Synthesis and resolution of 2-hydroxyhexahelicene

Article abstract of DOI:10.1016/j.tetlet.2012.11.036

2-Hydroxyhexahelicene has been prepared in good yield and purity via a three-step sequence involving palladium-catalysed Heck coupling and classical oxidative photocyclisation reactions. The two enantiomers of this hexacyclic helicenol have been separated using (S)-(-)-camphanoyl chloride as the chiral resolving agent.

Full text of DOI:10.1016/j.tetlet.2012.11.036

Tetrahedron Letters xxx (2012) xxx–xxx
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Tetrahedron Letters
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Synthesis and resolution of 2-hydroxyhexahelicene
⇑
Mourad Ben Braiek, Faouzi Aloui, Béchir Ben Hassine
Laboratoire de Synthèse Organique Asymétrique et Catalyse Homogène (O1UR1201), Faculté des Sciences, Avenue de l’environnement, 5019 Monastir, Tunisia
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Hydroxyhexahelicene has been prepared in good yield and purity via a three-step sequence involving
palladium-catalysed Heck coupling and classical oxidative photocyclisation reactions. The two enantio-
mers of this hexacyclic helicenol have been separated using (S)-(ꢀ)-camphanoyl chloride as the chiral
resolving agent.
Received 21 September 2012
Revised 31 October 2012
Accepted 8 November 2012
Available online xxxx
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Helicenes
Heck coupling
Photocyclisation
Enantiomeric resolution
Helicenes constitute a fascinating class of chiral helical mole-
cules that possess a unique screw-shaped -conjugated aromatic
compound as a ligand, or for broader exploitation. To our knowl-
edge, no process for the resolution for 1 has been described.
In this Letter, we report the synthesis of 2-hydroxyhexahelicene
(1) using palladium-catalysed Heck coupling and classical oxidative
photocyclisation reactions. Our synthetic approach is based on the
utilisation of the tetracyclic ring system 2 as a suitable key building
block to provide the helicene precursor 3, which is then easily con-
verted into the hexacyclic helicene 1 by oxidative photocyclisation.
The methoxy group in this chiral compound serves as an appropriate
functional group for increasing the solubility of diarylethene 3 when
subjected to photolysis in toluene, as it increases the solubility of the
target helicene in organic solvents.
p
system consisting of all ortho-annelated aromatic (and/or heteroar-
omatic) rings. On increasing the number of condensed rings (typi-
cally, n > 4), these molecules adopt a helical conformation to avoid
overlapping of the terminal aromatic nuclei, resulting in left- and
right-handed chiral helical structures of M and P configuration,
respectively.1,2 Helicene backbones have attracted a significant
interest owing to their properties and practical applications in
photo- and optoelectronics, as well as their ability to act as poten-
tially useful components in chiral discotic liquid crystalline mate-
rials,3 as building blocks for helical conjugated polymers4,5 and as
rotors.6 In particular, functionalised hexahelicenes and larger
[n]helicenes are promising candidates as chiral catalysts7 and li-
gands8 in asymmetric syntheses because they have a rigid helical
framework and possess high optical stability.
The synthesis of the helically chiral phenol 1 began with the
coupling of 2-bromobenzo[c]phenanthrene (2) with 4-methoxy-
styrene in the presence of sodium acetate and Hermann’s
palladacycle {trans-di(l-acetato)-bis[o-(di-o-tolylphosphino)benzyl]-
Typically, most of the strategies adopted for the synthesis of
these compounds suffer from a lack of general applicability and
dipalladium} as the catalyst, in N,N-dimethylacetamide (DMA)
according to Scheme 1. The mixture was heated for about 48 h at
140 °C to afford diarylethene 3 in 76% yield.
´
low yields. In an independent study, Teply et al. reported the syn-
thesis of 2-hydroxyhexahelicene (1) using a multistep procedure
based on a key intramolecular [2+2+2] cycloisomerisation of a
substituted triyne.9 The authors did not report the resolution of
this helical phenol or its use in catalysis. Moreover, in their se-
quence, the helicenol was obtained in a low overall yield using
harsh reaction conditions. A shorter access to the helical phenol
1 than that previously described, and/or by another higher yielding
procedure would be desirable for the examination of this
The starting material, 2-bromobenzo[c]phenanthrene (2), was
available in 2 steps and in good yield, by photocyclisation of
2-(4-bromostyryl)naphthalene, which is conveniently prepared
via a palladium-promoted Mizoroki–Heck reaction.10
The resulting coupled product 3 was found to have E-stereo-
chemistry at the double bond, based on a 1H NMR study.11 It was
then subjected to photocyclisation using a 500 W high-pressure
mercury immersion lamp. The photolysis was carried out on
300 mg scale per run in a reactor containing toluene (1.5 L), for
about 2 h in the presence of a stoichiometric amount of iodine
and excess propylene oxide12 to provide the expected 2-methoxy-
hexahelicene (4) in 65% yield, after purification by column chroma-
tography (Scheme 1).13 No other regioisomer was isolated from the
⇑
Corresponding author. Tel.: +216 73500279; fax: +216 73500278.
