-
substituent on the aryl group was supported by DFT calculation
as well as X-ray crystal structural analysis (Figure 2), and this
structural property was applied to the design of an
unprecedented acid-decelerated molecular rotor caused by the
protonation at remote position (remote proton brake, Figure 2).
X
H3N
H+
H2N
R1
Me
Me
R1
N
N
N
R2
R2
R3
R3
tBu
"proton
brake"
"chiral
axis"
X = EWG (higher !G‡)
higher !G‡
lower !G‡
‡
X = EDG (lower !G )
[a]
Y. Iwasaki, R. Morisawa, Prof. O. Kitagawa
Department of Applied Chemistry
Shibaura Institute of Technology
3-7-5 Toyosu, Kohto-ku, Tokyo, 135-8548, Japan
E-mail: kitagawa@shibaura-it.ac.jp
Figure 2. Considerable change of rotational barriers by the electronic
effect in N-C axially chiral amines and the application to a remote proton
brake.
[b]
Prof. S. Yokojima, Dr. H. Hasegawa
School of Pharmacy
Tokyo University of Pharmacy and Life Sciences,
1432-1, Horinouchi, Hachioji, Tokyo, 192-0392, Japan
Prof. C. Roussel, Dr. N. Vanthuyne
[c]
Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille, France
Dr. E. Caytan
[d]
Univ Rennes, CNRS, ISCR – UMR 6226, F-35000 Rennes, France
Supporting information for this article is given via a link at the end of the
document
This article is protected by copyright. All rights reserved.

10.1002/chem.201706115
Chemistry - A European Journal
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Results and Discussion
Eyring relation (Table 1). It was found that the rotational barriers
show decreasing tendency with increasing the electron-donating
character of para-substituents X. The energy difference (ΔΔG‡)
between para-nitro derivative 1a possessing the highest
As mentioned above, although various N-C axially chiral
compounds have been reported, almost all the compounds have
amide or nitrogen-containing aromatic heterocyclic structures.
rotational barrier (ΔG‡
= 29.4 kcal/mol) and para-amino
derivative 1f possessing the lowest rotational barrier (ΔG‡ = 24.8
Meanwhile, only a handful of reports on N-C axially chiral
amines have been published.[4c,
When we investigated the
6]
kcal/mol) was 4.6 kcal/mol (Table 1).
synthesis of rotationally stable N-C axially chiral amines (N-Aryl-
N-methyl-2-tert-butyl-6-methylaniline derivatives), a considerable
change of the rotational barriers by para-substituents on aryl
group was found. That is, N-(4-nitrophenyl)aniline 1a has
rotationally stable N-C axially chiral structure and the ee (99%
ee) is almost unchanged on standing for 24 h at 50 °C in CCl4,
while in N-(4-aminophenyl)aniline derivatives 1f prepared via the
hydrogenation of 1a, the initial ee (98% ee) significantly
decreased (12% ee) on standing for 6 h at 50 °C (Figure 3).
Table 1. Rotational barriers of N-C axially chiral amines 1a-f bearing
various para-substituted phenyl groups.
X
X
Me
Me
Me
N
N
tBu
Me
tBu
CCl4
ent-1a-f
1a-f
ΔG‡
(kcal/mol)b
1
O2N
X
ΔG‡
t1/2•298K
H2N
H2/Pd-C
entry
exp
calcd
50 °C
24 h
50 °C
6 h
Me
Me
Me
Me
(kcal/mol)a (days)
N
N
1
2
3
4
5
6
NO2
1a
29.4
28.2
26.7
26.5
26.1
24.8
2475
304
27.1
19.0
9.2
30.1
29.1
27.8
27.5
26.9
25.7
CCl4
CCl4
tBu
tBu
CO2Et 1b
"chiral
axis"
Cl
H
Me
NH2
1c
1d
1e
1f
1a (99% ee)
1f (98% ee)
1a (98% ee)
1f (12% ee)
1.0
[a] ΔG‡ value at 298 K based on racemization experiment. [b] ΔG‡ value at
298 K based on DFT calculation (M06-2X/cc-pVTZ level) for the N-C bond
rotation.
Figure 3. Rotationally stability of a chiral axis in N-C axially chiral
anilines.
This result suggests that the rotational barrier around the N-
C bond (the rate of N-C bond rotation) is significantly influenced
by the electronic effect of remote para-substituent on aryl group.
