Benzannulated cycloheptanones from binaphthyl platforms

Article abstract of DOI:10.1002/ejoc.201201370

Preparations of benzannulated cycloheptanones starting from unique binaphthyl molecular platforms are described. Binaphthyl acetic acids proved suitable percursors for fused cycloheptanone architectures. Seven-membered rings embedded in binaphthyl units were selectively generated by use of Eaton's reagent. Isomeric helical architectures arising from electrophilic cyclisation processes at second reaction sites in the precursors could also be obtained under different acidic conditions. Unambiguous discrimination between isomeric geometries was provided by multiple quantum NMR sequences. DFT calculations were performed and gave evidence of different behaviour of the substrates towards intramolecular electrophilic substitution. The theoretical approach confirmed the experimental results, agreeing completely with X-ray data. Preparations of benzannulated cycloheptanones starting from binaphthyl molecular platforms are described. Copyright

Full text of DOI:10.1002/ejoc.201201370

FULL PAPER
DOI: 10.1002/ejoc.201201370
Benzannulated Cycloheptanones from Binaphthyl Platforms
Grégory Pieters,[a] Kamal Sbargoud,[a] Alexandre Bridoux,[a] Anne Gaucher,*[a]
Sylvain Marque,[a] Flavien Bourdreux,[a] Jérôme Marrot,[a] David Flot,[b]
Guillaume Wantz,[c] Olivier Dautel,[d] and Damien Prim*[a]
Keywords: Helical structures / Density functional calculations / NMR spectroscopy / Multiple quantum NMR
Preparations of benzannulated cycloheptanones starting
from unique binaphthyl molecular platforms are described.
Binaphthyl acetic acids proved suitable percursors for fused
acidic conditions. Unambiguous discrimination between iso-
meric geometries was provided by multiple quantum NMR
sequences. DFT calculations were performed and gave evi-
cycloheptanone architectures. Seven-membered rings em- dence of different behaviour of the substrates towards intra-
bedded in binaphthyl units were selectively generated by
use of Eaton’s reagent. Isomeric helical architectures arising
from electrophilic cyclisation processes at second reaction
sites in the precursors could also be obtained under different
molecular electrophilic substitution. The theoretical ap-
proach confirmed the experimental results, agreeing com-
pletely with X-ray data.
ent on the ease of generation of the electrophile, the nucleo-
philicities of the two reaction sites and the alkyl chain
length.
Introduction
Benzannulated cycloalkanones have been a focus of con-
tinuous interest over the last decades. Textbook and ad-
vanced methodologies to install small- to medium- and
large-sized carbocycles in phenyl or naphthyl derivatives
have been developed.[1] Such motifs based on cyclohep-
tanone cores are key intermediates in the preparation of
complex molecular architectures and natural products.[2]
The presence both of distorted and of planar units usually
induces a deformation of the overall carbon framework, a
key factor in the modulation of properties of porphyrin-like
compounds,[3] potent tumourigenic activity[4] and inhibition
of mammalian aminopeptidases.[5]
In this large family of fused molecules, we became inter-
ested in naphthylannulated cycloheptanones. In this con-
text, naphthyl alkanoic acids or derivatives are common
and obvious starting materials for the elaboration of
naphthylcycloalkanone backbones. Electrophilic activation
of the acid derivative and further cyclisation can afford two
products, however. As shown below, cyclisation is depend-
Cyclisation reactions of 2-(1-naphthyl)acetic acid deriva-
tives (n = 1, Scheme 1) exclusively afforded the expected
[d,e]-fused acenaphthenone motif.[6] In contrast, (1-naphth-
yl)propionic acid derivatives (n = 2) gave mainly mixtures of
both [d,e]- and [a]-fused motifs – phenalenone and naphth-
ylcyclopentanone, respectively – depending on experimen-
tal conditions and the use of the carboxylic acid or the acyl
chloride as substrate.[6,7] A further increase in the length of
the alkyl chain by one carbon atom, to give (1-naphthyl)-
butanoic acid (n = 3), led to the exclusive formation of the
[a]-fused naphthylcyclohexanone.[8] In these cases, the [d,e]-
fused naphthylcycloheptanone motif was not reported
(Scheme 1). Attempts to modify the selectivity through in-
corporation of a rigid phenyl group in the alkyl chain re-
mained unsuccessful.[9]
[a] Université de Versailles St Quentin, Institut Lavoisier de
Versailles, UMR CNRS 8180,
45, Avenue des Etats-Unis, 78035 Versailles cedex, France
Fax: +33-1-39254452
E-mail: gaucher@chimie.uvsq.fr; prim@chimie.uvsq.fr
Homepage: http://www.ilv.uvsq.fr/recherche/Echo/echo.htm
[b] European Molecular Biology Laboratory,
Scheme 1. Access to naphthylcycloalkanones from ω-(1-naphthyl)-
alkanoic acids.
