Synthesis of biomimetic light-driven molecular switches via a cyclopropyl ring-opening/nitrilium ion ring-closing tandem reaction

Article abstract of DOI:10.1016/j.tet.2007.03.141

A cyclopropyl ring-opening/nitrilium ion ring-closing tandem reaction has been conveniently used in an expeditious synthetic approach to light-driven Z/E molecular switches featuring an imine function conjugated to olefin groups that mimics natural proton

Full text of DOI:10.1016/j.tet.2007.03.141

Tetrahedron 63 (2007) 4975–4982
Synthesis of biomimetic light-driven molecular switches
via a cyclopropyl ring-opening/nitrilium ion ring-closing
tandem reaction
a
a
a
b
Vinicio Zanirato,a, Gian P. Pollini, Carmela De Risi, Filippo Valente, Alfonso Melloni,
*
Stefania Fusi,b Jacopo Barbettib and Massimo Olivuccib,c,
*
aDipartimento di Scienze Farmaceutiche, Universitaꢀ di Ferrara, Via Fossato di Mortara 17-19, I-44100 Ferrara, Italy
bDipartimento di Chimica, Universitaꢀ di Siena, Via Aldo Moro 2, I-53100 Siena, Italy
cChemistry Department, Bowling Green State University, Bowling Green, 43403 OH, USA
Received 14 December 2006; revised 27 February 2007; accepted 22 March 2007
Available online 27 March 2007
Abstract—A cyclopropyl ring-opening/nitrilium ion ring-closing tandem reaction has been conveniently used in an expeditious synthetic
approach to light-driven Z/E molecular switches featuring an imine function conjugated to olefin groups that mimics natural protonated
Schiff bases.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
unidirectional isomerization motion. In previous reports8,9
we have shown, through combined computational and exper-
imental studies, that conformationally locked PSBs provide
a novel class of potential molecular switches capable to
mimic the photoisomerization of the retinal PSBs of rhodop-
sins. In that context, we prepared a small set of molecules fea-
turing a poly-conjugated iminium system (Fig. 1). The low
E/Z isomerization quantum yield measured for the
initially prepared p-substituted-4-benzylidene-3,4-dihydro-
2H-pyrrolinium salts PSBI (first generation PSBs)8 promp-
ted us to look at related structures with the aim of increasing
the photoisomerization efficiency. We envisaged the devel-
opment of a second generation PSB switches by decreasing
the number of torsional degrees of freedom of the PSBI back-
bone and especially the potential competitive rotation around
the benzylic single bond. We translated these concepts into
a simple working hypothesis for the synthesis of a novel
unnatural protonated Schiff base (PSBII) system9 where the
carbon–carbon exocyclic double bond appears to be the
only conformationally free site in the excited state electronic
structure.
The fascinating idea of casting single molecules capable to
convert light-energy into ‘mechanical’ motion prompted
chemists to develop, in different contexts, systems capable
of undergoing light-driven structural changes. Currently,
the design and preparation of molecular switches (i.e., mol-
ecules that can interconvert among two or more states) based
on photochemical E/Z isomerization constitutes an attractive
research target to obtain novel materials for nanotechnol-
ogy.1 Indeed, switches based on the photoisomerization of
the azobenzene chromophore have been used to control
ion complexation,2 electronic properties3 and catalysis,4 or
to trigger folding/unfolding of oligopeptide chains.5 Most
remarkably, a sophisticated application of the above princi-
ple led to the preparation of light-driven molecular rotors6
where chirality turned out to be an essential feature to
impose unidirectional rotation. In these systems helical
bis-arylidene scaffolds featuring a single exocyclic double
bond have been employed to achieve photoinduced unidirec-
tional rotary motion.
The retinal protonated Schiff base (PSB) chromophores of
rhodopsin proteins,7 a class of trans-membrane photorecep-
tors, constitute examples of natural E/Z switches undergoing
We disclose herein the results of our investigation to achieve
an effective preparation of PSBII, a molecule featuring a pyr-
rolinium moiety conjugated to an aromatic ring, the latter
being embedded in a conformationally locked indanylidene
nucleus. We addressed this compound through different
pathways. As we will discuss below one of these pathways
not only provides a flexible synthetic route but also opens
the way to the preparation of chiral PSBII systems and there-
fore to novel light-powered and biomimetic single-molecule
rotors.
Keywords: Light-driven molecular switches; Tandem reaction; Nitrilium ion
cyclization; Cyclopropylcarbinyl cation.
* Corresponding authors. Tel.: +39 0532 291285; fax: +39 0532 291296
(V.Z.); tel.: +39 0577 234274; fax: +39 0577 234278 (M.O.); e-mail
addresses: znv@unife.it; olivucci@unisi.it; molivuc@bgnet.bgsu.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.141

4976
V. Zanirato et al. / Tetrahedron 63 (2007) 4975–4982
Visible light
Lys
chromophore of
rhodopsin
NH
(the visual pigment
of superior animals)
11
second generation PSBs
first generation PSBs
PSBI
PSBII
6'
nitrilium ion
cyclization
G
G
G
7'
1'
NH
5
NH
2
N
4'
4
3
3'
2'
UV-Visible light
UV-Visible light
Figure 1.
2. Results and discussion
The PSBII retrosynthetic analysis led us to identify the com-
mercially available 5-methoxy-1-indanone 1 as a convenient
starting material, bearing a suitably located methoxy group
able to favour the pivotal cationic cyclization (Fig. 2).
Thus, the synthesis called for the installation of the homo-
allyl acetamido group at the C-1 carbon of the 5-methoxy-
1-indanone scaffold.
