Sterically congested adamantylnaphthalene quinone methides

Article abstract of DOI:10.1021/jo3002479

Five new (2-adamantyl)naphthol derivatives (5-9, quinone methide precursors, QMP) were synthesized and their photochemical reactivity was investigated by preparative photolyses, fluorescence spectroscopy, and laser flash photolysis (LFP). Excitation of QMP 5 to S₁ leads to efficient excited state intramolecular proton transfer (ESIPT) coupled with dehydration, giving quinone methide QM5 which was characterized by LFP (in CH ₃CN-H₂O, λ_max = 370 nm, τ = 0.19 ms). On irradiation of QMP 5 in CH₃OH-H₂O (4:1), the quantum yield of methanolysis is Φ = 0.70. Excitation of naphthols QMP 6-8 to S₁ in CH₃CN leads to photoionization and formation of naphthoxyl radicals. In a protic solvent, QMP 6-8 undergo solvent-assisted PT giving QM6 or zwitterion QM8 that react with nucleophiles delivering adducts, but with a significantly lower quantum efficiency. QMP 9 in a protic solvent undergoes two competitive processes, photosolvolysis via QM9 and solvent-assisted PT to carbon atom of the naphthalene giving zwitterion. QM9 has been characterized by LFP (in CH₃CN-H₂O, λ_max > 600 nm, τ = 0.9 ms). In addition to photogenerated QMs, two stable naphthalene QMs, QM10 and QM11 were synthesized thermally and characterized by X-ray crystallography. QM10 and QM11 do not react with H₂O but undergo acid-catalyzed fragmentation or rearrangement. Antiproliferative activity of 5-9 was investigated on three human cancer cell lines. Exposure of MCF-7 cells treated with 5 to 300 nm irradiation leads to an enhanced antiproliferative effect, in accordance with the activity being due to the formation of QM5.

Full text of DOI:10.1021/jo3002479

Article
pubs.acs.org/joc
Sterically Congested Adamantylnaphthalene Quinone Methides
Jelena Veljkovic,† Lidija Uzelac,‡ Kresimir Molcanov,§ Kata Mlinaric-Majerski,† Marijeta Kralj,‡
́
̌
̌
́
Peter Wan,∥ and Nikola Basaric*,†
́
†Department of Organic Chemistry and Biochemistry, ‡Department of Molecular Medicine, and §Department of Physical Chemistry,
̌ ́ ̌
Ruđer Boskovic Institute, Bijenicka cesta 54, 10 000 Zagreb, Croatia
∥Department of Chemistry, University of Victoria, Box 3065 Stn CSC, Victoria, BC V8W3 V6, Canada
S
* Supporting Information
ABSTRACT: Five new (2-adamantyl)naphthol derivatives
(5−9, quinone methide precursors, QMP) were synthesized
and their photochemical reactivity was investigated by
preparative photolyses, fluorescence spectroscopy, and laser
flash photolysis (LFP). Excitation of QMP 5 to S1 leads to
efficient excited state intramolecular proton transfer (ESIPT)
coupled with dehydration, giving quinone methide QM5
which was characterized by LFP (in CH3CN−H2O, λmax = 370
nm, τ = 0.19 ms). On irradiation of QMP 5 in CH3OH−H2O
(4:1), the quantum yield of methanolysis is Φ = 0.70.
Excitation of naphthols QMP 6−8 to S1 in CH3CN leads to
photoionization and formation of naphthoxyl radicals. In a
protic solvent, QMP 6−8 undergo solvent-assisted PT giving
QM6 or zwitterion QM8 that react with nucleophiles delivering adducts, but with a significantly lower quantum efficiency. QMP
9 in a protic solvent undergoes two competitive processes, photosolvolysis via QM9 and solvent-assisted PT to carbon atom of
the naphthalene giving zwitterion. QM9 has been characterized by LFP (in CH3CN−H2O, λmax > 600 nm, τ = 0.9 ms). In
addition to photogenerated QMs, two stable naphthalene QMs, QM10 and QM11 were synthesized thermally and characterized
by X-ray crystallography. QM10 and QM11 do not react with H2O but undergo acid-catalyzed fragmentation or rearrangement.
Antiproliferative activity of 5−9 was investigated on three human cancer cell lines. Exposure of MCF-7 cells treated with 5 to 300
nm irradiation leads to an enhanced antiproliferative effect, in accordance with the activity being due to the formation of QM5.
nucleophiles and antiproliferation activity would be investigated
and structure−activity relationship established.