Quite recently, Clayden et al. reported the synthesis of a focused
library of axially chiral N-aryl-2-tert-butyl-6-methylanilines (diaryl
amines), their crystal structures and two examples of rotational
barriers.[7] However, there is no mention on such electronic
effect. To elucidate the relationship between the electronic effect
and the rotational barriers, racemic N-aryl-N-methyl-2-tert-butyl-
6-methylaniline derivatives rac-1a-f bearing various para-
substituents (X = NO2, CO2Et, Cl, H, Me, NH2) on aryl group
were prepared through Buchwald-Hartwig amination of 2-tert-
butyl-6-methylaniline with para-substituted iodobenzene followed
by N-methylation, and their enantiomers were separated by
chiral HPLC method (Scheme 1).
Furthermore, in the analysis using Hammett plot, relatively
good linear relationship was observed between Hammett σ-
values and the rotational barriers (R2=0.97, Figure 4). Thus, the
rotational barriers in N-C axially chiral amines 1a-f were
quantitatively related to the electronic character of para-
substituent.
30
1a (NO2)ꢀ
ꢀ
29
28
1b (CO2Et)ꢀ
27
1c (Cl)ꢀ
1e (CH3)ꢀ
1d (H)ꢀ
26
!"#"$%$&'&(")"*%+'++"
1f (NH2)ꢀ
,-"#"$%././"
25
4 mol% Pd(OAc)2
10 mol% phosphine
1.5 equiv tBuONa
NH2
1.5 equiv NaH
1.5 equiv Me-I
24
I
tBu
Me
-0.80 -0.60 -0.40 -0.20 0.00
0.20
0.40
0.60
0.80
1.00
+
DMF
Hammett substituent constant !ꢀ
toluene, 100-130 °C
(41-92%)
X
(65-99%)
Figure 4. Hammett plot of the rotational barriers in anilines1a-f.
X
Me
Me
HPLC using
chiral column
Kondo et al have reported similar relationship between the
electronic effect and rotational barriers in N-C axially chiral
imides bearing various para-substituted benzoyl groups.[8]
However, the para-substituents possessing negative resonance
effect such as nitro and ester groups were not investigated, and
the energy difference between para-CF3 derivative possessing
the highest rotational barrier and para-dimethylamino derivative
possessing the lowest rotational barrier was slight (ΔΔG‡=1.4
kcal/mol) in comparison with that of our N-C axially chiral amines
(ΔΔG‡=4.6 kcal/mol). In addition, although they postulated the
transition state structure during the N-C bond rotation and used
N
+
tBu
1a-e
ent-1a-e
(99% ee)
rac-1a-e
1a (X = NO2), 1b (X = CO2Et), 1c (X = Cl), 1d (X = H), 1e (X = Me)
Scheme 1. Synthesis of N-C axially chiral anilines 1a-f bearing various
para-substituents.
Subsequently the racemization rates of 1a-f were measured
in CCl4 and their rotational barriers were evaluated through the
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10.1002/chem.201706115
Chemistry - A European Journal
FULL PAPER
it to explain the change of ΔG‡ by the electronic effects, the
analysis by computational method such as MO or DFT
calculation was not conducted.
ortho-methyl group. Meanwhile, the twisting should cause the
disappearance of the resonance stabilization which occurs in the
ground state. The resonance stabilization energy in the ground
state is linked to the magnitude of electron-withdrawing effect of
para-substituent (X), and it follows that the loss of the
stabilization energy by the twisting of para-substituted phenyl
groups in the transition state increases with increasing the
electron-withdrawing character of X. As a result, N-C axially
chiral amines bearing stronger electron-withdrawing para-
substituent possess higher rotational barrier.
We attempted the elucidation of the relationship between the
electronic effect and the rotational barriers in amines 1 by
considering the transition state structure based on the DFT
calculation as well as the X-ray crystal structural analysis.