Among the possible retrosynthetic approaches to PSBII, we
initially selected the intramolecular capture of a nitrilium
ion by a suitably located olefin group as the most promising
one (Fig. 1). Nitrilium salts undergo various types of reac-
tions, being key intermediates in a number of named reac-
tions,10 including ring-closing reactions to form five- and
six-membered nitrogen heterocycles.11 These interesting re-
agents are usually prepared by N-alkylation of nitriles with
relatively stable carbocations, in turn generated by a plethora
of reagents,12 a common drawback being the unavoidable
formation of mixtures of nitrilium species13 derived from
the rearrangement of initially formed carbocations.
To this end, the well-established acid-catalyzed cyclo-
propylcarbinol ring-opening, also called the homoallyl
transposition, a widely exploited strategy to prepare 3-halo-
n-propylidene derivatives by treatment of cyclopropylcarbi-
nols with HX in acetic acid, could be a convenient starting
step.17
A rather different approach to nitrilium ions entailed a
Beckmann rearrangement of oximes,14 but the efficiency
of the process is seriously limited by the low stereospecific-
ity, a single geometric isomer of the oxime being required to
obtain the desired nitrilium ion. This hurdle seems to be
overcome in the protocol introduced by Gawley and Chem-
burkar,15 the nitrilium ions being generated by the action of
trimethylsilyl polyphosphate (PPSE) on secondary amides.
Recently, Angelastro et al.16 described a vinylogous Bischler–
Napieralski approach to quinolizidines by employing the
PPSE protocol, showing that the p-methoxy substituted styryl
group was the terminator of choice for the cationic cyclization.
Thus, we turned our attention to the protocol successfully
employed to prepare 1-(3-chloro-propylidene)-1,2,3,4-tetra-
hydro-naphthalene from 1-cyclopropyl-1-tetralol by Perrone
et al.,18 who stressed the importance of a short reaction time
in the treatment with 15% HCl in AcOH in order to obtain
the kinetically favoured isomer rather than the thermody-
namically favoured one having an endocyclic double bond.
Consequently, the crude adduct resulting from addition of
cyclopropylmagnesium bromide to the indanone 1 was
treated with HCl in acetic acid for 1 h at room temperature.
Unfortunately, only the undesired thermodynamically fav-
oured indenyl derivative 2 endo could be isolated in low
MeO
nitrilium ion
cyclization
PSBII
NHAc
MeO
MeO
homoallyl
transposition
MeO
OH
O
X
1
Figure 2.

V. Zanirato et al. / Tetrahedron 63 (2007) 4975–4982
4977
Z-7a
yield from the reaction mixture, a result, which could be
explained in the presence of mobile protons in position
C-2 leading to a dominant [1,3] shift (Scheme 1).
7'
H
MeO
5
N
MeO
Cl
Figure 3.
MeO
2 exo
i
carbon (d, d¼7.2) and the methyl at the C-5 of the pyrroline
ring (m, d¼2.2) was observed for the predominant isomer to
which Z configuration could be assigned (Fig. 3).
O
30%
MeO
1
Cl
Conversion of the imine function of 7a to an iminium ion,
initially accomplished by protonation with HCl, was subse-
quently effected by N-methylation with methyl triflate,
a more stable compound being produced. Their photochemi-
cal characterization has shown9 that they constitute proto-
types for the development of a novel class of light-driven
biomimetic switches featuring a rigid molecular framework
and a fully selective Z/E photoisomerization.
2 endo
Scheme 1. Reagents and conditions: (i) 1, Mg, cyclopropyl bromide, THF,
reflux, 3 h and 2, HCl, AcOH, rt, 1 h.
Given the vital role played by the exo-olefin function in the
nitrilium ion cyclization, we were forced to modify our
original plan by removing the a-hydrogen atoms of the start-
ing 5-methoxy-1-indanone 1. This operation was easily
achieved via exhaustive methylation19 of the indanone 1 to
give the bis-methyl derivative 1a, which on treatment with
cyclopropylmagnesium bromide afforded the cyclopropyl-
carbinol derivative 3a. Its exposure to the action of HBr in
AcOH promoted the expected rearrangement with the for-
mation of the bromopropylidene derivative 4a as a 3:1 mix-
ture of diastereomers for which the Z/E descriptors were not
assigned (Scheme 2).
In view of this, the rather long (six-step) and low-yielding
(33%) synthetic pathway described above (Scheme 2)
prompted us to devise a new and more convenient synthesis,
taking advantage of the alternative possibilities to generate
nitrilium ions i.e., through direct N-alkylation of acetonitrile.
Thus, the direct transformation of alcohols into secondary
amides21 provides a nice example of the use of alkyl triflates
as electrophilic species able to react with nitriles. Moreover,
Shi and Huang22 have recently reported the one-pot reaction
of nitriles, disubstituted methylenecyclopropanes (MCPs)
and triflic acid (TfOH) to yield [3+2] cycloaddition products.
The two interesting processes have in common the in situ
generation of nitrilium ions, in the first case quenched with
water, in the second one intercepted by the olefin group
originating from the cyclopropyl ring-opening.
Conversion of 4a to 6a was obtained in high yield through
bromide displacement with sodium azide followed by the
one-pot transformation of the corresponding azido group
to acetamide by chemoselective hydrogenation in the pres-
ence of acetic anhydride.20 The resulting secondary amide
was eventually submitted to Gawley’s protocol: a CCl4 solu-
tion containing an excess of PPSE was added to the ace-
tamide 6a and the resulting mixture heated at reflux for 2 h.
After aqueous work up the desired pyrroline derivative 7a
was isolated as the main product in 71% yield.
