Synthesis of higher helicenes via olefin metathesis and C-H activation

Article abstract of DOI:10.1055/s-0028-1088165

Functionalized heterohelicenes were prepared using sequential olefin metathesis and direct arylation reactions. Functionalization via C-H activation always occurs at the least hindered position of the [5]helicene carbon skeleton. Attempts at blocking the

Full text of DOI:10.1055/s-0028-1088165

PAPER
1499
Synthesis of Higher Helicenes via Olefin Metathesis and C–H Activation
S
ynthesis
u
of
H
igher
H
e
l
licene
i
e Côté, Shawn K. Collins*
Département de Chimie, Université de Montréal, C. P. 6128, Succursale Centre-ville, Montréal H3C 3J7, QC, Canada
Fax +1(514)3437586; E-mail: shawn.collins@umontreal.ca
Received 27 October 2008; revised 16 December 2008
Abstract: Functionalized heterohelicenes were prepared using se-
quential olefin metathesis and direct arylation reactions. Function-
alization via C–H activation always occurs at the least hindered
position of the [5]helicene carbon skeleton. Attempts at blocking
the least hindered positions to force arylation at the interior of the
helicene skeleton result in decomposition of the starting material.
Installation of larger aromatic groups via arylation can form heli-
cenes albeit with limited solubility in common organic solvents.
Key words: helicene, olefin metathesis, C–H activation, hetero-
helicene, arylation
Figure 1 Electron density map of a substituted helicene 1
Helicenes continue to be a subject of interest due to their
conjugated structures and optoelectronic properties.1
These can vary considerably by changing the length of the
Cl
O
helix or through the addition or subtraction of substitu-
O
ents. Thus, scientific advancements are often directly
2
linked to the availability of synthetic methods for making
Cl
new well-defined molecular architectures.2 Although new
C–H activation and
strategies for helicene construction continue to be devel-
arylation
oped,2–4 methods to functionalize the termini of carbohe-
licenes, particularly those which extend an already
existing helical skeleton, are rare. Only the photocycliza-
tion of stilbenes, chemistry extensively popularized by
O
O
O
O
O
O
Martin and co-workers over 30 years ago,3 and more re-
cently, the Diels–Alder reaction with benzoquinones,4 ex-
ists to extend the frameworks of small [4]- and
[5]carbohelicenes. The installation of additional benzene
rings into the helicene skeleton requires the construction
of new carbon–carbon bonds. Considering the advances in
cross-coupling technology, it is surprising that this syn-
thetic challenge has not been revisited. Herein we wish to
report the application of olefin metathesis and the investi-
gation of a direct arylation protocol for the preparation of
functionalized heterohelicenes.
3
4
5
helical/
pseudolinear
product
bispseudolinear
product
all helical
product
Figure 2 Possible products of arylation using the symmetric heli-
cene 2
Extension of the carbon skeleton of [5]helicene in a heli-
cal fashion would require the installation of a new car-
bon–carbon bond at its most sterically hindered position
(C1 of helicene 1, Figure 1).8 Molecular modeling re-
vealed that helicene 1, appended with a 2-chlorobenzyl-
oxy group in the 2-position shows a distinct distribution of
electron density whereby the protons in the interior of the
helicene are richer in electron density, making the proton
at position 3 the most acidic. This points to both an elec-
tronic and steric preference for cyclization at the exterior
of the helical structure. To investigate the stereochemical
course of direct arylations on [5]helicenes, we prepared
the C2 symmetric helicene 2. If the direct arylation reac-
tion is efficient, then three different products could be ex-
pected: the helical product 3 would result from both
We have recently developed two complimentary olefin
metathesis protocols for the formation of various [5]heli-
cenes, and the higher [6]- and [7]helicenes.5 In an effort to
construct functionalized helicenes,6 we sought to apply
methods traditionally used for the formation of biaryls for
the functionalization of the termini of a substituted [5]he-
licene 1 (Figure 1). We were intrigued by the possibility
of applying a direct arylation reaction for this purpose, as
no prior activation of C1 or C3 in 1 would be required.7
SYNTHESIS 2009, No. 9, pp 1499–1505
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x
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Advanced online publication: 25.03.2009
DOI: 10.1055/s-0028-1088165; Art ID: M06508SS
© Georg Thieme Verlag Stuttgart · New York

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J. Côté, S. K. Collins
PAPER
Table 1 Direct Arylation of Helicene 2a
arylations occurring at the interior of the [5]helicene
framework, while the bispseudolinear product 5 would re-
sult from both arylations at the exterior and the mixed
product 4 would result from one coupling each at the inte-
rior and exterior of the core [5]helicene (Figure 2).