6, rue Jules Horowitz, BP181, 38042 Grenoble cedex 9, France
[c] Laboratoire IMS - ENSCBP-IPB, UMR CNRS 5218,
16, Avenue Pey Berland, 33607 Pessac cedex, France
[d] Institut Charles Gerhardt de Montpellier, UMR CNRS 5253,
ENSCM-AM2N,
Interestingly, the influence of further rigidification of
such substrates on the cyclisation process and issues of se-
lective synthetis have not yet been reported. By a similar
analysis, the unique analogously substituted nonplanar bi-
8, rue de l’école normale, 34296 Montpellier cedex 05, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201370.
490
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Benzannulated Cycloheptanones from Binaphthyl Platforms
naphthyl core would be expected to afford either the [d,e]-
fused cycloheptanone derivative or the [a]-fused [5]-keto-
helicene. In this work we show that a binaphthyl platform
incorporating an electrophilic carboxylic acid moiety
(Scheme 2) is a suitable starting material for the preparation
of angular fused cycloheptanones (brown cyclisation site in
Figure 2, below). Depending on the reaction conditions and
the relative nucleophilicities of the two reactions sites, a sec-
ond cyclisation process (green cyclisation site in Figure 2)
can also take place, allowing the formation of [5]-helicene
derivatives (Scheme 2). The formation of binaphthyl-based
cycloheptanones is confirmed by multiple quantum NMR
sequences, X-ray analysis and theoretical calculations.
Scheme 4. Possible ketone architectures accessible from carboxylic
acid 1.
Careful examination of NMR spectra raised the problem
of the cyclisation site and the possibility of the obtainment
of seven-membered ring ketone 5, arising from rotation of
one naphthyl group around the binaphthyl axis and cycli-
sation at the brown site in Figure 2, below, rather than the
more classical and expected six-membered ring ketone 4.
The two structures are isomers. The determination of the
exact molecular architecture was successfully achieved by
means of a multiple quantum NMR sequence (MQS).[12]
Indeed, such a sequence, initially developed for particularly
crowded proton NMR spectra of multicomponent mixtures,
proved very useful in our case and allowed us to discrimi-
nate multiple proton patterns on an aromatic core. As
shown in Scheme 5, the two possible isomeric structures
have different substitution patterns: one four-consecutive-
proton series for compound 5 and two four- consecutive-
proton series in the case of the ketone 4. As shown below,
the MQS unambiguously showed the presence of only one
four-consecutive-proton pattern (labelled a–d), characteris-
tic of the seven-membered ring ketone structure 5 (Fig-
ure 1).
Scheme 2. Access to angular cycloheptanones and/or [5]-helicene
motifs starting from binaphthyl precursors.
Results and Discussion
Our first goal was to prepare carboxylic acid 1
(Scheme 3) from easily accessible precursors. As shown,
compound 1 was readily obtained through Suzuki coupling
between naphthalene boronic acid and nitrile 2.[10] The
transformation of the nitrile group was achieved in H2O by
treatment with conc. H2SO4 at 100–130 °C to afford the
carboxylic acid 1 in high yield.
Scheme 3. Preparation of carboxylic acid 1.
Gratifyingly, acid 1 underwent smooth cyclisation into a
new cyclic ketone on treatment with Eaton’s reagent
[MeSO3H (MSA), P2O5] at room temperature
(Scheme 4).[11] The proton NMR spectra clearly supported
the obtainment of a methyl ketone fragment, exhibiting two
Scheme 5. Possible architectures obtained.
Attempts to optimise the reaction led to mixtures of sev-
doublets at δ = 4.36 and 3.90 ppm corresponding to the eral products depending on the reaction conditions.
geminal protons α to the carbonyl moiety. The presence of Scheme 5 shows the possible architectures obtained and
a carbonyl group was detected by IR and exact mass analy- Table 1 lists reactions conditions together with ratios be-
ses and confirmed the general structure of this molecule.
tween plausible products.
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deed not observed. MQS again proved a useful tool for un-
ambiguous discrimination between architectures in these
series (see the Supporting Information). Compounds 5 and
the helicenes 7 are the result of the reaction of a common
electrophile, generated from the parent carboxylic acid in
the presence of a proton source, at two different cyclisation
sites (green and brown sites in Figure 2). As confirmed by
quantum chemical calculations[12] at the B3LYP/6-
31+G(d,p) level of theory,[13] the two sites have similar
capabilities for cyclisation, their similar HOMO coefficients
confirming the potential for formation of both products.
Figure 1. Characteristic MQS and assignment of Ha–Hd protons
for ketone 5.
Table 1. Preparation of compounds 5–7.