The chemistry described above supports the conjecture that
the triflate ester of compound 3a could be the precursor of
the cyclopropylcarbinyl cation I, which, according to Shi’s
domino process, would lead to compound 7a via the ni-
trilium ion II and the tertiary-benzylic carbocation III
(Scheme 3). Accordingly, treatment of the cyclopropylcarbi-
nol 3a with acetonitrile in presence of Tf2O smoothly fur-
nished compound 7a together with trace amounts of the
1
The H NMR spectrum of 7a showed the presence of two
diastereomers in 92:8 ratio, the respective geometry being
inferred on the basis of NOE difference spectroscopy. In de-
tail, a positive NOE between the proton at the aromatic C-70
MeO
MeO
MeO
OH
i
ii
iii
O
1
Br
85%
88%
79%
1a
3a
4a
iv
96%
MeO
MeO
MeO
N
vi
71%
v
NHAc
N3
84%
7a
6a
5a
Scheme 2. Reagents and conditions: (i) MeI, t-BuOK, t-BuOH, Et2O, reflux, 7 h; (ii) Mg, cyclopropyl bromide, THF, reflux, 3 h; (iii) HBr, AcOH, <10 ꢀC,
10 min; (iv) NaN3, DMF, 60 ꢀC, 2.5 h; (v) Lindlar catalyst, Ac2O, AcONa, 60 psi H2, 6 h and (vi) P2O5, HMDSO, CCl4, reflux, 2 h.

4978
V. Zanirato et al. / Tetrahedron 63 (2007) 4975–4982
MeO
MeO
ii
O
R2
R2
R1
8 R2 = H (79%)
1 R1 = R2 = H
iv
4-methoxy
propiophenone
8b R2 = Me (76%)
1b R1 = H; R2 = Me
60%
v
MeO
MeO
MeO
H
N
C Me
N
N
R2
R2
R2
R1
R1
II
R1
III
I
iii
MeO
MeO
N
i, ii
OH
R2
1
R2
75%
R1
R1
E-7 R1 = R2 = H (81%)
Z-7a R1 = R2 = Me (83%)
E-7b R1 = H; R2 = Me (35%)
3a R1 = R2 = Me
Scheme 3. Reagents and conditions: (i) MeI, t-BuOK, t-BuOH, Et2O, reflux, 7 h; (ii) Mg, cyclopropyl bromide, THF, reflux, 3 h; (iii) Tf2O, CH3CN, 3 h; (iv) 1,
morpholine, aqueous formaldehyde, AcOH, reflux, 5 h and 2, H2SO4, 60 ꢀC, 1 h and (v) TfOH, CH3CN, rt, 3 h.
amide 6a. In such a way, a more direct and fruitful approach
to 7a was obtained (three steps from 1 with a 62% overall
yield). The relief of the cyclopropyl ring strain associated
with the installation of an extended p-system on the back-
bone of the final compound provided the driving force for
this transformation.
Accordingly, treatment of 8 and 8b with 1 equiv of TfOH in
CH3CN solution at room temperature yielded the desired
cyclic imines 7 and 7b as single geometric isomers. Photo-
chemical studies are currently being undertaken on the
iminium salts obtained by N-methylation of compounds 7
and 7b.
The possibility that the transformation described in Scheme
3 would prove to be insensitive to the presence of protons at
C-2 of indanone 1 (in contrast with the synthetic route of
Scheme 2), opened the way to the preparation of switches
7 and 7b featuring a decreased steric encumbrance in the
proximity of the exocyclic carbon–carbon double bond. Ac-
cordingly, both the indanone 1 and its monomethyl deriva-
tive 1b, in turn obtained from 4-methoxypropiophenone
via Mannich a-methylenation followed by acid catalyzed
cyclization of the resulting acrylophenone,23 were submitted
to reaction with cyclopropylmagnesium bromide.
With the aim of defining the spatial relationships throughout
the new molecules, once again we resorted to NOE difference
spectroscopy as outlined below (Fig. 4). For compound 7, ir-
radiation of the signal at d¼2.3 (the methyl at C-5 of pyrro-
line) showed a NOE to the hydrogens at the C-20 carbon of
the indane. In addition, irradiation of the signal at d¼7.4 (the
hydrogen at C-70 of indane) showed a NOE to the hydrogens
at the C-3 carbon of the pyrroline ring. For compound 7b, ir-
radiation of the signal at d¼1.1 (the methyl at C-20 of indane)
showed a NOE to the methyl at C-5 of pyrroline and vice
versa. Moreover, the hydrogen at C-20 of indane showed
NOEenhancements to the methyl at C-5 of pyrroline nucleus.
The data collected for compounds 7 and 7b support an E
geometry that is opposite to that observed for compound 7a.
Surprisingly, in both cases the indenyl dehydrated deriva-
tives 8 and 8b were isolated in high yields after silica gel col-
umn chromatography of the crude reaction mixtures instead
of the expected Grignard adducts. Compounds 8 and 8b may
be considered as the conjugated bases of cyclopropylcar-
binyl cations that could potentially trigger the domino pro-
cess described above.
E-7
E-7b
7'
MeO
MeO
H
H
H
3
N
N
5
H
At this stage, we were confident that the regioselective pro-
tonation of the indenyl derivatives 8 and 8b in the presence
of acetonitrile would promote the cyclopropyl ring-opening/
nitrilium ion ring-closing sequence.
H
2'
H
Figure 4.

V. Zanirato et al. / Tetrahedron 63 (2007) 4975–4982
4979
Moreover, the presence of a stereogenic centre adjacent to
the photoisomerizable carbon–carbon double bond in 7b
can induce a helical molecular framework, consistent with
computational results previously reported by us.8 Thus, the
photoinduced isomerization of the iminium salt of 7b may
occur with control over the direction of rotation, as for
Feringa’s second generation light-driven molecular rotors.6a
We were confident that compound 7b may provide a precur-
sor of a new class of single-molecule light-powered motors
able to mimic rhodopsin both in terms of photoisomerization
mechanism and unidirectionality of the rotation.
