Studies on rotational barriers of N-C axially chiral compounds: Increase in the rotational barrier by aromatization

Article abstract of DOI:10.1016/j.tetlet.2012.06.007

The rotational barriers in axially chiral quinolin-2-one and quinazolin-2-one possessing N-(ortho-tert-butyl)phenyl group were found to significantly increase in comparison with those of corresponding dihydroquinolin-2-one and dihydroquinazolin-2-one. Ana

Full text of DOI:10.1016/j.tetlet.2012.06.007

Tetrahedron Letters 53 (2012) 4332–4336
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studies on rotational barriers of N–C axially chiral compounds: increase
in the rotational barrier by aromatization
Naomi Suzumura a, Masato Kageyama a, Daichi Kamimura a, Takahiro Inagaki a, Yasuo Dobashi b,
Hiroshi Hasegawa b, Haruhiko Fukaya b, Osamu Kitagawa a,
⇑
a Department of Applied Chemistry, Shibaura Institute of Technology, 3-7-5 Toyosu, Kohto-ku, Tokyo 135-8548, Japan
b School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The rotational barriers in axially chiral quinolin-2-one and quinazolin-2-one possessing N-(ortho-tert-
butyl)phenyl group were found to significantly increase in comparison with those of corresponding dihy-
droquinolin-2-one and dihydroquinazolin-2-one. Analysis of transition state structure during N–Ar bond
rotation based on DFT calculation indicates that the increase in the rotational barrier is due to consider-
able distortion of the nitrogen-containing heterocyclic part.
Received 7 May 2012
Revised 31 May 2012
Accepted 4 June 2012
Available online 12 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Axially chiral
Aromatization
Quinolinone
Quinazolinone
Rotational barrier
Recently, atropisomeric compounds with an N–C chiral axis
have received much attention as novel chiral molecules. Various
N–C axially chiral compounds such as I–VI owing to rotational
restriction around an N–Ar bond have been reported to date
(Fig. 1).1–8 Almost all the N–C axially chiral compounds have
ortho-substituted aniline skeletons as a common structure, and it
is well known that their stabilities (rotational barrier around a chi-
ral axis) strongly depend on the bulkiness of the ortho-substituent.
For example, although ortho-tert-butylanilides IA and N-(2-tert-
butylphenyl)imides IIA are stable atropisomeric compounds hav-
because aromatic heterocycles possessing an N-(ortho-substi-
tuted)phenyl group such as III (methaqulone: a sedative-hypnotic
ing high rotational barriers (
ortho-methyl derivatives IB and IIB, the rotation around the N–Ar
bond easily occurs at RT (
G– = 19–20 kcal/mol).1g,m,2b,f On the
D
G– = 28–30 kcal/mol),2 in their
D
other hand, a considerable number of stable atropisomeric com-
pounds having an ortho-methyl group such as III–VI1b-d,11 have
been also known (
D
G– ’ 30 kcal/mol).3 However, there has been
no report on the origin of the remarkable difference of the rota-
tional barrier between IB–IIB and III–VI. In general, the relation-
ship between the structure and the atropisomerism in N–C
axially chiral compounds has not been investigated in detail to
date.4
The elucidation of the factor, which influences the rotational
barrier around an N–C chiral axis, is important from the viewpoint
of not only atropisomeric chemistry but also medicinal chemistry,
⇑
Corresponding author. Tel.: +81 3 5859 8161; fax: +81 3 5859 8101.
E-mail address: kitagawa@shibaura-it.ac.jp (O. Kitagawa).
Figure 1. Various N–C axially chiral compounds.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.007

N. Suzumura et al. / Tetrahedron Letters 53 (2012) 4332–4336
4333
drug) frequently have strong pharmacological activity, and the
activities differ significantly between enantiomers due to an axial
chirality.1c,k,5 In connection with our previous study on N–C axially
chiral chemistry,2c,6,7 we had an interest in elucidating the un-
known factor which brings about an increase in the rotational
barrier.
