Toward a stable α-cycloalkyl amino acid with a photoswitchable cationic side chain

Article abstract of DOI:10.1021/jo2022263

The N-alkylated indanylidenepyrroline (NAIP) Schiff base 3 is an unnatural α-amino acid precursor potentially useful for the preparation of semisynthetic peptides and proteins incorporating charged side chains whose structure can be modulated via Z/E phot

Full text of DOI:10.1021/jo2022263

Article
pubs.acs.org/joc
Toward a Stable α-Cycloalkyl Amino Acid with a Photoswitchable
Cationic Side Chain
Riccardo Rossi Paccani,† Donato Donati,† Stefania Fusi,† Loredana Latterini,# Grazia Farina,‡
Vinicio Zanirato,*,‡ and Massimo Olivucci*,†,§
†Dipartimento di Chimica, Universita
̀
̀
di Siena, via Aldo Moro 2, I-53100 Siena, Italy
#Dipartimento di Chimica, Universita
di Perugia, via Elce di Sotto 8, I-06123 Perugia, Italy
‡Dipartimento di Scienze Farmaceutiche, Universita
§Chemistry Department, Bowling Green State University, Bowling Green Ohio 43403, United States
̀
di Ferrara, via Fossato di Mortara 17-19, I-44100 Ferrara, Italy
S
* Supporting Information
ABSTRACT: The N-alkylated indanylidenepyrroline (NAIP) Schiff
base 3 is an unnatural α-amino acid precursor potentially useful for the
preparation of semisynthetic peptides and proteins incorporating
charged side chains whose structure can be modulated via Z/E
photoisomerization. Here we report that the heteroallylic protons of 3
led to partial loss of ethanol accompanied by formation of the novel
heterocyclic system 4 during attempted deprotection. We also show
that the same protons catalyze the thermal isomerization of 3, making
the light-driven conformational control concept ineffective for times
longer than a few hours. These problems are not present in the
previously unreported compound 5 where the acidic methyl group is
replaced by an H atom. Therefore, 5, rather than 3, constitutes a
promising prototype for the design of building blocks capable to
modulate the electrostatic potential of a protein in specific locations via
light irradiation.
electrostatic14 switches. As illustrated in Figure 2A for 2, upon
INTRODUCTION
■
photoisomerization of the exocyclic double bond, the pyrroline
unit undergoes a ca. 180° twisting yielding a spatial relocation
of the charges and, in turn, a change in the orientation of the
electric dipole moment with respect to the indanylidene
framework. We have reported14 that the photolysis of 2 may
induce a ca. 30 D dipole moment change which modulates the
spectra of nearby fluorophores. Since NAIPs are photochromic
compounds, irradiation at different wavelengths can be used to
establish the isomer dominating the system photostationary
state (see the histogram of Figure 2B) and implement the
electrostatic switching concept.
It is apparent that the properties mentioned above provide
the basis for achieving novel functional building blocks capable
of modulating steric and electrostatic interactions in diverse
macromolecular or supramolecular environments (see examples
in ref 16). In spite of their interest for the preparation of novel
photoresponsive materials, 1, 2, and their analogues (see for
instance ref 17) cannot be used in a block synthesis due to the
lack of suitable functional groups for the coupling to a
macromolecular or solid-state framework. For this reason, we
have recently reported the preparation of 3, a NAIP switch
Photochemical switches are bistable compounds that can be
interconverted between two different isomers (states) via light
irradiation. The most widely used photoswitch is azobenzene
that has been employed to control different biomolecular
functions1−3 via a −NN− double-bond photoisomerization
interconverting its Z and E states. Owing to the significant
change in molecular length (ca. 3.5 Å between the two p-
carbons) but limited change in dipole moment (ca. 3 D)
between its Z- and E-isomers,4 azobenzene is considered a
mechanical rather than electrostatic switch. Literature examples
of electrostatic photoswitches are compounds of the spiropyr-
an-type5,6 that can be changed between a neutral state and a
zwitterionic state via a photochemical ring-opening reaction.
Such property has been employed to reversibly modulate α-
helix→random coil conformational transitions7 and the activity
of enzymes8 and channel proteins9 and to achieve novel
sensors.10
N-Alkylated indanylidenepyrroline Schiff bases (NAIPs) are
novel biomimetic photochemical switches that replicate the
efficient −CC− double-bond photoisomerization occurring
in visual pigments (e.g., the dim-light receptor rhodopsin).11−13
These molecules, which feature a permanently charged12 or
zwitterionic14 pyrroline unit (see 1 and 2 in Figure 1), have
been proposed to function both as mechanical11,15 and/or
Received: November 7, 2011
Published: January 12, 2012
© 2012 American Chemical Society
1738
dx.doi.org/10.1021/jo2022263 | J. Org. Chem. 2012, 77, 1738−1748

The Journal of Organic Chemistry
Article
Figure 1. Structures discussed in the present work. Compound 3 is an α-cycloalkyl amino acid derivative of 1, and 4 is an undesirable tetracyclic
synthesis byproduct obtained during the synthesis of 3. Compound 5 represents the main synthesis target.
Figure 2. Zwitterionic NAIP switch. (A) Schematic representation of an electrostatic switch based on the Z/E isomerization of 2. The absorption
maxima of the E- and Z-isomers in methanol solution are given in parentheses. The 180° rotation of the pyrrolinium unit will invert the dipole
moment vector with respect to the indanylidene unit. The angle between the simulated dipole moment vectors of the E- and Z-isomers is from ref
14. The computed dipole moment values are 15.7 and 14.8 D, respectively. (B) Observed E/Z photostationary state ratio of 2 as a function of the
irradiation wavelength.
featuring an indanylidene unit bearing protected amino and
carboxylic groups at position C2′.14 The NAIP switch 3
constitutes an α-cycloalkyl amino acid building block that could
potentially be employed for the preparation of photoresponsive
peptides or proteins. Indeed, methods for the incorporation of
bulky α-alkyl amino acid in synthetic peptides have been
established.18−23 On the other hand, such incorporation
requires, invariably, the deprotection of the amino and carboxyl
functions.
In the next section we show that compound 3 is not a
suitable building block for the preparation of photoresponsive
peptides due to its chemical and thermal instability. With the
aim to overcome the above drawbacks, we embarked on a
combination of kinetic, synthesis, and structural studies whose
main goal is represented by the successful preparation of the
unprecedented unnatural α-cycloalkyl amino acid precursor 5.
Besides being stable both to acidic and basic environments, the
new aldimine-type NAIP has been found to display the wanted
stable light-driven switching behavior in the presence of
protecting groups mimicking, locally, the incorporation in a
peptide side chain.
RESULTS AND DISCUSSION
■
Nitrilium Cyclization and Formation of a Tetracyclic
Byproduct. In the past,24 we have shown that an indanylidene
nucleus can be successfully transformed into a polyconjugated
iminium ion featuring a protonated or alkylated Schiff base
function. Therefore, we envisioned that the same nitrilium
cyclization chemistry could be employed to introduce the
amino and carboxyl functional groups on the indanylidene
portion of 1 giving access to a new class of unnatural α-
cycloalkyl amino acids suitable for peptide synthesis. Accord-
ingly, we successfully prepared14 the NAIP switch 3: a
protected α-amino acid featuring a quaternary α-carbon locked
into a rigid indanylidene ring.
As shown in Scheme 1, the ethoxycarbonylated 5-
methoxyindan-1-one, subjected to the action of N-bromosucci-
nimide and Amberlyst-15,25,26 gave almost quantitatively the
brominated compound 6. The C-2 nitrogen introduction, easily
accomplished via bromide displacement with sodium azide,
followed by Staudinger reduction and trifluoroacetylation of the
resulting primary amine,27 gave compound 7. The structure of
the protected α-amino acid featuring a quaternary stereocenter
1739
dx.doi.org/10.1021/jo2022263 | J. Org. Chem. 2012, 77, 1738−1748

The Journal of Organic Chemistry
Article
Scheme 1. Synthesis of Free Base Protected α-Cycloalkyl Amino Acid 10
was confirmed by RX crystallography (see the Supporting
Information).
Scheme 2. Mechanism Assumed for the Formation of
Tetracyclic Compound 11
The subsequent steps were devoted to the installation of the
homoallyl acetamide group on the indan nucleus by exploiting
the previously reported homoallyl rearrangement of cyclo-
propylindanol derivatives.24,28 Thus, the Grignard adduct 8
exposed to the action of triflic anhydride in the presence of
acetonitrile afforded compound 9. Dehydration of the
secondary amide by using trimethylsilyl polyphospate (PPSE)
and the quenching of the resulting nitrilium ion on the internal
olefin yielded the expected free base 10 (Scheme 1) as a
mixture of geometric isomers (E/Z 1:2).