E-mail address: bechirbenhassine@yahoo.fr (B. Ben Hassine).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.036
Please cite this article in press as: Ben Braiek, M.; et al. Tetrahedron Lett. (2012), http://dx.doi.org/10.1016/j.tetlet.2012.11.036

2
M. Ben Braiek et al. / Tetrahedron Letters xxx (2012) xxx–xxx
OMe
1%[Pd], NaOAc
OMe
+
DMA, 140 °C, 48 h
76%
Br
2
3
OMe
OH
hν, toluene
BBr3
propylene oxide, I2
CH2Cl2, 0 °C
65%
95%
4
1
Scheme 1. Synthesis of 2-hydroxyhexahelicene (1).
reaction mixture indicating that the ring-closure of diarylethene 3
had occurred at the peri position of the tetracyclic moiety.
For the photoconversion of larger amounts of alkene 3, it was
preferable to carry out irradiation using portions of 0.5 mmol or
less. The total irradiation time required for complete conversion of
a large amount of 3 was not affected significantly by dividing the
reactant into small batches, and the irradiated batches were com-
bined for work-up. Also, this photochemical method has the advan-
tage that the tedious and difficult purification of the product is
avoided. Treatment of compound 4 with boron tribromide in dichlo-
romethane provided the corresponding 2-hydroxyhexahelicene (1)
in 95% yield.
O
OH
O
+
Cl
O
(P,M)-1
1) Et3N, CH2Cl2
0°C
2) SiO2 column chromatography
31%
23%
O
O
Having obtained the helically chiral phenol 1, we next studied
its resolution. To perform this resolution we investigated the utility
of (S)-(ꢀ)-camphanoyl chloride as a chiral resolving agent, which is
used to convert related alcohols into their corresponding ester
camphanates.14 Thus, treatment of racemic phenol 1 with
(S)-(ꢀ)-camphanoyl chloride, in the presence of triethylamine
and dichloromethane at room temperature, led to a 1:1 mixture
of two diastereomeric helicene camphanates (M,S)-5 and (P,S)-5
in 90% combined yield (Scheme 2). Attempts to separate these
camphanate esters by fractional crystallisation were not success-
ful. However, the diastereoisomers were satisfactorily separated
by chromatography. The diastereomeric mixture (136 mg) was
eluted at room temperature on a silica gel column with cyclohex-
ane/EtOAc (98:2–90:10) as the eluent. The fractions eluted were
analysed by TLC. The earlier eluting fractions consisted of the dia-
stereomer (P,S)-5, exhibiting a positive optical rotation, which was
obtained in 31% yield (42 mg) with a diastereomeric excess of
>98%.15 Later eluting fractions gave the second diastereomer
(M,S)-5 in 23% yield (31 mg) with >98% de.15 The purities of both
diastereomers were determined by 1H NMR spectroscopy.
In the 1H NMR spectra, the H-3 protons gave characteristic sig-
nals at 6.99 ppm (dd, J1 = 8.7 Hz, J2 = 2.4 Hz) and 7.04 ppm (dd,
J1 = 8.7 Hz, J2 = 2.4 Hz), for (P,S)-5 and (M,S)-5, respectively.
The specific rotation values obtained for (P,S)-5 and (M,S)-5
O
O
O
O
O
O
(P,S)-5
(M,S)-5
KOH, EtOH
90%
KOH, EtOH
90%
OH
OH
(P)-(+)-1
(M)-(-)-1
Scheme 2. Enantiomeric resolution of the helically chiral phenol 1.
synthesis of racemic 1 in only 3 steps with an overall 47% yield.