In this Letter, we report on the notable relationship between the
aromatic structure and the rotational barrier in N–C axially chiral
compounds. Namely, we found that the rotational barrier around
an N–C chiral axis significantly increases by the aromatization
(the conversion to the corresponding aromatic compounds). The
origin of increase in the rotational barrier based on DFT calculation
is also described.
After a detailed survey of the literature on N–C axially chiral
compounds, we noticed that most of the stable atropisomeric com-
pounds possessing a small substituent at the ortho-position are
nitrogen-containing aromatic heterocycles.3 That is, in stable
atropisomeric compounds III–VI, the nitrogen atom of the chiral
axis is contained in the aromatic skeleton such as quinazolinone,
pyrimidinone, thiazolone, and indole (the lone pair on nitrogen
of III–VI contributes to aromaticity), while the nitrogen of the achi-
ral IB and IIB exists in the non-aromatic part. These may indicate
that aromatic structure plays an important role on the atropisom-
erism in N–C axially chiral compounds.
Scheme 2. The conversion to 3a and rotational barriers of 2a and 3a.
Meanwhile, since the steric circumstances between IB–IIB and
III–VI are remarkably different, it would not be possible to deny
the contribution of the steric factor on the rotational barrier (steric
repulsion during N–Ar bond rotation). To clarify the contribution of
aromatic skeleton, a comparison of the rotational barriers of
aromatic and non-aromatic compounds having similar steric
circumstances is required.
We previously reported on the highly enantioselective
synthesis of atropisomeric 1-(2,5-di-tert-buthyphenyl)dihydro-
quinolin-2-one 2a (98%ee) and 1-(2,5-di-tert-buthyphenyl)-3-ben-
zyl-dihydroquinazolin-2-one 2b-Bn (95%ee) through (R)-BINAP-
Pd(OAc)2 catalyzed intramolecular Buchwald-Hartwig amination
(Scheme 1).7 Firstly, we investigated the conversion of 2a and
2b-Bn to the aromatic versions 3a and 3b. Quinolin-2-one 3a
(98%ee) and quinazolin-2-one 3b (95%ee) were prepared without
racemization through the conversion shown in Schemes 2 and 3,
respectively. It was expected that the contribution of aromatic
structure on the rotational barrier should be clarified by the com-
parison of the rotational barriers between 2a and 3a (2b and 3b)
because the steric circumstances of 3a (3b) are very similar to that
of 2a (2b).
Thermal isomerization with 2a (98%ee) having a non-aromatic
lactam part and aromatic quinolin-2-one 3a (98%ee) was per-
formed under toluene reflux conditions (Scheme 2). After 48 h,
the ee of 2a was reduced by 71%ee, and the rotational barrier of
2a was estimated to be 33.1 kcal/mol (at 110 °C) by Eyring plot
(t1/2 = 98 h at 110 °C).9 Under the same conditions, with 3a, a
detectable change of the ee was not observed. Since the rotational
barrier of 3a was difficult to estimate by a thermal isomerization
Scheme 3. The conversion to 3b and rotational barriers of 2b and 3b.
experiment (further heating resulted in the decomposition of 3a),
the estimation based on DFT calculation was investigated.10 The
D
G– values of 2a and 3a, which were calculated at the B3LYP/6-
31G(d) level, were 33.2 and 43.5 kcal/mol (at 110 °C), respectively.
The calculated
G– value (33.2 kcal/mol) of 2a was almost the
same as the experimental
G– value (33.1 kcal/mol), and this indi-
cates the high reliability of the present DFT method. In addition, it
should be noted that the
G– value of 3a dramatically increases in
D
D
D
comparison with that of 2a (more than 10 kcal/mol).