Entry Conditions
Conv.[a] Ratio
Yield
[%]
[%]
5/7
1
2
3
4
5
MSA, P2O5, 20 °C
MSA, P2O5, 25 °C
MSA, P2O5, reflux
MSA, P2O5, DCE, 80 °C 100
AcOH, Ac2O, ZnCl2 100
50
100
100
100:0
5 (40)
55:45[b] 5 (51)/7a (38)
[c]
[c]
–
–
42:58[b] 5 (40)/7a (55)
40:60 7c (63)
[a] Levels of conversion were determined from NMR spectra of the
crude materials. [b] Products were not isolated, but were obtained
as a mixture of 7a (major) and 7b. [c] These reaction conditions led
to degradation of both reactants.
At 25 °C, with Eaton’s reagent, two types of architectures
were obtained in similar amounts (Entry 2). Characteristic
NMR signals showed the presence of the ketone 5, which
was isolated in 51% yield. Careful analysis of NMR spectra
revealed the presence of two additional products. With the
absence of aliphatic protons allowing the formation of com-
pound 4 to be ruled out, the presence of singlets could
Figure 2. DFT calculations for carboxylic acid 1 + H+.
In the light of these first results we next focused on three
correspond to the formation of the enol forms 6 and/or 7. new carboxylic acid derivatives, incorporating phen-
Again, NMR Q4–Q1 correlation unambiguously showed anthrene, acenaphthene and pyrene subunits (Figure 3).
the presence of [5]-helicene architectures. Indeed, the pres- Our objective was to determine whether we could influence
ence of two characteristic four-consecutive-proton patterns the balance between the two cyclisation sites.
is in full agreement with 7, thus ruling out the possible enol
DFT calculations afforded insightful forecasts as shown
form of the seven-membered ring ketone 6. We were indeed below.
able to isolate compound 7a (R = OMs), plausibly arising
The theoretical approach revealed different behaviour of
from the mesylation of the parent six-membered enol 7b, in substrates 8–10 towards intramolecular electrophilic substi-
38% yield. Although 7b (R = H) could not be isolated, its tution. In their HOMOs, protonated substrates 8 and 9
formation could be shown by the presence of a characteris- each displayed two valid atomic orbital coefficients, thus
tic singlet in the NMR spectra and was confirmed by mass potentially affording two products arising from electrophilic
analysis. It was assumed that 7b was in fact produced first substitution at both cyclisation sites. In contrast, the
under the acidic conditions, but was rapidly transformed HOMO of the protonated acid 10 showed the presence of
into the corresponding mesylate 7a.
a nodal plane responsible for a unique nucleophilic site that
Heating of 1 at reflux in MSA afforded only degradation would lead to exclusive cyclisation to form the seven-mem-
byproducts (Entry 3). In contrast, heating of 1 at 80 °C in bered ring ketone. Interestingly, the substrate 10, bearing
DCE (1,2-dichloroethane) led to the formation of both 5 the pyrene unit, would be expected to afford the best cycli-
and 7a in a 4:6 ratio (Entry 4). A change from Eaton’s rea- sation results because its protonated form exhibited the
gent to AcOH/ZnCl2 in Ac2O led to the formation of 7c (R highest HOMO value (–8.00 eV) and the strongest interac-
= Ac, 63% yield), resulting from in situ acetylation of the tion between frontier orbitals (1.55 eV). In contrast, as
parent 7b enol form, as the sole product.
shown by their lower HOMO values, ranging from –8.80 to
It is worth noting that neither the ketone 4 nor the enol –8.33 eV, and increased interactions, ranging from 2.53 to
6 could be isolated. In the [5]-helicene series, the enol form 1.89 eV, the two protonated substrates 8 and 9, respectively,
7b could plausibly be directly converted into sulfonate 7a appeared less nucleophilic and less reactive towards the
or acetate 7c derivatives depending on the reaction condi- cyclisation process. Carboxylic acids 8–10 were prepared as
tions. In contrast, the twisting of the seven-membered ring in Scheme 1, through Suzuki couplings followed by hydrol-
likely favoured the formation of the ketone 5 over the corre- ysis of the resulting nitriles under strongly acidic reaction
sponding nonplanar potential enol form 6, which was in- conditions (Figure 4).
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Benzannulated Cycloheptanones from Binaphthyl Platforms
though the formation of a second architecture could not be
fully ruled out, heating of 8 in MSA at reflux led to intrac-
table mixtures and did not allow us to gain more infor-
mation. Gratifyingly, though, a change from MSA to
AcOH, Ac2O and ZnCl2 at 120 °C proved successful and
allowed us to obtain helicene 12 selectively in a good 63%
yield.
The formation of the helicene 12 can be explained in
terms of the following mechanism (Scheme 7), which plaus-
ibly involves enol 13 as the first intermediate formed. Com-
pound 13 was not isolated but was probably acetylated un-
der those reaction conditions. A Claisen-type reaction un-
der acidic conditions followed by a final cyclisation step
would occur from the newly formed ketoacetate intermedi-
ate under acidic catalysis conditions.[14]
Figure 3. HOMO representations for isovalues at 98%.
Figure 4. Carboxylic acids 8–10.