While we demonstrated that the above protocol leads to the
wanted Schiff base precursor, evidence for undesirable
instabilities of the IP framework and Z/E ratio started to
emerge. First, it was found that protons of the methyl group at
δ = 2.27 ppm of 10 underwent a fast exchange in CD3OD
indicating a prototropic tautomeric equilibration of the Schiff
base function with the corresponding enamine via the methyl
group in vinyl position (see first line in Scheme 2). The acidity
of the same methyl group was also held responsible for the
transformation of the prepared 10E/10Z mixture into the
tetracyclic compound 11 by simple elution through a column of
silica gel. The structure of compound 11 is confirmed by RX
crystallography (see the Supporting Information). On the basis
of these data, we assume that 11 results from an intramolecular
enamine acylation reaction whose mechanism is shown in
Scheme 2. Notice that the equilibration between the E/Z
steroisomers, as well as the tautomerization to the reacting
enamine, are prerequisites for the acylation step.
Their treatment with methyl triflate gave the target isomers 3E
and 3Z (Scheme 3), whose geometrical identity was ascertained
Scheme 3. Methylation of Free Base NAIP Precursor 10
In spite of the undesirable transformation described above, it
was possible to prepare the geometric isomers of 10 by flash
chromatographic separation on silica gel conditioned with TEA.
1740
dx.doi.org/10.1021/jo2022263 | J. Org. Chem. 2012, 77, 1738−1748

The Journal of Organic Chemistry
Article
Scheme 4. Synthesis of the NAIP Schiff Base Phenyl Derivative 13E/Z
Figure 3. Kinetic studies on 2. (A) Kinetic analysis of the spectrophotometric data obtained at 292 K. (B) Arrhenius plot giving an Ea = 12100 cal
mol−1.
Scheme 5. Proposed Bimolecular Mechanism for the Isomerization of the NAIP Schiff Base 2E
by NOESY experiment. These isomers were stable enough to
be well-characterized; however, attempts to perform the
hydrolysis of their ethoxycarbonyl groups, as a step toward
the corresponding α-amino acid, were completely unsuccessful.
The only detectable material in the reaction mixture was the
tetracyclic compound 4 that similarly to 11 could result from an
intramolecular enamine acylation. The structure of compound
4 was demonstrated via RX diffraction analysis (see the
Supporting Information). This finding reinforced the idea that,
in order to access a photoresponsive amino acid that could be
employed in peptide synthesis, it is necessary to access NAIP
frameworks not bearing a methyl group (or any other alkyl
group) in position C5 on the pyrroline ring. In other words, the
behavior of both 3 and 10 indicated that the ethoxycarbonyl
group at the C-2 indanylidene carbon suffered from the
presence of hydrogens in heteroallylic position with respect to
the C−C5N bond and that the presence of the methyl
substituent on the pyrroline ring has, therefore, to be avoided.
To demonstrate our mechanistic hypothesis for the
formation of 4, we prepared compound 12 where the methyl
substituent on the pyrroline ring was replaced with a phenyl
group. As expected, the absence of C−H bonds capable to
conjugate with the C5N double bond led to the stable Schiff
base. The preparation of 12 and of the final NAIP 13
corresponding to a protected α-amino acid was accomplished
by following the synthetic strategy used to prepare 10 but using
1741
dx.doi.org/10.1021/jo2022263 | J. Org. Chem. 2012, 77, 1738−1748

The Journal of Organic Chemistry
Article
Figure 4. Retrosynthetic analysis of compound 15.
Scheme 6. Synthesis of the NAIP 20
benzonitrile instead of acetonitrile in the homoallylic rearrange-
ment step (see Scheme 4).
the Z and E isomers to determine the increase in the
concentration of 2Z. The results of the measurements are
reported in Figure 3A, which shows that the inverse of the
concentration of the reacting 2E isomer fits the experimental
data while the logarithm of the same concentration does not.
This indicates a second order rather that the expected (for a net
monomolecular isomerization) first-order kinetics. The same
procedure was followed at different temperatures in the 276−
313 K range to determine the rate constants. Figure 3B shows
the corresponding Arrhenius plot whose linear correlation
allows to determine a value of 12.1 kcal mol−1 for the activation
energy.
The observed second order kinetics is hypothetically
explained on the basis of the reaction mechanism given in
Scheme 5. This suggests that two molecules of 2E are required
to achieve the observed rate. Taking into account the results of
the previous subsection, which demonstrate the presence of
acidic hydrogens in all Schiff bases prepared using the nitrilium
cyclization route, we propose the initial formation of a transient
dimer. One monomer in the dimer acts as a proton donor while
the other as a proton acceptor. The proton is added to the
exocyclic C1′C4 double bond in such a way to produce a
stable benzyl cation which is further stabilized by the electron-
releasing methoxy substituent. In the cationic intermediate the
twisting about the C1′−C4 single bond must be controlled by a
small barrier leading to a fast Z/E equilibration. Back proton
transfer then leads to reconstitution of the double bond with a
2Z stereochemistry.
Thermal Isomerization. As anticipated above, an addi-
tional unfavorable feature of compounds 1, 2 and 3 is the
thermal isomerization of the exocyclic C1′C4 double bond.
For instance, for 1 we have reported that, in the dark, a 1:1.4
1Z/1E photostationary state, generated via a 440 nm
irradiation, evolves to 1:0.6 ratio in 24 h at 0 °C.11 At −40
°C, the same mixture only evolves to a 1.0:1.2 ratio indicating a
barrier controlled change toward a thermal equilibrium
dominated by 1Z. In order to clarify the origin of this process,
we carried out kinetic studies taking 2 as a model system. As
previously reported,14 the room-temperature 2Z/2E ratio in the
dark is 1:0.01, and it is therefore fully dominated by 2Z.
Irradiation with a 440 nm wavelength leads to a room
temperature photostationary state with a 1.0:1.2 composition
dominated by 2E; however, such a mixture reverts in the dark
eventually leading to a reconstitution of the original
composition (in more than 24 h).
The kinetic of the thermal re-equilibration process has been
investigated by monitoring the 2E concentration as a function
of time via spectrophotometric analysis after the composition of
the starting photoequilibrated mixture was determined via
HPLC analysis and found to be consistent with the data
reported in ref 14. The thermal isomerization was spectropho-
tometrically monitored at regular times via absorption spec-
troscopy. The spectrophotometric data were then analyzed
using the previously determined absorption coefficients14 for
1742
dx.doi.org/10.1021/jo2022263 | J. Org. Chem. 2012, 77, 1738−1748

The Journal of Organic Chemistry
Article
Scheme 7. Synthesis of NAIP 5Z
An evidence in favor of the above mechanism is based on the
observation that the phenyl derivative 13 (see Scheme 4),
lacking acidic hydrogens, not only does not undergo any
cyclization but has a fully stable thermally E/Z ratio at room
temperature.
Scheme 6). The structure of compound 18E was confirmed by
RX diffraction analysis (see the Supporting Information). The
next step led to the one-pot formation of the desired
polyconjugated aldimine 19, by reduction, cleavage of the N-
Boc group and condensation to yield the E isomer.33 The free
base 19E provided the NAIP 20E through N-quaternarization
performed with methyl triflate. The geometry of the exocyclic
double bond of 20E was inferred by NOESY experiment.
The successful preparation of 19 and 20 prompted the
extension of the aldolic approach to the indanone derivative 7
so as to obtain a photomodulable α-cycloalkyl amino acid
precursor potentially useful, after deprotection, for peptide
synthesis (Scheme 7). We found that 7 features a diminished
electrophilic character of the indanone carbonyl, maybe due the
presence of the secondary trifluoroacetamide group and/or
steric congestion around the reactive center which renders
partially incisive the BF3-activating role. However, apart from a
lower yield in the aldolic reaction and the need of promoting
dehydration with the use of a Tf2O−DMAP system, we
smoothly reproduced all steps. Interestingly, we observed that,
for both 14 and 18, the multistep one-pot process leading to
the cyclic aldimine 15 and 19 yielded a single geometric isomer.
The pure free base 15Z, treated with methyl triflate, gave the
NAIP switch 5Z whose geometry was ascertained by NOESY
experiment.
The Aldolic Approach to NAIPs. Because of its chemical
and conformational stability, compound 13 would constitute a
first possible precursor of a α-cycloalkyl amino acid building
block featuring a NAIP side chain. On the other hand, the bulky
phenyl group located in an allylic position with respect to the
light-responsive exocyclic double bond imposes serious steric
impediment to the isomerization motion. For this reason, it is
desirable to replace the original methyl group with a hydrogen
atom that also results in the removal of hyperconjugating C−H
bonds. In other words, we would like to prepare NAIPs
featuring an unsubstituted pyrroline ring. The preparation of
such compounds via the hitherto used nitrilium strategy
appeared to be unachievable as the insertion of an alkyl or
aryl (i.e., depending on the employed nitrile) substituent on the
pyrroline ring is inevitable. Little consolation came from the
potential accessibility to the hexahydroindeno[1,2-e]indole
framework related to known polycyclic compounds endowed
with potent cytotoxic activities toward cancer cells.29,30 Clearly,
a new synthesis route, avoiding the nitrilium cyclization, was
required.