Similar results were also obtained in the case of dihydroquinaz-
olin-2-one 2b and quinazolin-2-one 3b. That is, after heating for
14 h at 90 °C in toluene, the ee of 2b was reduced by 60% from
95%, while the ee of 3b was not changed even after 24 h under tol-
uene reflux conditions (Scheme 3). The
D
G– value of 2a based on
Eyring plot was 30.7 kcal/mol (at 110 °C, t1/2 = 4.3 h at 110 °C).11
The DFT calculations of 2b and 3b were subsequently performed,
and these
mol (at 110 °C), respectively.10 Similar to the case of 2a and 3a,
the
G– value of 3b remarkably increased in comparison with that
D
G– values were calculated to be 30.8 and 37.5 kcal/
D
of 2b (6.8 kcal/mol).
Thus, it was found that the rotational barrier of N–C axially chi-
ral compounds significantly increased by the conversion to the cor-
responding aromatic compounds. To elucidate the origin of the
increase in the rotational barrier by the aromatization, X-ray crys-
tallography of dihydroquinolinone 2a and quinolinone 3a was
investigated. Unfortunately, since a good single crystal of 2a was
not obtained, the crystal structure of the
a-methylated derivative
2a-Me,12 which has a similar rotational barrier to 2a, was com-
pared with that of 3a (Fig. 2).13
In both compounds 3a and 2a-Me, the 2,5-di-tert-butylphenyl
group is perpendicular toward the quinolinone ring (<C2-N1-C10-
C20 = ꢀ95.8° and ꢀ95.9°), and understandably, each amide part
Scheme 1. Highly enantioselective synthesis of atropisomeric compounds 2a and
2b-Bn.

4334
N. Suzumura et al. / Tetrahedron Letters 53 (2012) 4332–4336
< C2-N1-C1'-C2' = -95.8°
5
8
4
4a
8a
< O-C2-N1-C1' = 3.1°
< C1'-N1-C8a-C8 = 3.9°
< C5-C4a-C4-C3 = 179.5°
< C2-N1-C1' = 116.9°
< C2-N1-C8a = 123.7°
< C8a-N1-C1' = 119.3°
C2-N1 = 1.400 Å
3
2
6
7
1
N
O
t-Bu
1'
6'
5'
2'
3'
t-Bu
4'
N1-C1' = 1.453 Å
3a
N1-C8a = 1.402 Å
C2-O = 1.230 Å
5
4
< C2-N1-C1'-C2' = -95.9°
< O-C2-N1-C1' = -4.5°
< C1'-N1-C8a-C8 = 24.6°
< C5-C4a-C4-C3 = 144.7°
< C2-N1-C1' = 119.1°
< C2-N1-C8a = 122.6°
< C8a-N1-C1' = 117.9°
C2-N1 = 1.377 Å
Me
O
4a
3
6
2
8
1
N
7
8a
t-Bu
1'
2'
6'
5'
3'
t-Bu
4'
2a-Me
N1-C1' = 1.448 Å
N1-C8a = 1.427 Å
C2-O = 1.223 Å
Figure 2. X-ray crystal structures of 3a and 2a-Me.
has almost a planar structure (<O-C2-N1-C10 = 3.1° and ꢀ4.5°). On
the bond lengths of the carbonyl group (C–O) and the chiral axis
(N-C10), the sp2 character of the nitrogen atom, and the three bond
angles around the nitrogen atom (<C8a-N1-C10, <C2-N1-C10, <C2-
N1-C8a), significant difference between 3a and 2a-Me was not ob-
served. Although it was found that the amide C–N bond (C2-N1) of
3a is slightly longer (0.023 Å) than that of 2a-Me and the N1-C8a
bond distance of 3a is shorter (0.025 Å) in comparison with that
of 2a-Me, the high rotational barrier of 3a cannot be rationalized
on the basis of the differences of these bond lengths.
