Vinylidene-quinone methides, photochemical generation and β-silicon effect on reactivity

Article abstract of DOI:10.1021/jo300115f

Irradiation of 2-alkynylphenols resulted in the generation of vinylidene-quinone methides (QMs), which were detected by laser flash photolysis in organic solvents and aqueous acetonitrile. QMs' spectroscopic properties and electrophilicity were both significantly affected by β-silicon effect. The hydration of the alkynyl moiety (22 and 900 M^-1 s^-1for QM-1 and QM-2, in aqueous acetonitrile) was an acid- and base-catalyzed process. The addition of amines was fast (9.2 × 10³ M^-1 s^-1 < k₂ < 1.3 × 10⁸ M^-1 s^-1), yielding ketimines, with primary amines.

Full text of DOI:10.1021/jo300115f

Note
pubs.acs.org/joc
Vinylidene−Quinone Methides, Photochemical Generation
and β-Silicon Effect on Reactivity
Filippo Doria, Claudia Percivalle, and Mauro Freccero*
̀
Dipartimento di Chimica, Universita di Pavia, V.le Taramelli 10, 27100 Pavia, Italy
S
* Supporting Information
ABSTRACT: Irradiation of 2-alkynylphenols resulted in the
generation of vinylidene−quinone methides (QMs), which
were detected by laser flash photolysis in organic solvents and
aqueous acetonitrile. QMs' spectroscopic properties and
electrophilicity were both significantly affected by β-silicon
effect. The hydration of the alkynyl moiety (22 and 900 M−1 s−1
for QM-1 and QM-2, in aqueous acetonitrile) was an acid- and
base-catalyzed process. The addition of amines was fast (9.2 × 103 M−1 s−1 < k2 < 1.3 × 108 M−1 s−1), yielding ketimines, with
primary amines.
xcited state intramolecular proton transfer (ESIPT) from
an ortho-aromatic OH (phenol or naphthol) to unsatu-
Scheme 1. Photogeneration of Vinylidene−Quinone
E
Methides
rated systems such as carbonyls,1 alkenes,2,3 and aromatics4−6
has been extensively investigated in the last 15 years. While the
proton transfer to a carbonyl group is a highly reversible
process, the ESIPT to a carbon atom or to a leaving group
are often irreversible ones, leading to further reactivity with the
generation of reactive quinone methides (QMs).7−10 QMs
received a great deal of attention thanks to their useful applications
in organic synthesis11 and as selective alkylating agents targeting
DNA.12−19 The main effort on the mechanistic aspects of ESIPT
to carbon atoms has been focused on alkenes and aromatics,
collecting a great amount of spectroscopic and kinetic data related
to substituted QMs.10,20−23 Despite the original and pioneering
work on the photohydration of o-hydroxyphenylacetylenes by
Ferris24 and Yates and co-workers,25 spectroscopic and kinetic data
related to the intermediate generated by ESIPT have not yet been
published. It is interesting to underline in this contest that a
dipolar carbocation-like structure was suggested as key inter-
mediate on the basis of product distribution analysis from the
photohydration reaction of o-hydroxyphenylacetylene (1).24,25
Only 25 years later, such an intermediate has been rewritten as
vinylidene−QM structure.26 The lack of direct evidence for
vinylidene−QMs combined to our interest in photogenerated
alkylating species, prompted us to investigate the properties and
reactivity of the vinylidene−quinone methides QM-1 and QM-2
(Scheme 1).
Photolysis of both 1 and 2 in ACN and CH2Cl2 solutions in the
presence of propylamine (n-PrNH2) was quantitative and
completely stereoselective, yielding (E)-2-(1-propyliminoethyl)-
phenol (3) (Scheme 2). The E stereochemistry of the resulting
imine has been assigned on the basis of a NOE experiment, which
highlighted the cis relationship between the methyl group and the
CH2 moiety on the imine (Supporting Information). The
generation of 3 from 2 is probably the result of a fast thermal
desilylation on the intermediate 2-(1-propylimino-2-
trimethylsilanylethyl)phenol (in brackets, Scheme 2), after the
QM-2 has been trapped by n-PrNH2. Unfortunately, we have
been unable to isolate and characterize the primary photoproduct,
even at low conversion.
The formation and reactivity of both QMs in aqueous and
organic solutions (neat ACN and CH2Cl2) were monitored by a
nanosecond spectrometer equipped with pulsed Nd:YAG laser.