Compound 15 (see Figure 4), featuring a polyconjugated
aldimine system, was selected as the target chemically stable
NAIP amino acid precursor. We considered the retrosynthetic
analysis of 15 disconnecting the indan and heterocycle
moieties. After adjusting the oxidation state as in 14, the N-
protected pyrrolidone could be disconnected from the
indanone derivative 7. Accordingly, we conceived a synthesis
route relying on the reactivity of the electrophile 7 with a
nucleophile obtained via α-deprotonation of a suitable γ-
lactam.31
In order to test the feasibility of the proposed pivotal aldol
reaction, we started employing the known indanone derivative
16 and the commercially available N-protected γ-lactam A. We
found that the lithium enolate of A adds to the BF3-activated32
carbonyl group of 16 giving the corresponding aldol 17, which
then yields 18 by spontaneous dehydration in CHCl3 (see
Spectral and Photochemical Characterization. The UV
spectra of a mixture of 3E/Z, 13E/Z, and 20E and 5Z were
recorded, and their photochemical behavior was explored. The
solution has been irradiated at room temperature in an NMR
Pyrex tube at different wavelength until reach the photosta-
tionary state. The E/Z isomer ratio at the photostationary state
1
has been calculated by integration of distinctive H NMR
signals. All compounds undergo Z→E and E→Z photo-
isomerization displaying a photomodulable stationary state.
Below we report the photostationary states achieved using three
different wavelength in the 350−450 nm range for NAIP 3, 5
and 20. Notice that in all cases (see Tables 1−3) we were able
to invert the E/Z isomer ratio which resulted in a dominant E
isomer for 3 and 5 and a dominant Z isomer for 20 upon
irradiation with low wavelength values (ca. 350 nm). This
indicates that the λmax value of the 3Z, 5Z, and 20E must be
1743
dx.doi.org/10.1021/jo2022263 | J. Org. Chem. 2012, 77, 1738−1748

The Journal of Organic Chemistry
Article
Table 1. Changes of the Photostationary-State Composition
for Compound 3
CONCLUSIONS AND PERSPECTIVES
■
The Z/E photoisomerization of NAIPs provides the basis for
the development of electrostatic light-driven switches to be
inserted in specific positions of a synthetic peptide or protein
backbone in the form of unnatural residues featuring a
quaternary α-carbon and, consequently, a conformationally
rigid (with respect to the local backbone) side chain. The
change in the local electrostatic field following the photo-
chemically driven ca. 180° rotation of the pyrroline unit could,
in principle, be exploited to control different structural
interactions such as salt bridges, protonation states and
hydrogen bonds in nearby residues (for a recent study of the
effect of the change in electrostatic field on protein functions
see ref 35). At the same time, these changes may be followed by
looking at the fluorescence or absorption of an internal reporter
(e.g., the 3-methylindole side chain of tryptophan) as
previously proposed.14
λ (nm)
Z
E
350
400
450
1
1
1
1.37
0.93
0.34
Table 2. Changes of the Photostationary-State Composition
for Compound 20
λ (nm)
E
Z
365
394
440
1
1
1
1.60
1.05
0.00
Table 3. Changes of the Photostationary-State Composition
for Compound 5
Until now, no NAIP-based compounds had been reported
featuring both thermally stable states (i.e., constant Z/E isomer
ratios) at room temperature and the presence of functional
groups allowing for the incorporation of the switch in a peptide
chain. We have demonstrated above that it is indeed possible to
achieve such desired structures in the form of protected α-
cycloalkyl amino acids (structure 5). Because of the similarity
between the quaternary carbon environment of 5 and a local
peptide backbone, the data of Table 3 indicate that the control
of the Z/E ratio via irradiation with light of different
wavelength should also be effective in a protein environment.
Further studies aiming to uncover an effective protocol for
removing the protecting groups are presently being carried out
in our laboratory.
λ (nm)
Z
E
360
400
440
1
1
1
0.80
0.69
0.00
blue-shifted with respect to the λmax value of the alternative
isomer. (Notice that the backbone and, consequently, the π-
system geometry of 3Z, 5Z, and 20E are consistent. The E label
for the dominating isomer of compound 20 is only due to a
change in the substituent priorities). NAIP 13 featuring the
bulk phenyl group at C5 has also been irradiated at room
temperature in a NMR pyrex tube at different wavelength (λ =
380, 430, 480 nm) and the reaction followed by 1H NMR. After
irradiation at 380 nm we see a photostationary state containing
only one of two geometric isomers (the one already presents in
greater amount in the initially mixture). The irradiation at 480
nm shifts the mixture equilibrium toward the other geometric
isomer indicating that the bulk phenyl group does not
represents an impediment to the photoisomerization. This
result is consistent with the demonstrated ability of crowded
alkenes to photoisomerize.34
EXPERIMENTAL METHODS
■
Synthesis and Structure Analysis. Experimental Data.
General: melting points were measured with a hot-stage
1
apparatus. The H and 13C NMR spectra were recorded with
an instrument operating at 200.13 and at 50.33 MHz,
respectively, or with an instrument operating at 400.13 and at
100.62 MHz, respectively. Chemical shifts are reported in part
per million from internal TMS. Mass spectra were recorder in
the positive or negative ion mode with an instrument by using
electrospray ionization. All solvents were previously dried
according to standard procedures. Analytical TLC was
performed on silica gel 60 F254 plates. Flash column
chromatography was carried out on silica gel 60 (0.040−
0.063 mm). Irradiation was made with a Rayonet apparatus.
Ethyl 2-Bromo-5-methoxy-1-oxo-2,3-dihydro-1H-indene-2-car-
boxylate (6). A solution of 5-MeO-1-indanone (5.00 mmol, 810
mg) in diethyl carbonate (20 mL) was added dropwise to a stirred
suspension of NaH (11.00 mmol, 60% in mineral oil, 440 mg) in
diethyl carbonate (2 mL) at rt. Heating at 100 °C in an oil bath
yielded a solid spongy which, after cooling to rt, was diluted in CH2Cl2
and treated with aqueous 1N HCl. The aqueous phase was separated
and extracted with CH2Cl2. The combined organic extracts were dried
(Na2SO4) and concentrated under reduced pressure.
As expected, in contrast with compound 3, the 13, 20, and 5
E/Z ratio achieved after 24 h irradiation in CDCl3 is stable
when the solution was maintained in the dark and at room
temperature.
Difficulties in Achieving a Deprotected α-Cycloalkyl
Amino Acid with a NAIP Side Chain. The simultaneous and
selective cleavage of the protective groups of the NAIP switch
5Z to obtain the corresponding α-amino acid was attempted via
both hydrolysis or reaction with different nucleophiles.
Regrettably, the attempted hydrolysis in acid (HCl, triflic
acid) and basic (LiOH, K2CO3, NaOH) conditions at 0 °C and
room temperature using various solvents mixture (THF/H2O,
MeOH/H2O, CH3CN/H2O) highlighted an unusual stability
of the protective groups which did not react. During the same
treatment, we observed no change in the structure of
compound 5Z. However, a total decomposition of the starting
material was observed when using reflux conditions. The same
lack of reactivity was demonstrated with nucleophiles (NH3
solution in methanol, MeNH2 solution in methanol, hydrazine
hydrate) at 0 °C, room temperature and, in contrast to acid and
basis conditions, also in refluxing conditions pointing to a
considerable stability of compound 5 framework.
The crude residue (5.00 mmol), N-bromosuccinimide (5.25 mmol,
935 mg), and Amberlyst-15 (3.75 g) in ethyl acetate (50 mL) was
stirred at rt for 30 min. After completion of the reaction, as indicated
by TLC, the reaction mixture was filtered and washed with ethyl
acetate. The combined organic extracts were dried over anhydrous
Na2SO4 and concentrated in vacuo, and the residue was purified by
chromatography (3:7, ethyl acetate/petroleum ether) to afford 1450
1
mg (93%) of compound 6 as a yellow oil. H NMR (CDCl3, 400
MHz) δH: 1.17 (t, J = 7.2 Hz, 3H), 3.52 (d, J = 18.4 Hz, 1H), 3.81 (s,
3H), 4.06 (d, J = 18.0 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 6.81−6.88
(m, 2H), 7.64 (d, J = 8.4 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δC:
1744
dx.doi.org/10.1021/jo2022263 | J. Org. Chem. 2012, 77, 1738−1748

The Journal of Organic Chemistry
Article
13.89, 43.80, 55.89, 59.35, 63.34, 109.45, 116.68, 125.04, 127.43,
153.38, 166.62, 167.05, 193.17. ESI-MS, m/z: [M + H+] = 313−315,
[M + Na+] = 335−337, [2M + Na+] = 648. Anal. Calcd for
C13H13BrO4: C, 49.86; H, 4.18. Found: C, 49.70; H, 4.19.