4.1.1. 3-(3-Chloro-propyl)-6-methoxy-1H-indene (2-
endo). To magnesium turnings (0.24 g, 9.8 mmol) in dry
THF (8 mL), a solution of cyclopropyl bromide (0.8 mL,
9.8 mmol) in dry THF (5 mL) was added dropwise with
mild reflux. After the addition was completed, a solution
of 1 (0.8 g, 4.9 mmol) in dry THF (8 mL) was added drop-
wise and the mixture was heated at 60 ꢀC for 3 h. Saturated
NH4Cl solution (20 mL) was added and the mixture was ex-
tracted with ether (3ꢁ20 mL). The organic phases were
combined, dried and concentrated in vacuo. The crude resi-
due was stirred with 15% HCl solution in acetic acid
(10 mL) for 1 h at room temperature, then 10% NaOH was
added until pH 8. The mixture was extracted with CH2Cl2
(3ꢁ20 mL) and the combined organic layers were dried
and evaporated. The residue was purified by column chro-
matography (CH2Cl2/petroleum ether 3:7) to give 2-endo
(0.33 g, 30%) as a yellow oil. Rf (CH2Cl2/petroleum ether
3:7) 0.55; IR (film): n 2954, 1742, 1606, 1492, 1255,
3. Conclusion
We described an intriguing sequential cyclopropyl ring-
opening/nitrilium ion ring-closing reaction, which allowed
for the development of a convenient synthesis of the confor-
mationally locked molecular switches PSBII featuring a
polyene protonated Schiff base framework. The formation
of compounds such as 7, 7a and 7b is likely to involve a
cyclopropylcarbinyl cation triggering the domino process.
In particular, the electrophilic carbocations were produced
via homoallylic rearrangement of the first formed intermedi-
ates, generated both by departure of triflate anion from a
benzylic and tertiary carbon atoms or by regioselective pro-
tonation of 1H-indenyl derivatives (Scheme 3). The derived
nitrilium ions eventually collapse into an internal olefin af-
fording the required pyrroline heterocycles. The new struc-
tures constitute biomimetic light-driven Z/E molecular
switches that promise to be an attractive alternative (e.g.,
with high polarity and reduced molecular size) to the widely
used azobenzene switch. Moreover, the chiral compound 7b
constitutes the first example of a potential light-driven bio-
mimetic single-molecule rotor whose Z/E and E/Z rota-
tion directions are ultimately determined by the absolute
configuration of the stereogenic centre at C-20.
1
732 cmꢂ1; H NMR (200 MHz, CDCl3): d 2.04–2.23 (2H,
m, CH2CH2CH2Cl), 2.67–2.78 (2H, m, CH2CH2CH2Cl),
3.34 (2H, d, J 1.8 Hz, ArCH2), 3.65 (2H, t, J 6.4 Hz,
CH2CH2CH2Cl), 3.87 (3H, s, MeO), 6.14 (1H, m,
ArCH2CH]), 6.90 (1H, dd, J 8.4, 2.4 Hz, Ar), 7.10 (1H,
d, J 2.4 Hz, Ar), 7.29 (1H, d, J 8.4 Hz, Ar); 13C NMR
(50 MHz, CDCl3): d 24.9, 30.87, 37.73, 44.8, 55.6, 110.4,
111.6, 119.1, 126.4, 138.2, 142.4, 146.3, 158.0. Anal. Calcd
for C13H15ClO: C, 70.11; H, 6.79. Found: C, 70.14; H, 6.75.
4.1.2. 5-Methoxy-2,2-dimethyl-indan-1-one (1a). A solu-
tion of t-BuOK (3.4 g, 30.36 mmol) in t-BuOH (20 mL)
was added dropwise to a cooled (0 ꢀC) solution of 1 (1.5 g,
9.3 mmol) and methyl iodide (2.9 mL, 46.2 mmol) in ether
(40 mL). The mixture was heated at reflux for 7 h, then water
(10 mL) was added. The organic phase was separated, and
the aqueous phase was extracted with ether (3ꢁ50 mL). Af-
ter the combined organic phases were dried, the solvent was
removed in vacuo. The residue was purified by column chro-
matography (ether/petroleum ether 3:7) to give 1a (1.5 g,
85%) as a colourless oil. Rf (ether/petroleum ether 3:7)
0.41; IR (film): n 2960, 2926, 1704, 1599, 1264,
4. Experimental
1
1089 cmꢂ1; H NMR (400 MHz, CDCl3): d 1.16 (6H, s,
4.1. General methods
Me2C), 2.89 (2H, s, ArCH2C), 3.81 (3H, s, MeO), 6.80–
6.85 (2H, m, Ar), 7.62 (1H, d, J 8.4 Hz, Ar); 13C NMR
(100 MHz, CDCl3): d 25.3 (2C), 42.9, 45.6, 55.6, 109.7,
115.4, 125.9, 128.4, 155.1, 165.4, 209.6. Anal. Calcd for
C12H14O2: C, 75.76; H, 7.42. Found: C, 75.69; H, 7.47.
Solvents were distilled prior to use, following standard
procedures, and reactions were performed under nitrogen
or argon atmosphere. Silica gel 60 F254 plates were used
to monitor synthetic transformations, visualization being
done under UV light or using 2% KMnO4 solution. Organic
solutions were dried over anhydrous magnesium sulfate and
evaporated with a rotary evaporator. Chromatographic puri-
fications were carried out using 70–230 mesh silica gel.