Initially, X-ray crystal structural analyses of para-nitro derivative
1a possessing the highest rotational barrier and para-methyl
derivative 1e possessing the second lowest rotational barrier
were conducted (Figure 5, para-amino derivative 1f possessing
the lowest rotational barrier was oil).[9] The crystal structures of
1a and 1e show that the para-substituted phenyl groups are
periplanar with the nitrogen plane (<Me-N-C1’-C2’: 1a = -
172.64°, 1e = -169.85 °) while the 2-tert-butyl-6-methylphenyl
groups are almost perpendicular to the nitrogen plane (<Me-N-
C1-C6: 1a = 85.52 °, 1e = 77.23 °). Thus, a lone pair on the
nitrogen in 1a and 1e should mainly interact with the para-
substituted phenyl group but not with the 2-tert-butyl-6-
methylphenyl group in the ground state. Indeed, the distances
of N-C1’ bond in 1a and 1e are significantly shorter than other
two N-C bonds (N-C1 and N-Me bonds). Understandably, N-C1’
bond in 1a is shorter than that in 1e because of the strong
negative resonance effect associated to the para-nitro group.
‡
‡
Me
Me
tBu
Me
Me
Ar
Me
Ar
tBu
Ar
path a
path b
N
N
N
Me
tBu
lower !G‡
higher !G‡
!G‡ = 30.1 kcal/mol
!G‡ = 25.7 kcal/mol
!G‡ = 35.9 kcal/mol
!G‡ = 29.5 kcal/mol
1a (Ar = 4-NO2C6H4)
1f (Ar = 4-NH2C6H4)
Figure 6. The rotational barriers of two possible rotation pathways
evaluated by DFT calculation.
N-C1' = 1.436 Å
‡
3'
6'
O2N 4'
5'
N-C1 = 1.421 Å
N-Me = 1.475 Å
2'
1'
Me
N-C1' = 1.372 Å
N-C1 = 1.451 Å
N-Me = 1.469 Å
< C1-N-Me = 115.3 °
< C1'-N-Me = 107.7 °
< C1-N-C1' = 118.1 °
N
1
3'
O2N
4'
341.1 °
Me
tBu
2'
1'
6
5
2
3
Me
5'
< C1-N-Me = 116.33 °
< C1'-N-Me = 119.41 °
< C1-N-C1' = 120.19 °
< Me-N-C1-C6 = -143.1 °
N
1
6'
Me
4
355.93 °
< Me-N-C1'-C2' = -105.9 °
tBu
!G‡calcd = 30.1 kcal/mol
2
TS-1a (higher !G‡) !G‡exp = 29.4 kcal/mol
6
3
5
< Me-N-C1-C6 = 85.52 °
< Me-N-C1'-C6' = -172.64 °
1a
4
‡
N-C1' = 1.444 Å
N-C1 = 1.422 Å
N-Me = 1.463 Å
H2N
3'
6'
4'
5'
N-C1' = 1.402 Å
N-C1 = 1.449 Å
N-Me = 1.465 Å
2'
1'
3'
Me
4'
2'
1'
Me
N
1
Me
< C1-N-Me = 124.7 °
5'
Me
tBu
N
1
< C1-N-Me = 116.40 °
< C1'-N-Me = 105.9 °
< C1-N-C1' = 114.5 °
< Me-N-C1-C6 = -176.0°
< Me-N-C1'-C2' = -80.4 °
345.1 °
6'
Me
6
5
2
3
< C1'-N-Me = 118.33 °
< C1-N-C1' = 118.25 °
< Me-N-C1-C6 = 77.23 °
352.98 °
tBu
2
6
4
3
5
1e
TS-1f (lower !G‡)
!G‡calcd =25.7 kcal/mol
!G‡exp = 24.8 kcal/mol
4
< Me-N-C1'-C6' = -169.85 °
Figure 7. The transition state structures during N-C bond rotation
evaluated by DFT calculation and the origin of electronic effect.
Figure 5. X-Ray crystal structures of 1a and 1e.
The transition states during N-C bond rotation in 1a and 1f
were subsequently estimated by DFT method (Figures 6 and 7).
The rotational barriers of 1a and 1f calculated at M06-2X/cc-
pVTZ level corresponded reasonably well with the experimental
ΔG‡ values (entries 1 and 6 in Table 1), and the transition state
structures and the pathway during the N-C bond rotation
provided beneficial information for elucidation of the electronic
effect. Among two possible rotation pathways (path a and b),
path a which proceeds via the rotation of ortho-tert-butyl group
toward N-methyl group side, is favored more than path b which
occurs via the rotation of ortho-tert-butyl group toward para-
substituted phenyl group (Figure 6, The rotational barriers via
path a in 1a and 1f were 5.8 and 3.8 kcal/mol lower than those
via path b).
