Synthesis and stereochemical properties of chiral hetero[7]helicenes structured by a benzodiheterole ring core

Article abstract of DOI:10.1246/cl.170410

A new hetero[7]helicene 1_NN structured by a diazabenzodiheterole (pyrroloindole) ring core was successfully synthesized by catalytic domino cyclodehydrogenation with Pd(OAc)₂ and O₂ as the key step. Significantly, 1_NN was stereochemically stable at room temperature and could be subjected to optical resolution by chiral HPLC. Furthermore, kinetic analysis of 1_NN and DFT calculations on its variants revealed that the stereo-chemical stability of the benzodiheterole-based helicenes was highly dependent on not only the heteroaromatic ring component but also on the N-substituent of the pyrrole ring unit.

Full text of DOI:10.1246/cl.170410

Advance Publication Cover Page
Synthesis and Stereochemical Properties of Chiral Hetero[7]helicenes
Structured by a Benzodiheterole Ring Core
Sachie Arae, Takaaki Mori, Takahiro Kawatsu, Daiki Ueda, Yusuke Shigeta, Nobutsugu Hamamoto,
Hitoshi Fujimoto, Michinori Sumimoto, Tatsushi Imahori, Kazunobu Igawa, Katsuhiko Tomooka,
Tharmalingam Punniyamurthy, and Ryo Irie*
Advance Publication on the web June 3, 2017
doi:10.1246/cl.170410
© 2017 The Chemical Society of Japan
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1
Synthesis and Stereochemical Properties of Chiral Hetero[7]helicenes
Structured by a Benzodiheterole Ring Core
Sachie Arae,1 Takaaki Mori,1 Takahiro Kawatsu,1 Daiki Ueda,1 Yusuke Shigeta,1 Nobutsugu Hamamoto,1 Hitoshi Fujimoto,1
Michinori Sumimoto,2 Tatsushi Imahori,3 Kazunobu Igawa,4 Katsuhiko Tomooka,4 Tharmalingam Punniyamurthy,5 and Ryo Irie∗
1
1Department of Chemistry, Faculty of Advanced Science and Technology, Kumamoto University,
2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan
2Graduate School of Science and Technology for Innovation, Yamaguchi University, Ube, Yamaguchi 755-8611, Japan
3Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science,
1-3 Kagurazaka, Shinjyuku-ku, Tokyo 162-8601, Japan
4Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga, Fukuoka 816-8580, Japan
5Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
(E-mail: irie@kumamoto-u.ac.jp)
A new hetero[7]helicene 1NN structured by a diaza-
low oxidation potential, thereby creating useful organic
functional materials such as those exhibiting hole-transport
properties.4 Thus, heterole-containing helicenes should also be
attractive as chiral functional molecules.2a In particular, our
primary concern has been the benzodiheterole-based helicenes
A, the two heterole rings of which may introduce some more
unique physical properties through electronic interactions of
the heteroatoms at the para position on the central benzene
ring.5 However, there still remain issues concerning the
development of catalytic and practical syntheses of chiral non-
racemic variants of A.6
benzodiheterole (pyrroloindole) ring core was successfully
synthesized by catalytic domino cyclodehydrogenation with
Pd(OAc)2 and O2 as the key step. Significantly, 1NN was
stereochemically stable at room temperature and could be
subjected to optical resolution by chiral HPLC. Furthermore,
kinetic analysis of 1NN and DFT calculations on its variants
revealed that the stereochemical stability of the
benzodiheterole-based helicenes was highly dependent on not
only the heteroaromatic ring component but also the N-
substituent of the pyrrole ring unit.
In order to overcome the synthetic issue described above,
we recently introduced a new concept of domino
cyclodehydrogenation (non-classical Bergman-Masamune
reaction)7 of ethenylene-linked diynes with suitable hetero-
nucleophilic units at the alkyne termini to construct
benzodiheterole frameworks (Scheme 1a).8-10 This strategy
was suitable for the synthesis of dioxa-benzodiheteroles
(benzodifurans) in heterohelicenes from o-phenylene-linked
diynes with nucleophilic phenol groups by the action of a
palladium catalyst and molecular oxygen (Scheme 1b,
previous work).8 In this work, we have designed a new
Phenanthrene is one of the basic aromatic hydrocarbons
composed of an angularly fused three-benzene ring unit
(Figure 1a). Fusing additional rings of benzene into the c and
g sides of this carbocycle leads to p-extended helical
architectures known as carbo-helicenes or simply helicenes.
Since the discovery of the elegant chiral helical form and
chiroptical properties of carbo[6]helicene by Newman and co-
workers,1 much effort has been devoted to the synthesis of
helicene derivatives and the evaluation of their structural
characteristics and physical properties.2 In this context,
introduction of a heteroaromatic ring to the helical framework
has gained increasing attention for modulating the electronic
states of helicenes.2a Hence, we have been interested in the
structural motif of A based on benzodiheteroles, heterocyclic
congeners of phenanthrene (Figure 1b).3
(a) Cyclodehydrogenation: our general approach to benzodiheteroles
–H2
X
Y
HX
YH
Heteroles such as furan, pyrrole, and thiophene are
typical electron-rich heteroarenes. They have been used to
constitute extended p-conjugated systems with a characteristic
(b) Pd-catalyzed cyclodehydrogenation for the synthesis
of the benzodiheterole-based helicenes
R
R
Previous work (X, Y = O)
dioxa-benzoheterole systems
O
O
(a) phenanthrene as a core structure of helicenes
R
R
Ar
Ar
π-extension
Pd catalyst
O2
Ar
n
Ar
HX
YH
c
g
m
e.g.) carbo[6]helicenes
Ar
Ar
helicenes
TsN
NTs
(b) benzodiheteroles as phenthrene congeners for heterohelicenes
Y
This work (X, Y = NTs)
diaza-benzoheterole systems
X
π-extension
X
Y
n
OMe
benzodiheteroles
(typically X, Y = NR, O, S)
m
MeO
heterohelicenes A (our interest)
1NN
Figure 1. (a) Phenanthrene and its angularly fused p-extended systems
(helicenes), (b) benzodiheteroles and its heterohelicene-derivatives
Scheme 1. Our cyclodehydrogenation strategy for the synthesis of
benzodiheterole-based helicenes

