Synthesis of [5]helicenes with a substituent exclusively on the interior side of the helix by metal-catalyzed cycloisomerization

Article abstract of DOI:10.1021/ol400332j

[5]Helicenes with a substituent exclusively oriented toward the interior curvature of the helix are synthesized by metal-catalyzed cycloisomerization. In addition, novel azulene-fused helicenes have been found through cycloisomerization studies. These [5]helicenes shows a high enough configurationally stability to allow resolution by HPLC on a chiral stationary phase.

Full text of DOI:10.1021/ol400332j

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of [5]Helicenes with a
Substituent Exclusively on the Interior
Side of the Helix by Metal-catalyzed
Cycloisomerization
Kosuke Yamamoto, Mieko Okazumi, Hiroshi Suemune,* and Kazuteru Usui*
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi,
Higashi-ku, Fukuoka, 812-8582, Japan
usui@phar.kyushu-u.ac.jp; suemune@phar.kyushu-u.ac.jp
Received February 4, 2013
ABSTRACT
[5]Helicenes with a substituent exclusively oriented toward the interior curvature of the helix are synthesized by metal-catalyzed cyclo-
isomerization. In addition, novel azulene-fused helicenes have been found through cycloisomerization studies. These [5]helicenes shows a high
enough configurationally stability to allow resolution by HPLC on a chiral stationary phase.
In the past decade, helicenes have received considerable
attention for potential application in chiral materials and
asymmetric catalysis owing to their unique π-conjugated
screw-shaped structure,1 extraordinary chiroptical prop-
erties,2 and self-assembly.3 To extend the field of applica-
tion of configurationally stable helicenes as functional
materials and chiral catalysis, it is important to develop a
facile synthetic method for the preparation of function-
alized helicenes. In addition to the previously reported
photochemical cyclization of stilbenes,4 several new strate-
gies using DielsꢀAlder cycloaddition,5 olefin metathesis,6
FriedelꢀCrafts cyclization,7 and transition metal-catalyzed
[2þ2þ2] cycloisomerization8 of triynes or dienetriynes have
been reported. In particular, the development of concise
synthetic routes to configurationally stable functionalized
helicenes is important in the design of optically active
organic π-conjugated materials. Despite remarkable prog-
ress in the field of helicene chemistry, the development of
new synthetic routes for configurationally stable [5]helicenes
that allow exclusive functionalization on the interior side
of the helix remains a challenge, except for photochemical
cyclization.4a The synthesis of a series of helicenes with a
substituent exclusively on the interior side of the helix is
necessary toclarify the relationships betweenthegeometric
parameters and configurational stability such as the race-
mization energy barrier of strained or sterically hindered
aromatic hydrocarbons.
(1) (a) Shen, Y.; Chen, C.-F. Chem. Rev. 2011, 112, 1463. (b) Gingras,
M. Chem. Soc. Rev. 2013, 42, 968.
€
(2) (a) Torricelli, F.; Bosson, J.; Besnard, C.; Chekini, M.; Burgi, T.;
Lacour, J. Angew. Chem., Int. Ed. 2013, 52, 1796. (b) Katz, T. J. Angew.
Chem., Int. Ed. 2000, 39, 1921.
(3) (a) Nakano, K.; Oyama, H.; Nishimura, Y.; Nakasako, S.;
Nozaki, K. Angew. Chem., Int. Ed. 2012, 51, 695. (b) Shcherbina,
M. A.; Zeng, X. -B.; Tadjiev, T.; Ungar, G.; Eichhorn, S. H.; Phillips,
K. E. S.; Katz, T. J. Angew. Chem., Int. Ed. 2009, 48, 7837.
(4) (a) Mallory, F. B.; Mallory, C. W. J. Org. Chem. 1983, 48, 526. (b)
Pearson, M. S. M.; Carbery, D. R. J. Org. Chem. 2009, 74, 5320. (c)
Kogiso, T.; Yamamoto, K.; Suemune, H.; Usui, K. Org. Biomol. Chem.