Pd(OAc)2
(2 mol %)
1
Cl
ligand (4 mol %)
O
O
additive
K2CO3 (4 equiv),
DMA, 130 °C, 12 h
Helicene 2 was prepared from the diester 6 (Scheme 1).
Reduction with lithium aluminum hydride provided a diol
which was treated with boron tribromide to effect depro-
tection of the methoxy groups and transformation of the
primary alcohols into the corresponding bromides, afford-
ing the dibromide 7 in approximately 85% isolated yield
over two steps. Oxidation using a bis(collidine)silver(I)
salt,9 alkylation with 2-chlorobenzyl chloride (8) and
Wittig reaction provided the divinyl compound 9. Ring-
closing metathesis of 9 mediated by Grubbs–Hoveyda
2nd Generation catalyst GH2 afforded helicene 2 in 60%
yield. With the C2-symmetric helicene 2 in hand, we next
investigated various direct arylation conditions to investi-
gate whether arylation at the most hindered positions of
the helicene skeleton was possible.
2
3
Cl
O
O
O
O
Cl
10
5
Entry
Ligand
S-Phos
Additive
Yield (%)
5
10
–
1
2
3
4
5
6
7
8b
none
none
none
none
KF
–
DavePhos
13
20
11
13
41
40
95
5
PMe(t-Bu)2HBF4
PCy3HBF4
31
50
44
20
11
–
a) LiAlH4,
Br
Br
THF, 99%
MeO
MeO
CO2Me
CO2Me
HO
HO
b) BBr3,
CH2Cl2,
85%
PCy3HBF4
PCy3HBF4
PivOH
BzOH
none
6
7
Cl
PCy3HBF4
a) Ag(collidine)2PF6,
DMSO, 70%
MesN
NMes
Cl
Cl
b) 8 (2.1 equiv), KOt-Bu,
NaI, NMP, 77%
c) MePPh3Br, n-BuLi,
THF, 85%
PCy3HBF4
a DMA = N,N-dimethylacetamide.
Ru
O
Cl
GH2
8
b Catalyst and ligand loadings were increased to Pd(OAc)2 (10 mol%)
and Cy3PHBF4 (20 mol%).
i-Pr
Cl
GH2
product 10 (entry 3). Similar reactivity was also observed
with tricyclohexylphosphine tetrafluoroborate as ligand
(entry 4).11 Consequently, we examined the effect of var-
ious additives using this ligand. If a chloride anion re-
mains bound as a ligand to palladium, it was believed that
substituting it for a less bulky fluoride anion might affect
the selectivities. Unfortunately, the addition of potassium
fluoride resulted in little change in reactivity or selectivity
(entry 5). Fagnou and co-workers have reported that piv-
alic acid can have a dramatic effect on reactivities in direct
arylations, effectively replacing the halide ligands on the
palladium center.12 Indeed, upon addition of 10% of piv-
alic acid to the reaction mixture the yield of the product 5
increased to 41% (entry 6). Substituting pivalic acid for
benzoic acid had a no effect and ratios were almost iden-
tical. Finally, by simply increasing the catalyst and ligand
loading, we are able to isolate high yields (95%) of the
arylated helicene 5 (entry 8).13 The reluctance of 2 to un-
dergo arylation at the interior of the helicene skeleton is
not surprising. Although electronics may play a role, it is
likely that the factor determining the site of arylation is
mainly steric in nature.14 During the course of our work,
Kamikawa and co-workers reported on the formation of
(10 mol%)
Cl
O
O
O
O
CH2Cl2,
60 °C
24 h,
Cl
2
60%
Cl
9
Scheme 1 Synthesis of helicene 2
Although, all attempts to affect direct arylation at C1 of
the [5]helicene skeleton of 2 failed, we were able to effec-
tively develop a procedure to functionalize the termini of
[5]helicene 2 at C3 (Table 1). The direct arylation of 2
was initially studied using ligands that had been reported
by Fagnou and co-workers as being effective for intramo-
lecular direct arylation.10 The biaryl ligand S-Phos
showed little reactivity towards helicene 2 (Table 1, entry
1), but DavePhos did produce 5% isolated yield of 10
and a 13% yield of the C2-symmetric helicene 5 (entry 2).