We also demonstrated that (S)-(ꢀ)-camphanoyl chloride was a
suitable resolving agent for the helically-chiral phenol. This heli-
cene could serve as a ligand in asymmetric synthesis or as a build-
ing block for supramolecular architectures. Work in this field is
currently in progress.
were found to be ½aꢁD +1882 (c 0.085, CHCl3) and ꢀ1792 (c 0.07,
CHCl3), respectively. Very high specific rotation values are a known
feature of helical structures, while the sign of the optical rotation
allows reliable assignment of the helical configuration.16,17
Treatment of the resulting optically active diastereoisomers
(P,S)-5 and (M,S)-5 separately, with a solution of potassium
hydroxide in refluxing ethanol gave the corresponding alcohols
(P)-(+)-1 and (M)-(ꢀ)-1, respectively, in good yields (Scheme 2).18
In summary, we have developed an efficient synthetic approach
and resolution of 2-hydroxyhexahelicene (1). We completed the
Acknowledgment
The authors are grateful to the DGRS (Direction Générale de la
Recherche Scientifique) of the Tunisian Ministry of Higher
Education for the financial support of this research.
Please cite this article in press as: Ben Braiek, M.; et al. Tetrahedron Lett. (2012), http://dx.doi.org/10.1016/j.tetlet.2012.11.036

M. Ben Braiek et al. / Tetrahedron Letters xxx (2012) xxx–xxx
3
silica gel using cyclohexane/EtOAc (98:2–90:10) as the eluent. These
conditions also allowed separation of the two diastereomeric esters. The
earlier eluting fractions consisted of diastereomer (P,S)-5 which was obtained
in 31% yield (42 mg). Later eluting fractions gave the second diastereomer
(M,S)-5 in 23% yield (31 mg).
Spectroscopic data for diastereomer (P,S)-5: pale-yellow solid, >98% de;
mp = 202–204 °C; Rf = 0.34 (cyclohexane/EtOAc, 90:10); ½aDꢁ +1882 (c 0.085,
CHCl3); 1H NMR: (CDCl3, 300 MHz); d 0.59 (s, 3H, CH3), 0.66 (s, 3H, CH3), 0.98
(s, 3H, CH3), 1.36 (m, 2H), 1.65 (m, 2H), 6.69 (ddd, J1 = 8.9 Hz, J2 = 6.9 Hz,
J3 = 1.5 Hz 1H), 6.99 (dd, J1 = 8.7 Hz, J2 = 2.4 Hz, 1H, H-3), 7.18–7.24 (m, 2H),
7.53 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.81 (d,
J = 8.7 Hz, 1H), 7.82–7.95 (m, 6H), 7.96 (d, J = 8.1 Hz, 1H); 13C NMR (CDCl3,
References and notes
1. Newmann, M. S.; Lednicer, D. J. Am. Chem. Soc. 1956, 78, 4765–4770.
2. Martin, R. H.; Marchant, M. J. Tetrahedron 1974, 30, 347–349.
3. Nuckolls, C.; Katz, T. J.; Katz, G.; Collings, P. J.; Castellanos, L. J. Am. Chem. Soc.
1999, 121, 79–88.
4. Fox, J. M.; Lin, D. J. Org. Chem. 1998, 63, 2031–2038.
5. Dai, Y.; Katz, T. J. J. Org. Chem. 1997, 62, 1274–1285.
6. Kelly, T. R.; Silva, R. A.; De Silva, H.; Jasmin, S.; Zhao, Y. J. Am. Chem. Soc. 2000,
122, 6935–6949.
7. (a) Dreher, S. D.; Katz, T. J.; Lam, K. C.; Rheingold, A. L. J. Org. Chem. 2000, 65,
´
815–822; (b) Šámal, M.; Míšek, J.; Stará, I. G.; Stary, I. Collect. Czech. Chem.
75 MHz):
d (ppm): 10.14, 17.10, 29.24, 30.10, 30.73, 54.78, 55.19, 91.06,
Commun. 2009, 74, 1151–1159; (c) Carbery, D. R.; Crittall, M. R.; Rzepa, H. S.
Org. Lett. 2011, 13, 1250–1253; (d) Chen, J. S.; Takenaka, N. Chem. Eur. J. 2009,
15, 7268–7276; (e) Takenaka, N.; Sarangthem, R. S.; Captain, B. Angew. Chem.,
Int. Ed. 2008, 47, 9708–9710.