2012, 10, 2934.
We now report the synthesis of [5]helicene derivatives 1
with a functional group (R = OMe, Me, or OH) in position
1 and discuss their structures, electronic properties, and
(7) Ichikawa, J.; Yokota, M.; Kudo, T.; Umezaki, S. Angew. Chem.,
Int. Ed. 2008, 47, 4870.
(5) (a) Liu, L.; Katz, T. J. Tetrahedron Lett. 1990, 31, 3983. (b)
Urbano, A.; Carreno, M. C. Org. Biomol. Chem. 2013, 11, 699.
^ ꢀ
(6) Collins, S. K.; Grandbois, A.; Vachon, M. P.; Cote, J. Angew.
ꢀ
(8) (a) Heller, B.; Hapke, M.; Fischer, C.; Andronova, A.; Stary, I.;
ꢀ
~
Stara, I. G. J. Organomet. Chem. 2013, 723, 98. (b) Sawada, Y.; Furumi,
S.; Takai, A.; Takeuchi, M.; Noguchi, K.; Tanaka, K. J. Am. Chem. Soc.
Chem., Int. Ed. 2006, 45, 2923.
2012, 134, 4080.
r
10.1021/ol400332j
XXXX American Chemical Society

thermodynamicproperties(Scheme1). Inaddition, a novel
synthetic reaction of azulene-fused helicenes (7, 8) has been
found through these studies.
and THF as a solvent, afforded the corresponding alkynes
2a and 2b in 97 and 97% yields, respectively.
Alkyne products 2a and 2b were subjected to metal-
catalyzed cycloisomerization for construction of [5]helicene
frameworks (Table 1). When 2a was treated with 10 mol %
of AuCl in toluene at 120 °C for 24 h, 1-methoxy[5]helicene
1a was exclusively obtained in 24% yield (entry 1). Use of
AuCl3 slightly increased the yield (30%, entry 2). On the
other hand, the cycloisomerization of 2a with PtCl2 in
toluene affordednot only the desired product1a(45%) but
also 7a (27%) and 8a (5%) with an azulene moiety (entry 3).
Remarkably, PtCl2 in CH3CN led to an improvement in
the reaction yield of 1a (57%, entry 4). Although the origin
of this effect is not clear, a possible explanation is that the
reaction selectivity is affected by PtCl2(CH3CN)2 formed
in situ.12 Further, 1a was obtained in 66% yield when an
CH3CN/toluene (1:1) mixture was employed as a solvent
(entry 5). Alkyne 2b was converted into the corresponding
1-methyl[5]helicene 1b (44%) and 7b (7%) using the
optimized conditions for solvent mixture of CH3CN/toluene
(entry 6).
Scheme 1. Synthetic Approach to 1-Functionalized [5]Helicenes
Our synthetic strategy to construct 1-functionalized
[5]helicenes (1) was to conduct metal-catalyzed cyclo-
isomerization by using corresponding alkynes 2 as the key
precursor. The connection to the target molecules involves
the closure of ring B by formation of an aromatic ring. This
key reaction has already proven effective for the synthesis
of a variety of phenanthrenes, polycyclic heteroarenes, and
€
9
[5]helicene, as reported by Furstner. Moreover, a double
cycloisomerization catalyzed by a platinum salt was re-
cently reported by Storch and co-workers for making a
1-methoxy[6]helicene.10
Table 1. Optimization of Metal-catalyzed Cycloisomerizationa
Scheme 2. Synthesis of Alkynes 2a and 2b
entry
substrate
catalyst
time (h)
1b:7c:8c
1d
2e
3
4f
5g
6g
2a, R = OMe
2a, R = OMe
2a, R = OMe
2a, R = OMe
2a, R = OMe
2b, R = Me
AuCl
AuCl3
PtCl2
PtCl2
PtCl2
PtCl2
24
24
2
24%:0%:0%
30%:0%:0%
45%:27%:5%
57%:7%:0%
66%:8%:2%
44%:7%:0%
12
7
7
a The reaction was performed on a 0.16 mmol scale. b Isolated yields.
c Yields were determined by 1H NMR analysis. d 70% of 2a was
recovered. e 66% of 2a was recovered. f CH3CN was used instead of
toluene. g CH3CN/toluene (1:1) mixture was used instead of toluene.
