Synthesis and resolution of a new helically chiral azahelicene

Article abstract of DOI:10.1016/j.tetlet.2008.04.135

Helically chiral azahexahelicene 3 was prepared in four steps using the Mizoroki-Heck coupling followed by classical oxidative photodehydrocyclisation. Resolution of this new chiral system was achieved through separation by HPLC providing (-)- and (+)-3 in high optical purity. The absolute configurations of (-)- and (+)-3 were assigned as M and P, respectively, by means of circular dichroism. Each of the hexacyclic systems (M)-(-)- and (P)-(+)-3 was reacted with boron tribromide to provide the corresponding helical pyridophenols in good yields.

Full text of DOI:10.1016/j.tetlet.2008.04.135

Tetrahedron Letters 49 (2008) 4092–4095
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Tetrahedron Letters
journal homepage: http://www.elsevier.com/locate/tetlet
Synthesis and resolution of a new helically chiral azahelicene
Faouzi Aloui a, Riadh El Abed a, Angéla Marinetti b, Béchir Ben Hassine a,
*
a Laboratoire de Synthèse Organique Asymétrique et Catalyse Homogène (O1UR1201), Faculté des Sciences, Avenue de l’environnement, 5019 Monastir, Tunisia
b Institut de Chimie des Substances Naturelles—CNRS UPR 2301, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Helically chiral azahexahelicene 3 was prepared in four steps using the Mizoroki–Heck coupling followed
by classical oxidative photodehydrocyclisation. Resolution of this new chiral system was achieved
through separation by HPLC providing (À)- and (+)-3 in high optical purity. The absolute configurations
of (À)- and (+)-3 were assigned as M and P, respectively, by means of circular dichroism. Each of the hexa-
cyclic systems (M)-(À)- and (P)-(+)-3 was reacted with boron tribromide to provide the corresponding
helical pyridophenols in good yields.
Received 13 March 2008
Revised 14 April 2008
Accepted 23 April 2008
Available online 27 April 2008
Keywords:
Helicenes
Ó 2008 Elsevier Ltd. All rights reserved.
Heck reaction
Enantiomeric resolution
Photodehydrocyclisation
Azahelicenes
Helicenes constitute a fascinating class of chiral helical mole-
cules comprising ortho-fused aromatic rings. They have a powerful
inherently dissymmetric chromophore which exhibits a very high
specific rotation, and are further characterised by strong inter-
actions with electron-deficient analytes. The unique structure of
helicenes makes them very stable towards acids, bases and rela-
tively high temperature.1 These molecules are considered as poten-
tially useful new materials such as discotic liquid crystals2 or
conjugated polymers.3 In particular, functionalised hexahelicenes
and larger [n]helicenes are promising candidates for chiral cata-
lysts4 and ligands5 in asymmetric syntheses because they have a
rigid helical framework and possess high optical stability.
HN
R
N
R
R
NH
MeO
R
3
1: R = H
2: R = Me
Figure 1. Structures of azahexahelicenes 1, 2 and 3.
In recent years, the preparation of heterohelicenes has been
studied extensively in order to exploit the unique properties of
these molecules.6 However, aza[6]helicenes were not elaborated
sufficiently and only a few reports have described the synthesis
of such compounds despite their possible applications in various
branches of chemistry. A well-known representative of this family
is the racemic pyrrolo[6]helicene 1, which has been prepared, in
two steps, by Fuchs and Niszel (Fig. 1).7 Following the same meth-
od, Pischel et al. reported the synthesis of the corresponding tetra-
methyl derivative 2 in low yield. Resolution was achieved only
on an analytical scale by chiral HPLC.8 Finally, Staab et al. have
described the synthesis of 1,16-diaza[6]helicene, but they have
not reported its resolution.9
phines,10,11 using palladium-promoted Mizoroki–Heck coupling
reactions and classical oxidative photocyclisation, while searching
for new chiral ligands. Due to the small number of aza[6]helicenes
we wanted to extend our approach to the synthesis of various
functionalised nitrogen-containing species. Our strategy makes
use of 2-bromo-10-methoxybenzo[c]phenanthrene 7 as the start-
ing material for the preparation of the nitrogen-containing olefin
8, via palladium catalysed Mizoroki–Heck reaction. The olefin is
then converted into the corresponding helically chiral hexacyclic
system by photolysis. The nitrogen atom in this chiral helicene
could serve as a hydrogen acceptor as well as a metal chelating
agent for chirality recognition.
We have previously reported the synthesis and characterisation
of various functionalised helically chiral alcohols and phos-
The synthesis of the helically chiral hexacyclic framework 3 was
performed as shown in Schemes 1 and 2. The Mizoroki–Heck
coupling12 of 1,4-dibromobenzene 4 with excess of commercially
available 6-methoxy-2-vinylnaphthalene 5 in the presence of
* Corresponding author. Tel.: +216 73500279; fax: +216 73500278.
E-mail address: bechirbenhassine@yahoo.fr (B. B. Hassine).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.135