X-ray crystal structure analysis was used to confirm the
identity of the products formed via arylation (Figure 3).
The phosphine salt di-tert-butylmethylphosphine tetra-
fluoroborate showed much better reactivity, producing
20% of 5 and 31% isolated yield of the monocoupled
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PAPER
Synthesis of Higher Helicenes
1501
[5]- and [6]helicenes via C–H activation.15 However, they
disclosed that all attempts at forming the more sterically
encumbered [7]helicene skeletons failed. Our results
agree with those of Kamikawa, in that arylation at the in-
terior of the [5]helicene skeleton to form a [7]- or [9]heli-
cene was not possible.
a) LiAlH4,
THF
Br
Br
99%
HO
HO
MeO
MeO
CO2Me
CO2Me
b) BBr3,
CH2Cl2,
99%
12
11
a) Ag(collidine)2PF6,
DMSO, 70%
b) 8 (2.1 equiv), KOt-Bu, NaI,
NMP, 77%
c) MePPh3Br, n-BuLi,
THF, 85%
Cl
GH2
(10 mol%)
O
Cl
O
O
O
CH2Cl2
Figure 3 X-ray crystal structures of 10 and 516
60 °C
Cl
14
24 h, 60%
13
Cl
In an effort to force the formation of helical products such
as 3, we decided to construct a new [5]helicene precursor
where the hydrogen atoms at C3 and C12 positions would
be blocked with methyl groups. The dimethyl[5]helicene
14 was prepared using the same methodology as 2 starting
from the diester 11 (Scheme 2). Reduction with lithium
aluminum hydride provided a diol, which was treated with
boron tribromide to effect deprotection of the methoxy
groups and transformation of the primary alcohols into the
corresponding bromides, affording the dibromide 12 in
quantitative yield. Once again, a series of oxidation, alky-
lation, and Wittig reactions afforded the desired divinyl
compound 13. Ring-closing metathesis of 13 mediated by
Grubbs–Hoveyda 2nd generation catalyst GH2 afforded
14 in 60% yield. Unfortunately, when [5]helicene 14 was
treated under forcing conditions [10 mol% Pd(OAc)2, 20
mol% PCy3HBF4] no cyclization to the desired helical
product was observed. A complex mixture was formed
and no insertion into the methyl groups was observed.17
Analysis of the mixture by mass spectrometry revealed
the dehalogenated product 15 as one of the constituents. In
addition, products resulting from benzyl cleavage and/or
monodehalogenation could also be identified.
Pd(OAc)2
(10 mol%),
PCy3HBF4
(20 mol%),
DMA, 130 °C,
12 h
O
O
15
Scheme 2 Synthesis of helicene 14 and attempted arylation
the bromide 17 in 54% yield (Scheme 3). The bromide 17
was converted into the corresponding styrene via oxida-
tion with bis(collidine)silver(I) hexafluorophosphate and
subsequent Wittig olefination (99% and 80% isolated
yields, respectively). The aldehyde intermediate was un-
stable and also poorly soluble in tetrahydrofuran. As such,
the addition of dimethyl sulfoxide to the reaction mixture
was necessary to improve conversion and the overall yield
(80%). The ring-closing olefin metathesis protocol was
found to be tolerant of the nitro functionality present and
19 was formed in 75% isolated yield. Although the meta-
thesis reaction was tolerant of the nitro functionality, the
subsequent arylation was not. This is surprising as in-
tramolecular arylation of nitro-containing substrates has
been previously reported.11a The arylation of 19 seemed to
form a soup of products. Analysis of the crude reaction
mixture by mass spectrometry suggests the presence of
the product 20. However, despite repeated attempts, the
product 20 could never be cleanly isolated. In addition to
the problem of separating various products with similar
polarities, the products of the arylation tend to co-elute
with each other and with residual tricyclohexylphosphine,
even in various solvent systems.
Despite the fact that no arylation could be conducted at the
interior of the [5]helicene skeleton, the arylation condi-
tions developed still provided a convenient access to func-
tionalized helicenes with extended skeletons. To further
probe the scope of the tandem olefin metathesis/arylation
strategy, we attempted to prepare heterohelicenes 19 and
24a. The arylation to form 19 would be of interest as it is
difficult to access nitro- or amine-containing helicenes via
photocyclization. The arylation of heterohelicene 24a
would represent an extension of six cycles to the [5]heli-
cene core.