4.1.3. 1-Cyclopropyl-5-methoxy-2,2-dimethyl-indan-1-ol
(3a). To magnesium turnings (0.2 g, 8.4 mmol) in dry THF
(8 mL), a solution of cyclopropyl bromide (0.67 mL,
8.4 mmol) in dry THF (5 mL) was added dropwise with
mild reflux. A solution of 1a (0.8 g, 4.2 mmol) in dry THF
(8 mL) was then added dropwise and the mixture heated at
60 ꢀC for 3 h. Saturated NH4Cl solution was added
(20 mL) and the mixture was extracted with ether (3ꢁ
20 mL). The combined organic phases were dried and con-
centrated in vacuo. The residue was purified by column chro-
matography (ether/petroleum ether 3:7) to furnish 3a (0.86 g,
88%) as a colourless oil. Rf (ether/petroleum ether 3:7) 0.39;
IR (film): n 3514, 2959, 2870, 1607, 1490, 1268, 1142, 1032,
808 cmꢂ1; 1H NMR (400 MHz, CDCl3): d 0.10–0.20 (1H, m,
cyclopropyl), 0.35–0.47 (3H, m, cyclopropyl), 1.04 (3H, s,
MeCMe), 1.20 (3H, s, MeCMe), 1.53 (1H, s, cyclopropyl),
€
Melting points were determined on a Buchi–Tottoli appara-
tus and are uncorrected. Infrared (IR) spectra were recorded
on a FTIR Paragon 500 spectrometer. Light petroleum re-
fers to the fractions boiling in the range 40–60 ꢀC and ether
to diethyl ether. Nuclear magnetic resonance spectra (1H
NMR and 13C NMR) were recorded on a Mercury Plus
spectrometer at 400 MHz and 100 MHz, respectively.
Chemical shifts (d values) are given in parts per million
downfield from tetramethylsilane as the internal standard.
Elemental analyses were effected by the microanalytical
laboratory of Dipartimento di Chimica, University of
Ferrara.

4980
V. Zanirato et al. / Tetrahedron 63 (2007) 4975–4982
2.63 (1H, d, J 15.6 Hz, ArCHaHbC), 2.71 (1H, d, J 15.6 Hz,
ArCHaHbC), 3.76 (3H, s, MeO), 6.70–6.72 (2H, m, Ar),
7.18–7.23 (1H, m, Ar); 13C NMR (100 MHz, CDCl3):
d ꢂ0.5, ꢂ0.2, 15.3, 23.6, 23.7, 45.5, 48.5, 55.2, 83.0,
110.2, 111.7, 124.6, 138.8, 143.6, 159.7. Anal. Calcd for
C15H20O2: C, 77.55; H, 8.68. Found: C, 77.60; H, 8.65.
NaOAc (0.11 g, 1.2 mmol) and Ac2O (0.12 mL, 1.2 mmol)
in EtOAc (20 mL) was stirred under 60 psi of hydrogen, in
the presence of Lindlar catalyst (0.04 g), for 6 h at room tem-
perature. The catalyst was removed by filtration and the fil-
trate was washed with water (15 mL) and brine (15 mL).
The combined organic phases were dried and concentrated
in vacuo. The residue was purified by column chromato-
graphy (EtOAc) to give 6a (Z/E mixture, 0.23 g, 84%) as
a yellow oil. Rf (EtOAc) 0.37; IR (film): n 3290, 3084,
4.1.4. 1-(3-Bromo-propyliden)-5-methoxy-2,2-dimethyl-
indan (4a). A cooled (<10 ꢀC) solution of 33% HBr in acetic
acid (2.5 mL) and acetic acid (10 mL) was poured into a flask
containing 3a (0.45 g, 1.94 mmol) and stirring was continued
for 10 min with ice bath cooling. After evaporation under
reduced pressure, the residue was partitioned between H2O
(20 mL) and ether (20 mL). The aqueous phase was extracted
with ether (3ꢁ20 mL), the combined organic extracts were
dried and evaporated. The residue was purified by column
chromatography (ether/petroleum ether 5:95) to afford 4a
(Z/E mixture, 0.45 g, 79%) as a yellow oil. Rf (ether/petro-
leum ether 5:95) 0.68; IR (film): n 2956, 2836, 1604, 1487,
1308, 1263, 1034 cmꢂ1; 1H NMR (400 MHz, CDCl3): d (iso-
meric ratio 3:1) 1.24 (6H, s, Me2C, major), 1.39 (6H, s, Me2C,
minor), 2.81 (2H, s, ArCH2C, major), 2.84 (2H, s, ArCH2C,
minor), 2.95 (2H, q, J 7.2 Hz, CHCH2CH2Br, minor), 3.03
(2H, q, J 7.2 Hz, CHCH2CH2Br, major), 3.45 (2H, t,
J 7.2 Hz, CHCH2CH2Br, minor), 3.53 (2H, t, J 7.2 Hz,
CHCH2CH2Br, major), 3.82 (3H, s, MeO, minor), 3.84
(3H, s, MeO, major), 5.30 (1H, t, J 7.2 Hz, C]CHCH2-
CH2Br, major), 5.72 (1H, t, J 7.2 Hz, C]CHCH2CH2Br,
minor), 6.74–6.85 (4H, m, Ar, major and minor), 7.32 (1H,
d, J 8.6 Hz, Ar, minor), 7.48 (1H, d, J 9.2 Hz, Ar, major);
13C NMR (100 MHz, CDCl3): d (major isomer) 29.4 (2C),
32.0, 32.6, 43.9, 46.9, 55.3, 110.3, 112.7, 115.1, 125.6,
132.4, 146.5, 151.80, 159.7. Anal. Calcd for C15H19BrO:
C, 61.03; H, 6.49. Found: C, 61.08; H, 6.44.