Excitation of alkyne 2 in both argon purged ACN (Figure 1a) and
CH2Cl2 (Figure 1c) with 10 ns 266 nm pulses of a Nd:YAG laser
resulted in the formation of a short-lived transient with λmax
330 nm, together with a long-lived species at λmax 390−400 nm,
which did not appreciably decay within 10 ms in neat ACN
(Figure 1a, with a long time delay from the laser pulse, and 1b).
Excitation of alkyne 2 in aqueous ACN (H2O/ACN = 1:9) at
pH 7 generated a transient species that exhibited a very similar
spectrum (37.6 μs after laser pulse; Figure 1d). However, in this
The o-hydroxyphenylacetylenes 1 and 2,27 which are
potential precursors of QM-1 and QM-2, respectively, were
synthesized according to a Sonogashira protocol and
subsequent TMS cleavage by fluoride (for QM-1).27 Irradiation
of aqueous ACN solutions of both 1 and 2 at 310 nm yielded
o-hydroxyacetophenone as the only photoproduct, which was
isolated by chromatography and characterized by comparison
to a commercial sample. Under the same irradiation conditions
(4 lamps, 15 W), 1 resulted twice as reactive as 2 (irradiation
time: 90 min, 48% yield and 150 min, 44% yield, respectively).
Received: January 15, 2012
Published: March 7, 2012
© 2012 American Chemical Society
3615
dx.doi.org/10.1021/jo300115f | J. Org. Chem. 2012, 77, 3615−3619

The Journal of Organic Chemistry
Note
Scheme 2. Photohydration and Ketimine Formation by Irradiation of 1 and 2 at 310 nm in ACN, Aqueous ACN and CH2Cl2
Figure 1. Transient spectra obtained by photolysis of (a) an argon purged ACN solution of 2 (0.1 mM; from 8.5 μs to 3.6 ms, after the laser pulse);
(b) an air purged ACN solution of 2 (0.1 mM; from 0.72 to 3.6 ms, after the laser pulse); (c) an air purged CH2Cl2 solution of 2 (0.1 mM; from 0.4
to 3.6 ms, after the laser pulse); and (d) an air purged aqueous ACN solution (H2O 10% v) of 2 at pH 7 (0.1 mM; from 37.6 to 363.6 μs, after the
laser pulse). Inset: effect of water on the QM-2 kinetic in ACN solution.
case, the transient species followed a single exponential decay
that became faster, increasing the amount of water added to
ACN (inset of Figure 1d). Alkyne 1 exhibited a very similar
spectroscopic behavior, but the long-lived species was blue-
shifted by 25 nm (λmax 375 nm) (Figure 2). The decay kinetic
was dramatically affected by amine addition as highlighted in
the inset of Figure 2.
The transient at 330 nm has been assigned to the triplet
excited states of both alkynes 1 and 2, as they were efficiently
quenched by molecular oxygen. The identity of the longer lived
species has been established on the basis of their reactivity
toward water and several nucleophiles and from the results of
the product distribution analysis obtained from both steady
state and pulsed (by laser) irradiations. Taking also into
account the striking similarity of their spectroscopic properties
Figure 2. Transient spectra obtained by photolysis of an air purged
solution of 1 (0.1 mM) in neat ACN (0.2 and 1.0 ms, after the laser
to that of the prototype o-QM,10,21 we have assigned them to
the vinylidene−QM structures: QM-1 and QM-2. They were
both fairly long-lived in neat ACN and CH2Cl2, as no
significant decay was recorded within the limit of our LFP
equipment (time ≤ 10 ms). Nevertheless, both slowly decayed
in acetonitrile in the presence of small amount of water, with
pulse). Inset: effect of n-PrNH2 (from 0.01 to 0.09 M in ACN) on the
QM-1 decay kinetics.