Scheme 7. Plausible mechanism for the formation of helicene 12.
Compounds 8–10 were obtained in 39, 48 and 54%
yields, respectively (Figure 4). Under hydrolysis conditions,
no traces of cyclisation products were detected in the crude
materials.
Carboxylic acids 8–10 were next subjected to cyclisation
under acidic conditions. Surprisingly, when 8 and Eaton’s
reagent were mixed together at 25 °C, the seven-membered
ring ketone 11 was obtained as the sole product in a fair
48% yield (Scheme 6).
Both ketone 11 and helicene 12 were characterized by
NMR spectroscopy. Again, MQS allowed clear discrimi-
nation between both architectures (see the Supporting In-
formation).
Similarly, the carboxylic acid 9 was subjected to electro-
philic substitution with MSA as the proton source
(Scheme 8).
Scheme 8. Preparation of the ketone 14.
Scheme 6. Preparation of ketone 11 and helicene 12.
At 25 °C or in DCE at 80 °C, we were able to isolate
Unfortunately, attempts to achieve the formation of the the ketone 14 as the exclusive cyclisation product in yields
helicene architecture by increasing the reaction temperature ranging from 60 to 87%. The architecture 14Ј, which might
failed, in good agreement with theoretical calculations. Al- be obtained with AcOH, Ac2O and ZnCl2 as cyclisation
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A. Gaucher, D. Prim et al.
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conditions, could not be isolated. Its presence could, how-
As shown in Figure 6, the optimised geometry obtained
ever, be detected by mass spectroscopy analysis. In this case, from theoretical calculations is in good agreement with X-
observed yields higher than 80% are nevertheless indicative ray data; relevant comparison of selected data is given in
of an almost exclusive product and suggest a major impact Table 2.
of the substitution of the naphthalene core on the electro-
philic cyclisation process. The presence of only one four-
consecutive-proton series, characteristic of the seven-mem-
bered ring ketone structure, was observed by MQS (see
ESI).
Finally, the ketone 15 (Scheme 9) was obtained as the
exclusive cyclisation product, as expected from theoretical
calculations. Indeed, 15 was the sole compound formed
Figure 6. Comparison between X-ray-determined structure 15 (left)
during the MSA-promoted cyclisation process whatever re-
actions conditions, such as temperature and dilutions, were
used. Even the use of AcOH, Ac2O and ZnCl2 at 120 °C for
48 h led exclusively to ketone 15. No traces of the possible
helicene analogues to 7c or 12, previously obtained under
such reactions conditions, could be detected, confirming ex-
clusive selectivity observed when starting from the carb-
oxylic acid 10. MQS results were in good agreement with
the structure of ketone 15, which contains the characteristic
four-consecutive-proton series.
and theoretical data [gas phase B3LYP/6-31+G(d,p)] (right).
Table 2. Selected geometric data and comparison for ketone 15.
Entry Geometric
parameters
X-ray cyrstal
structure determination calculation
Quantum chemical
1
2
3
4
5
6
C1–O1 [Å]
C4–C5 [Å]
C5–C27 [Å]
C1–C2–C3 [°]
C1–C2–C3–C4 [°]
1.223
1.497
2.980
104.8
65.6
1.2228
1.4952
2.9882
106.4
66.36
C3–C4–C5–C6 [°] –54.7
–53.23
The geometric comparisons focused mainly on the seven-
membered ring, which is central to the overall molecular
architecture. Interestingly, geometric optimisation achieved
through quantum chemical calculation proved reliable for
the solid-state geometrical parameters. As an example, the
C=O double bond and C4–C5 bond that link the two
planar fragments together revealed very high levels of accu-
racy (Entries 1 and 2). In addition, the calculated and deter-
mined C5–C27 interatomic distances are almost identical
(Entry 3). Moreover, the C1–C2–C3 angle (Entry 4) and the
dihedral angles (Entries 5 and 6) that characterize the con-
tortion of the seven-membered ring are very close.
The absorption and emission spectra of 5, 11, 14 and 15
in CH2Cl2 are shown in Figure 7. As expected, compounds
5 and 14, which differ from one another only by an ethylene
fragment, exhibited closely similar absorption data. The
presence of an extended aromatic system, such as in 11 and
15, bearing a phenanthrene and a pyrene unit, respectively,
induced broad red-shifted absorption peaks in comparison
with 5.
Scheme 9. Preparation of ketone 15.
Single crystals of 15 suitable for X-ray analysis (Figure 5)
could be obtained by slow evaporation of an ethyl acetate
solution.[15] X-ray analysis confirmed the formation of a
seven-membered ring arising from cyclisation at the peri-
position of the pyrene moiety. The strained conformation
adopted by the seven-membered ring embedded in the bisa-
romatic core including one pyrene and one naphthalene
fragment, might explain the absence of enolisation even in
a concentrated acidic medium. As depicted in Figure 5, the
presence of a central nonplanar seven-membered ring dic-
tates the overall geometry of the molecular architecture.