F. Aloui et al. / Tetrahedron Letters 49 (2008) 4092–4095
4093
OCH3
Br
OCH3
1%[Pd], NaOAc
+
DMA, 140 ˚C, 48 h
85%
Br
4
5
Br
6
OCH3
hν, cyclohexane
propylene oxide, I2
70%
Br
7
Scheme 1. Synthesis of the benzo[c]phenanthrene moiety 7.
OCH3
OCH3
1% [Pd], NaOAc
+
N
DMA, 140 ˚C, 48 h
76%
Br
7
8
N
OCH3
N
hν, cyclohexane
propylene oxide, I2
53%
3
Scheme 2. Synthesis of the helically chiral hexacyclic system 3.
sodium acetate and 1% of Hermann’s palladacycle [trans-di(l-ace-
tato)-bis[o-(di-o-tolylphosphino)-benzyl]dipalladium] as the cata-
lyst, in N,N-dimethylacetamide (DMA), afforded the diarylethene
6 in 85% yield after purification by column chromatography. Previ-
ously, we have demonstrated that the condensation reaction
between 2-bromo-6-methoxynaphthalene and p-bromostyrene,
via Heck conditions, produced only a small amount of the expected
product 6.10a Olefin 6 was then irradiated using a 150 W high pres-
sure mercury immersion lamp on a 500 mg scale to give 2-bromo-
10-methoxybenzo[c]phenanthrene 7 in 70% yield (Scheme 1).
The benzo[c]phenanthrene derivative 7 and 3-vinylpyridine
(1.5 equiv) undergo a Mizoroki–Heck coupling using 1% of Her-
mann’s catalyst. The desired coupled product 8, possessing E-
stereochemistry at the double bond, was obtained in 76% yield
after heating for 48 h at 140 °C, according to Scheme 2. To com-
plete the synthesis of [6]helicene 3, olefin 8 was photocyclised in
the presence of a stoichiometric amount of iodine as oxidising
agent and an excess of propylene oxide as a hydrogen iodide scav-
enger.13 Thus, photolysis of 8 in cyclohexane for about 120 min, on
a 200 mg scale afforded the expected 3-aza-14-methoxy[6]heli-
cene 3 in 53% yield, and an overall 24% yield over four steps
(Scheme 2). For the photoconversion of larger amounts of the ole-
fin 8 it was preferable to carry out the irradiation using portions of
0.55 mmol or less. The total irradiation time required for complete
conversion of a large amount of 8 was not affected significantly by
dividing the reactant into small batches, and the irradiated batches
were combined for work-up.
The ring closure of olefin 8 is not completely regioselective
since 1-aza-14-methoxyhexahelicene 9 was isolated in 8% yield
as a minor product (Fig. 2).14 Helicenes 3 and 9 were successfully
separated by column chromatography on silica gel. No other
OCH3
N
9
Figure 2. Structure of the helically chiral compound 9.