INTRODUCTION
■
In past two decades, quinone methides (QM) have become a
subject of significant scientific interest. They are important
intermediates in many chemical and biological processes.1
Their electrophilic nature makes them potent reagents with
nucleophiles. It has been demonstrated that QMs alkylate
amino acids and proteins2 and in that way induce enzyme
inhibition.3 QMs inhibit tyrosine hydroxylases,4 β-lactamase,5
β-glucosidases,6 phosphatase,7 or ribonuclease-A.8 Further-
more, QMs react with nucleosides9 and induce alkylation of
DNA.10 It is now well-established that QMs cross-link DNA,11
which renders them as potential anticancer therapeutics.12
Some antineoplastic agents such as mitomycin,13 daunomycin,
and similar anthracyclines,14 as well as CC 1065 and the
synthetic cyclopropylpyrroloindole analogues,15 base their
antiproliferative action on the metabolic formation of QMs
that alkylate DNA. Furthermore, Freccero et al. recently
reported on antiproliferative activity of some BINOL−QM
derivatives.16 However, for the ultimate application of simple
QM derivatives in anticancer therapy it is of pivotal importance
to understand their reactivity with nucleophiles, particularly
with nucleosides. Furthermore, several libraries of new QM
derivatives should be prepared whose reactivity with
QMs can be formed under mild conditions in photochemical
reactions of suitably substituted phenols, such as photo-
dehydroxylation of hydroxybenzylphenols,17 photoelimination
of acetic acid18 or amines.19 We became interested in the
photochemical formation of sterically congested QMs with
potential biological applicability.20 The steric congestion with a
bulky adamantyl substituent at the methylene position stabilize
the QM structure, making it longer-lived and more selective in
reactions with nucleophiles.20 In continuation of this line of
research, the 2-hydroxyadamantyl moiety was introduced into
2-, 3-, and 4-phenylphenols, and formation and reactivity of
QMs was studied by LFP.21 In addition, we performed an
investigation of antiproliferative activity on three human cancer
cell lines and found that alkyl substitution (e.g., with
adamantane) at the methylene position leads to an enhance-
ment of the antiproliferative activity of 3- and 4-phenylphenols
upon 300 nm irradiation, in accordance with the enhancement
being due to the formation of QMs.
Received: February 10, 2012
© XXXX American Chemical Society
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The logical extension of the study is photochemical
formation of naphthalene QM derivatives and investigation of
their antiproliferative action. To date, four isomeric naph-
thalene QMs have been reported. Arumugam and Popik have
reported photochemical generation of naphthalene QM1 and
QM2 by irradiation of 3-hydroxymethyl-2-naphthol (1) or 1-
hydroxymethyl-2-naphthol (2), respectively (eqs 1 and 2).22
QMs react with nucleophiles to give addition products22 or
with electron-rich dienophiles to give chromanes.23 Freccero
and co-workers have reported on photochemical generation of
naphthalene QM3 from the ammonium salt 3 (eq 3),24
whereas Wan and co-workers have reported on photo-
dehydration of 4 giving QM4 (eq 4).25
coupled in a Grignard reaction with 2-adamantanone, and the
methoxy group was removed by use of BBr3 (eq 5). However,
Prompted by the discovery of lead compounds with
enhanced antiproliferative activity on irradiation in the biphenyl
series21 and by reports22−25 on photochemical generation of
naphthalene QMs, we investigated chemistry and photo-
chemistry of (2-hydroxyadamantyl)naphthalenes. The inves-
tigation was conducted on a series of five adamantylnaphthols
5−9 that are expected to undergo excited-state intramolecular
proton transfer (ESIPT) or solvent-assisted proton transfer
(PT) coupled with a dehydration (or deamination in case of 7)
to deliver naphthalene QMs. Indeed, on irradiation in
nucleophilic solvents 5−9 undergo photosolvolysis. The
mechanism of the photochemical reaction was studied by
preparative irradiations, fluorescence spectroscopy and laser
flash photolysis (LFP). In addition, we attempted to synthesize
naphthalene derivatives 10 and 11, but instead we obtained
stable QM derivatives QM10 and QM11 that were fully
characterized and their reactivity investigated. Antiproliferatve
activity was investigated for derivatives 5−9 on three human
cancer cell lines, with and without irradiation.