k2(QM-1) = 22 M−1 s−1 and k2(QM-2) = 900 M−1 s−1 at 25 °C,
respectively. Addition of several amines both in CH2Cl2 and in
3616
dx.doi.org/10.1021/jo300115f | J. Org. Chem. 2012, 77, 3615−3619

The Journal of Organic Chemistry
Note
ACN accelerated the rate of the quenching processes [104 M−1 s−1
≤
Such a reactivity gap has to be ascribed to a β-silicon effect.28 In
fact, the hyperconjugation in QM-2 is apparent in the orbital
plots for the LUMO (Figure S5, Supporting Information) as
sketched in Figure 3a. The LUMO for QM-2 is primarily a pπ
orbital on the carbenium-like carbon (in the dipolar limit
structure, Figure 3a) with an out-of-phase mixture of the
k2(QMs) ≤ 108 M−1 s−1, see Table 1). The quenching reactions
Table 1. Second Order Rate Constants for Addition
Reactions to QM-1 and QM-2, Photogenerated by LFP at
266 nm, and Monitored at 375 and 395 nm, Respectively,
in Organic Solvents (CH2Cl2 and ACN) and Aqueous ACN,
at 25°C
a
a
HNu
solvent →
n-PrNH2
QM-1 k2/M−1 s−1
QM-2 k2/M−1 s−1
CH2Cl2 ACN
CH2Cl2
ACN
H2O
7.8 × 104 2.2 × 105 8.9 × 105 9.3 × 106
pentylamine 8.5 × 104 1.9 × 105 7.2 × 105 7.2 × 106
t-BuNH2
pyrrolidine
piperidine
i-Pr2NH
morpholine
Et3N
9.2 × 103 5.6 × 104 2.2 × 105 6.4 × 106
1.4 × 106 4.7 × 106 3.5 × 107 1.3 × 108
4.3 × 105 2.4 × 106 5.3 × 106 6.4 × 107
1.8 × 104 9.9 × 104 2.0 × 105 9.8 × 106
4.2 × 105 4.2 × 105 1.1 × 106 8.4 × 106
9.1 × 105 1.1 × 106 2.1 × 107 3.4 × 107
3.7 × 105 5.8 × 105 1.2 × 107 1.7 × 107
4.6 × 104 1.2 × 105 1.8 × 106 4.7 × 106
Figure 3. (a) Schematic representation of the β-silicon effect in QM-2,
involving the pπ orbital on the carbenium-like carbon and the eclipsing
σ(C−Si) bond orbital. (b) Selected geometrical bond lengths (in Å) and
vibrational frequencies (in cm−1) computed for QM-1 and QM-2 at
B3LYP/6-31+G(d,p) level of theory, in gas (red) and in ACN (blue).
eclipsing σ(C−Si) bond orbital. Such a silicon hyperconjugation,
involving the electrophilic carbon atom and the C−Si bond,
should be responsible for the enhancement of the dipolar
nature (described by the zwitterionic limit structure in Figure 3a)
and hardness of QM-2 at β-carbon atom, in comparison to
QM-1. In the past, it has been shown that the nucleophilic
addition of NH3 to the prototype o-QM exhibits a TS with an
enhanced dipolar character in comparison to the reactant.29
This should also be the case of amine addition to vinylidene−
quinone methides, as the experimental kinetic data revealed a
systematic higher reactivity in polar solvents. Therefore, it is
reasonable to expect a selective stabilization of the TS, induced
by β-silicon effect, which accounts for the improved reactivity
passing from QM-1 to QM-2.
The antiperiplanar relationship between the two interacting
orbital fragments, the empty pπ orbital on the carbenium
carbon and the filled σ(C−Si) (which is the key prerequisite for
an effective beta-silicon effect) has been confirmed, optimizing
the geometries of both QM-1 and QM-2 by computational
means, at B3LYP/6-31+G(d,p) level of theory, in gas and
condensed phase (ACN) (Figure 3b).
The enhanced dipolar nature of QM-2, in comparison to
QM-1, is further supported by additional geometric and
spectroscopic evidence computed at the same level of theory.
In fact, the optimized geometries and the computed IR
vibrational spectra in gas phase (in red, Figure 3b) suggested
that both the CO and the exocyclic CC double bonds
in QM-1 are shorter and stronger [CO = 1.230 Å; ν(CO) =
1709 cm−1, CC = 1.330 Å; ν(CC) = 2009 cm−1] than in QM-2
[CO = 1.234 Å, ν(CO) = 1697 cm−1; CC = 1.337 Å; ν(CC) =
1979 cm−1]. In addition, the solvation by a polar solvent
(modeled by PCM solvation model at the same level of
theory), further elongated the above bond lengths, reducing the
frequencies of both CO and asymmetric CC stretching
modes (in blue, Figure 3b). Such computational evidence
unambiguously suggests that the electrophilicity and the dipolar
character of the vinylidene−QMs (Figure 3a), which relates
with its hardness, are enhanced by both β-silicon effect and
n-Bu3N
N-Me-
morph
NH2NH2
H2O
3.6 × 105 3.2 × 105 3.8 × 106
2.2 × 101
9.0 × 102
4.2 × 102 3.8 × 102
CH3OH
H3O+
2.7 × 105
1.4 × 106
2-propanol
OH−
6.6 × 103
octane-1-
thiol
2.9 × 103
a
Estimated errors on the reported values are 4%.