2
synthetic route to hetero[7]helicene 1NN with a diaza-
benzodiheterole (pyrroloindole) unit based on the Pd-
catalyzed cyclodehydrogenation (Scheme 1b, this work).11,12
Since we had demonstrated that the related dioxa-
following kinetic analysis based on Eyring’s theory revealed
the unexpectedly high activation free energy to racemization
of 1NN: DG‡
31.7 kcal/mol. 1NN was found to be
298K
stereochemically much more stable than 2NN(H).
benzodiheterole-based
[7]helicene
2OO
undergoes
racemization in solution at room temperature,8a it was a
crucial point to evaluate the stereochemical behavior of its
aza-variants prior to their synthetic study. It has been claimed
that pyrrole constitutes stereochemically more stable
heterohelicenes than furan.3c,12c Accordingly, we performed
DFT calculations on energy barriers to the racemization of
2NO(H) and 2NN(H), which substituted one or two pyrrole
rings for the furan rings of 2OO (Figure 2).13 The order of
–12.0
–13.0
–14.0
kinetic parameters
slope: –16.925
intercept: 26.891
R2 = 0.998
a
Temp. (ºC)
120
k (s–1
)
R2
3.66 x 10–5
1.17 x 10–4
2.93 x 10–4
8.70 x 10–4
0.998
0.986
0.990
0.987
130
140
–15.0
150
aRrate constant k was calculated from
the plot of ln(% ee) vs. time. See the
Supporting Information for detail.
–16.0
–17.0
2.3
2.4
2.5
2.6
T–1/10–3·K–1
stereochemical stability was indeed indicated to be 2OO
<
2NO(H) < 2NN(H), the substitution of furan by pyrrole leading
to about 2 kcal/mol increase in the racemization barrier. These
preliminary results encouraged us to pursue the synthesis of
1NN, a synthetically more accessible analogue of 2NN(H).14
Figure 3. Eyring plot for the racemization of 1NN; ln(k/T) vs. T–1/10–3·K–1,
where k stands for rate constant with a unit of s–1
In order to evaluate the effects of the substituents on the
high racemization barrier of 1NN, we performed DFT
calculations on 2NN(Ts), which was structurally the same as
that of 1NN, except for the absence of any substituents on the
benzene rings (Figure 4). The result indicates that 2NN(Ts)
also has a high-energy barrier to racemization (34.9 kcal/mol)
like 1NN, considerably exceeding that of the related NH-free
2NN(H) (26.5 kcal/mol). Thus, the N-Ts group of the pyrrole
ring in 1NN is crucial for stereochemical stabilization, its
contribution to the increase in the racemization barrier being
estimated to about 4 kcal/mol per group.18 The same
calculation was also applied to 2NN(t-Bu) with a bulky N-t-
butyl group for comparison, and its racemization barrier (27.4
kcal/mol) was found to be close to that of 2NN(H).13 This
indicates that the N-Ts group should affect the racemization
process of 1NN electronically, rather than sterically. To the
best of our knowledge, this is the first proof for the significant
effect of the N-substituent on the stereochemical stability of
heterohelicenes.
O
O
HN
O
HN
NH
2OO
(22.5 kcal/mol)
2NO(H)
(24.8 kcal/mol)
2NN(H)
(26.5 kcal/mol)
Figure 2. DFT calculations at a B3LYP/6-311G(d,p) level on the
racemization barriers (DG‡
shown in parentheses) of the
,
298K
hetero[7]helicenes 2OO, 2NO(H), and 2NN(H) with a dioxa-, aza-oxa, and
diaza-benzodiheterole unit, respectively
15
We synthesized o-phenylenediynes 3NN and examined its
cyclodehydrogenation for the production of 1NN (Scheme 2).
Consequently, the reaction produced 1NN in 47% yield under
almost the same reaction conditions as those for the synthesis
of 2OO8a: Pd(OAc)2 (10 mol%) and molecular oxygen (1 atm)
in DMSO in the presence of aq. NaOH (1 M, 4 eq.) and MS
racemization barriers (ΔG‡
)
298K
4A at 50 °C. Without the base additive, the yield of 1NN
2NN(H):
R = H,
R = Ts, 34.9 kcal/mol
26.5 kcal/mola
16
significantly decreased, as in the synthesis of 2OO
.
2NN(Ts)
RN
NR
2NN(t-Bu): R = t-Bu, 27.4 kcal/mol
cf. 1NN: 31.7 kca/molb
aData taken from Figure 2.
bKinetic analysis.
Pd(OAc)2 (10 mol%)
O2 (1 atm)
2NN(R)
TsN
NTs
TsHN
NHTs
DMSO, MS 4A
aq. NaOH (1 M, 4 eq.)
50 °C, 12 h
Figure 4. Evaluation of the N-substituent effect on the racemization
barriers of benzodipyrrole-based [7]helicenes 2NN(R) by DFT calculations
at a B3LYP/6-311G(d,p) level
47%
OMe
MeO
1NN
MeO
OMe
3NN
In summary, the new chiral hetero[7]helicene 1NN based
Scheme 2. Pd-catalyzed cyclodehydrogenation to synthesize 1NN
on a diaza-benzodiheterole ring core was successfully
synthesized
by
palladium-catalyzed
domino
cyclodehydrogenation of o-phenylene-linked diyne 3NN as the
key step. Subsequent enantiomeric separation by chiral HPLC
afforded 1NN in an optically pure form. Kinetic analysis of 1NN
and DFT calculations on its variants revealed that the
stereochemical stability of the benzodiheterole-based
helicenes was highly dependent on not only the
heteroaromatic ring component but also on the N-substituent
of the pyrrole ring unit.
We next attempted to evaluate the stereochemical
stability of 1NN. Chiral HPLC analysis of 1NN at room
temperature resulted in complete peak separation of
enantiomers.17 This indicates that 1NN has sufficient
stereochemical stability for optical resolution, as predicted by
the DFT calculation on its model 2NN(H). Indeed,
enantiomerically pure 1NN was obtained by the chiral HPLC
separation of rac-1NN. Further experiments were performed to
measure its rate of racemization at 120-150 ºC (Figure 3). The