The synthesis of alkynes 2a (R = OMe) and 2b (R =
Me), a precursor of 1-methoxy-(1a) and 1-methyl[5]helicene
1b, was initiated with a VilsmeierꢀHaack reaction of cyclic
ketone 3to afford β-chloroacrolein 4in 95% yield (Scheme 2).
The Suzuki-Miyaura cross-coupling of 4 with corresponding
of arylboronic acids afforded 5a and 5b in 96% and 94%
yields, respectively. The subsequent oxidative aromatiza-
tion of 5 with DDQ gave 6 in high yields. Finally, the
Seyferth-Gilbert homologation, using the Ohira-Bestmann
reagent11 and potassium phosphate in a mixture of methanol
The proposed mechanism for the platinum-catalyzed
reactionof2aisillustrated in Scheme 3. Initially, activation
of the triple bond occurs in catalytic processes to produce
the corresponding π complex A. In the case of 6-endo-
cyclization, nucleophilic addition of the carbon atom C1ꢀC6
(path a) and C1ꢀC2 (path b) of the phenyl moiety to the π
(12) PtCl2 formed PtCl2(CH3CN)2 by prolonged heating in acetoni-
trile, see: Nakamura, I.; Bajracharya, G. B.; Wu, H.; Oishi, K.; Mizushima,
Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 15423.
(13) (a) Soriano, E.; Marco-Contelles, J. Organometallics 2006, 25,
4542. (b) Carreras, J.; Patil, M.; Thiel, W.;Alcarazo, M.J. Am. Chem. Soc.
€
(9) Mamane, V.; Hannen, P.; Furstner, A. Chem.;Eur. J. 2004, 10,
€
4556. (b) Furstner, A.; Mamane, V. J. Org. Chem. 2002, 67, 6264.
ꢁ
(10) Storch, J.; Sykora, J.; Cermak, J.; Karban, J.; Cısarova, I.;
Ruzicka, A. J. Org. Chem. 2009, 74, 3090.
(11) Kosobokov, M. D.; Titanyuk, I. D.; Beletskaya, I. P. Mendeleev
ꢀ
ꢀ
ꢁ ꢀ
ꢁ ꢁ
ꢂ
2012, 134, 16753. (c) Poriel, C.; Barriere, F.; Thirion, D.; Rault-Berthelot, J.
Commun. 2011, 21, 142.
Chem.;Eur. J. 2009, 15, 13304.
B
Org. Lett., Vol. XX, No. XX, XXXX

activated alkyne would give the key cyclopropyl platinum
carbene intermediates B and C, respectively.13 Opening of the
(A value = 0.6) > H (Figure 1). Furthermore, the X-ray
analysis of 1c revealed an intramolecular OH π inter-
3 3 3
0
cyclopropane bond C1ꢀC1 of B then gives Wheland-type
action, which may serve to stabilize the helical geometry.
Compound 7a and 8a revealed that the five (B)- and
seven (A)-membered ring of the azulene unit has a highly
strained nonplanar structure (Figure 2). The angles be-
tween the mean plane of the five-membered ring and the
seven-membered ring of 7a and 8a were 8.2ꢀ8.9° and 10.4°
respectively, which is larger than that (2.6°) of naphth[1,2-R]-
azulene derivative.18 The strained geometry of the azulene
unit is due to the steric interaction between terminal
aromatic rings and/or methoxy group. This is the first
example of azulene-fused helicene derivatives with unam-
biguously helical geometry. Moreover, X-ray structure
analysis of 7a and 8a revealed substantial bond-length
alternation in the azulene π system (Figure S9, Supporting
Information). The bond-length alternation would be in-
duced by either highly twisted noncoplanar azulene ring, the
fusion of the aromatic ring19 to the azulene skeleton, or both.