(E/Z)-Ethyl 5-Methoxy-1-(5-methyl-2H-pyrrol-4(3H)-ylidene)-2-
(2,2,2-trifluoroacetamido)-2,3-dihydro-1H-indene-2-carboxylate
(10). A trimethylsilyl polyphosphate (PPSE) solution, prepared by
heating at reflux for 1.5 h a mixture of P2O5 (3.50 mmol, 497 mg) and
hexamethyldisiloxane (4.91 mmol, 1.04 mL) in CCl4 (5 mL), was
added to 9 (0.35 mmol, 150 mg) at rt. The reaction mixture was
heated at reflux for 5 h, cooled to room temperature, diluted with
CH2Cl2, and quenched with NaOH 2 N. The aqueous layer was
extracted with CH2Cl2, dried over Na2SO4, and concentrated under
vacuum. The residue was purified by flash column chromatography on
silica gel conditioned with TEA and ethyl acetate as eluent to give 90
Ethyl 5-Methoxy-1-oxo-2-(2,2,2-trifluoroacetamido)-2,3-dihydro-
1H-indene-2-carboxylate (7). Sodium azide was added (4.36 mmol,
283 mg) to a solution of 6 (2.18 mmol, 680 mg) in dry DMF (3 mL)
under nitrogen atmosphere, and the resulting mixture was stirred at
room temperature for 1 h. After addition of H2O, the aqueous layer
was extracted in Et2O. The combined organic layers were washed with
brine and then dried over Na2SO4. Removal of solvents gave a crude
which dissolved in dry THF (40 mL) under nitrogen atmosphere, and
Ph3P (6.54 mmol, 1713 mg) was added. After 10 min at 0 °C, the
cooling bath was removed and the clear solution was stirred at rt
overnight. Trifluoroacetic anhydride (4.14 mmol, 1.21 mL) was added
and the mixture stirred for 1 h before adding H2O and Et2O. The
organic layer dried over Na2SO4 and concentrated under reduced
pressure gave a residue which was purified by flash chromatography
(4:6, ethyl acetate/petroleum ether) to afford 1430 mg (95%) of the
1
mg (63%) of product 10 as yellow oil. H NMR (CDCl3, 400 MHz)
δH: 1.06 (t, J = 7.2 Hz, 3H, E isomer), 1.14 (t, J = 7.2 Hz, 3H, Z
isomer), 2.13 (s, 3H, Z isomer), 2.27 (s, 3H, E isomer), 2.51−2.64 (m,
2H, mix E/Z), 3.00−3.06 (m, 2H, mix E/Z), 3.36−3.66 (m, 4H, mix
E/Z), 3.72−4.08 (m, 4H, mix E/Z), 3.78 (s, 6H, mix Z/E), 4.13 (q, J =
7.2 Hz, 2H, E isomer), 4.21 (q, J = 7.2 Hz, 2H, Z isomer), 6.73−6.84
(m, 4H, E/Z mix), 7.31 (d, J = 8.4 Hz, 1H, E isomer), 7.50 (d, J = 8.8
Hz, 1H, Z isomer), 7.75 (s, 1H, E isomer), 7.92 (s, 1H, Z isomer). ESI-
MS, m/z: [M + H+] = 411, [M + Na+] = 433, [M − H+] = 409. Anal.
Calcd for C20H21F3N2O4: C, 58.53; H, 5.16; N, 6.83. Found: C, 58.71;
H, 5.17; N, 6.63.
(E/Z)-4-(2-(Ethoxycarbonyl)-5-methoxy-2-(2,2,2-trifluoroacetami-
do)-2,3-dihydro-1H-inden-1-ylidene)-1,5-dimethyl-3,4-dihydro-2H-
pyrrolium trifluoromethanesulfonate (3). Methyl trifluoromethane-
sulfonate (0.22 mmol, 25 μL) was added to a solution of 10 (0.22
mmol, 90 mg) in anhydrous benzene (5 mL). The product of reaction
was recovered quantitatively as a yellow-orange oil. 1H NMR (CDCl3,
400 MHz) (mix 1:1 Z/E) δH: 1.11 (t, J = 7.2 Hz, 3H, Z), 1.11 (t, J =
7.5 Hz, 3H, E), 2.56 (s, 3H, E), 2.72 (s, 3H, Z), 3.13 (d, J = 16.6 Hz,
1H, E), 3.18−3.30 (m, 4H, mix E/Z), 3.40 (d, J = 16.6 Hz, 1H, Z),
3.52 (s, 3H, E), 3.54 (s, 3H, Z), 3.77 (d, J = 16.6 Hz, 1H, E), 3.90 (d, J
= 16.6 Hz, 1H, Z), 4.10−4.30 (m, 8H, mix E/Z), 6.83−7.00 (m, 4H,
mix E/Z), 7.51 (d, J = 9.7 Hz, 1H, Z), 7.54 (d, J = 9.2 Hz, 1H, E), 8.52
(s, 1H, E), 8.90 (s, 1H, Z). 13C NMR (CDCl3, 100 MHz) δC: 13.51
(Z/E), 17.30 (E), 17.43 (Z), 28.33 (E), 32.03 (Z), 37.63 (E), 37.90
(Z), 43.18 (E), 45.38 (Z), 55.70 (Z/E), 57.68 (Z), 58.12 (E), 63.46
(E), 63.57 (Z), 69.36 (Z), 71.67 (E), 109.18 (Z), 109.44 (E), 114.43
(E), 114.84 (Z), 115.41 (q, J1 = 287 Hz, Z/E), 127.94 (E), 128.12 (Z),
129.28 (E), 129.63 (Z), 130.92 (E), 131.31 (Z), 149.74 (Z), 150.36
(E), 151.19 (Z), 154.65 (E), 156.60 (q, J2 = 38 Hz, Z), 156.70 (q, J2 =
38 Hz, E), 163.57 (Z), 164.35 (E), 167.65 (E), 168.67 (Z). ESI-MS,
m/z: [M+] = 425. Anal. Calcd for C22H24F6N2O7S: C, 45.99; H, 4.21;
N, 4.88. Found: C, 46.14; H, 4.20; N, 4.89.
2, 2, 2-Trifluoro-N-(8-methoxy-5-oxo-1, 2, 3, 5, 5a, 6-
hexahydroindeno[1,2-e]indol-5a-yl)acetamide (11). Compound 11
was recovered as crystalline yellow solid (mp >210 °C dec) from a
solution of 10E/Z in CDCl3. 1H NMR (CD3OD, 400 MHz) δH:
2.86−2.92 (m, 1H), 2.95 (d, J = 16.2 Hz, 1H), 3.19−3.26 (ddd, J1 =
12.0 Hz, J2 = 8.3 Hz, J3 = 3.5 Hz, 1H), 3.59 (d, J = 16.2 Hz, 1H),
3.78−3.95 (m, 5H), 6.92 (dd, Jo = 8.4 Hz, Jm = 1.6 Hz, 1H), 7.01 (s,
1H), 7.45 (d, Jo = 8.4 Hz, 1H). 13C NMR (CD3OD, 50.33 MHz) δC:
25.46, 40.89, 55.99, 67.59, 112.47, 114.98, 116.8 (q, J1 = 287 Hz),
125.90, 128.59, 131.39, 145.07, 147.07, 157.73 (q, J2 = 36 Hz), 162.63,
168.79, 192.81. ESI-MS, m/z: [M + H+] = 365. Anal. Calcd for
C18H15F3N2O3: C, 59.34; H, 4.15; N, 7.69. Found: C, 59.18; H, 4.16;
N, 7.71.