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This work was financially supported by a Grant-in-Aid
for Scientific Research (C) (No. 24550059) and pursued under
the Cooperative Research Program “CORE Lab” of Network
Joint Research Center for Materials and Devices: Dynamic
Alliance for Open Innovation Bridging Human, Environment
and Materials.
Supporting
Information
is
available
on
http://dx.doi.org/10.1246/cl.******.
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13
14
For details of calculations, see the Supporting Information.
We also synthesized the racemic aza-oxa-variant 1NO, which was
structurally comparable to 1NN but had a furan and an N-Ts-pyrrole
ring such as 2NO, in the similar manner, although its enantiomeric
separation by chiral HPLC has so far been unsuccessful. For further
details of 1NO, see the Supporting Information.
8
9
15
16
For the synthesis of 3NN, see the Supporting Information.
In the absence of the base additive and under otherwise the
identical conditions, 1NO and 1NN were obtained in lower yields.
See the Table S1 in the Supporting Information.
17
18
For the HPLC conditions, see the Supporting Information.
To gain an experimental evidence about the N-Ts group effect on
the stereochemical stability of 1NN, we attempted to prepare the
NH-free derivative of 1NN for its stereochemical analysis. After
various attempts, detosylation of 1NN was performed by treatment
with KOH to provide the desired product. However, it was difficult
to isolate for further experiments due to its high air-sensitivity. We
are currently revisiting the synthesis, isolation, analysis of the NH-
free derivative of 1NN under a strictly inert atmosphere.