On the basis of the above results, we expected that the
addition of protic acid to para-amino derivative 1f may generate
the para-ammonium derivative 1f-H+ to bring about
a
considerable increase in the rotational barriers due to the strong
electron-withdrawing character of the ammonium group. In this
case, the rotational barrier will be controlled by an external factor
but not by internal substituents such as 1a-f. In addition, in
contrast to acid-accelerated molecular rotors (proton grease)
shown in Figure 1, the protic acid will act as a remote brake
during N-C bond rotation (proton brake). [10]
As already mentioned, the rotational barrier of 1f was not so
high (ΔG‡=24.8 kcal/mol), and the initial ee (97% ee) of 1f
lowered to 46% ee after standing for 24 h at 30 °C in CCl4
(Scheme 2). In contrast, in the presence of MeSO3H, the
decrease in the ee of 1f was slight (Scheme 2). That is, after
standing CCl4 solution of 1f involving 1.5 equiv of MeSO3H for
24 h at 30 °C, the neutralization by aqueous Na2CO3 solution
and the extraction with ethyl acetate were conducted to recover
Interestingly, in the transition state structures TS-1a and TS-
1f via path a, para-substituted phenyl groups are almost
perpendicular to the nitrogen plane (<Me-N-C1’-C2’: 1a = -
105.9 °, 1f = -80.4 °, Figure 7). The large twisting of para-
substituted phenyl group may alleviate the steric repulsion with
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10.1002/chem.201706115
Chemistry - A European Journal
FULL PAPER
1f which presented 95-96% ee by chiral HPLC analysis (The
slight decrease in the ee may be due to the N-C bond rotation of
1f but not 1f-H+).
two aromatic hydrogens (Hb) was scarcely changed. Since the
protonation at tertiary amino group is not preferred because of
the severe steric hindrance, this result indicates that the
protonation selectively occurs at NH2 group, and Ha and Hb
being respectively situated in ortho- and meta-position of the
NH2 group.
H2N
H3N
1.5 equiv
MeSO3H
30 °C
24 h
30 °C
24 h
Me
Me
N
N
VT NMR experiment with 2f in toluene-d8 was conducted in
the presence or absence of MeSO3H. The VT NMR chart of two
Me groups at iso-propyl part are shown in Figure 9. In 2f, the
two Me groups were completely equivalent and observed as a
sharp signal bearing doublet coupling at ambient temperature
(295 K). The broadening of a signal of the Me groups was
observed around 220 K, and the signals of diastereotopic Me
group due to an N-C axial chirality (slow rotation around an N-C
bond) were formed around 175 K (left NMR chart). In the
presence of 1.5 equiv of MeSO3H, two Me groups of 2f showed
CDCl3
CDCl3
then
Me
tBu
Me
tBu
Na2CO3
1f
(46% ee)
1f-H+
1f
(97% ee)
1f
(95-96% ee)
Scheme 2. The ee change of 1f in the presence or absence of MeSO3H.
Although we attempted to experimentally evaluate the
rotational barrier of 1f-H+, it was difficult because the ee of 1f
(24.8 kcal/mol) easily changed during the neutralization and the
extraction process. Therefore, the rotational barrier of 1f-H+ was
evaluated by DFT method. The ΔG‡ value of 1f-H+ (28.7
kcal/mol) calculated at M06-2X/6-311++G(d) level is similar to
the experimental and calculated ΔG‡ values of para-ester
derivative 1b (28.2 and 29.1 kcal/mol), and this value was 3.9
and 3.0 kcal/mol higher, respectively, in comparison with the
experimental and the calculated values of 1f.
Variable temperature NMR (VT-NMR) is the method of
choice to evaluate rotational barriers,[11] however this method
could not be applied to 1f-H+ which presents a too high barrier
and is not equipped with suitable diastereotopic protons. After a
screening of several compounds, N-(4-aminophenyl)-N-propyl-2-
iso-propylaniline 2f was found to be an appropriate molecule for
VT-NMR measurement.
a
broad signal even at 315 K, and the formation of
diastereotopic Me signals was observed around 260 K (right
NMR chart). Thus, the addition of MeSO3H obviously reduced
the rate of N-C bond rotation.