intermediate D, which finally undergoes two consecutive
[1,2]-H shifts to give 1a. The intermediate B may also
evolve to platinum carbene intermediate Fwith a 7-membered
ring by 6-electron electrocyclic opening14 of cyclopropane
bond C1ꢀC6. A subsequent [1,2]-H shift of intermediate
F might afford 8a via intermediate G. On the other
hand, 6-electron electrocyclic opening of cyclopropane
bond C1ꢀC2 of C would give intermediate H with a
7-membered ring, which would finally give 7a through a
[1,2]-H shift.
Scheme 3. Proposed Reaction Mechanism for
Platinum-catalyzed Cycloisomerization
To accomplish the preparation of 1-hydroxy[5]helicene
1c, the O-demethylation was examined. The treatment of
1a with sodium ethanethiolate at 110 °C afforded 1c in
87% yield (Table 1).15
The structures of 1a, 1b, 1c, 7a, and 8a were confirmed
by X-ray crystal structure analysis (Figures 1 and 2).16
The nonbonded intramolecular distance (d) of 1a, 1b, 1c
Figure 1. ORTEP representations (ellipsoids set at 50%
probability) of (a) 1a, (b) 1b, and (c) 1c. (d) Plots of the
nonbonded intramolecular distance (d) of [5]helicene, 1a, 1b,
and 1c against the A value.
˚
˚
˚
and parent [5]helicene are 2.82 A, 3.24 A, 3.02 A and ca.
˚
The separation of the enantiomers was accomplished
via HPLC on a chiral column (Daicel Chiralpak IA,
4.6 mm ꢁ250 mm) using a UV light detector at 254 nm.20
The chromatogram showed successful separation of the
2.59 A, respectively, implying that the extent of steric size is
Me (A value17 = 1.7) > HO (A value = 0.9) > MeO
(14) (a) Scott, L. T.; Minton, M. A.; Kirms, M. A. J. Am. Chem. Soc.
1980, 102, 6311. (b) Kane, J. L., Jr.; Shea, K. M.; Crombie, A. L.;
Danheiser, R. L. Org. Lett. 2001, 3, 1081. (c) Kramer, S.; Odabachian,
(17) For the A value, see: Table of Conformational Energies-1967;
Hirsch, J. A. Topics in Stereochemistry; Wiley: New York, 1967; Vol. 1,
199.
€
Y.; Overgaard, J.; Rottlander, M.; Gagosz, F.; Skrydstrup, T. Angew.
Chem., Int. Ed. 2011, 50, 5090.
(18) Yamamura, K.; Kawabata, S.; Kimura, T.; Eda, K.; Hashimoto,
M. J. Org. Chem. 2005, 70, 8902.
(15) The use of boron tribromide afforded 1c (29%) and benzo-
[ghi]perylene 9 (71%) under mild conditions (Supporting Information).
(16) CCDC 901876 (1a), CCDC 909678 (1b), CCDC 917297 (1c),
CCDC 901883 (7a),and CCDC 901877 (8a) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
(19) (a) Lu, Y.; Lemal, D. M.; Jasinski, J. P. J. Am. Chem. Soc. 2000,
122, 2440. (b) Ito, S.; Kubo, T.; Kondo, M.; Kabuto, C.; Morita, N.;
Asao, T.; Fujimori, K.; Watanabe, M.; Harada, N.; Yasunami, M. Org.