Interestingly, the emission spectra of all of the cyclohept-
anones each exhibited at least two emission peaks, suggest-
ing similar behaviour of all targeted ketones. In fact, all the
ketones seem to behave as two structurally independent
units. The first (naphthyl, phenanthrenyl, acenaphthyl and
pyrenyl), directly linked to the ketone moiety and the sec-
ond (naphthalenyl), correspond to withdrawing and donat-
ing groups, respectively. In this context, each emission spec-
Figure 5. Single-crystal X-ray diffraction analysis of ketone 15.
Two different intermolecular π–π interactions between trum would reflect the presence of a monomer and an exci-
planar fragments of the molecule dictate the molecular ar- plex, characterized by the clear presence of two emission
rangement. Two adjacent molecules are linked together peaks and a broad red-shifted emission of the exciplex. The
through two consecutive pyrene units with an average dis- nonplanar and rigid molecular arrangement of the two aro-
tance of 3.74 Å on one hand, and two naphthalene units matic units linked together through the cycloheptanone
with a distance of 3.97 Å on the other hand.
core rather restrict cofacial interactions between the two
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Benzannulated Cycloheptanones from Binaphthyl Platforms
solvent peaks (δ =7.26 ppm for CHCl3, 5.32 ppm for [D2]dichloro-
1
methane, 3.58 ppm for [D8]THF for H spectra and δ =77.00 ppm
for CDCl3, 53.8 ppm for [D2]dichloromethane, 67.4 ppm for [D8]-
THF) for 13C spectra. HRMS data were recorded with an Autospec
Ultima (Waters/Micromass) device with a resolution of 5000 RP at
5%. 1-Bromo-2-(cyanomethyl)naphthalene was prepared as de-
scribed in reference S1 in the Supporting Information. UV/Vis
analyses were performed with
a Perkin–Elmer UV/Vis/NIR
Lambda 19 spectrophotometer; 1 cm path quartz cells were used
for the measurements. Steady-state fluorescence measurements
were recorded with a FluoroMax-3 spectrofluorimeter with a
150 W Xenon lamp and a slit width of 5 nm. For all measurements,
the samples used for fluorescence are the same for UV/Vis.
Typical Procedure for the Preparation of Carboxylic Acid 1: Con-
centrated H2SO4 (4 mL) was added at 0 °C to a stirred suspension
of nitrile reactant (0.46 mmol) in H2O. The mixture was stirred at
130 °C for 2 d. The resulting solution was extracted with dichloro-
methane (4ϫ10 mL). The organic phase was then washed with
water. The combined organic layers were dried, filtered and concen-
trated under vacuum. The crude product was purified by flash
chromatography. After purification on silica gel (PE/EtOAc 50:50),
1 was obtained (108 mg, 75%) as a yellow solid. 1H NMR
(300 MHz, CDCl3): δ = 10.70 (br., 1 H), 8.05–7.90 (m, 4 H), 7.65–
7.56 (m, 2 H), 7.42–7.50 (m, 3 H), 7.30–7.17 (m, 4 H), 3.47 (m, 2
H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 177.4, 137.4,
135.9, 133.6, 133.4, 132.7, 132.6, 130.1, 128.3, 128.3, 128.3, 128.2,
128.2, 127.9, 127.7, 126.8, 126.3, 126.1, 126.0, 125.8, 125.5,
Figure 7. a) Absorption spectra of 10 μm solutions of 5, 14 and 15
and a 94 μm solution of 11 in CH2Cl2. b) Fluorescence spectra of
5 (λexc = 293 nm), 11 (λexc = 323 nm), 14 (λexc = 293 nm) and 15
(λexc = 295 nm) in CH2Cl2.
39.1 ppm. IR: ν = 3150, 2450, 1703, 1405, 1290, 1225, 824,
˜
759 cm–1. HRMS (ESI): calcd. for C22H16O2Na [M + Na]+
335.1057; found 335.1048.
aromatic planes within the same molecule.[16] The excitation
transfer between the donor and acceptor moieties thus most
plausibly occurred through intermolecular interactions be-
tween two exci-partners. The most pronounced batho-
chromic shift between the two emission peaks is observed
in the pyrenyl series, which is consistent with previous re-
ports in extended aromatic series.[17]
Compound 8: After purification on silica gel (PE/EtOAc 50:50), 8
was obtained (100 mg, 39%) as a brown solid. 1H NMR (300 MHz,
CDCl3): δ = 10.32 (br., 1 H), 8.82 (d, J = 8.2 Hz, 2 H), 8.06–7.83
(m, 3 H), 7.78–7.64 (m, 4 H), 7.59–7.28 (m, 6 H), 3.78–3.37 (m, 2
H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 177.0, 137.2,
134.5, 133.6, 132.7, 131.7, 130.4, 130.3, 129.1, 128.7, 128.2, 128.1,
127.9, 127.7, 127.6, 127.3, 126.9, 126.8, 126.7, 126.3, 126.2, 126.0,
125.8, 122.8, 122.6, 39.1 ppm. IR: ν = 3039 (OH), 1698 (CO) cm–1.