2956, 1651, 1487, 1262, 1033, 816 cmꢂ1
;
1H NMR
(400 MHz, CDCl3): d (isomeric ratio 3:1) 1.13 (6H, s,
Me2C, major), 1.30 (6H, s, Me2C, minor), 1.91 (3H, s,
MeC]O, major), 1.92 (3H, s, MeC]O, minor), 2.51 (2H,
q, J 7.2 Hz, CHCH2CH2NHAc, minor), 2.59 (2H, q, J
7.2 Hz CHCH2CH2NHAc, major), 2.73 (2H, s, ArCH2C,
major), 2.79 (2H, s, ArCH2C, minor), 3.31–3.42 (4H, m,
CHCH2CH2NHAc, major and minor), 3.75 (3H, s, MeO,
minor), 3.76 (3H, s, MeO, major), 5.17 (1H, t, J 7.2 Hz,
C]CHCH2CH2NHAc, major), 5.64 (1H, t, J 7.2 Hz,
C]CHCH2CH2NHAc, minor), 6.15 (2H, br, AcNH, major
and minor), 6.63–6.76 (4H, m, Ar, major and minor), 7.25
(1H, d, J 8.8 Hz, Ar, minor), 7.48 (1H, d, J 8.4 Hz, Ar, major);
13C NMR (100 MHz, CDCl3): d (major isomer) 23.2, 29.3
(2C), 39.6, 43.8, 46.9, 49.3, 55.3, 110.1, 112.5, 114.9,
125.7, 132.6, 146.3, 151.5, 159.5, 170.4. Anal. Calcd for
C17H23NO2: C, 74.69; H, 8.48; N, 5.12. Found: C, 74.72;
H, 8.45; N, 5.08.
4.1.7. 4-(5-Methoxy-2,2-dimethyl-indan-1-ylidene)-5-
methyl-3,4-dihydro-2H-pyrrole (7a). Pathway A (step vi
in Scheme 2): A trimethylsilyl polyphosphate (PPSE) solu-
tion, prepared by heating at reflux for 1.5 h a mixture of
P2O5 (1.6 g, 11 mmol) and hexamethyldisiloxane (HMDSO,
3.3 mL, 15.4 mmol) in CCl4 (15 mL), was added at room
temperature to 6a (0.3 g, 1.1 mmol). The reaction mixture
was heated at reflux for 2 h, cooled to room temperature
and quenched with water (5 mL). The organic phase was
separated and washed with 10% HCl (2ꢁ30 mL). The com-
bined aqueous layers were cooled to 0 ꢀC, brought to pH 9
by treatment with 6 N NaOH solution, and extracted with
CH2Cl2 (2ꢁ60 mL). The combined organic layers were
washed with water (100 mL), dried and concentrated in va-
cuo. The residue was purified by column chromatography
(EtOAc/MeOH/Et3N 9:1:0.2) to give 7a (92:8 Z/E mixture,
0.2 g, 71%) as a yellow oil.
4.1.5. 1-(3-Azido-propylidene)-5-methoxy-2,2-dimethyl-
indan (5a). Sodium azide (1.66 g, 25.5 mmol) was added
to a solution of 4a (1.5 g, 5.1 mmol) in DMF (25 mL) and
the mixture was heated at 60 ꢀC for 2.5 h. After addition
of water (100 mL), the solution was extracted with CH2Cl2
(2ꢁ50 mL). The combined organic layers were washed
with water (100 mL), dried and evaporated. Purification of
the residue by column chromatography (ether/petroleum
ether 5:95) afforded 5a (Z/E mixture, 1.25 g, 96%) as a yel-
low oil. Rf (ether/petroleum ether 5:95) 0.68; IR (film): n
1
2957, 2096, 1604, 1487, 1464, 1262, 1034, 849 cmꢂ1; H
NMR (400 MHz, CDCl3) d (isomeric ratio 3:1) 1.21 (6H,
s, Me2C, major), 1.37 (6H, s, Me2C, minor), 2.69 (2H, q, J
7.6 Hz, CHCH2CH2N3, minor), 2.75 (2H, q, J 7.2 Hz,
CHCH2CH2N3, major), 2.78 (2H, s, ArCH2C, major), 2.85
(2H, s, ArCH2C, minor), 3.34–3.47 (4H, m, CHCH2CH2N3,
major and minor), 3.79 (3H, s, MeO, minor), 3.82 (3H, s,
MeO, major), 5.25 (1H, t, J 7.2 Hz, C]CHCH2CH2N3, ma-
jor), 5.71 (1H, t, J 7.6 Hz, C]CHCH2CH2N3, minor), 6.61–
6.82 (4H, m, Ar, major and minor), 7.31 (1H, d, J 8.8 Hz, Ar,
minor), 7.48 (1H, d, J 8.0 Hz, Ar, major); 13C NMR
(100 MHz, CDCl3): d (major isomer) 28.4, 29.4 (2C),
43.9, 47.0, 51.3, 55.3, 110.4, 112.6, 113.9, 125.7, 132.5,
146.5, 151.9, 159.7. Anal. Calcd for C15H19N3O: C, 70.01;
H, 7.44; N, 16.33. Found: C, 70.06; H, 7.40; N, 16.30.
Pathway B (step iii in Scheme 3): To a stirred solution of
triflic anhydride (0.15 mL, 0.9 mmol) in CH3CN (2 mL),
a solution of 3a (0.21 g, 0.9 mmol) in CH3CN (1 mL) was
added dropwise at 0 ꢀC. The reaction mixture was slowly
warmed to room temperature and stirred for 3 h. The solu-
tion was washed with 10% NaOH (5 mL) and the phases
were separated. The aqueous phase was extracted with
CH2Cl2 (3ꢁ10 mL). The combined organic phases were
dried and concentrated in vacuo. The residue was purified
by column chromatography (EtOAc/MeOH/Et3N 9:1:0.2)
to afford 7a (0.19 g, 83%) as a yellow oil.