2,2,2-Trifluoro-N-(8-methoxy-3-methyl-5-oxo-1,2,3,5,5a,6-
hexahydroindeno[1,2-e]indol-5a-yl)acetamide (4). Compound 4
was obtained after chromatography on SiO2 or treatement with
LiOH of mixture of 3E/Z as yellow solid (mp >200 °C dec). 1H NMR
(CD3OD, 400 MHz) δH: 2.85−2.93 (m, 1H), 2.96 (d, J = 16.4 Hz,
1H), 3.12 (s, 3H), 3.17−3.24 (m, 1H), 3.60 (d, J = 16.0 Hz, 1H),
3.76−3.82 (m, 1H), 3.85 (s, 3H), 3.93−4.01 (m, 1H), 5.14 (s, 1H),
6.92 (dd, Jo = 8.8 Hz, Jm = 1.6 Hz, 1H), 7.01 (s, 1H), 7.44 (d, Jo = 8.4
Hz, 1H). 13C NMR (CDCl3, 100 MHz) δC: 25.08, 40.89, 56.40, 67.57,
111.95, 114.73, 125.66, 126.00, 129.13, 131.49, 147.03, 162.64, 166.46,
193.18. ESI-MS, m/z: [M + H+] = 379. Anal. Calcd for
C19H17F3N2O3: C, 60.32; H, 4.53; N, 7.40. Found: C, 60.53; H,
4.51; N, 7.42.
1
corresponding pure product 7 as a white solid (mp 106−108 °C). H
NMR (CDCl3, 400 MHz) δH: 1.09 (t, J = 6.0 Hz, 3H), 3.37 (d, J =
17.2 Hz, 1H), 3.73 (d, J = 17.2 Hz, 1H), 3.84 (s, 3H), 4.13 (q, J = 7.2
Hz, 2H), 6.88−6.92 (m, 2H), 7.66−7.70 (m, 2H). 13C NMR (CDCl3,
100 MHz) δC: 13.70, 37.99, 55.78, 63.39, 68.16, 109.40, 115.37 (q, J1 =
286 Hz), 116.35, 126.75, 127.01, 155.00, 156.54 (q, J2 = 37 Hz),
166.62, 167.60, 193.66. ESI-MS, m/z: [M + H+] = 346, [M − H+] =
344, [M + Na+] = 368, [2M + Na+] = 712, [2M + K+] = 729. Anal.
Calcd for C15H14F3NO5: C, 52.18; H, 4.09; N, 4.06. Found: C, 52.09;
H, 4.07; N, 4.07.
Ethyl 1-Hydroxy-5-methoxy-2-(2,2,2-trifluoroacetamido)-1-cyclo-
propyl-2,3-dihydro-1H-indene-2-carboxylate (8). Cyclopropylmag-
nesium bromide solution (0.5 M in THF dry, 24.00 mL) was added to
a cooled (0 °C) solution of 7 (4.00 mmol, 1380 mg) in dry THF (40
mL). After 30 min at 0 °C, NH4Cl (s.s.) was added and the mixture
extracted with Et2O. The combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure. The residue was
purified by flash chromatography (1:9, ethyl acetate/petroleum ether)
to afford 1200 mg (78%) of compound 8 as a white solid (mp 92−95
1
°C). H NMR (CDCl3, 400 MHz) δH: 0.08 (m, 1H), 0.40−0.48 (m,
3H), 0.91−0.98 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H), 2.32 (bs, 1H), 3.35
(d, J = 16.8 Hz, 1H), 3.78 (s, 3H), 3.86 (d, J = 16.8 Hz, 1H), 4.18−
4.36 (m, 2H), 6.71−6.79 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 7.72 (bs,
1H). 13C NMR (CDCl3, 50 MHz) δC: 0.30, 1.11, 13.79, 16.63, 37.99,
55.17, 61.89, 73.25, 84.51, 109.72, 113.21, 115.38 (q, J1 = 286 Hz),
125.14, 132.33, 140.59, 156.89 (q, J2 = 36 Hz), 160.64, 169.73. ESI-
MS, m/z: [M − H+] = 386, [M + Na+] = 410. Anal. Calcd for
C18H20F3NO5: C, 55.81; H, 5.20; N, 3.62. Found: C, 55.61; H, 5.21;
N, 3.61.
Ethyl 1-(3-Acetamidopropylidene)-5-methoxy-2-(2,2,2-trifluoroa-
cetamido)-2,3-dihydro-1H-indene-2-carboxylate (9). Compound 8
(0.26 mmol, 100 mg) was added to a cooled (0 °C) solution of
trifluoromethanesulfonic anhydride (0.26 mmol, 43 μL) in dry
CH3CN (3 mL) under nitrogen atmosphere. The mixture was stirred
for 30 min at rt, diluted with CH2Cl2, and quenched with 2 N NaOH.
The combined organic layers were dried over Na2SO4 and
concentrated under vacuum. The residue was purified by flash column
chromatography on silica gel (ethyl acetate) to give 90 mg (81%) of
the pure product 9 as a yellow solid (mp 46−48 °C). 1H NMR
(CDCl3, 400 MHz) δH: 1.14 (t, J = 7.2 Hz, 3H), 1.70 (s, 3H), 2.38−
2.44 (m, 1H), 2.83−2.88 (m, 1H), 3.11−3.16 (m, 1H), 3.34 (d, J =
17.2 Hz, 1H), 3.50−3.55 (m, 1H), 3.71 (d, J = 17.2 Hz, 1H), 3.78 (s,
3H), 4.13−4.17 (m, 2H), 5.47 (dd, 1H, J1 = 6.4 Hz, J2 = 9.6 Hz), 6.04
(m, 1H), 6.75−6.78 (m, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.96 (bs, 1H).
13C NMR (CDCl3, 100 MHz) δC: 13.77, 22.81, 28.65, 38.65, 41.40,
55.32, 62.52, 67.54, 109.48, 113.83, 115.53 (q, J1 = 286 Hz), 120.56,
125.52, 130.01, 141.13, 145.34, 156.60 (q, J2 = 38 Hz), 160.42, 170.83,
171.14. ESI-MS, m/z: [M + H+] = 429, [M − H+] = 427, [M + Na+] =
451. Anal. Calcd for C20H23F3N2O5: C, 56.07; H, 5.41; N, 6.54.
Found: C, 56.25; H, 5.39; N, 6.55.
1745
dx.doi.org/10.1021/jo2022263 | J. Org. Chem. 2012, 77, 1738−1748

The Journal of Organic Chemistry
Article
(1E/Z)-Ethyl 2-(2,2,2-Trifluoroacetamido)-2,3-dihydro-2-phenyl-
pyrrol-3-ylidene)-5-methoxy-1H-indene-2-carboxylate (12E/Z).
Compound 8 (0.26 mmol, 100 mg) was added to a cooled (0 °C)
solution of trifluoromethanesulfonic anhydride (0.26 mmol, 43 μL) in
dry PhCN (3 mL) under nitrogen atmosphere. The mixture was
stirred for 30 min at rt, diluted with CH2Cl2, and quenched with 2 N
NaOH. The combined organic layers were dried over Na2SO4 and
concentrated under vacuum to give a mixture of 12a and 12E/Z.
A trimethylsilyl polyphosphate (PPSE) solution, prepared by
heating at reflux for 1.5 h a mixture of P2O5 (2.58 mmol, 367 mg)
and hexamethyldisiloxane (3.62 mmol, 769 μL) in CCl4 (5 mL), was
added at room temperature to the previous crude of 12a and 12E/Z.
The reaction mixture was heated at reflux for 3 h, cooled to room
temperature, diluted with CH2Cl2, and quenched with NaOH 2 N.
The aqueous layer was extracted with CH2Cl2, dried over Na2SO4, and
concentrated under vacuum. The residue was purified by flash column
chromatography on silica gel (3:7, Et2O/petroleum ether) to give 80
mg (66%) of the pure product 12E/Z as yellow oil. 1H NMR (CDCl3,
400 MHz) (mix Z/E) δH: 1.08 (t, J = 7.1 Hz, 3H, major), 1.08 (t, J =
7.1 Hz, 3H, minor), 2.64 (dd, J1 = 14.8 Hz, J2 = 5.4 Hz, 1H, major),
2.71−2.82 (m, 1H, major), 3.04 (d, J = 16.7 Hz, 1H, minor), 3.16 (dd,
J1 = 14.5 Hz, J2 = 5.5 Hz, 1H, minor), 3.20−3.26 (m, 1H, minor), 3.29
(d, J = 16.4 Hz, 1H, major), 3.66 (d, J = 16.7 Hz, 1H, minor), 3.68 (s,
3H, major), 3.71−3.82 (m, 3H, major and minor), 4.01−4.08 (m, 2H,
minor), 4.11 (q, J = 7.1 Hz, 4H, major and minor), 6.13 (dd, Jo = 8.8
Hz, Jm = 1.5 Hz, 1H, major), 6.21 (d, Jo = 8.8 Hz, 1H, major), 6.61 (s,
1H, major), 6.70 (s, 1H, minor), 6.81−6.88 (m, 2H, minor), 7.20−
7.52 (m, 10H, major and minor), 7.88 (s, 2H, major and minor). 13C
NMR (CDCl3, 100 MHz) δC: 13.51 (minor), 13.68 (major), 34.21
(major), 37.84 (minor), 42.07 (major), 44.78 (minor), 55.19 (major),
55.40 (minor), 58.82 (major), 59.20 (minor), 62.67 (minor), 63.13
(major), 67.45 (minor), 69.54 (major), 108.26 (major), 109.04
(minor), 112.42 (major), 113.67 (minor), 115.58 (q, J1 = 290 Hz,
minor and major), 126.39 (minor), 127.49 (major), 128.50, 129.37,
129.64, 129.75, 130.37, 130.62, 133.76 (minor and major), 133.77
(major), 134.16 (minor), 135.16 (minor), 135.49 (major), 136.74
(major), 137.91 (minor), 144.01 (minor), 145.19 (major), 154.86 (q,
J2 = 37 Hz, minor and major), 160.16 (major), 160.67 (minor), 170.38
(minor), 171.38 (major), 173.34 (minor), 174.06 (major). ESI-MS,
m/z: [M + H+] = 473. Anal. Calcd for C25H23F3N2O4: C, 63.55; H,
4.91; N, 5.93. Found: C, 63.74; H, 4.92; N, 5.92.