in an attempt to prepare 9−11 from the corresponding
methoxy compounds 9a−11a, the adamantyl moiety was
cleaved off by BBr3 giving α-naphthol or β-naphthol as main
product. The cleavage of the adamantane also took place by use
of sodium thiolate.26 Therefore, a synthetic approach with the
use of benzyl protection of the phenol was undertaken. Benzyl
ethers 12 were prepared from the corresponding bromonaph-
thols (Scheme 1) and coupled in a Grignard reaction with 2-
adamantanone. The subsequent hydrogenolysis (H2, 60 Psi,
Pd/C) gave cleanly in high yields phenols 5, 8, and 9. On the
other hand, hydrogenation of 10b surprisingly gave QM10
(83%, Scheme 2). QM11 was also obtained as a stable product
in a ground-state reaction (48%) by treatment of 1-bromo-2-
hydroxynaphthalene with 2.5 equiv of BuLi and 2-adamanta-
none (Scheme 3). The ammonium derivative 7 was prepared
from 6 (overall yield 17%) in a reaction with sodium azide
giving 13 that was reduced to the corresponding amine and
transformed to the HCl salt 7 (eq 6).
RESULTS AND DISCUSSION
■
Synthesis. Compounds 5, 6 and 8 were obtained by the
standard synthetic protocol from the corresponding boromo-
methoxynaphthalenes, similar to the synthesis of adamantyl-
phenol20 and (adamantylphenyl)phenol derivatives,21 that were
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Scheme 1
nucleophiles. Interestingly, stirring of the CH3CN−H2O (1:1)
solution of QM11 for several days did not result in H2O
addition. However, in acidic media, in the presence of conc.
H2SO4, besides cleavage delivering α-naphthol, QM underwent
a rearrangement of the adamantane skeleton giving proto-
adamantane derivative 14 (20%, eq 7, for the crystal structure
Scheme 2
see the Supporting Information). Under less acidic conditions,
e.g., in the presence of HOAc, QM11 is stable. Similarly,
QM10 did not react in H2O under neutral conditions, whereas
in the presence of concd H2SO4 it was cleaved (several days;
conversion 40%) to furnish α-naphthol and adamantanone.
Photochemistry. After preliminary irradiations in UV−vis
cuvettes (see the Supporting Information), photolyses of 5−9
were performed in CH3OH which is a nucleophilic solvent that
is expected to react with QMs and give photomethanolysis
products (formal substitution of the benzyl alcohol or the
NH3Cl by OCH3). Typically, 10−100 mg of the compound
was dissolved in 100 mL of CH3OH or CH3OH−H2O and
irradiated (254 or 300 nm, 1 min−1 h). Progress of the
photoreaction was monitored by HPLC (see the Supporting
Information). Addition of H2O significantly increased the
efficiency of methanolysis, except for 5 wherein the efficiency
did not depend on the H2O content. The observed increase is
in line with the mechanism of the photomethanolysis involving
a proton transfer to solvent, which is more efficient in the
aqueous solvent than in neat CH3OH because of a faster
transfer of proton to the clusters of H2O than CH3OH.27
Photomethanolyses were clean and gave rise to the
methanolysis products 5c−9c in medium to high yields (eq
8) that were separated from the unreacted starting material by
QM10 and QM11 were unusually stable molecules, which
enabled us to characterize them by spectroscopic methods as
well as X-ray crystallography (Figure S61, Supporting
Information). In addition, we investigated their reactivity with
Scheme 3
preparative TLC. However, on attempts of purifying methyl
ethers 6c and 8c on silica gel, elimination of CH3OH took place
giving the starting materials. For the purpose of character-
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ization, 6c and 8c were obtained from 6 and 8, respectively, by
acidic (H2SO4) thermal methanolysis. Irradiation of 5 was also
performed in CH3CN in the presence of ethanolamine as a
nucleophile. It gave adduct 15 in 59% yield.