119.43, 120.15, 124.35, 125.50, 126.57, 126.66, 126.96, 127.40, 127.67, 127.72,
127.76, 127.85, 127.89, 127.96, 128.22, 129.44, 130.05, 130.35, 131.05, 131.81,
132.03, 132.08, 133.56, 147.60, 165.73 (CO), 178.33 (CO); ESI-MS: m/z = 547.1
[M+Na]+; HRMS (MALDI-TOF) Calcd for C36H28O4Na [M+Na]+: 547.1885.
Found: 547.1893.
8. Kawasaki, T.; Suzuki, K.; Licandro, E.; Bossi, A.; Maiorana, S.; Soai, K.
Tetrahedron: Asymmetry 2006, 17, 2050–2053.
Spectroscopic data for diastereomer (M,S)-5: yellow solid, >98% de; mp = 199–
201 °C; Rf = 0.32 (cyclohexane/EtOAc, 90:10); ½aDꢁ ꢀ1792 (c 0.07, CHCl3); 1H
NMR: (CDCl3, 300 MHz); d 0.68 (s, 3H, CH3), 0.71 (s, 3H, CH3), 0.97 (s, 3H, CH3),
1.24 (m, 2H), 1.72 (m, 2H), 6.78 (ddd, J1 = 8.9 Hz, J2 = 6.9 Hz, J3 = 1.5 Hz, 1H),
7.04 (dd, J1 = 8.7 Hz, J2 = 2.4 Hz, 1H, H-3), 7.26–7.31 (m, 2H), 7.63 (d, J = 8.7 Hz,
1H), 7.78 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H),
7.94–8.00 (m, 6H), 8.04 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): d (ppm):
9.76, 16.91, 29.02, 29.76, 30.63, 54.39, 54.83, 90.71, 119.22, 119.84, 123.97,
125.11, 126.09, 126.36, 126.63, 127.10, 127.32, 127.41, 127.50, 127.57, 127.65,
127.83, 128.88, 129.11, 129.74, 130.03, 130.79, 130.98, 131.49, 131.68, 133.25,
147.12, 165.21 (CO), 177.82 (CO); HRMS (MALDI-TOF) Calcd for C36H28O4Na
[M+Na]+: 547.1885. Found: 547.1898.
´
´
ˇ
9. Teply, F.; Stará, I. G.; Stary, I.; Kollárovic, A.; Luštinec, D.; Krausová, Z.; Šaman,
D.; Fiedler, P. Eur. J. Org. Chem. 2007, 4244–4250.
10. Aloui, F.; El Abed, R.; Ben Hassine, B. Tetrahedron Lett. 2008, 49, 1455–1457.
11. Spectroscopic data for diarylethene 3: colorless solid, showing a violet colour
when dissolved in CH2Cl2 or CHCl3; mp = 157–159 °C; 1H NMR (CDCl3,
300 MHz): d (ppm) = 2.89 (s, 3H, OCH3), 6.95–7.55 (m, 4H), 7.65 (t, J = 7.2 Hz,
1H), 7.71 (t, J = 7.2 Hz, 1H), 7.85 (d, J = 16.5 Hz, 1H, H-vinyl), 7.88 (d, J = 16.5 Hz,
1H, H-vinyl), 7.90–7.95 (m, 5H), 8.00 (d, J = 8.7 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H),
9.15 (s, 1H, H-1), 9.20 (d, J = 8.4 Hz, 1H, H-12); 13C NMR (CDCl3, 75 MHz): d
(ppm) = 55.76 (OCH3), 114.60 (2 ꢂ CH), 123.52, 126.26, 126.61, 127.07, 127.11,
127.29, 127.56, 127.71 (2 ꢂ CH), 127.93, 128.04, 128.23, 129.00, 129.12,
129.29, 130.58, 130.76, 131.07, 131.73, 132.12, 133.22, 133.92, 135.93,
159.80 (C–O); HRMS (MALDI-TOF) Calcd for C27H20O [M]+: 360.1514. Found:
360.1523.
16. For an early review, see: Martin, R. H. Angew. Chem., Int. Ed. Engl. 1974, 13, 649–
660.
17. In carbohelicenes known so far, (ꢀ)-enantiomers always have the (M) helicity
Grimme, S.; Harren, J.; Sobanski, A.; Vögtle, F. Eur. J. Org. Chem. 1998, 1491–
1509.