were identified as hydration and nucleophilic additions of the
amines. In fact, o-hydroxyacetophenone was detected as the only
product after 20 laser shots (at 266 nm) on an aqueous ACN
solution of 1. The replacement of water by n-PrNH2, in ACN
solution, resulted in the photogeneration of imine 3 as the only
detectable product. The direct measurement of the second-order
rate constants (k2) listed in Table 1 (Figures S1−S4, Supporting
Information) for the addition reactions on both QM-1 and QM-2
by several amines, water, methanol, and octane-1-thiol by LFP
allowed a quantitative evaluation of the electrophilicity of QM-1
vs QM-2, together with the selectivity toward N (amines), O
(water and alcohols), and S (thiols) nucleophiles. QM-1 and
QM-2 are fast and efficient carbon electrophiles that are very
selective toward amines. In fact, the reactivity of vinylidene−QMs
spans 5 orders of magnitude on passing from water to amines.
From this point of view, the chemical behavior of QM-1 and QM-
2 mirrors that of prototype o-QM.21 Nevertheless, the modest
reactivity toward thiols [k2(QM-2) = 2.9 × 103 M−1 s−1] came as
a surprise because, on the contrary, the prototype o-QM was much
more reactive [k2(o-QM) = 1.9 × 105 M−1 s−1].21 The reactivity
toward amines is strongly affected by solvent polarity, as both
QM-1 and QM-2 are much more reactive in ACN than in
CH2Cl2.
The difference in reactivity between QM-1 and QM-2 is also
noteworthy, as the more bulky QM-2 is always much more
reactive than the unsubstituted counterpart (QM-1, Table 1).
3617
dx.doi.org/10.1021/jo300115f | J. Org. Chem. 2012, 77, 3615−3619

The Journal of Organic Chemistry
Note
acetate = 8:2) affording 3 (56 and 44% yields, starting from 1 and 2,
respectively).
solvation. This also accounts for the lower reactivity of QM-2
toward thiols, in comparison to the prototype o-QM.
In conclusion, we have described the photogeneration of
vinylidene−quinone methides by ESIPT in organic and
aqueous solvents. Furthermore, we have characterized their
UV−vis properties and the remarkable electrophilicity, which is
enhanced by a β-silicon effect and solvent polarity. Despite
some similarity with the prototype quinone methide (o-QM), at
least with amines and water, vinylidene−quinone methides are
much less reactive toward thiols than QMs because of their
harder character. Because of the selectivity toward amines, they
should be considered as promising activatable electrophiles to
achieve a photogeneration of imines (photoimination) of
amino acids and nucleic acids. Currently, work on water-soluble
2-alkynylphenols and derivatives of more complex structure is
in progress.
(E)-2-(N-Propyl-1-iminoethyl)phenol (3). Pale yellow oil; 1H
NMR (CDCl3) δ 1.07 (t, J = 7.4 Hz, 3H), 1.80 (m, 2H), 2.36 (s, 3H),
3.56 (t, J = 6.9 Hz, 2H), 6.77 (dt, J = 1.0, 7.3 Hz, 1H), 6.93 (dd, J =
1.0, 8.3 Hz, 1H), 7.29 (dt, J = 1.0, 7.3 Hz, 2H), 7.52 (dd, J = 1.0, 8.3
Hz, 2H), 16.5 (broad s, 1H); 13C NMR (CDCl3) δ 11.8, 14.0, 23.4,
50.4, 116.3, 119.2, 127.8, 132.5, 165.3, 171.35. Anal. Calcd for
C11H15NO: C, 74.54; H, 8.53; N, 7.90; O, 9.03. Found: C, 74.49; H,
8.22; N, 8.01.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR, 13C NMR, and COSY of 3. QM-1 and QM-2
geometries and frequencies at B3LYP/6-31+G(d,p) level of
theory in gas and ACN (by PCM). This material is available
free of charge via Internet at http://pubs.acs.org.