˜
Conclusions
HRMS (ESI): calcd. for C25H17 [M – CO2 – H]– 317.1334; found
317.1330.
In summary, we have shown that benzannulated cyclo-
heptanones can be efficiently prepared from versatile bi-
naphthyl molecular platforms. Several binaphthyl acetic ac-
ids, each containing two potential cyclisation sites, have
been studied. Seven- and six-membered rings were gener-
ated selectively, depending on the reaction conditions and
on the relative nucleophilicities of the precursor cyclisation
sites. Multiple quantum NMR sequences allowed clear dis-
crimination between potential isomeric molecular architec-
tures arising from cyclisation at different sites. DFT predic-
tive calculations were performed; they agreed completely
with the observed selectivity and were confirmed by the X-
ray data to be highly reliable.
Compound 9: After purification on silica gel (PE/EtOAc 50:50), 9
was obtained (75 mg, 48%) as a brown solid. H NMR (300 MHz,
1
CDCl3): δ = 7.93 (t, J = 8.5 Hz, 2 H), 7.55 (d, J = 8.5 Hz, 1 H),
7.48–7.29 (m, 5 H), 7.27–7.19 (m, 2 H), 6.89 (d, J = 7.5 Hz, 1 H),
3.63–3.42 (m, 6 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
177.9, 146.0, 139.3, 137.1, 133.4, 132.6, 130.9, 130.2, 129.8, 128.0,
127.7, 127.4, 126.8, 126.5, 126.4, 126.1, 126.0, 125.5, 120.9, 119.4,
119.0, 39.6, 30.4, 30.1 ppm. IR: ν = 3050 (OH), 1701 (CO) cm–1.
˜
HRMS (ESI): calcd. for C24H17O2 [M – H]– 337.1249; found
337.1229.
Compound 10: After purification on silica gel (PE/EtOAc 50:50), 10
was obtained (59 mg, 54%) as a yellow solid. 1H NMR (300 MHz,
CDCl3): δ = 8.16 (d, J = 7.8 Hz, 1 H), 8.10 (d, J = 8.1 Hz, 1 H),
8.04 (s, 1 H), 7.95–7.78 (m, 6 H), 7.69 (d, J = 8.5 Hz, 1 H), 7.47
(d, J = 8.5 Hz, 1 H), 7.38–7.29 (m, 2 H), 7.15–7.08 (m, 1 H), 6.97
(d, J = 7.5 Hz, 1 H), 3.42–3.25 (m, 4 H, CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 177.2, 137.9, 133.6, 133.4, 132.7, 131.4,
131.1, 131.0, 130.5, 128.4, 128.3, 128.2, 127.9, 127.8 (2 C), 127.7,
127.5, 127.0, 126.4, 126.2, 126.1, 125.9, 125.3, 125.2, 124.8 (2 C),
Experimental Section
General: Unless otherwise noted, all starting materials were ob-
tained from commercial suppliers and used without purification.
Petroleum ether was distilled under argon. NMR spectra were re-
corded with 400 MHz, 300 MHz and 200 MHz Bruker spectrome-
ters. Chemical shifts are reported in ppm relative to the residual
124.7, 39.1 ppm. IR: ν = 3026 (OH), 1702 (CO) cm–1. HRMS
˜
(ESI): calcd. for C28H18O2Na [M + Na]+ 409.1203; found 409.1204.
Eur. J. Org. Chem. 2013, 490–497
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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495

A. Gaucher, D. Prim et al.
FULL PAPER
Typical Procedure for Cyclisation of Carboxylic Acids with Eaton’s
Reagent: Acid 1 (190 mg, 0.6 mmol) in DCE (2 mL) was solubilized
in MSA (10 mL)/P2O5 (20 mg) and the red solution was stirred at
room temperature for 3 d. The resulting dark red solution was
poured into ice (50 g), and the aqueous phase was extracted with
dichloromethane (3ϫ20 mL) The combined organic layers were
dried, filtered and concentrated under vacuum. The crude product
was purified by flash chromatography on silica gel (PE/EtOAc 9:1)
to give the ketone 5 (91 mg, 51%) as a yellow paste and the helicene
7a (86 mg, 38%) as a brown solid.
128.7, 128.6, 128.4, 128.2, 127.6, 127.1, 126.7, 126.6, 126.4, 126.3,
125.8, 125.5, 125.3, 124.4, 50.7 ppm. IR: ν = 1676 (CO) cm–1.
˜
HRMS (ESI): calcd. for C28H15O [M – H]– 367.1220; found
367.1123.