Compound 7a: Rf (EtOAc/MeOH/Et3N 9:1:0.2) 0.32; IR
n ;
1702, 1600, 1576, 1291 cmꢂ1 1H NMR
(film):
(400 MHz, CDCl3): d 1.25 (6H, s, Me2C), 2.22 (3H, m,
MeC]N), 2.77–2.80 (4H, m, CH2CH2N and ArCH2C),
3.82–3.84 (5H, m, MeO and CH2CH2N), 6.70 (1H, dd,
4.1.6. N-[3-(5-Methoxy-2,2-dimethyl-indan-1-ylidene)-
propyl]-acetamide (6a). A solution of 5a (0.26 g, 1 mmol),

V. Zanirato et al. / Tetrahedron 63 (2007) 4975–4982
4981
J 8.4, 2.0 Hz, Ar), 6.75 (1H, d, J 2.0 Hz, Ar), 7.20 (1H, d,
J 8.4 Hz, Ar). A positive NOE between signal at d 2.22
(methyl at C-5 of 3,4-dihydro-2H-pyrrole) and signal at
d 7.24 (H-7 on the aromatic ring) could be detected; 13C
NMR (100 MHz, CDCl3): d 19.7, 25.1, 42.9, 49.0, 49.4,
55.5, 56.8, 109.9, 111.7, 126.1, 128.9, 131.4, 131.7, 148.0,
160.5, 174.6. Anal. Calcd for C17H21NO: C, 79.96; H,
8.29; N, 5.49. Found: C, 79.93; H, 8.22; N, 5.54.
Calcd for C13H14O: C, 83.83; H, 7.58. Found: C, 83.87;
H, 7.53.
8b: colourless oil (0.74 g, 76%). Rf (CH2Cl2/petroleum ether
3:7) 0.65; IR (film): n 3000, 2906, 1478, 1266, 1037,
1
809 cmꢂ1; H NMR (400 MHz, CDCl3): d 0.62–0.67 (2H,
m, cyclopropyl), 0.83–0.89 (2H, m, cyclopropyl), 1.57–
1.63 (1H, m, cyclopropyl), 2.12 (3H, s, MeC]), 3.22 (2H,
s, ArCH2CMe), 3.82 (3H, s, MeO), 6.81 (1H dd, J 8.4,
2.6 Hz, Ar), 6.97 (1H, d, J 2.6 Hz, Ar), 7.28 (1H, d, J
8.4 Hz, Ar); 13C NMR (100 MHz, CDCl3): d 4.4 (2C), 7.3,
14.5, 42.7, 55.7, 10.1, 111.3, 119.0, 136.4, 138.3, 140.3,
144.1, 157.1. Anal. Calcd for C14H16O: C, 83.96; H, 8.05.
Found: C, 83.92; H, 8.11.
4.1.8. 5-Methoxy-2-methyl-indan-1-one (1b). Aqueous
formaldehyde solution 36% (5.5 mL, 68.6 mmol) was added
dropwise over 5 h to a refluxing mixture of 4-methoxypro-
piophenone (2 g, 12.2 mmol) and morpholine (0.53 mL,
6.1 mmol) in glacial acetic acid (20 mL). The mixture was
refluxed overnight, then acetic acid was stripped off under
reduced pressure and the residue was diluted with EtOAc
(30 mL). The organic layer was washed successively with
10% HCl (15 mL), saturated NaHCO3 (20 mL) and brine
(20 mL), and then dried. The solvent was evaporated in va-
cuo and the residue was used in the next step without further
purification.
4.1.10. 4-(5-Methoxy-indan-1-ylidene)-5-methyl-3,4-
dihydro-2H-pyrrole (7) and 4-(5-methoxy-2-methyl-
indan-1-ylidene)-5-methyl-3,4-dihydro-2H-pyrrole (7b).
To a stirred and cooled (0 ꢀC) solution of triflic acid
(115 mL, 1.3 mmol) in CH3CN (2 mL), a solution of indene
8 or 8b (1.3 mmol) in CH3CN (1 mL) was added dropwise.
The reaction mixture was slowly warmed to room tempera-
ture and stirring was continued for 3 h, before quenching
with 10% NaOH (5 mL). The aqueous phase was extracted
with CH2Cl2 (3ꢁ10 mL) and the combined organic phases
were dried and concentrated in vacuo. The residue was puri-
fied by column chromatography (EtOAc containing 2%
Et3N) to give 7 or 7b.
The crude product was poured slowly into concentrated
H2SO4 (10 mL) and the solution heated at 60 ꢀC for 1 h.
After being cooled at room temperature, the mixture was
poured into water (50 mL) and extracted with ether
(3ꢁ50 mL). The organic layer was washed with 10%
NaHCO3, dried and evaporated. The residue was purified
by column chromatography (ether/petroleum ether 2:8) to
afford 1b (1.3 g, 60%) as a white solid, mp 66–68 ꢀC. Rf
(ether/petroleum ether 2:8) 0.29; IR (KBr): n 1701, 1595,
Compound 7: brown solid (0.24 g, 81%), mp 58–60 ꢀC. Rf
(EtOAc containing 2% Et3N) 0.33; IR (KBr): n 3434,
1253, 1086, 851 cmꢂ1
;
1H NMR (200 MHz, CDCl3):
2921, 1583, 1293, 1248, 1024 cmꢂ1; H NMR (400 MHz,
1
d 1.28 (3H, d, J 7.0 Hz, MeCH), 2.62–2.72 (2H, m,
ArCH2), 3.27–3.40 (1H, m, MeCH), 3.87 (3H, s, MeO),
6.85–6.90 (2H, m, Ar), 7.67 (1H, d, J 8.8 Hz, Ar); 13C
NMR (50 MHz, CDCl3): d 16.6, 35.1, 42.2, 55.7, 109.7,
115.4, 125.7, 129.6, 156.5, 165.4, 207.8. Anal. Calcd for
C11H12O2: C, 74.98; H, 6.86. Found: C, 74.93; H, 6.90.