4094
F. Aloui et al. / Tetrahedron Letters 49 (2008) 4092–4095
OCH3
OH
N
BBr3, CH2Cl2
N
3 h, 90%
34%
OCH3
N
(P)-(+)-3
(P)-(+)-10
HPLC
column
OCH3
N
OH
N
(P,M)-3
38%
BBr3, CH2Cl2
3 h, 90%
(M)-(-)-3
(M)-(-)-10
Scheme 3. Resolution of azahexahelicene 3 and synthesis of helically chiral pyridophenol derivatives 10.
isomer indicating that ring closure of 8 had occurred from the
other side of the four-membered ring system, was isolated from
the reaction mixture.
Having established a short and effective route to the azaheli-
cene 3, we next investigated its demethylation in order to obtain
new helically chiral pyridophenols. Thus, treatment of (M)-(À)-3
and (P)-(+)-3 with BBr3 solutions in CH2Cl2 at room temperature
provided the corresponding optically pure derivatives (M)-(À)-10
and (P)-(+)-10, respectively, in 90% yields19 according to Scheme
3 (>99% ee as shown by chiral HPLC analysis).20 The optical rotation
obtained for the M-configured pyridophenol was À1559 (c 0.30,
MeOH).
In summary, we have prepared chiral azahexahelicene 3 in four
steps, with an overall yield of 24%. Resolution of the latter was suc-
cessfully achieved affording the corresponding enantiomers in high
optical purity. This hexacyclic system was found to be a useful pre-
cursor for the preparation of helically chiral pyridophenols, which
could serve as N–O bidentate ligands in asymmetric synthesis or as
building blocks for supramolecular architectures. Work in this field
is currently in progress.
The separation of rac-3 into its enantiomers was achieved on
preparative scale by HPLC using a column packed with cellulose-
tris(3,5-dimethylphenylcarbamate)15 (250 Â 20 mm) and n-hep-
tane/2-propanol (95:5) mixture as the mobile phase. Thus, starting
from 100 mg of rac-3, a total of 72 mg of pure product were sepa-
rated, equivalent to a yield of 72%. The earlier eluting fractions,
>99% ee, consisted of the enantiomer exhibiting a negative optical
rotation (À) which was isolated in 38% yield. Later eluting fractions
gave compound (+)-3 in 34% yield (>99% ee) (Scheme 3).16 The
enantiomeric purity of the products (À)- and (+)-3 was determined
by chiral HPLC using the same stationary phase as above.17
The specific rotation values obtained for (À)-3 and (+)-3 were
found to be [a]D À1373 (c 0.20, CH2Cl2) and +1363 (c 0.20, CH2Cl2),
respectively. The chiroptical properties of 3-aza-14-methoxyhexa-
helicene 3 in the form of the CD spectrum were also measured (Fig.
3), which indicated that complete optical resolution had occurred,
which makes assignment of the absolute configurations possible.
The CD spectrum of the dextrorotatory enantiomer (P)-(+)-3 exhib-
ited a distinct positive maximum at 333 nm and a negative maxi-
mum at 253 nm, as depicted in Figure 3, demonstrating no
significant change relative to the CD of unsubstituted hexaheli-
cene.18 Thus, the absolute configuration of (À)- and (+)-helicenes
3 must be M (left-handed helix) and P (right-handed helix),
respectively.
Acknowledgement
The authors are grateful to DGRSRT (Direction Générale de la
Recherche Scientifique et de la Rénovation Technologique) of the
Tunisian Ministry of Higher Education, Scientific Research and
Technology for the financial support.
References and notes
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250
300
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450
-20
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-60
-80
-100
λ [nm]
Figure 3. CD spectra of (P)-(+)-3 and (M)-(À)-3 in CH2Cl2.