Typical Procedure for Cyclisation of Carboxylic Acids with AcOH/
Ac2O/ZnCl2: Acid 1 (50 mg, 0.16 mmol) was solubilized in an
AcOH/Ac2O (3:2) mixture (10 mL), and then ZnCl2 (436 mg,
3.2 mmol, 20.0 equiv.) was added. The solution was stirred at reflux
for 48 h. H2O (10 mL) was added to the resulting dark solution,
and the aqueous phase was extracted with EtOAc (3ϫ20 mL); the
organic phase was then washed with H2O (20 mL). The combined
organic layers were dried, filtered and concentrated under vacuum.
The crude product was purified by flash chromatography on silica
gel (PE/EtOAc 6:4) to give the helicene 7c (35 mg, 63%) as a yellow
solid.
1
Ketone 5: H NMR (300 MHz, CDCl3): δ = 8.20 (d, J = 7.1 Hz, 1
H, 17-H), 8.15 (d, J = 8.3 Hz, 1 H, 15-H), 8.11 (t, J = 8.1 Hz, 1
H, 14-H), 7.95 (d, J = 8.4 Hz, 1 H, 4-H), 7.93–7.85 (m, 3 H, 5-H,
12-H), 7.75 (t, J = 6.9 Hz, 1 H, 13-H), 7.64–7.57 (m, 3 H, 8-H, 3-
H, 16-H), 7.47–7.42 (m, 1 H, 6-H), 7.39–7.34 (m, 1 H, 7-H), 4.34
(d, J = 10.8 Hz, 1 H, 22-H), 3.90 (d, J = 10.8 Hz, 1 H, 22-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 192.2, 135.7, 135.5, 134.3, 134.0,
133.9, 133.8, 133.4, 132.7, 130.4, 130.0, 129.9, 129.6, 129.5, 128.4,
Helicene 7c: 1H NMR (300 MHz, CDCl3): δ = 8.49 (d, J = 8.7 Hz,
1 H, 18-H), 8.44 (d, J = 8.7 Hz, 1 H, 8-H), 7.97–7.80 (m, 6 H, 15-
H, 14-H, 13-H, 5-H, 4-H, 3-H), 7.68 (s, 1 H, 22-H), 7.58–7.48 (m,
2 H, 6-H, 16-H), 7.32–7.23 (m, 2 H, 7-H, 17-H), 2.55 (s, 3 H, 23-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.6, 145.2, 132.5,
132.4, 131.7, 130.7, 130.6, 129.3, 129.0, 128.6, 128.1, 128.0, 127.9,
127.8, 126.7, 126.2, 126.0, 125.8, 125.3, 124.7, 125.5, 118.9, 118.6,
126.7, 126.4, 126.3, 125.3, 125.1, 124.9, 51.1 ppm. IR: ν = 1674
˜
(CO) cm–1. HRMS (ESI): calcd. for C22H15O [M + H]+ 295.1204;
found 295.1123.
Helicen-13-yl Methanesulfonate 7a: 1H NMR (300 MHz, CDCl3):
δ = 8.47 (d, J = 8.6 Hz, 1 H, 8-H), 8.42 (d, J = 8.6 Hz, 1 H, 18-
H), 8.20 (d, J = 8.5 Hz, 1 H, 3-H), 8.02 (d, J = 8.8 Hz, 1 H, 4-H),
7.99–7.94 (m, 4 H, 22-H, 13-H, 15-H, 5-H), 7.84 (d, J = 8.6 Hz, 1
H, 14-H), 7.60–7.48 (m, 2 H, 6-H, 16-H), 7.31–7.25 (m, 2 H, 7-H,
17-H), 3.28 (s, 3 H, SO2Me) ppm. 13C NMR (75 MHz, CDCl3): δ
= 143.7, 132.6, 132.5, 131.3, 130.4, 130.3, 129.1, 128.9, 128.8, 128.6,
128.5, 128.0, 127.9, 127.1, 126.6, 126.0, 125.9, 125.7, 124.9, 124.8,
21.1 ppm. IR: ν = 1797 (CO) cm–1. HRMS (ESI): calcd. for
˜
C22H13O [M – MeCO]– 293.1770; found 293.1760.
Helicene 12: 1H NMR (300 MHz, CDCl3): δ = 10.11 (d, J = 9.0 Hz,
1 H, 3-H), 9.14 (d, J = 7.8 Hz, 1 H, 23-H), 8.74 (d, J = 8.0 Hz, 1
H, 26-H), 8.57 (d, J = 9.0 Hz, 1 H, 15-H), 8.18 (d, J = 8.0 Hz, 1
H, 8-H), 8.10 (d, J = 8.1 Hz, 1 H, 4-H), 8.07 (d, J = 9.0 Hz, 1 H,
18-H), 7.96 (d, J = 7.0 Hz, 1 H, 5-H), 7.80–7.75 (m, 2 H, 25-H, 24-
H), 7.61 (t, J = 6.0 Hz, 1 H, 16-H), 7.49 (t, J = 6.0 Hz, 1 H, 6-H),
7.26–7.16 (m, 2 H, 17-H, 7-H), 6.49 (s, 1 H, 29-H), 2.59 (s, 3 H,
Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 180.1, 162.9, 155.7,
134.1, 132.1, 131.0, 130.9, 130.5, 130.4, 130.1, 129.6, 129.5, 128.7,
128.5, 128.2, 127.8, 127.6, 127.5, 127.4, 126.3, 126.0, 124.8, 123.8,
118.8, 118.6, 37.9 ppm. IR: ν = 1445 (S=O), 1171 (S–O) cm–1.