Biomol. Chem. 2003, 1, 2572. (c) Yamamura, K.; Kusuhara, N.; Houda,
Y.; Sasabe, M.; Takagi, H.; Hashimoto, M. Tetrahedron Lett. 1999, 40,
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Org. Lett., Vol. XX, No. XX, XXXX
C

Figure 3. CD spectra of (þ)-(P)-1a (blue solid line), (ꢀ)-(M)-1a
(blue dashed line), (þ)-(P)-1b (black solid line), (ꢀ)-(M)-1b
(black dashed line), (þ)-(P)-1c (red solid line), (ꢀ)-(M)-1c (red
dashed line) in in CHCl3 (1.0 ꢁ 10ꢀ5 M). The gray lines show the
CD spectrum for (P)-1a calculated by the TD-DFT method at
the CAM-B3LYP/6-31þG(d,p) level of theory with SMD
(CHCl3) solvation.
Figure 2. ORTEP representations (ellipsoids set at 50% probability)
of (a) 7a and (b) 8a.
enantiomers (Table S1, Supporting Information). To as-
sign the helicity to the resolved enantiomers, their CD
spctra were measured (Figure 3). In all cases, they display
mirror-image values of the (þ) and (ꢀ) enantiomers within
the experimental errors. Quantitative predictions with
TD-DFT further validated the assigment of absolute config-
uration shown in Figure 3. Using the optimized molecular
geometry of (P)-1a, rotational strengths were calculated
and used to simulate the CD spectrum. Cotton effects at
>230 nm with intensity patterns similar to those experi-
mentally observed for (P)-1a.
of 1c could not be determined because it was thermally
decomposed to some unknown products.
In summary, we have successfully prepared [5]helicenes
witha substituent oriented toward the interior curvature of
the helix by using simple cycloisomerization. The enantio-
mers of 1-functionalized [5]helicenes (1a, 1b, and 1c) were
separated by HPLC on a chiral column and, accordingly,
the racemization barriers could be measured for the heli-
cenesexceptfor1c. Moreover, novelazulenoheliceneshave
been obtained through these studies. The unexpected
formation of anazulene skeleton from analkyne derivative
by using a catalytic amount of PtCl2 opens a new door for
azulenohelicene chemistry.
To characterize the stability of the 1-functionalized
[5]helicenes 1 toward racemization, their Gibbs’ free en-
ergy barriers to racemization (ΔGq) were measured on the
basis of the time-dependent conversion rate (% ee) esti-
mated from chiral HPLC analysis (Figure S3, Supporting
Information). Although, the ΔGq at 423 K of 1a (31.7
kcal molꢀ1) was slightly less than that of [6]helicene (36.3
kcal molꢀ1),21 it is clear that the presence of the 1-methoxy
substituent significantly increased the racemization barrier.
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Young Scientists (B) from the Japan
Society for the Promotion of Science (No. 23790013). We
also thank Dr. Toshihiro Murafuji at Yamaguchi University
for valuable discussion. We also thank Dr. Satoru Karasawa
at Kyushu University for the X-ray analysis of 1c.
On the other hand, the ΔGq at 473 K of 1b (38.6 kcal molꢀ1
)
was drastically increased compared to that of 1a.22 This
could be due to a larger loss of entropy during the racemiza-
tion of 1b than 1a and [5]helicene.23 Thermal racemization
(20) Azulenohelicens possess helicene-like axial chirality, but the
racemization barriers are small (Figure S2, Supporting Information).
(21) (a) Martin, R. H.; Marchant, M. J. Tetrahedron Lett. 1972, 13,
3707. (b) Martin, R. H.; Marchant, M. J. Tetrahedron 1974, 30, 347.
(22) For 1,3,6-trimethyl[5]helicene, ΔGq = 38.6 kcal molꢀ1, see:
Supporting Information Available. Experimental de-
tails including synthesis and characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
€
Scherubl, H.; Fritzsche, U.; Mannschreck, A. Chem. Bar 1984, 117, 336.
(23) (a) Borkent, J. H.; Laarhoven, W. H. Tetrahedron 1978, 34, 2565.
€
(b) Janke, R. H.; Haufe, G.; Wurthwein, E. -U.; Borkent, J. H. J. Am.
The authors declare no competing financial interest.
Chem. Soc. 1996, 118, 6031.
D
Org. Lett., Vol. XX, No. XX, XXXX