The nitro-containing styrene 18 was prepared from the di-
bromide 7 using an analogous protocol as described in
Schemes 1 and 2. Alkylation of 7 using the established
protocol utilizing potassium tert-butoxide failed and a
Mitsunobu protocol using alcohol 16 was used to provide
We also attempted to perform arylation with aromatic
groups such as substituted naphthalenes, which would re-
sult in the formation of larger helically chiral systems
Synthesis 2009, No. 9, 1499–1505 © Thieme Stuttgart · New York

1502
J. Côté, S. K. Collins
PAPER
R
NO2
Cl
Cl
16, Ph3P,
Br
21a or 21b
Br
Br
DIAD, THF
Cl
Cl
HO
HO
Ph3P, DIAD THF,
reflux
O
O
Br
Br
Br
Br
HO
HO
reflux
Br
O
O
54%
for 22a = 56%
for 22b = 15%
7
17
NO2
7
HO
R = H 22a
R = OC7H15 22b
a) Ag(collidine)2PF6,
DMSO, 99%
HO
Cl
b) MePPh3Br, n-BuLi,
DMSO–THF (5:1), 80%
R
Cl
16
O2N
a) Ag(collidine)2PF6,
DMSO
NO2
22a and 22b = 99%
for
b) MePPh3Br, n-BuLi,
DMSO:THF (5:1),
staring from 22a = 85%
starting from 22b = 96%
R
R = H 21a
R = OC7H15 21b
Cl
GH2
Cl
O
(10 mol%)
O
O
R
CH2Cl2
60 °C
O2N
O2N
O
24 h
75%
Cl
19
R
Cl
18
Cl
NO2
GH2
Cl
O
(10 mol%)
O
arylation
O
CH2Cl2
60 °C
24 h
O2N
O
Cl
O
O
Cl
for 23a = 85%
for 23b = 74%
R = H 23a
R = OC7H15 23b
R
20
R
O2N
R = H 24a
R = OC7H15 24b
Scheme 3 Synthesis and arylation of helicene 19
Scheme 4 Synthesis and arylation of helicenes 24a and 24b
was performed to confirm the structure (Figure 4). Subse-
quent arylation of the crude helicene 24a was also found
to be difficult, probably due to its purity.
We then attempted to improve the solubility of 24a
through the installation of an alkyl chain on the naphthyl
group. Following an analogous synthetic route as was
used for helicene 24a, the starting material 7 was alkylat-
ed with naphthyl alcohol 21b in the presence of diisopro-
pyl azodicarboxylate in tetrahydrofuran at reflux to afford
the dibromide 22b in poor isolated yield (15%). The fol-
lowing oxidation and olefination occurred in good yields
(99% and 96% yields, respectively). The divinyl product
23b was then treated with the Grubbs–Hoveyda 2nd gen-
eration catalyst resulting in 100% conversion of the start-
ing material, and the helicene 24b was isolated in 74%
yield without the problematic solubility profile that
plagued the isolation of 24a. When the arylation of 24b
was carried out under the optimized conditions, the
pseudolinear product 25, and the product arising from a
monocoupling 26 were identified by mass spectrometry
(Scheme 5). However, the purification of products was
continually problematic due to co-elution with residual
quantities of tricyclohexylphosphine. Reducing the
amount of phosphine to 10 mol% and adding 60 mol% of
pivalic acid reduced the conversion to 76%, but 25 and 26
could be isolated with only ~5% of tricyclohexylphos-
Figure 4 X-ray crystal structure 24a16
(Scheme 4). Our initial investigations began with Mit-
sunobu alkylation of 7 using the naphthyl alcohol 21a.
Treatment of 7 with alcohol 21a and diisopropyl azodicar-
boxylate in tetrahydrofuran at room temperature resulted
in no conversion. However, when the reaction was heated
to reflux the corresponding dibromide 22a was isolated in
modest yield (56%). The dibromide 22a could be then be
oxidized with bis(collidine)silver(I) hexafluorophosphate
(99% yield) and the corresponding dialdehyde subjected
to Wittig olefination using the dimethyl sulfoxide–tet-
rahydrofuran solvent mixture (85% yield) to afford the di-
vinyl product 23a. Treatment of 23a with the Grubbs–
Hoveyda 2nd generation catalyst resulted in 100% con-
version of the starting material; however, isolation of the
helicene 24a was complicated by its poor solubility in
common organic solvents and the tendency to co-elute
during column purification with residual tricyclohexyl-
phosphine. As such, an X-ray crystal structure analysis
1
phine observable by H NMR. Based upon recovered
Synthesis 2009, No. 9, 1499–1505 © Thieme Stuttgart · New York

PAPER
Synthesis of Higher Helicenes
1503
C7H15O
All chemical products were obtained from Sigma-Aldrich Chemical
Company or Strem Chemicals and were reagent quality. NMR spec-
tra were taken in deuterated CDCl3 using Bruker AV-300, AMX
300 and AMX 400 instruments unless otherwise noted. HRMS was
done by the Centre régional de spectrométrie de masse at the Dépar-
tement de Chimie, Université de Montréal from an Agilent LC-
MSD TOF system using ESI mode of ionization.