H2N
H3N
nPr
nPr
1.5 equiv
MeSO3H
N
N
CHMe2
CHMe2
toluene-d8
lower !G‡
2f-H+ higher !G‡
2f
315 K
315 K
305 K
295 K
280 K
265 K
255 K
305 K
295 K
290 K
285 K
280 K
277 K
274 K
271 K
268 K
265 K
262 K
259 K
256 K
253 K
240 K
230 K
220 K
MeSO3H
Ha
245 K
235 K
225 K
215 K
210 K
207 K
H2N
Ha
Hb
N
Hb
CHMe2
200 K
195 K
190 K
2f
x equiv
185 K
180 K
175 K
165 K
158 K
MeSO3H
CDCl3
Ha
H3N
Ha
Hb
N
Figure 9. VT NMR spectra of iso-propyl (dimethyl) group in 2f and 2f-H+
Hb
CHMe2
in toluene-d8.
2f-H+
The rotational barriers of 2f and 2f-H+ were evaluated by the
line shape simulation using WinDNMR program.[11]
The
Figure 8. 1H-NMR spectra of aromatic hydrogen of 2f in the
presence or absence of MeSO3H in CDCl3.
calculated ΔG‡ values of 2f and 2f-H+ were 8.8 ± 0.3 kcal/mol at
175-185 K and 12.8 ± 0.3 kcal/mol at 259-271 K, respectively.
These results show that the addition of protic acid led to the
brake of 4 kcal/mol, a value similar to that (3.9 kcal/mol) of
proton brake in 1f evaluated by DFT method.
In 2f, the selective protonation of para-amino group was also
observed. When 0.32 equiv of MeSO3H was added to 2f in
CDCl3, a downfield shift of two aromatic hydrogens (Ha) on
para-aminophenyl group was noticed (Figure 8). The magnitude
of the downfield shift is related to the amount of added MeSO3H
and reached a maximum limit by addition of 1.05 equiv of
MeSO3H. In the proton addition, the chemical shift of the other
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10.1002/chem.201706115
Chemistry - A European Journal
FULL PAPER
= 1.2, 7.6 Hz), 6.71 (1H, dd, J = 2.8, 9.2 Hz), 5.98 (1H, dd, J = 2.8,
9.6 Hz), 3.27 (3H, s), 1.97 (3H, s), 1.28 (9H, s); 13C -NMR (CDCl3) δ:
154.3, 148.1, 142.0, 137.9, 137.7, 130.2, 128.2, 127.1, 126.6, 125.4,
113.3, 109.0, 40.6, 35.9, 32.1, 18.2; MS (m/z) 321 (MNa+); HRMS.
Calcd for C18H22N2NaO2 (MNa+) 321.15790. Found: 321.15843.
N-(4-Aminophenyl)-N-methyl-2-tert-butyl-6-methylaniline
Conclusions
In conclusion, we found that N-aryl-N-methyl-2-tert-butyl-6-
methylaniline derivatives have stable N-C axially chiral structure
and their rotational barriers were considerably changed
(controlled) by the para-substituent on aryl group. On the basis
of X-ray crystal structural analysis and the DFT method, the
considerable change of the rotational barriers by the electronic
effect of para-substituents arose from resonance stabilization
energy caused by the coplanarity of para-substituted phenyl
group with the nitrogen plane in the ground state whereas that
resonance stabilization energy was no more operating in the
twisted transition state. Furthermore, the control of the rotational
barrier through electronic factor was applied to design proton
brake molecules where the rotation rate around an N-C bound is
decelerated by protonation at a remote position.
(1f). 10% Pd-C was added to (+)-1a (52.2 mg, 0.175 mmol) in EtOH
(1.6 mL)-THF (0.4 mL) and the mixture was stirred for 1.5 h at 0° C
under H2 atmosphere. AcOEt was added to the mixture and 10%
Pd-C was removed by filtration. The filtrate was evaporated to
dryness. Purification of the residue by column chromatography
(hexane/AcOEt = 4) gave (+)-1f (37.8 mg, 80%). The ee of 1f was
determined by HPLC analysis using CHIRALCEL OD-3 [25 cm x
0.46 cm i.d.; 10% i-PrOH in hexane; flow rate, 1.0 mL/min; (+)-1f; tR
= 9.6 min, (-)-1f; tR = 10.8 min]. 1f: dark brown oil; [α]D = +61.0 (c =
0.26, CHCl3, 98% ee); IR (neat) 2957 cm-1; 1H-NMR (CDCl3) δ: 7.38
(1H, dd, J = 1.2, 7.6 Hz), 7.17 (1H, t, J = 7.6 Hz), 7.12 (1H, d, J = 6.4
Hz), 6.76 (1H, brs), 6.60 (1H, brs), 6.51 (1H, brs), 5.84 (1H, brs),
3.10 (3H, s), 1.94 (3H, s), 1.29 (9H, s); 13C -NMR (CDCl3) δ: 149.6,
144.8, 143.2, 139.8, 135.9, 130.0, 126.8, 126.0, 117.0, 116.6, 115.1,
110.6, 40.2, 35.7, 32.0, 18.5; MS (m/z) 269 (MH+); HRMS. Calcd for
C18H25N2 (MH+) 269.20177. Found: 269.20173.