12. Liu, L.; Yang, B.; Katz, T. J.; Poindexter, M. K. J. Org. Chem. 1991, 56, 3769–3775.
13. Spectroscopic data for 2-methoxyhexahelicene (4):9 pale-yellow solid; mp = 206–
208 °C; 1H NMR (CDCl3, 300 MHz):
d (ppm) = 2.91 (s, 3H, OCH3), 6.76
18. Experimental procedure for (P)-(+)-1 and (M)-(ꢀ)-1: diastereomer (P,S)-5
(30 mg, 0.05 mmol) was dissolved in EtOH (20 mL) and then a solution of
KOH (200 mg, 3.5 mmol) in H2O (5 mL) was added. The mixture was heated at
reflux for 4 h. After cooling, the mixture was poured into H2O (50 mL) and then
extracted with EtOAc (4 ꢂ 30 mL). The combined organic extracts were dried
over MgSO4, filtered and concentrated. The residue was purified by column
chromatography using cyclohexane/EtOAc (80:20) to give compound (P)-(+)-1
(17 mg, 90%); pale-yellow solid; Rf = 0.23 (cyclohexane/EtOAc 90:10);
mp = 242–244 °C, ½aDꢁ +1889 (c 0.08, CHCl3); 1H NMR (CDCl3, 300 MHz): d
(ppm) = 4.12 (s, 1H, OH), 6.77 (t, J = 7.2 Hz, 1H), 6.84 (dd, J1 = 8.7 Hz, J2 = 2.4 Hz,
1H), 6.95 (d, J = 2.4 Hz, 1H, H-1), 7.29 (t, J = 7.5 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H),
(t, J = 8.1 Hz, 1H), 6.90 (dd, 1H, J1 = 8.7 Hz, J2 = 2.7 Hz, H-3), 7.01 (d, J = 2.7 Hz,
1H, H-1), 7.29 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H),
7.84 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 9 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.97–8.00
(m, 5H), 8.03 (d, J = 8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d (ppm) = 54.29
(OCH3), 107.75, 117.59, 123.94, 124.22, 124.94, 126.02, 126.63, 126.93,
127.04, 127.12, 127.34, 127.41, 127.44, 127.51, 127.58, 127.64, 127.72,
129.10, 130.30, 131.11, 131.28, 131.68, 131.90, 133.13, 157.16 (C–O);
ESI-MS: m/z = 358.1 [M]+; HRMS (MALDI-TOF) Calcd for C27H18
O
[M]+:
358.1357. Found: 358.1365.
14. (a) Thongpanchang, T.; Paruch, K.; Katz, T. J.; Rheingold, A. L.; Lam, K.-C.;
Liable-Sands, L. J. Org. Chem. 2000, 65, 1850–1856; (b) Pearson, M. S. M.;
Carbery, D. R. J. Org. Chem. 2009, 74, 5320–5325.
7.74 (d, J = 8.7 Hz, 1H), 7.78–8.01 (m, 9H); 13C NMR (CDCl3, 75 MHz):
d
(ppm) = 111.60, 116.04, 123.92, 124.24, 124.94, 126.02, 126.63, 126.93, 127.04,
127.12, 127.34, 127.41, 127.51, 127.58, 127.64, 127.72, 129.10, 129.39, 130.30,
131.11, 131.28, 131.68, 131.90, 132.13, 133.13, 153.18 (C–O); ESI-MS:
m/z = 345.1 [M+H]+; Anal Calcd for C26H16O: C, 90.67; H, 4.68. Found: C,
90.47; H, 4.66.
(M)-(ꢀ)-1 was prepared from diastereomer (M,S)-5 (20 mg, 0.03 mmol) as
described for (P)-(+)-1; pale-yellow solid; Rf = 0.23 (cyclohexane/EtOAc 90:10);
mp = 243–245 °C; ½aDꢁ ꢀ1813 (c 0.075, CHCl3).
15. Enantiomeric resolution: helicenol 1 (100 mg, 0.29 mmol) was dissolved in
anhydrous CH2Cl2 (10 mL) under argon. (S)-(ꢀ)-camphanoyl chloride (69 mg,
0.32 mmol) and Et3N (40 lL, 0.32 mmol) were added successively at 0 °C. The
mixture was stirred for 30 min at 0 °C and then allowed to warm to room
temperature. The solution was stirred for an additional 12 h, washed
successively with HCl (1 M, 5 mL) and saturated NaHCO3 (10 mL) and finally
dried over MgSO4. The solvent was evaporated and the resulting
diastereomeric mixture (136 mg, 90%) was purified by chromatography on
Please cite this article in press as: Ben Braiek, M.; et al. Tetrahedron Lett. (2012), http://dx.doi.org/10.1016/j.tetlet.2012.11.036