On the other hand, in the crystal structure of 2a-Me, a slight dis-
tortion of the amide part from the benzene plane was found (<C10-
N1-C8a-C8 = 24.6°), while in aromatic 3a, the benzene and lactam
rings are almost on the co-planar (<C10-N1-C8a-C8 = 3.9°). The
distorted structure of 2a-Me may alleviate the steric repulsion be-
tween ortho-substituent (C20-H or ortho-tBu group) and C8-hydro-
gen during the N–Ar bond rotation to lead to a decrease in the
rotational barrier in comparison with planar compounds 3a.
However, it is still unclear that such a slight distortion in the
ground state is the primary factor for the remarkable difference
of the rotational barrier between 2a and 3a. Therefore, we consid-
ered the structure of the transition state during the N–Ar bond
rotation by DFT method.10 The structures of the ground state and
transition state of 2a, which was estimated by DFT, are shown in
Figure 3. The calculated ground state structure is similar to the
crystal structure of 2a-Me.
As the transition state structures during the N–Ar bond rotation
in 2a, TS-2a or TS-2A through the rotation of the ortho-tert-butyl
group toward the carbonyl group or benzene C8 sides, should be
possible. DFT calculation indicates that the rotation proceeds via
TS-2a but not TS-2A because TS-2A has an extremely high activa-
tion energy in comparison with TS-2a (the steric repulsion be-
tween the C8-hydrogen and the ortho-tert-butyl group in TS-2A
may be stronger than that between the carbonyl oxygen and the
ortho-tert-butyl group in TS-2a).
In TS-2a having almost a parallel 2,5-di-tert-butylphenyl group
toward the dihydroquinolinone ring (<C2-N1-C10-C20 = ꢀ1.3°), con-
siderable changes on bond distances and angles around the nitro-
gen atom were found. Namely, the C2-N1 and the N1-C8a bonds
are elongated (0.034 Å and 0.027 Å), and the <C2-N1-C10 increase
by 14.6° while <C2-N1-C8a decrease by 15.2° from the ground
state conformer [the bond length of chiral axis (N1-C10) and
<C8a-N1-C10 hardly change]. In addition, it should be noteworthy
that remarkable distortion from planarity of amide part was found
(<O-C2-N1-C10 = ꢀ41.9°, sp2 character of amide nitrogen is main-
tained in the transition state).14 These structural changes may lead
to alleviation of the steric repulsion between the carbonyl oxygen
and the bulky ortho-tert-butyl group.
Such changes were also observed in the case of quinolinone 3a
(Fig. 4). The transition state structure TS-3a estimated by DFT
method indicates the considerable distortion of the amide part,
increase in the bond lengths (C2-N1, N1-C8a) and bond angle
(<C2-N1-C10), and decrease in <C2-N1-C8a in comparison with
the ground state structure. Furthermore, in TS-3a, the benzene
and lactam rings were found to be not on the co-planar (<C5-
C4a-C4-C3 = 159.3°).
We especially focused on the remarkable distortion of the
unsaturated lactam part in TS-3a (the twisting of the amide bond
and the distortion of the lactam ring from the benzene). Such dis-
tortion in rigid aromatic lactam 3a would bring about the larger
strain energy in comparison with that in flexible non-aromatic lac-
tam 2a as well as the decrease in the aromatic stabilization energy.
Hence, the rotational barrier of 3a may significantly increase more
than that of 2a.
The transition state structures TS-2b and TS-3b during N–Ar
bond rotation of dihydroquinazolin-2-one 2b and quinazolin-2-
one 3b by DFT method are shown in Figure 5. Similar to TS-2a
and TS-3a, in TS-2b and TS-3b, a remarkable distortion of the
amide part is caused (<O-C2-N1-C10: TS-2b; 50.9°, TS-3b;
ꢀ50.7°). Furthermore, in TS-3b, the distortion of the pyrimidinone
ring from the benzene plane was also found (<C5-C4a-C4-
N3 = 159.2°). Since TS-3b may bring about more significant
destabilization than TS-2b by an increase in the strain energy
and a decrease in the aromatic stabilization energy, the rotational
barrier of 3b considerably increases in comparison with that of 2b.