Cl
O
O
Cl
24b
2,13-Bis(2-chlorobenzyloxy)[5]helicene (2); Typical Procedure
for Olefin Metathesis Reactions
OC7H15
In a dry sealed tube was added rac-7,7¢-bis(2-chlorobenzyloxy)-
2,2¢-divinyl-1,1¢-binaphthyl (9, 59 mg, 0.1 mmol, 1.0 equiv). Anhyd
CH2Cl2 (1 mL) was added followed by the Grubbs–Hoveyda 2nd
generation catalyst (6.27 mg, 10 mol%) and the mixture was stirred
at 60 °C for 24 h. Silica gel was directly added to the mixture and
the solvent was evaporated under vacuum. The resulting solid was
purified by flash column chromatograph (silica gel, hexanes–
EtOAc, 30:1) to afford pure rac-2 as an off-white solid; yield: 34.1
mg (60%).
Pd(OAc)2
(10 mol%),
Cy3PHBF4 (10 mol%)
PivOH (60 mol%)
DMA, 130 °C, 12 h
78% conv. of 24b
C7H15
O
1H NMR (300 MHz, CDCl3): d = 8.00 (d, J = 1.5 Hz, 2 H), 7.94 (d,
J = 3.0 Hz, 2 H), 7.91 (d, J = 3.0 Hz, 2 H), 7.89 (d, J = 3.0 Hz, 2 H),
7.80 (d, J = 6.0 Hz, 2 H), 7.44–7.41 (m, 2 H), 7.32–7.27 (m, 4 H),
7.20–7.15 (m, 4 H), 4.97 (d, J = 12 Hz, 2 H), 4.85 (d, J = 12 Hz, 2
H).
Cl
O
OC7H15
O
O
O
13C NMR (125 MHz, CDCl3): d = 141.4, 122.3, 120.8, 120.7, 119.4,
117.8, 117.6, 117.3, 116.4, 115.9, 115.5, 115.3, 114.9, 113.1, 107.4,
101.1, 61.0, 29.6.
HRMS (ESI+): m/z [M + Na]+ calcd for C36H24Cl2O2Na: 581.1045;
found: 581.1043.
OC7H15
25
OC7H15
26
20%
(brsm)
37%
(brsm)
2,13-Bis(2-chlorobenzyloxy)-3,12-dimethyl[5]helicene (14)
Yield: 69.4 mg (60%).
Scheme 5 Arylation of helicene 24b
1H NMR (400 MHz, CDCl3): d = 7.91 (s, 2 H), 7.85–7.83 (m, 4 H),
7.78 (s, 2 H), 7.76 (d, J = 3.8 Hz, 2 H), 7.44–7.42 (m, 2 H), 7.28–
7.24 (m, 2 H), 7.19–7.13 (m, 4 H), 4.87 (d, J = 12.6 Hz, 2 H), 4.68
(d, J = 12.6 Hz, 2 H), 2.51 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 153.8, 134.4, 132.3, 131.8, 129.3,
128.9, 128.8, 128.3, 128.2, 127.7, 127.5, 126.6, 126.3, 126.1, 125.8,
123.9, 109.3, 66.2, 16.5.
starting material, 25 was isolated in 20% yield and 26 in
37% yield.
In summary, arylation of disubstituted [5]helicenes af-
fords products resulting from reaction at the C1 and C14
positions, such as extended helicenes 5 and 25. No aryla-
tion at the C2 and C11 positions was observed. The regio-
chemistry of the arylation was confirmed by X-ray
crystallographic analysis. Furthermore, blocking of the
C2 and C13 positions by methyl groups could not induce
cyclization at the most hindered positions at the interior of
the helicene skeleton. This demonstrates that despite the
recent advances in arylation technology, the activation of
HRMS (ESI+): m/z [M + H]+ calcd for C38H29Cl2O2: 587.1539;
found: 587.1528.