˜
HRMS (ESI): calcd. for C23H16O3SNa [M + Na]+ 395.0718; found
395.0671.
1
Ketone 11: H NMR (300 MHz, CDCl3): δ = 9.05 (d, J = 8.3 Hz,
1 H, 15-H), 8.84 (d, J = 8.1 Hz, 1 H, 26-H), 8.32 (d, J = 8.4 Hz, 1
H, 17-H), 8.09 (s, 1 H, 12-H), 8.00–7.93 (m, 2 H, 4-H, 23-H), 7.93
(d, J = 8.4 Hz, 1 H, 5-H), 7.85–7.65 (m, 3 H, 25-H, 16-H, 24-H),
7.61–7.57 (m, 2 H, 8-H, 3-H), 7.47–7.42 (m, 1 H, 6-H), 7.35–7.21
(m, 1 H, 7-H), 4.48 (d, J = 10.8 Hz, 1 H, 22-H), 3.92 (d, J =
10.8 Hz, 1 H, 22-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 192.2,
136.1, 135.8, 134.9, 133.8, 133.0, 131.2, 131.1, 130.6, 130.2, 130.1,
129.5, 129.2, 128.9, 128.4, 128.1, 127.6, 127.5, 126.6, 126.5, 126.1,
123.6, 123.5, 123.4, 121.2, 116.3, 113.9, 19.9 ppm. IR: ν = 1655
˜
(CO) cm–1. HRMS (ESI): calcd. for C30H19O2 [M + H]+ 411.1386;
found 411.1385.
Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR, 13C NMR and multiple quantum NMR spectra and
DFT calculations.
125.7, 125.3, 125.0, 122.8, 50.9 ppm. IR: ν = 1698 (CO) cm–1.
˜
HRMS (ESI): calcd. for C26H16O [M + H]+ 345.1281; found
345.1279.
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1
Ketone 14: H NMR (200 MHz, CDCl3): δ = 8.18 (d, J = 7.5 Hz,
1 H, 17-H), 7.97 (d, J = 7.8 Hz, 1 H, 12-H), 7.93–7.86 (m, 2 H, 4-
H, 5-H), 7.83 (d, J = 7.6 Hz, 1 H, 8-H), 7.61–7.55 (m, 2 H, 13-H,
3-H), 7.44–7.33 (m, 3 H, 6-H, 16-H, 7-H), 4.27 (d, J = 11.0 Hz, 1
H, 22-H), 3.90 (d, J = 11.0 Hz, 1 H, 22-H), 3.59–3.50 (m, 4 H, 23-
H, 24-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 192.6, 152.9,
147.6, 139.8, 135.4, 134.8, 133.8, 132.4, 132.4, 131.5, 130.1, 129.3,
128.9, 128.3, 128.2, 127.2, 127.0, 126.1, 125.1, 119.3, 118.8, 51.7,
30.9, 30.4 ppm. IR: ν = 1672 (CO) cm–1. HRMS (ESI): calcd. for
˜
C24H17O [M + H]+ 321.1279; found 321.1283.
1
Ketone 15: H NMR (300 MHz, CDCl3): δ = 8.86 (s, 1 H, 17-H),
8.39–8.11 (m, 6 H, 25-H, 27-H, 24-H, 23-H, 13-H, 12-H), 8.09 (t,
J = 7.7 Hz, 1 H, 26-H), 7.98 (d, J = 8.3 Hz, 1 H, 4-H), 7.91 (d, J
= 7.5 Hz, 1 H, 8-H), 7.58 (d, J = 8.4 Hz, 1 H, 3-H), 7.44 (d, J =
7.6 Hz, 1 H, 5-H), 7.44–7.35 (m, 1 H, 7-H), 7.35–7.29 (m, 1 H, 6-
H), 4.40 (d, J = 10.7 Hz, 1 H, 22-H), 4.01 (d, J = 10.7 Hz, 1 H,
22-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 192.5, 135.7, 134.5,
133.8, 133.1, 132.7, 132.4, 131.6, 131.2, 131.0, 130.0, 129.4, 129.0,
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[13]
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CCDC-850010 contains the supplementary crystallographic
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Received: October 16, 2012
Published Online: December 6, 2012
Eur. J. Org. Chem. 2013, 490–497
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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