In conclusion, we found that aromatic structure brings about a
remarkable increase in the rotational barrier of N–C axially chiral
compounds. Furthermore, through the analysis of the transition

N. Suzumura et al. / Tetrahedron Letters 53 (2012) 4332–4336
4335
N
O
t-Bu
TS-2A
t-Bu
< C2-N1-C1'-C2' = -94.2°
< O-C2-N1-C1' = 10.4°
< C1'-N1-C8a-C8 = 6.8°
< C5-C4a-C4-C3 = 145.6°
< C2-N1-C1' = 116.7°
< C2-N1-C8a = 122.7°
< C8a-N1-C1' = 119.9°
C2-N1 = 1.394 Å
X
5
4
4a
3
2
6
7
1
8a
N
O
t-Bu
8
1'
N1-C1' = 1.449 Å
6'
5'
2'
3'
N1-C8a = 1.425 Å
C2-O = 1.221Å
t-Bu
4'
2a
< C2-N1-C1'-C2' = -1.3°
< O-C2-N1-C1' = -41.9°
< C1'-N1-C8a-C8 = 53.3°
< C5-C4a-C4-C3 = 125.2°
< C2-N1-C1' = 131.3°
< C2-N1-C8a = 107.5°
< C8a-N1-C1' = 120.3°
C2-N1 = 1.428 Å
N
O
t-Bu
N1-C1' = 1.451 Å
t-Bu
N1-C8a = 1.452 Å
TS-2a
C2-O = 1.211Å
Figure 3. The ground state and transition state structures during N–Ar bond rotation of 2a on the basis of DFT calculation.
N
O
t-Bu
TS-3A
t-Bu
< C2-N1-C1'-C2' = -85.3°
< O-C2-N1-C1' = 7.5°
< C1'-N1-C8a-C8 = -7.9°
< C5-C4a-C4-C3 = 179.9°
< C2-N1-C1' = 116.2°
< C2-N1-C8a = 123.5°
< C8a-N1-C1' = 119.9°
C2-N1 = 1.413 Å
X
5
8
4
4a
8a
3
2
6
7
1
N
O
t-Bu
1'
6'
5'
N1-C1' = 1.451 Å
2'
3'
N1-C8a = 1.396 Å
C2-O = 1.228 Å
t-Bu
4'
3a
< C2-N1-C1'-C2' = -5.3°
< O-C2-N1-C1' = 41.8°
< C1'-N1-C8a-C8 = -39.7°
< C5-C4a-C4-C3 = 159.3°
< C2-N1-C1' = 126.1°
< C2-N1-C8a = 112.2°
< C8a-N1-C1' = 121.5°
C2-N1 = 1.431 Å
N
O
t-Bu
N1-C1' = 1.454 Å
t-Bu
TS-3a
N1-C8a = 1.432 Å
C2-O = 1.217 Å
Figure 4. The ground state and transition state structures during the N–Ar bond rotation of 3a on the basis of DFT calculation.

4336
N. Suzumura et al. / Tetrahedron Letters 53 (2012) 4332–4336
Tsuru, I.; Kohomoto, S.; Yamamoto, M.; Yamada, K. Chem. Lett. 1994, 1605; (c)
5
8
4
3
4a
8a
Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T.; Shiro, M. J. Org. Chem.
1998, 63, 2634; (d) Hughes, A. D.; Price, D. A.; Simpkins, N. S. J. Chem. Soc.,
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6
7
NH
2
1
N
O
t-Bu
1'
6'
5'
2'
3'
t-Bu
4'
TS-2b
3. In addition to III–VI, other stable N–C axially chiral aromatic heterocycles
(quinolin-2-one and pyridin-2-one) having an N-(ortho-methyl)phenyl group
have also been reported. (a) Mintas, M.; Mihaljevic, V.; Koller, H.; Schuster, D.;
Mannschreck, A. J. Chem. Perkin Trans. 2 1990, 619; (b) Sakamoto, M.; Utsumi,
N.; Ando, M.; Seki, M.; Mino, T.; Fujita, T.; Katoh, A.; Nishino, T.; Kashima, C.