CDCl3): d 2.37 (3H, m, MeC]N), 2.88–2.92 (2H, m,
CH2CH2N), 3.01–3.07 (2H, m, ArCH2CH2), 3.10–3.16
(2H, m, ArCH2CH2), 3.83 (3H, s, MeO), 3.91–3.99 (2H,
m, CH2CH2N), 6.79 (1H, dd, J 8.4, 2.6 Hz, Ar), 6.84 (1H,
d, J 2.6 Hz, Ar), 7.47 (1H, d, J 8.4 Hz, Ar); a positive
NOE between signal at d 2.37 (methyl at C-5 of pyrroline
ring) and signal at d 3.15 (hydrogens at C-20 carbon of indane
nucleus) was detected as well as between signal at d 7.47
(hydrogen at C-70 of indane nucleus) and signal at d 2.91
(hydrogen at C-3 carbon of pyrroline ring). 13C NMR
(100 MHz, CDCl3): d 21.2, 31.0, 31.1, 31.8, 55.5, 57.8,
109.9, 113.2, 1260, 135.1, 139.7, 147.3, 150.8, 160.4,
173.2. Anal. Calcd for C15H17NO: C, 79.26; H, 7.54; N,
6.16. Found: C, 79.21; H, 7.57; N, 6.21.
4.1.9. 3-Cyclopropyl-6-methoxy-1H-indene (8) and
3-cyclopropyl-6-methoxy-2-methyl-1H-indene (8b). To
magnesium turnings (0.23 g, 9.8 mmol) in dry THF (8 mL),
a solution of cyclopropyl bromide (0.78 mL, 9.8 mmol) in
dry THF (5 mL) was added dropwise with mild reflux. After
the addition was completed, a solution of ketone 1 or 1b
(4.9 mmol) in dry THF (8 mL) was added dropwise and
the mixture was heated at 60 ꢀC for 3 h. Saturated NH4Cl
solution was added (20 mL) and the mixture was extracted
with ether (3ꢁ20 mL). The combined organic solutions
were dried and evaporated. The residue was purified by
column chromatography (CH2Cl2/petroleum ether 3:7) to
yield 8 or 8b.
Compound 7b: brown solid (0.10 g, 35%), mp 61–63 ꢀC. Rf
(EtOAc containing 2% Et3N) 0.31; IR (KBr): n 3390, 2930,
1
1600, 1583, 1486, 1249, 1031 cmꢂ1; H NMR (400 MHz,
CDCl3): d 1.15 (3H, d, J 6.8 Hz, MeCH), 2.42 (3H, m,
MeC]N), 2.56 (1H, d, J 16.0 Hz, ArCHIHII), 2.79 (1H,
ddd, J 3.2, 8.0, 16.8 Hz, CHIHIICH2N), 2.99 (1H, ddd,
J 3.2, 8.0, 16.8 Hz, CHIHIICH2N), 3.19 (1H, dd, J 7.2,
16.0 Hz, ArCHIHII), 3.61–3.70 (1H, m, MeCH), 3.82 (3H,
s, MeO), 3.84–3.89 (1H, m, CH2CHIHIIN), 3.95–4.47 (1H,
m, CH2CHIHIIN), 6.80 (1H, dd, J 8.4, 2.6 Hz, Ar), 6.85
(1H, d, J 2.6 Hz, Ar), 7.45 (1H, d, J 8.4 Hz, Ar); a positive
NOE between signal at d 1.10 (methyl at C-20 of indane nu-
cleus) and signal at d 2.56 (methyl at C-5 of pyrroline ring)
was detected. 13C NMR (100 MHz, CDCl3): d 20.73, 23.96,
32.17, 36.88, 39.8, 55.4, 57.9, 110.6, 112.8, 126.5, 132.4,
133.9, 144.4, 148.5, 160.2, 171.9. Anal. Calcd for
Compound 8: white solid (0.72 g, 79%), mp 42–45 ꢀC. Rf
(CH2Cl2/petroleum ether 3:7) 0.68; IR (KBr): n 3447,
2960, 1604, 1258, 1073, 1015, 820 cmꢂ1
;
1H NMR
(400 MHz, CDCl3): d 0.63–0.69 (2H, m, cyclopropyl),
0.85–0.92 (2H, m, cyclopropyl), 1.78 (1H, m, cyclopropyl),
3.28 (2H, s, ArCH2CH]), 3.86 (3H, s, MeO), 5.91 (1H, m,
ArCH2CH]), 6.90 (1H, dd, J 8.4, 2.4 Hz, Ar), 7.07 (1H, d,
J 2.4 Hz, Ar), 7.42 (1H, d, J 8.4 Hz, Ar); 13C NMR
(100 MHz, CDCl3): d 6.2 (2C), 8.5, 37.4, 55.6, 110.3,
111.6, 119.3, 123.0, 139.0, 146.2, 146.4, 157.9. Anal.

4982
V. Zanirato et al. / Tetrahedron 63 (2007) 4975–4982
J. Am. Chem. Soc. 2000, 122, 12005; (d) Feringa, B. L. Acc.
Chem. Res. 2001, 34, 504.
C16H19NO: C, 79.63; H, 7.94; N, 5.80. Found: C, 79.60; H,
7.98; N, 5.84.
7. (a) Mathies, R. A.; Lugtenburg, J. Handbook of Biological
Physics; Stavenga, D. G., de Grip, W. J., Pugh, E. N., Eds.;
Elsevier Science B.V.: Amsterdam, 2000; Vol. 3, pp 56–90;
(b) Kandori, H.; Shichida, Y.; Yoshizawa, T. Biochemistry
(Moscow) 2001, 66, 1483; (c) Teller, D. C.; Okada, T.;
Behnke, C. A.; Palczewski, K.; Stenkamp, R. E. Biochemistry
2001, 40, 7761.
8. Sampedro, D.; Migani, A.; Pepi, A.; Busi, E.; Basosi, R.;
Latterini, L.; Elisei, F.; Fusi, S.; Ponticelli, F.; Zanirato, V.;
Olivucci, M. J. Am. Chem. Soc. 2004, 126, 9349.
Acknowledgements
This work was supported by the MIUR (PRIN 2004 and
2006) and the University of Ferrara (FAR 2006). We are
grateful to Dr. Alberto Casolari and Dr. Elisa Durini for
the NOE difference spectroscopy experiments and helpful
discussion.
9. Lumento, F.; Zanirato, V.; Fusi, S.; Busi, E.; Latterini, L.;
ꢁ
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