EXPERIMENTAL SECTION
■
AUTHOR INFORMATION
■
1 and 2 have been synthesized according to a published synthetic
procedure.27
Corresponding Author
General Methods. All organic solvents were dried and freshly
distilled before use. Purification of products by column chromatog-
raphy was performed using 40−63 μm silica gel. All NMR spectra were
recorded on a 300 MHz instrument in CDCl3 and referenced to TMS.
Solutions for photolysis were prepared using anhydrous CH2Cl2,
HPLC grade water, and acetonitrile. Preparative photolyses were
carried out using a photochemical reactor equipped with four
fluorescent UV lamps (15 W, 310 nm).
*E-mail: mauro.freccero@unipv.it. Tel.: +39 0382 987668. Fax:
+39 0382 987323.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by MIUR: PRIN 2009
(2009MFRKZ8), and Grant FIRB-Ideas (RBID082ATK).
Flash Photolysis Experiments. UV−vis spectra and rate
measurements of QM-1 and QM-2 reactions were performed using
a kinetic spectrometer by following spectral changes at 375 and
395 nm, respectively. Generation of QM-1 and QM-2 was achieved by
photolysis of 1 and 2, respectively, using the fourth (266 nm)
harmonic of a Q-switched Nd:YAG laser, delivering 3 mJ pulses with a
duration of ca. 10 ns. The signal from the spectrometer was digitized
by an oscilloscope, and the data were processed on a PC system. The
sample solution was kept constant at 25 °C. The disappearance of
both QM-1 and QM-2 was followed, under pseudo-first-order
conditions, by monitoring the absorbance decrease at 375 and
395 nm, respectively. Pseudo-first-order rate constants (kobsd) were
obtained from the fit of the absorbance data to a single exponential
function and were reproducible to 4%. The second-order rate
constants k2 (M−1 s−1) for the reaction of nucleophiles with QM-1 and
QM-2 were determined as the least-squares slopes of linear plots of
kobsd against the total concentration of the nucleophile (Figure S1−S4,
Supporting Information). Amines were used from 2 × 10−3 to 0.75 M
concentration range. Octane-1-thiol, methanol, and water required
higher concentrations: 0.5−0.8 M, 2−8 M, 5−12 M, respectively.
Computational Details. All calculations were carried out using
the Gaussian 2003 program packages.
The geometric structures of QM-1 and QM-2 were fully optimized
in the gas phase and in water solution using the hybrid density
functional method B3LYP with the 6-31+G(d,p) basis set. Frequency
calculations have been performed at the same level of theory, and they
have not been scaled. The bulk solvent effect on the geometries was
calculated via the self-consistent reaction field (SCRF) method using
the PCM as implemented in the C.02 version of Gaussian 2003.30 The
cavity was composed by interlocking spheres centered on non-
hydrogen atoms with radii obtained by the HF parametrization of
Barone known as the united atom topological model (UAHF).31
General Procedure for the Preparative Irradiation of 1 and 2
in the Presence of Propylamine. An argon-purged solution of the
o-hydroxyphenylacetylene (1 or 2) (1.05 mmol) together with propylamine
(0.59 g, 10 mmol) in dry CH2Cl2 (100 mL) was irradiated in 10 Pyrex
tubes, using a multilamps reactor fitted with four 15 W lamps, with
maximum emission centered at 310 nm. After 40 min (120 min, using 2),
the solutions were collected, and the solvent was removed under vacuum.
The crude residue was purified by flash chromatography (cyclohexane/ethyl
REFERENCES
■
(1) Cuma, M.; Scheiner, S.; Kar, T. J. Am. Chem. Soc. 1998, 120,
10497.
(2) Brousmiche, D. W.; Xu, M. S.; Lukeman, M.; Wan, P. J. Am.
Chem. Soc. 2003, 125, 12961.
(3) Chuang, W. T.; Hsieh, C. C.; Lai, C. H.; Lai, C. H.; Shih, C. W.;
Chen, K. Y.; Hung, W. Y.; Hsu, Y. H.; Chou, P. T. J. Org. Chem. 2011,
76, 8189.
(4) Lukeman, M.; Wan, P. J. Am. Chem. Soc. 2002, 124, 9458.
(5) Lukeman, M.; Wan, P. Chem. Commun. 2001, 1004.
(6) Lukeman, M.; Xu, M. S.; Wan, P. Chem. Commun. 2002, 136.