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Hirano, M. Synlett 2008, 1724. See also Ref. 1l..
4. In the course of study on atropisomeric lactams, we previously reported that
the ring size of lactam considerably influences the stability of the
atropisomerism. That is, a six-membered ring lactam possessing larger bond
angle (<CO-N-C = 124.1°) was found to have a higher rotational barrier than a
5
8
4
3
4a
6
7
N
2
1
8a
6'
N
O
t-Bu
1'
2'
3'
5'
t-Bu
4'
five-membered ring lactam possessing
a smaller bond angle (<CO-N-
C = 112.1°). However,
between imide IIB
a
remarkable difference of the rotational barrier
1m,2b,f
and thiazol-2-one V1d having a five-membered ring
TS-3b
structure cannot be rationalized on the basis of such bond angle. Kitagawa, O.;
Fujita, M.; Kohriyama, M.; Hasegawa, H.; Taguchi, T. Tetrahedron Lett. 2000, 41,
8539.
Figure 5. The transition state structures TS-2b and TS-3b during N–Ar bond
rotation of 2b and 3b on the basis of DFT calculation.
5. Reviews on medicinal drugs having atropisomeric structure (a) Clayden, J.;
Moran, W. J.; Edwards, P. J.; LaPlante, S. R. Angew. Chem., Int. Ed. 2009, 48, 6398;
(b) LaPlante, S. R.; Fader, L. D.; Fandrick, K. R.; Fandrick, D. R.; Hucke, O.;
Kemper, R.; Miller, S. P. F.; Edwards, P. J. J. Med. Chem. 2011, 54, 7005.
6. (a) Kitagawa, O.; Hirotaka, H.; Dobashi, A.; Taguchi, T.; Shiro, M. Tetrahedron
Lett. 1997, 38, 4447; (b) Kitagawa, O.; Taguchi, T. Yuki Gosei Kagaku Kyokaishi
2001, 59, 680; (c) Takahashi, M.; Kitagawa, O. Yuki Gosei Kagaku Kyokaishi 2011,
69, 985; (d) Ototake, N.; Morimoto, Y.; Mokuya, A.; Fukaya, H.; Shida, Y.;
Kitagawa, O. Chem. Eur. J. 2010, 16, 6752. and references cited therein.
7. (a) Kitagawa, O.; Takahashi, M.; Yoshikawa, M.; Taguchi, T. J. Am. Chem. Soc.
2005, 127, 3676; (b) Kitagawa, O.; Yoshikawa, M.; Tanabe, H.; Morita, T.;
Takahashi, M.; Dobashi, Y.; Taguchi, T. J. Am. Chem. Soc. 2006, 128, 12923.
8. Catalytic enantioselective synthesis of N-C axially chiral compounds by other
groups (a) Brandes, S.; Bella, M.; Kjoersgaard, A.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2006, 45, 1147; (b) Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc.
2006, 128, 4586; (c) Duan, W.; Imazaki, Y.; Shintani, R.; Hayashi, T. Tetrahedron
2007, 63, 8529; (d) Oppenheimer, J.; Hsung, R. P.; Figueroa, R.; Johnson, W. L.
Org. Lett. 2007, 9, 3969; (e) Clayden, J.; Turner, H. Tetrahedron Lett. 2009, 50,
3216; (f) Onodera, G.; Suto, M.; Takeuchi, R. J. Org. Chem. 2012, 77, 908; (g)
Shirakawa, S.; Liu, K.; Maruoka, K. J. Am. Chem. Soc. 2012, 134, 916.
9. The rate constants for the racemization of 2a were measured at three different
temperatures (96.0 °C, 103.1 °C, and 109.5 °C) in toluene. These data were
subjected to an Eyring plot to determine the rotational barrier (see
Supplementary data).