(E/Z)-4-(2-(Ethoxycarbonyl)-2-(2,2,2-trifluoroacetamido)-2,3dihy-
dro-1H-inden-1-ylidene)-methyl-5-phenyl-3,4-dihydro-2H-pyrro-
lium (13E/Z). Methyl trifluoromethanesulfonate (0.19 mmol, 22 μL)
was added to a solution of 12E/Z (0.19 mmol, 90 mg) in anhydrous
benzene (5 mL). The product of reaction was recovered quantitatively
as yellow oil. 1H NMR (CDCl3, 400 MHz) (mix Z/E) δH: 1.07 (t, J =
7.0 Hz, 3H, major), 1.08 (t, J = 7.1 Hz, 3H, minor), 2.97−3.08, 3.12−
3.23 (m, 2H, major), 3.00−3.38 (m, 2H, minor), 3.15 (d, J = 17.0 Hz,
1H, minor), 3.33 (s, 3H, minor), 3.43 (d, J = 16.3 Hz, 1H, major), 3.54
(d, J = 17.0 Hz, 1H, minor), 3.61 (s, 3H, major), 3.70 (d, J = 16.3 Hz,
1H, major), 3.70 (s, 3H, major), 3.74 (s, 3H, minor), 3.98−4.25 (m,
3H, major), 4.11−4.30 (m, 3H, minor), 4.45−4.60 (m, 1H, minor),
4.72−4.80 (m, 1H, major), 6.12 (dd, J1 = 8.9 Hz, J2 = 2.4 Hz, 1H,
major), 6.44 (d, J = 8.9 Hz, 1H, major), 6.60 (d, J = 2.4 Hz, 1H,
major) 6.76 (d, J = 1.4 Hz, 1H, minor), 6.95−7.03 (m, 3H, minor),
7.40−7.70 (m, 5H, major), 7.63−7.81 (m, 5H, minor), 8.21 (bs, 1H,
minor and major). 13C NMR (CDCl3, 100 MHz) δC: 13.41 (minor
and major), 28.97 (major), 33.25 (minor), 39.01 (minor and major),
42.47 (major), 45.65 (minor), 55.49 (major), 55.78 (minor), 58.91
(minor), 59.24 (major), 63.71 (minor), 64.35 (major), 67.39 (minor),
70.92 (major), 108.34 (major), 109.35 (minor), 113.92 (major),
115.32 (minor), 115.41 (q, J1 = 288 Hz, minor and major), 125.79
(minor and major), 126.72 (major), 126.82 (minor), 128.72, 129.59,
130.49, 130.66, 131.03 (minor and major), 133.15 (minor), 133.30
(major), 148.21 (minor), 149.56 (major), 155.83 (q, J2 = 37 Hz, minor
and major), 156.07 (minor), 157.33 (major), 163.21 (major), 164.13
(minor), 168.48 (minor and major), 176.59 (minor and major). ESI-
MS, m/z: [M+] = 487. Anal. Calcd for C27H26F6N2O7S: C, 50.94; H,
4.12; N, 4.40. Found: C, 50.76; H, 4.10; N, 4.41.
tert-Butyl 3-(5-Methoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-yli-
dene)-2-oxopyrrolidine-1-carboxylate (18E/Z). A 1 M solution of
lithium hexamethyldisilazide (LiHMDS) in anhydrous THF (1.80
mmol, 1.80 mL) was added at −78 °C under nitrogen atmosphere to
N-Boc-2-pyrrolidinone A (1.50 mmol, 278 mg) dissolved in anhydrous
THF (5 mL). After 1 h, a solution of the compound 16 (1.65 mmol,
314 mg) and BF3·Et2O (1.65 mmol, 206 μL) in anhydrous THF (8
mL) was added dropwise. The reaction mixture was stirred at −78 °C
for 3 h, NH4Cl (s.s.) was added, and the crude was extracted in Et2O.
The combined organic layers were dried over Na2SO4, concentrated
under reduced pressure and the residue purified by flash column
chromatography on silica gel (3:7, ethyl acetate/petroleum ether). The
obtained compound 17 poured in CHCl3 underwent spontaneous
dehydration (checked by ESI-MS) to afford 18 (410 mg, 76%) as a
white solid (1:1 mixture of E/Z isomers).
(E)-tert-Butyl 3-(5-Methoxy-2,2-dimethyl-2,3-dihydro-1H-inden-
1-ylidene)-2-oxopyrrolidine-1-carboxylate (18E). White solid. Mp:
1
170−173 °C. H NMR (CDCl3, 400 MHz) δH: 1.24 (s, 6H), 1.54 (s,
9H), 2.94 (s, 2H), 3.00 (t, J = 7.1 Hz, 2H), 3.76 (t, J = 7.1 Hz, 2H),
3.82 (s, 3H), 6.78−6.80 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H). 13C NMR
(CDCl3, 100 MHz) δC: 26.74, 27.39, 28.16, 29.66, 43.43, 50.98, 55.38,
82.11, 109.47, 113.47, 119.98, 128.06, 133.53, 143.04, 150.49, 151.05,
161.47, 167.02. ESI-MS, m/z: [M + Na+] = 380, [2M + Na+] = 737.
Anal. Calcd for C21H27NO4: C, 70.64; H, 7.61; N, 3.92. Found: C,
70.79; H, 7.58; N, 3.94.
(Z)-tert-Butyl 3-(5-Methoxy-2,2-dimethyl-2,3-dihydro-1H-inden-
1
1-ylidene)-2-oxopyrrolidine-1-carboxylate (18Z). H NMR (CDCl3,
400 MHz) δH: 1.26 (s, 6H), 1.51 (s, 9H), 2.78 (s, 2H), 2.86 (t, J = 7.0
Hz, 2H), 3.69 (t, J = 7.0 Hz, 2H), 3.76 (s, 3H), 6.65−6.69 (m, 2H),
8.54 (d, J = 8.7 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δC: 24.66,
26.56, 28.12, 43.34, 47.43, 49.21, 55.25, 82.10, 108.66, 112.54, 119.55,
130.33, 131.38, 149.28, 150.93, 160.43, 161.21, 167.76. ESI-MS, m/z:
[M + Na+] = 380, [2M + Na+] = 737. Anal. Calcd for C21H27NO4: C,
70.64; H, 7.61; N, 3.92. Found: C, 70.50; H, 7.62; N, 3.94.
(E)-4-(5-Methoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-ylidene)-
3,4-dihydro-2H-pyrrole (19E). Diisobutylaluminum hydride solution
in hexanes (0.34 mmol, 0.34 mL) was added dropwise to a cooled
(−78 °C) solution of compound 18 (0.22 mmol, 80 mg) in dry THF
(5 mL) under nitrogen atmosphere. After being stirred at −78 °C for 1
h (checked by TLC and ESI-MS), the reaction mixture was quenched
with H2O and 1 N HCl and extracted with CH2Cl2. Removal of
solvents gave a crude which dissolved in CH2Cl2 (5 mL) and was
cooled at −20 °C followed by treatment with trifluoromethanesulfonic
acid (2.24 mmol, 195 μL). The resulting solution was stirred for 1 h at
0 °C, NaHCO3 (s.s.) was added, and the mixture was extracted with
CH2Cl2. The organic layer was dried over Na2SO4 and concentrated
under vacuum to give a residue which was purified by flash column
chromatography (Et2O) on silica gel conditioned with TEA to give 40
1
mg (74%) of compound 19 as yellow oil. H NMR (CDCl3, 400
MHz) δH: 1.44 (s, 6H), 2.81−2.84 (m, 2H), 2.93 (s, 2H), 3.81 (s,
3H), 4.07−4.10 (m, 2H), 6.77−6.82 (m, 2H), 7.45 (d, J = 8.4 Hz,
1H), 8.45 (s, 1H). 13C NMR (CDCl3, 100 MHz) δC: 29.85, 30.58,
44.29, 49.90, 55.37, 59.78, 109.71, 113.50, 126.18, 131.57, 133.53,
148.14, 149.45, 160.71, 164.03. ESI-MS, m/z: [M + H+] = 242. Anal.