(7) Basaric, N.; Zabcic, I.; Mlinaric-Majerski, K.; Wan, P. J. Org.
Chem. 2010, 75, 102.
(8) Verga, D.; Nadai, M.; Doria, F.; Percivalle, C.; Di Antonio, M.;
Palumbo, M.; Richter, S. N.; Freccero, M. J. Am. Chem. Soc. 2010, 132,
14625.
(9) Kulikov, A.; Arumugam, S.; Popik, V. V. J. Org. Chem. 2008, 73,
7611.
(10) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2002, 124,
6349.
(11) Pathak, T. P.; Sigman, M. S. J. Org. Chem. 2011, 76, 9210.
(12) Rossiter, C. S.; Modica, E.; Kumar, D.; Rokita, S. E. Chem.
Commun. 2011, 47, 1476.
(13) Wang, H. A.; Rokita, S. E. Angew. Chem., Int. Ed. 2010, 49, 5957.
(14) Wang, H.; Wahl, M. S.; Rokita, S. E. Angew. Chem., Int. Ed. 2008,
47, 1291.
(15) Nadai, M.; Doria, F.; Di Antonio, M.; Sattin, G.; Germani, L.;
Percivalle, C.; Palumbo, M.; Richter, S. N.; Freccero, M. Biochimie
2011, 93, 1328.
(16) Di Antonio, M.; Doria, F.; Richter, S. N.; Bertipaglia, C.; Mella,
M.; Sissi, C.; Palumbo, M.; Freccero, M. J. Am. Chem. Soc. 2009, 131,
13132.
(17) Weng, X.; Ren, L.; Weng, L.; Huang, J.; Zhu, S.; Zhou, X.;
Weng, L. Angew. Chem., Int. Ed. 2007, 46, 8020.
(18) Zhou, Q.; Qu, Y.; Mangrum, J. B.; Wang, X. Chem. Res. Toxicol.
2011, 24, 402.
3618
dx.doi.org/10.1021/jo300115f | J. Org. Chem. 2012, 77, 3615−3619

The Journal of Organic Chemistry
Note
(19) Doria, F.; Richter, S. N.; Nadai, M.; Colloredo-Mels, S.; Mella,
M.; Palumbo, M.; Freccero, M. J. Med. Chem. 2007, 50, 6570.
(20) Weinert, E. E.; Dondi, R.; Colloredo-Melz, S.; Frankenfield,
K. N.; Mitchell, C. H.; Freccero, M.; Rokita, S. E. J. Am. Chem. Soc.
2006, 128, 11940.
(21) Modica, E.; Zanaletti, R.; Freccero, M.; Mella, M. J. Org. Chem.
2001, 66, 41.
(22) Arumugam, S.; Popik, V. V. J. Am. Chem. Soc. 2009, 131, 11892.
(23) Arumugam, S.; Popik, V. V. J. Org. Chem. 2010, 75, 7338.
(24) Ferris, J. P.; Antonucci, F. R. J. Am. Chem. Soc. 1974, 96, 2010.
(25) Isaks, M.; Yates, K.; Kalanderopoulos, P. J. Am. Chem. Soc. 1984,
106, 2128.
(26) Lukeman, M. In Wiley Series on Reactive Intermediates in
Chemistry and Biology: Quinone Methides; Rokita, S. E., Ed.; Wiley:
Hoboken, NJ, 2009; p 16.
(27) Pirali, T.; Gatti, S.; Di Brisco, R.; Tacchi, S.; Zaninetti, R.;
Brunelli, E.; Massarotti, A.; Sorba, G.; Canonico, P.-L.; Moro, L.;
Genazzani, A.-A.; Tron, G.-C.; Billington, R.-A. Chem. Med. Chem.
2007, 2, 437.
(28) Lambert, J. B.; Zhao, Y.; Emblidge, R. W.; Salvador, L. A.; Liu,
X.; So, J.-H.; Chelius, E. C. Acc. Chem. Res. 1999, 32, 183.
(29) Di Valentin, C.; Freccero, M.; Zanaletti, R.; Sarzi-Amade,
̀
M.
J. Am. Chem. Soc. 2001, 123, 8366.
(30) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.et al. Gaussian 03,
Revision C.02; Gaussian, Inc.: Wallingford, CT, 2004.
(31) Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995.
3619
dx.doi.org/10.1021/jo300115f | J. Org. Chem. 2012, 77, 3615−3619