2,13-Bis(2-chloro-5-nitrobenzyloxy)[5]helicene (19)
Yield: 101 mg (75%).
1H NMR (700 MHz, CDCl3): d = 8.33 (d, J = 2.8 Hz, 2 H), 8.035
(dd, J = 8.7, 2.7 Hz, 2 H), 7.98 (d, J = 9.1 Hz, 2 H), 7.94 (d, J = 8.4
Hz, 2 H), 7.92–7.91 (m, 4 H), 7.85 (d, J = 7.7 Hz, 2 H), 7.45 (d,
hindered C–H bonds such as those at the interior of heli- J = 8.4 Hz, 2 H), 7.35 (dd, J = 8.7, 2.5 Hz, 2 H), 4.90 (d, J = 14.0
Hz, 2 H), 4.80 (d, J = 14.0 Hz, 2 H).
cene skeletons is not yet possible. New C–H activation
13C NMR (175 MHz, CDCl3): d = 154.7, 146.6, 138.8, 136.6, 132.8,
131.0, 130.2, 130.0, 128.4, 127.6, 127.1, 126.1, 124.9, 123.6, 123.0,
118.2, 110.9, 65.9.
HRMS (ESI+): m/z [M + H]+ calcd for C36H23Cl2N2O6: 649.0928;
found: 649.0953.
protocols that exhibit highly selective reactions based on
electronic preferences, despite steric biases, will need to
be developed. Synthetic methods that are highly reactive
but do not require phosphine ligands might be preferable
for large aromatic systems. Elongated aromatic ribbon-
like structures such 5, 25, and 26 may be of interest in ma-
terials science applications, where helical aromatics can
assemble into nanofibers in columnar arrangements for
liquid crystals applications18 or as molecular glues.19 Al-
though new synthetic methodologies have allowed access
to new heterohelicene structures, it is important to point
out that the synthesis of macromolecular extended higher
helicenes remains a significant synthetic challenge.
2,13-Bis[(1-chloro-2-naphthyl)methoxy][5]helicene (24a)
Yield: 61.5 mg (85%).
1H NMR (400 MHz, CDCl3): d = 8.13 (d, J = 8.4 Hz, 2 H), 7.92 (d,
J = 8.4 Hz, 2 H), 7.83–7.78 (m, 6 H), 7.71 (d, J = 8.4 Hz, 2 H), 7.66
(d, J = 8.0 Hz, 2 H), 7.50–7.39 (m, 8 H), 7.16 (dd, J = 8.6, 2.2 Hz,
2 H), 5.08 (d, J = 13.2 Hz, 2 H), 4.96 (d, J = 13.2 Hz, 2 H).
Synthesis 2009, No. 9, 1499–1505 © Thieme Stuttgart · New York

1504
J. Côté, S. K. Collins
PAPER
13C NMR (75 MHz, CDCl3): d = 155.3, 133.7, 132.4, 131.8, 131.0,
130.5, 129.4, 129.3, 127.9, 127.8, 127.2, 127.0, 126.9, 126.8, 126.4,
126.0, 125.0, 124.1, 124.0, 117.9, 110.9, 67.1.
124.6, 124.4, 124.0, 122.9, 122.4, 122.2, 118.0, 115.4, 110.7, 68.2,
66.7.
HRMS (ESI+): m/z [M + Na]+ calculated for C36H23ClO2Na:
HRMS (ESI+): m/z [M + H]+ calcd for C44H29O2Cl2: 659.1532;
545.1278; found: 545.1274.
found: 659.1539.
2,17-Bis(heptyloxy)-7,12-dihydro[5]heliceno[2,3-a:13,12-
a]bis(naphtho[2,1-c]pyran) (25)
Following the typical procedure for 5, but PivOH (60 mol%) was
2,13-Bis{[1-chloro-7-(heptyloxy)-2-naphthyl]methoxy}[5]heli-
cene (24b)
Yield: 38 mg (74%).
added.
1H NMR (400 MHz, CDCl3): d = 8.07 (d, J = 2.2 Hz, 2 H), 7.94–
7.89 (m, 6 H), 7.79 (d, J = 8.5 Hz, 2 H), 7.63 (d, J = 9.0 Hz, 2 H),
7.50–7.44 (m, 4 H), 7.39 (d, J = 8.4 Hz, 2 H), 7.27–7.23 (m, 2 H),
7.16 (dd, J = 8.9, 2.5 Hz, 2 H), 5.19(d, J = 12.9 Hz, 2 H), 5.07 (d,
J = 13.0 Hz, 2 H), 4.14–4.12 (m, 4 H), 1.91–1.86 (m, 4 H), 1.60–
1.54 (m, 4 H), 1.44–1.37 (m, 12 H), 0.96–0.89 (m, 6 H).