Calcd for C16H19NO: C, 79.63; H, 7.94; N, 5.80. Found: C, 79.91; H,
7.91; N, 5.82.
(E)-4-(5-Methoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-ylidene)-
1-methyl-3,4-dihydro-2H-pyrrolium Chloride (20E). Methyl trifluor-
omethanesulfonate (0.16 mmol, 19 μL) was added to a solution of
19E (0.16 mmol, 40 mg) in anhydrous benzene (5 mL). The product
of reaction was recovered quantitatively as orange oil and was
subjected to ion-exchange chromatography on DOWEX 1X8, eluting
with water to provide the corresponding chloride salt. 1H NMR
(CDCl3, 400 MHz) δH: 1.62 (s, 6H), 3.01 (s, 2H), 3.29−3.35 (m,
2H), 3.86 (s, 3H), 4.02 (s, 3H), 4.20−4.26 (m, 2H), 6.83−6.91 (m,
2H), 7.51 (d, J = 8.8 Hz, 1H), 10.23 (s, 1H). 13C NMR (CDCl3, 100
MHz) δC: 29.09, 30.82, 40.44, 46.78, 50.24, 55.65, 57.44, 109.76,
115.33, 123.48, 128.76, 131.13, 153.02, 163.91, 168.69, 170.75. ESI-
MS, m/z: [M+] = 256. Anal. Calcd for C17H22ClNO: C, 69.97; H,
7.60; N, 4.80. Found: C, 70.18; H, 7.57; N, 4.81.
1746
dx.doi.org/10.1021/jo2022263 | J. Org. Chem. 2012, 77, 1738−1748

The Journal of Organic Chemistry
Article
tert-Butyl 3-(2-(Ethoxycarbonyl)-5-methoxy-2-(2,2,2-trifluoroace-
tamido)-2,3-dihydro-1H-inden-1-ylidene)-2-oxopyrrolidine-1-car-
boxylate (14Z). A 1 M solution of lithium hexamethyldisilazide
(LiHMDS) in anhydrous THF (1.80 mmol, 1.80 mL) was added at
−78 °C under nitrogen atmosphere to N-Boc-2-pyrrolidinone A (1.50
mmol, 278 mg) dissolved in anhydrous THF (5 mL). After 1 h, solid
compound 7 (1.65 mmol, 569 mg) and BF3·Et2O (1.65 mmol, 206
μL) were added, and stirring was continued for 3 h at the same
temperature. NH4Cl (s.s.) was added, and the mixture was extracted
with Et2O. The combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure, and the residue was purified by
flash column chromatography on silica gel (at the first dichloro-
methane until starting material was recovered then 1:1 ethyl acetate/
petroleum ether). The isolated aldolic compound 21 (240 mg) was
then dehydrated by the action of Tf2O−DMAP system. Thus,
trifluoromethanesulfonic anhydride (0.90 mmol, 152 μL) was added
to a cooled (0 °C) solution of 21 (0.45 mmol, 240 mg) and DMAP
(2.72 mmol, 332 mg) in dry CH2Cl2 (5 mL) under nitrogen
atmosphere. Stirring was continued overnight at rt, and then the
reaction mixture was quenched with H2O and extracted with CH2Cl2.
The organic layer, dried over Na2SO4 and concentrated under vacuum
gave a residue which was purified by flash column chromatography on
silica gel (3:7, Et2O/petroleum ether) to give 213 mg (28% over two
164.70, 168.16, 169.47. ESI-MS, m/z: [M+] = 411. Anal. Calcd for
C21H22F6N2O7S: C, 45.00; H, 3.96; N, 5.00. Found: C, 45.14; H, 3.94;
N, 4.99.
Kinetic Measurements. Absorption spectra were recorded on an
HP 8453 diode-array spectrophotometer. The sample irradiation was
carried out using a Xenon lamp equipped with a monochromator for
the selection of the excitation wavelength (380 or 440 nm). The
thermal reaction was followed keeping the sample in dark conditions
in the range temperature range 276-313 K. An Oxford Instruments
(Abingdon, UK) cryostat was used for the temperature control. The
chromatographic analysis has been performed by use of a Waters
apparatus equipped with analytical Symmetry C18 (4.6 × 250 mm; 5
μm) or Prontosil 200-3-C30 (4.6 × 250 mm; 3 μm) columns and a
UV Vis diode array detector.
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra for all new compounds and 2D NOESY (400
MHz, CDCl3, 298 K) for compounds 3, 5, 10, and 20.This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
steps) of compound 14Z as white solid. Mp: 157−160 °C. H NMR
AUTHOR INFORMATION
■
(CDCl3, 400 MHz) δH: 1.22 (t, J = 7.2 Hz, 3H), 1.51 (s, 9H), 3.03−
3.07 (m, 2H), 3.41 (d, J = 16.0 Hz, 1H), 3.78−3.83 (m, 3H), 3.83 (s,
3H), 4.21−4.26 (m, 2H), 6.82 (s, 1H), 6.88 (dd, Jo = 8.8 Hz, Jm = 2.0
Hz, 1H), 7.46 (d, Jo = 8.8 Hz, 1H), 8.29 (s, 1H). 13C NMR (CDCl3,
100 MHz) δC: 13.92, 24.19, 28.05, 43.51, 55,50, 62.48, 66.43, 82.85,
108.95, 114.86, 115.93 (q, J1 = 286 Hz), 120.98, 126.80, 132.44,
147.48, 149.03, 150.20, 155.47 (q, J2 = 37 Hz), 162.33, 167.44, 170.22.
ESI-MS, m/z: [M + Na+] = 535. Anal. Calcd for C24H27F3N2O7: C,
56.25; H, 5.31; N, 5.47. Found: C, 56.05; H, 5.32; N, 5.45.
Corresponding Author
*E-mail: znv@unife.it, molivuc@bgnet.bgsu.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Jacopo Barbetti (Dipartimento di Chimica,
(Z)-Ethyl 5-Methoxy-1-(2H-pyrrol-4(3H)-ylidene)-2-(2,2,2-trifluor-
oacetamido)-2,3-dihydro-1H-indene-2-carboxylate (15Z). Diisobu-
tylaluminum hydride solution in hexanes (0.39 mmol, 0.39 mL) was
added dropwise to a cooled (−78 °C) solution of compound 14Z
(0.16 mmol, 80 mg) in dry THF (5 mL) under nitrogen atmosphere.
After being stirred at −78 °C for 1 h (checking by TLC and ESI-MS),
the reaction mixture was quenched with H2O and 1 N HCl and
extracted with CH2Cl2. Removal of solvents gave a crude which
dissolved in CH2Cl2 (5 mL) and cooled at −20 °C was treated with
trifluoromethanesulfonic acid (1.56 mmol, 136 μL). The resulting
solution was stirred for 1 h at 0 °C, and then NaHCO3 (s.s.) was
added and the mixture extracted with CH2Cl2. The organic layer dried
over Na2SO4 and concentrated under vacuum gave a residue which
was purified by flash column chromatography (Et2O) on silica gel
conditioned with TEA to give 40 mg (64%) of compound 15Z as
yellow oil. 1H NMR (CDCl3, 400 MHz) δH: 1.15 (t, J = 6.8 Hz, 3H),
2.82−2.85 (m, 2H), 3.48 (d, J = 17.2 Hz, 1H), 3.74 (d, J = 17.2 Hz,
1H), 3.82 (s, 3H), 4.07−4.14 (m, 2H), 4.17−4.24 (m, 2H), 6.85−6.88
(m, 2H), 7.45 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 8.18 (s, 1H). 13C
NMR (CDCl3, 100 MHz) δC: 13.82, 29.67, 43.53, 55.45, 60.92, 63.26,
66.69, 109.25, 114.37, 115.39 (q, J1 = 289 Hz), 125.50, 131.81, 134.73,
146.02, 155.44 (q, J2 = 39 Hz), 161.21, 161.50, 171.54. ESI-MS, m/z:
[M + H+] = 397. Anal. Calcd for C19H19F3N2O4: C, 57.57; H, 4.83; N,
7.07. Found: C, 57.78; H, 4.90; N, 6.99.
(Z)-4-(2-(Ethoxycarbonyl)-5-methoxy-2-(2,2,2-trifluoroacetami-
do)-2,3-dihydro-1H-inden-1-ylidene)-1-methyl-3,4-dihydro-2H-pyr-
rolium trifluoromethanesulfonate (5Z). Methyl trifluoromethanesul-
fonate (0.18 mmol, 20 μL) was added to a solution of 15Z (0.18
mmol, 70 mg) in anhydrous benzene (1 mL). The product of reaction
was recovered quantitatively as yellow oil. 1H NMR (CDCl3, 400
MHz) δH: 1.19 (t, J = 7.2 Hz, 3H), 3.21 (d, J = 18.0 Hz, 1H), 3.25−
3.36 (m, 1H), 3.50−3.57 (m, 1H), 3.68 (s, 3H), 3.89 (s, 3H), 4.03−
4.31 (m, 2H), 4.35 (d, J = 18.0 Hz, 1H), 4.50−4.54 (m, 2H), 6.88 (s,
1H), 6.94 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 8.96 (s, 1H),
9.67 (s, 1H). 13C NMR (CDCl3, 50 MHz) δC: 13.79, 28.89, 40.79,
44.68, 55.84, 58.22, 63.57, 69.00, 109.54, 115.38 (q, J1 = 286 Hz),
116.30, 123.55, 127.57, 128.50, 152.16, 152.77, 158.27 (q, J2 = 39 Hz),
Universita
̀
di Siena) for technical help with the synthesis. This
work was supported in part by Bowling Green State University
and in part by Mitsubishi Chemical Corp. M.O. is grateful to
the Center for Photochemical Sciences and the School of Arts
& Sciences of Bowling Green State University for start-up
funds.
REFERENCES
■
(1) Harvey, J. H.; Trauner, D. ChemBioChem 2008, 9, 191−3.
(2) Numano, R.; Szobota, S.; Lau, A. Y.; Gorostiza, P.; Volgraf, M.;
Roux, B.; Trauner, D.; Isacoff, E. Y. Proc. Natl. Acad. Sci. U.S.A. 2009,
106, 6814−9.
(3) Schierling, B.; Noel, A. -J.; Wende, W.; Hien, L. T.; Volkov, E.;
Kubareva, E.; Oretskaya, T.; Kokkinidis, M.; Rompp, A.; Spengler, B.;
̈
̈
Pingoud, A. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 1361−6.
(4) Kumar, G. S.; Neckers, D. C. Chem. Rev. 1989, 89, 1915−1925.
(5) Hug, D. H.; O’Donnel, P. S.; Hunter, J. K. Photochem. Photobiol.
1980, 32, 841−848.
(6) Seefeldt, B.; Kasper, R.; Beining, M.; Mattay, J.; Arden-Jacob, J.;
Kemnitzer, N.; Drexhage, K. H.; Heilemann, M.; Sauer, M. Photochem.
Photobiol. Sci. 2010, 9, 213−20.
(7) Angelini, N.; Corrias, B.; Fissi, A.; Pieroni, O.; Lenci, F. Biophys. J.
1998, 74, 2601−2610.
(8) Aizawa, M.; Namba, K.; Suzuki, S. Arch. Biochem. Biophys. 1977,
180, 41−48.
(9) Kocȩ r, A.; Walko, M.; Meijberg, W.; Feringa, B. L. Science 2005,
309, 755−8.
(10) Folling, J.; Belov, V.; Kunetsky, R.; Medda, R.; Schonle, A.;
̈
̈
Egner, A.; Eggeling, C.; Bossi, M.; Hell, S. W. Angew. Chem., Int. Ed.
2007, 46, 6266−6270.
(11) Lumento, F.; Zanirato, V.; Fusi, S.; Busi, E.; Latterini, L.; Elisei,
́ ́
F.; Sinicropi, A.; Andruniow, T.; Ferre, N.; Basosi, R.; Olivucci, M.
Angew. Chem., Int. Ed. Engl. 2007, 46, 414−20.
(12) Sinicropi, A.; Martin, E.; Ryasantsev, M.; Helbing, J.; Briand, J.;
Sharma, D.; Leo
́
nard, J.; Haacke, S.; Cannizzo, A.; Chergui, M.;
1747
dx.doi.org/10.1021/jo2022263 | J. Org. Chem. 2012, 77, 1738−1748

The Journal of Organic Chemistry
Article
́
Zanirato, V.; Fusi, S.; Santoro, F.; Basosi, R.; Ferre, N.; Olivucci, M.
Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 17642−17647.
́ ́
(13) Briand, J.; Bram, O.; Rehault, J.; Leonard, J.; Cannizzo, A.;
̈
Chergui, M.; Zanirato, V.; Olivucci, M.; Helbing, J.; Haacke, S. Phys.
Chem. Chem. Phys. 2010, 12, 3178−3187.
(14) Melloni, A.; Rossi Paccani, R.; Donati, D.; Zanirato, V.;
Sinicropi, A.; Parisi, M. L.; Martin, E.; Ryazantsev, M.; Ding, W. J.;
́
Frutos, L. M.; Basosi, R.; Fusi, S.; Latterini, L.; Ferre, N.; Olivucci, M.
J. Am. Chem. Soc. 2010, 132, 9310−9319.
(15) Sinicropi, A.; Bernini, C.; Basosi, R.; Olivucci, M. Photochem.
Photobiol. Sci 2009, 8, 1639−49.
(16) Mayer, G.; Heckel, A. Angew. Chem., Int. Ed. 2006, 45, 4900−
4921.
(17) Rivado-Casas, L.; Sampedro, D.; Campos, P. J.; Fusi, S.;
Zanirato, V.; Olivucci, M. J. Org. Chem. 2009, 74, 4666−4674.
(18) Wenschuh, H.; Beyermann, M.; Krause, E.; Brudel, M.; Winter,
R.; Schuemann, M.; Carpino, L. A.; Bienert, M. J. Org. Chem. 1994, 59,
3275−3280.
(19) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243−2266.
(20) Albericio, F.; Cases, M.; Alsina, J.; Triolo, S. A.; Carpino, L. A.;
Kates, S. A. Tetrahedron Lett. 1997, 38, 4853−4856.
́
(21) Jensen, K. J.; Alsina, J.; Songster, M. F.; Vagner, J.; Albericio, F.;
Barany, G. J. Am. Chem. Soc. 1998, 120, 5441−5452.
(22) Martin, L.; Ivancich, A.; Vita, C.; Formaggio, F.; Toniolo, C. J.
Pept. Res. 2001, 58, 424−32.
(23) Springer, J.; de Cuba, K. R.; Calvet-Vitale, S.; Geenevasen, J. A.
J.; Hermkens, P. H. H.; Hiemstra, H.; van Maarseveen, J. H. Eur. J.
Org. Chem. 2008, 2008, 2592−2600.
(24) Zanirato, V.; Pollini, G. P.; De Risi, C.; Valente, F.; Melloni, A.;
Fusi, S.; Barbetti, J.; Olivucci, M. Tetrahedron 2007, 63, 4975−4982.
(25) Emelen, K. V.; De Wit, T.; Hoornaert, G. J.; Compernolle, F.
Tetrahedron 2002, 58, 4225−4236.
(26) Meshram, H. M.; Reddy, P. N.; Sadashiv, K.; Yadav, J. S.
Tetrahedron Lett. 2005, 46, 623−626.
́
(27) Kovacs, L. Tetrahedron 2001, 57, 4609−4621.
(28) Julia, M.; Julia, S.; Guegan, R. Bull. Soc. Chim. Fr. 1960, 1072−
1079.
(29) Li, G.; Wang, E.; Chen, H.; Li, H.; Liu, Y.; Wang, P. G.
Tetrahedron 2008, 64, 9033−9043.
(30) Boussard, M. F.; Truche, S.; Rousseau-Rojas, A.; Briss, S.;
Descamps, S.; Droual, M.; Wierzbicki, M.; Ferry, G.; Audinot, V.;
Delagrange, P.; Boutin, J. A. Eur. J. Med. Chem. 2006, 41, 306−20.
(31) Nishio, T.; Okuda, N.; Kashima, C. Liebigs Ann. 1996, 1996,
117−120.
(32) Ezquerra, J.; Pedregal, C.; Yruretagoyena, B.; Rubio, A.;
Carreno, M. C.; Escribano, A.; Ruano, J. L. G. J. Org. Chem. 1995,
60, 2925−2930.
(33) Yu, J.; Truc, V.; Riebel, P.; Hierl, E.; Mudryk, B. Tetrahedron
Lett. 2005, 46, 4011−4013.
(34) Feringa, B. L. Browne, W. R. In Molecular Switches; Feringa, B.
L., Ed.; Wiley-VCH: Weinheim, 2001; pp 123−163.
(35) Jha, S. K.; Ji, M.; Gaffney, K. J.; Boxer, S. G. Proc. Natl. Acad. Sci.
U.S.A. 2011, 108, 16612−7.
1748
dx.doi.org/10.1021/jo2022263 | J. Org. Chem. 2012, 77, 1738−1748