10. DFT calculations at the level of B3LYP1/6-31G(d) were performed by Firefly (PC
GAMESS) quantum chemical package (version 7.1.G, Alex A. Granovsky, Firefly
version 7.1.G, www http://classic.chem.msu.su/gran/firefly/index.html). All
structures were fully optimized and then subjected to the frequency
analysis. For the ground state, the absence of the imaginary frequency was
confirmed in every case. Transition states relevant to the rotational barrier
were identified by the following two criteria: (1) The frequency analysis gave
only one imaginary frequency. (2) The exhaustive IRC calculations provided
one pair of enantiomeric atropisomers. Schmidt, M. W.; Baldridge, K. K.; Boatz,
J. A.; Elbert, S. T.; Gordon, M. S.; Jensen, J. H.; Koseki, S.; Matsunaga, N.; Nguyen,
K. A.; Su, S.; Windus, T. L.; Dupuis, M.; Montgomery, J. A.; J. Comput. Chem.
1993, 14, 1347.
state structure during the N–Ar bond rotation based on DFT calcu-
lation, the origin of increase in the rotational barrier of aromatic
compounds was strongly suggested to be due to the significant
twisting of the nitrogen-containing heterocyclic part. This result
indicates that in aromatic heterocycles possessing an ortho-substi-
tuted phenyl group on the nitrogen atom, there is a high possibility
of having stable axial chirality. In addition, this knowledge is
important from the viewpoint of not only N–C axially chiral chem-
istry but also medicinal chemistry, because aromatic heterocycles
possessing an N-(ortho-substituted)phenyl group frequently have
strong pharmacological activity.
Acknowledgments
This work was partly supported by a Grant-in-Aid (C22590015)
for Scientific Research and the Ministry of Education, Science,
Sports, and Culture of Japan.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.
007.
References and notes
11. The rate constants for the racemization of 2b were measured at four different
temperatures (74.4 °C, 82.2 °C, 88.8 °C, and 98.5 °C) in toluene. These data were
subjected to an Eyring plot to determine the rotational barrier (see
Supplementary data).
1. Typical examples of atropisomeric compounds having an N–C chiral axis: (a)
Bock, L. H.; Adams, R. J. Am. Chem. Soc. 1931, 53, 374; (b) Kashima, C.; Katoh, A.
J. Chem. Soc., Perkin Trans. 1 1980, 1599; (c) Mannschreck, A.; Koller, H.; Stühler,
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Roussel, C.; Adjimi, M.; Chemlal, A.; Djafri, A. J. Org. Chem. 1988, 53, 5076; (e)
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H. O.; Adams, R. D. Tetrahedron Lett. 2000, 41, 5431; (j) Tetrahedron
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12. The crystal structure of 2a-Me; see Supplementary data in Ref. 7a.
13. CCDC-866228 (3a) contains the supplementary crystallographic data for this
Letter. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.com.ac.uk/data_request/cif.
14. Ab initio studies of axially chiral quinazolin-4-one derivatives such as III
(Fig. 1) have been reported by Sapse and co-workers. The transition state
structures during the N–Ar bond rotation estimated by an ab initio calculation
with a HF/6-31G⁄ basis set are similar to those shown in Figures 3–5. That is,
the considerable distortion of the amide part and an increase in the bond
length (C2-N1, N1-C8a) and bond angle (<C2-N1-C10) were found. However,
there has been no previous mention of the relationship between the aromatic
structure and the rotational barrier. Azanli, E.; Rothchild, R.; Sapse, A-M.
Spectrosc. Lett. 2002, 35, 257.
2. Typical papers on atropisomeric ortho-tert-butylanilides: (a) Curran, D. P.; Qi,
H.; Geib, S. J.; DeMello, N. C. J. Am. Chem. Soc. 1994, 116, 3131; (b) Kishikawa, K.;