13C NMR (101 MHz, CDCl3): d = 157.9, 155.3, 132.1, 131.7, 129.3,
129.2, 129.1, 128.9, 127.6, 127.0, 126.6, 126.3, 126.2, 124.0, 122.5,
119.3, 119.2, 117.7, 110.9, 103.0, 102.9, 67.8, 67.3, 31.5, 28.9,
28.8, 25.8, 22.3, 13.8.
Yield: 14 mg (20% based on recovered 24b).
1H NMR (500 MHz, CDCl3): d = 8.61 (s, 2 H), 8.35 (s, 2 H), 7.94
(d, J = 5.0 Hz, 2 H), 7.89 (s, 2 H), 7.84 (d, J = 5.0 Hz, 2 H), 7.82 (d,
J = 5.0 Hz, 2 H), 7.73 (d, J = 10.0 Hz, 2 H), 7.26–7.24 (m, 4 H),
7.12 (d, J = 10.0 Hz, 2 H), 5.09 (d, J = 15.0 Hz, 2 H), 4.89 (d,
J = 15.0 Hz, 2 H), 4.30–4.22 (m, 4 H), 1.98–1.93 (m, 4 H), 1.61–
1.57 (m, 4 H), 1.38–1.35 (m, 12 H), 0.94–0.90 (m, 6 H).
13C NMR (176 MHz, CDCl3): d 158.5, 153.6, 134.6, 132.8, 131.2,
130.8, 130.4, 129.8, 128.8, 128.2, 127.6, 127.5, 126.8, 126.7, 125.7,
125.2, 124.5, 120.2, 118.7, 116.0, 104.8, 70.1, 68.3, 31.9, 29.8,
29.3, 26.2, 22.7, 14.2.
HRMS (ESI+): m/z [M + H]+ calcd for C58H57O4Cl2: 887.3628;
found: 887.3610.
HRMS (ESI+): m/z [M + Na]+ calcd for C58H54O4Na: 837.3914;
found: 837.3949.
5,10-Dihydro[5]heliceno[2,3-c:13,12-c]bis(2-benzopyran) (5);
Typical Procedure
18-{[1-Chloro-7-(heptyloxy)-2-naphthyl]methoxy}-9-(heptyl-
oxy)-14H-[5]heliceno[2,3-b]naphtho[2,1-d]pyran (26)
Following the typical procedure for 5, but PivOH (60 mol%) was
added.
In a glovebox, to a dry sealed tube was added Pd(OAc)2 (1.24 mg,
0.005 mmol, 10 mol%), PCy3HBF4 (4.05 mg, 0.01 mmol, 20
mol%), and K2CO3 (30.4 mg, 0.22 mmol, 4 equiv). A soln of rac-
2,13-bis(2-chlorobenzyloxy)[5]helicene (2, 25.8 mg, 0.046 mmol, 1
equiv) in anhyd DMA was added to the sealed tube. The sealed tube
was removed from the glovebox and the mixture was stirred at 130
°C for 12 h. Silica gel was directly added to the mixture and the sol-
vent was evaporated under vacuum. The resulting solid was purified
by flash column chromatograph (silica gel, hexanes–EtOAc, 30:1)
to afford pure 5 as an off-white solid; yield: 22 mg (95%).
1H NMR (300 MHz, CDCl3): d = 8.27 (s, 2 H), 8.14 (s, 2 H), 8.00
(d, J = 8.1 Hz, 2 H), 7.93 (d, J = 8.6 Hz, 2 H), 7.83 (s, 2 H), 7.76 (d,
J = 8.5 Hz, 2 H), 7.50 (td, J = 7.8, 1.5 Hz, 2 H), 7.36 (td, J = 7.5, 0.9
Hz, 2 H), 7.18 (d, J = 7.5 Hz, 2 H), 5.16 (d, J = 13.4 Hz, 2 H), 4.99
(d, J = 13.2 Hz, 2 H).
Yield: 26 mg (37% based on recovered 24b).