Experimental Section
Melting points were uncorrected. 1H and 13C NMR spectra were
recorded on a 400 MHz spectrometer. In H and 13C NMR spectra,
1
chemical shifts were expressed in δ (ppm) downfield from CHCl3
(7.26 ppm) and CDCl3 (77.0 ppm), respectively. HRMS were
recorded on a double focusing magnetic sector mass spectrometer
using electron impact ionization. Column chromatography was
performed on silica gel (75-150 µm). Medium-pressure liquid
chromatography (MPLC) was performed on a 25 x 4 cm i. d.
prepacked column (silica gel, 10 µm) with a UV detector. High-
performance liquid chromatography (HPLC) was performed on a 25
x 0.4 cm i. d. chiral column with a UV detector.
Acknowledgements
This work was partly supported by JSPS KAKENNHI
(C17K08220).
Keywords: axially chiral • amines • rotational barriers •
electronic effect • proton brake
N-Methyl-N-(4-nitrophenyl)-2-tert-butyl-6-methylaniline
(1a).
References
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extracts were washed with brine, dried over Na2SO4, and evaporated
to dryness. Purification of the residue by column chromatography
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10)
gave
N-(4-nitrophenyl)-2-tert-butyl-6-
methylaniline (525 mg, 92%). Under N2 atmosphere, to NaH (60%
assay, 80 mg, 2.0 mmol) in THF (6.0 mL) were added N-(4-
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iodomethane (93 µL, 1.5 mmol), and then the mixture was stirred for
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aqueous NH4Cl solution and extracted with AcOEt. The AcOEt
extracts were washed with brine, dried over Na2SO4, and evaporated
to dryness. Purification of the residue by column chromatography
(hexane/AcOEt = 10) gave 1a (295 mg, 99%). Enantiomers of 1a
were separated through MPLC using CHIRALPAK AY-H column [25
cm x 1.0 cm i.d.; 10% i-PrOH in hexane; flow rate, 2.0 mL/min; (+)-1a;
tR = 10.0 min, (-)-1a; tR = 22.5 min]. The ee of separated (+)-1a (less
retained enantiomer) was determined by HPLC analysis using
CHIRALPAK AS-H [25 cm x 0.46 cm i.d.; 15% i-PrOH in hexane; flow
rate, 1.0 mL/min; (-)-1a; tR = 6.3 min, (+)-1a; tR = 7.6 min]. 1a: yellow
[3]
solid; mp 116-119 °C (racemic), 116-119 °C [(+)-1a, 99% ee]; [α]D
=
+34.6 (c = 0.21, CHCl3, 99% ee); IR (neat) 2955 cm-1; 1H-NMR
(CDCl3) δ: 8.23 (1H, dd, J = 2.4, 8.8), 7.92 (1H, dd, J = 2.8, 9.6 Hz),
7.45 (1H, dd, J = 1.6, 8.0 Hz), 7.26 (1H, t, J = 7.6 Hz), 7.19 (1H, dd, J
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10.1002/chem.201706115
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10.1002/chem.201706115
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FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
Yumiko Iwasaki, Ryuichi Morisawa,
high
X
X
H3N
H+
H2N
Satoshi Yokojima, Hiroshi Hasegawa,
Christian Roussel, Nicolas Vanthuyne ,
Elsa Caytan and Osamu Kitagawa*
NO2
CO2Et
Cl
Me
Me
R1
R1
N
N
N
!G‡
R2
R2
R3
R3
tBu
H
"proton
brake"
"chiral
axis"
Me
NH2
Page No. – Page No.
lower !G‡
higher !G‡
low
N-C Axially Chiral Anilines: Electronic
Effect on Barrier to Rotation and A
Remote Proton Brake
for Table of Contents
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