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(500 MHz, CDCl3): d (ppm): 3.87 (s, 3H, OCH3), 6.41 (dd, J1 = 3 Hz, J2 = 9.5 Hz,
1H, H-15), 7.23 (d, J = 2.5 Hz, 1H, H-13), 7.36 (d, J = 6.3 Hz, 1H, H-2), 7.46 (d,
J = 9 Hz, 1H, H-16), 7.85 (d, J = 6.3 Hz, 1H, H-1), 7.92 (d, J = 8.5 Hz, 1H), 7.97 (d,
J = 8.5 Hz, 1H), 8.00–8.04 (m, 4H), 8.09 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 8.5 Hz,
1H), 9.23 (s, 1H, H-4); 13C NMR (75 MHz, CDCl3): d (ppm): 55.20 (OCH3), 107.34
(C-13), 116.17 (C-15), 120.10 (C-2), 123.88 (C), 124.72 (C), 125.91 (CH), 125.98
(C and CH), 126.34 (C), 126.68 (CH), 127.06 (CH), 127.61 (C), 127.82 (CH),
127.88 (CH), 127.95 (CH), 128.91 (C-16), 128.96 (CH), 130.57 (C), 133.07 (C),
133.30 (C), 133.42 (C), 133.77 (C), 142.78 (C-1), 151.33 (C-4), 157.54 (C-14);
ESI-MS: m/z = 360.1 [M+H]+; HRMS (MALDI-TOF) calcd for C26H18NO [M+H]+:
360.1388. Found: 360.1382.
7. Fuchs, W.; Niszel, F. Chem. Ber. 1927, 60, 209–217.
8. Pischel, I.; Grimme, S.; Kotila, S.; Nieger, M.; Vögtle, F. Tetrahedron: Asymmetry
1996, 7, 109–116.
(M)-(À)-3-Aza-14-methoxyhexahelicene
3 (>99% ee): pale yellow solid;
mp = 242–244 °C; [a]D À1373 (c 0.20, CH2Cl2); ESI-MS: m/z = 360.1 [M+H]+.
17. Determination of
% ee was accomplished using the following analytical
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conditions. Column: Chiralcel OD (250 Â 4.6 mm); mobile phase: n-C6H14/2-
propanol = 80/20 v/v; flow rate 1.0 mL minÀ1; temperature 303; detection: UV,
k = 270 nm; retention times of the two enantiomers were: 10.054 and 11.999
(the enantiomer exhibiting negative optical rotation (À) was the first to be
eluted).
18. Newmann, M. S.; Darlak, R. S.; Tsai, L. J. Am. Chem. Soc. 1967, 89, 6191–6193.
19. Selected spectral data for (P)-(+)-3-aza-14-hydroxyhexahelicene 10 (>99% ee):
pale yellow solid; mp >300 °C; [a]D +1551 (c 0.30, MeOH); 1H NMR (selected
data, 300 MHz, CD3OD): d (ppm): 6.16 (dd, J1 = 9 Hz, J2 = 2.4 Hz, 1H, H-15), 7.08
(d, J = 2.4 Hz, 1H, H-13), 7.13 (d, J = 9 Hz, 1H, H-16), 7.32 (d, J = 5.7 Hz, 1H, H-2),
7.59 (br s, 1H, H-1), 7.74 (d, J = 8.7 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.89 (d,
J = 8.1 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H); 8.05 (d, J = 8.4 Hz,
1H); 8.10 (d, J = 8.1 Hz, 1H); 8.13 (d, J = 8.4 Hz, 1H), 9.18 (s, 1H, H-4); 13C NMR
(selected data, 75 MHz, CD3OD): d (ppm): 111.88 (C-13), 117.60 (C-15), 123.01
(CH), 124.95 (C), 125.35 (C), 127.22 (C), 127.29 (CH), 127.38 (CH), 128.12 (CH),
128.49 (CH), 128.89 (C), 129.34 (2CH), 129.99 (CH), 130.14 (CH), 131.15 (CH),
131.88 (CH), 132.41 (CH), 135.30 (C), 135.75 (C), 135.89 (C), 136.73 (C), 139.77
(C), 150.68 (C), 157.25 (C-14); ESI-MS: m/z = 346.1 [M+H]+.
12. (a) El Abed, R.; Ben Hassine, B.; Genêt, G.-P.; Gorsane, M.; Marinetti, A. Eur. J.
}
Org. Chem. 2004, 1517–1522; (b) Harrmann, W. A.; Brossmer, C.; Ofele, K.;
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1995, 34, 1844–1848.
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14. Selected spectral data for 1-aza-14-methoxyhexahelicene 9: yellow solid;
mp = 227–229 °C; 1H NMR (300 MHz, CDCl3): d (ppm): 3.86 (s, 3H, OCH3),
6.27 (dd, J1 = 2.7 Hz, J2 = 9.3 Hz, 1H, H-15), 7.15 (dd, J1 = 4.2 Hz, J2 = 8.1 Hz, 1H,
H-3), 7.21 (d, J = 2.7 Hz, 1H, H-13), 7.46 (d, J = 9.3 Hz, 1H, H-16), 7.82–7.92 (m,
4H), 7.96–8.02 (m, 4H), 8.09 (d, J = 8.1 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d (ppm): 55.23 (OCH3), 106.83 (C-13), 115.27 (C-15), 120.77
(C-3), 123.96 (C), 125.23 (C–H), 126.18 (C–H), 126.39 (C–H), 126.53 (C), 126.62
(C–H), 126.72 (C–H), 127.36 (C–H), 127.44 (C–H), 127.94 (C–H), 128.31 (C–H),
128.57 (C), 128.77 (C–H), 129.85 (C), 130.12 (C), 132.69 (C), 133.14 (C), 133.47
(C), 135.47 (C), 145.59 (C), 146.75 (C–H), 156.61 (C–O); ESI-MS: m/z = 360.1
([M+H]+); HRMS (MALDI-TOF) calcd for C26H18NO [M+H]+: 360.1388. Found:
360.1380.
(M)-(À)-3-Aza-14-hydroxyhexahelicene 10 (>99% ee): pale yellow solid; mp
>300 °C; [a]D À1559 (c 0.30, MeOH); ESI-MS: m/z = 346.1 [M+H]+.
20. Analytical conditions are as follows. Column: Chiralcel OD (250 Â 4.6 mm);
mobile phase: n-C6H14/2-propanol = 90/10 v/v; flow rate 1.0 mL minÀ1
;
temperature 303; detection: UV, k = 270 nm; retention times of the two
enantiomers were: 14.903 and 18.374 (the enantiomer exhibiting negative
optical rotation (À) was the first to be eluted).
15. Okamoto, J.; Aburatani, J. R.; Hamato, K.; Hatada, K. J. Liq. Chromatogr. 1988, 11,
2147.
16. Selected spectral data for (P)-(+)-3-aza-14-methoxyhexahelicene 3 (>99% ee):
pale yellow solid; mp = 243–245 °C; [a]D +1363 (c 0.20, CH2Cl2); 1H NMR