1H NMR (400 MHz, CDCl3): d = 8.61 (s, 1 H), 8.24 (d, J = 8.0 Hz,
2 H), 7.94–7.88 (m, 6 H), 7.82 (d, J = 8.0 Hz, 1 H), 7.74 (d, J = 8.0
Hz, 1 H), 7.47 (m, 4 H), 7.34 (dd, J = 8.7, 2.4 Hz, 1 H), 7.26–7.23
(m, 2 H), 7.11 (d, J = 8.0 Hz, 1 H), 7.06 (d, J = 4.0 Hz, 1 H), 7.00
(dd, J = 8.8, 2.4 Hz, 1 H), 5.24 (d, J = 12.0 Hz, 1 H), 5.17 (d,
J = 12.0 Hz, 1 H), 5.06 (d, J = 16.0 Hz, 1 H), 4.89 (d, J = 12.0 Hz,
1 H), 4.24–4.18 (m, 1 H), 4.10–4.04 (m, 1 H), 3.93–3.88 (m, 2 H),
1.93–1.88 (m, 2 H), 1.85–1.80 (m, 2 H), 1.57–1.49 (m, 4 H), 1.39–
1.37 (m, 6 H), 1.30–1.26 (m, 6 H), 0.95–0.92 (m, 3 H), 0.88–0.85
(m, 3 H).
13C NMR (126 MHz, CDCl3): d = 158.5, 158.0, 156.0, 153.4, 134.6,
132.9, 132.8, 132.7, 131.8, 131.6, 131.1, 130.9, 130.4, 129.9, 129.6,
129.3, 129.0, 128.8, 128.2, 128.1, 127.7, 127.6, 127.4, 127.3, 127.4,
126.8, 126.6, 126.5, 126.4, 125.7, 125.2, 124.4, 124.3, 122.4, 120.3,
119.4, 118.6, 118.5, 116.4, 111.4, 105.0, 102.8, 70.0, 68.2, 68.0,
67.9, 31.9, 31.8, 29.7, 29.4, 29.3, 29.2, 26.2, 26.1, 22.7, 22.6, 14.2,
14.1.
13C NMR (176 MHz, CDCl3): d = 151.5, 133.0, 130.9, 128.8, 128.6,
128.4, 127.9, 126.8, 126.4, 125.9, 125.1, 124.6, 124.0, 123.5, 123.3,
121.2, 115.9, 68.9.
HRMS (ESI+): m/z [M + H]+ calcd for C36H23O2: 487.1693; found:
487.1684.
16-(2-Chlorobenzyloxy)-12H-[5]heliceno[2,3-c][2]benzopyran
(10)
Yield: 12 mg (50%).
HRMS (ESI+): m/z [M + Na]+ calcd for C58H55O4ClNa: 873.3681;
found: 873.3682.
1H NMR (300 MHz, CDCl3): d = 8.27 (s, 1 H), 8.07 (d, J = 3.6 Hz,
2 H), 7.96–7.80 (m, 6 H), 7.77 (d, J = 2.1 Hz, 1 H), 7.74 (d, J = 1.8
Hz, 1 H), 7.48–7.39 (m, 2 H), 7.35–7.30 (m, 1 H), 7.27 (d, J = 2.4
Hz, 1 H), 7.16–7.06 (m, 4 H), 5.12 (d, J = 13.5 Hz, 1 H), 5.0 (d,
J = 10.8 Hz, 2 H), 4.89 (d, J = 12.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d =155.3, 151.5, 134.3, 132.4, 132.3,
132.2, 131.3, 131.0, 129.7, 129.1, 128.8, 128.7, 128.5, 128.3, 128.2,
128.1, 127.8, 127.6, 127.3, 127.0, 126.9, 126.8, 126.4, 126.3, 124.7,
Acknowledgment
We thank NSERC (Canada), FQRNT (Québec), CFI (Canada),
Boehringer Ingelheim (Canada) Ltd., Merck Frosst Centre for The-
rapeutic Research and the Université de Montréal for generous
financial support. The authors thank Prof. A. Schmitzer for the mo-
lecular modeling of helicene 1, Martin Vachon for the X-ray analy-
sis of compound 5 and Francine Bélanger-Gareipy for the X-ray
analysis of compounds 10 and 24a.
Synthesis 2009, No. 9, 1499–1505 © Thieme Stuttgart · New York

PAPER
Synthesis of Higher Helicenes
1505
(6) Collins, S. K.; Grandbois, A.; Vachon, M. P.; Côté, J.
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Synthesis 2009, No. 9, 1499–1505 © Thieme Stuttgart · New York