The finding is in line with the reported photochemical stability
of the parent 6-hydroxymethyl-2-naphthol by Freccero.24 The
ammonium derivative 7 exhibits higher efficiency in the
photosolvolysis than the benzyl alcohol 6. However, Φ for 7
́
is lower than for 8 for which formation of a Kekule-QM
derivative is not possible. Comparing the quantum yield of
photomethanolysis of 5, and the parent compound reported by
Popik et al (Φ = 0.17 0.02)22 indicates that incorporation of
the adamantane increased quantum yield of the photosolvolysis
about 3 times, similar to the observation in the simple phenol
series.20 However, measured Φ for 9 is about 3 times lower
0.04).25 The
Photomethanolysis can in principle take place via cations and
QMs.21 If the reaction takes place via cationic intermediates,
the efficiency for the methanolysis of naphthols 5−9 and the
corresponding methoxy derivatives 5a−9a should be similar.
To probe for the cationic pathway of photomethanolysis we
performed irradiations of 5, 6, 5a, and 6a in CH3OH (20 mg,
Rayonet, 16 lamps 300 nm, 30 min). Whereas irradiation of 5
and 6 gave the methanolysis products 5c (quantitatively) and
6c (23%), the methoxy derivatives 5a and 6a under the same
conditions remained unchanged. The finding strongly indicates
that the free naphthol OH is essential in the photomethanolysis
mechanism. Consequently, if the cationic mechanism takes
place its quantum efficiency is probably very low.
The importance of the free phenolic OH in the photo-
methanolysis suggests PT step and QM intermediates.
Therefore, the efficiency of the methanolysis should principally
depend on the pH of the solution. We have reported for 3-
phenylphenols that increased pH above the pKa of the phenol
OH decreased efficiency of the methanolysis,21c whereas some
4-phenylphenols undergo acid-catalyzed photomethanolysis.21b
To probe for the effect of pH on the efficiency of
photomethanolysis in the naphthol series, we performed
irradiations of CH3OH−H2O (2:1) solutions at different pH.
The pH of the aqueous part of the solvent was varied in the
range 2−10, and the conversion of the reaction was followed by
HPLC (see the Supporting Information). Increase of the acidity
below pH 2 gave rise to acid-catalyzed thermal methanolysis.
Therefore, the effect of acidity below pH 2 on the
photochemical reaction was not studied. Whereas the change
of the pH (in the range 2−10) had no effect on the efficiency of
the photomethanolysis of 5, we observed acid catalysis for 6
and 8 (see the Supporting Information). The finding suggests
that the benzylic OH becomes more basic in the S1 state.
Quantum yields for the photomethanolysis were determined
by use of a primary actinometer, photolysis of valerophenone in
aqueous solvent giving acetophenone (Φ = 0.65).28 The values
are compiled in Table 1. The measured value for 9 contains a
large uncertainty due to a high sensitivity of the reaction on
methanol supplier. The quantum yield for the photo-
methanolysis of 5 and 9 is significantly higher than for 6−8.
than for the parent compound 3 (Φ = 0.84
finding suggests that increase of the sterical hindrance at the
position 1 of the naphthalene decreased efficiency of the
photodehydration.
It has been demonstrated by D-exchange experiments that 1-
naphthol derivatives undergo solvent-assisted proton transfer
from the phenolic OH to the carbon atoms at the positions 5
and 8 of the naphthalene ring giving QM intermediates.25,29
Therefore, photosolvolysis and solvent-assisted PT should
principally be competitive reactions for 9. To probe for the
solvent-assisted PT in 9 we performed irradiations in CH3CN−
D2O. After the irradiations and H2O workup, the mixture was
analyzed by NMR and MS to determine the position and the
extent of the deuteration, respectively. Irradiation (Luzchem, 8
lamps) gave rise to 40% D-exchange at the position 8 of the
naphthalene ring (according to NMR), wheras MS idnicated
presnece of 37% monodeuterated and 7% of dideuterated
species. Competition between the D-exchange and photo-
solvolysis was investigated by irradiation in CH3OD. After the
irradiation NMR indicated presence of 10% of 9c, whereas
∼5% of molecules 9 and 9c contained D at the position 8 of the
naphthalene ring. The finding indicates that photosolvolysis is
about two times more efficient than the D-exchange (Φ ∼
0.15), which is in line with the reported value for 1-naphthol
(Φ ∼ 0.11).25
Fluorescence. It is generally accepted that PT reactions of
naphthols take place from the singlet excited state due to
increased acidity of naphthol in S1.27,29 Therefore, we
investigated fluorescence properties of 5−9 to get more
information about their singlet excited state properties and
reactivity. Fluorescence quantum yields were measured in
CH3CN and CH3CN−H2O (1:4) by use of two standards,
fluorene in CH3OH reference (Φ = 0.68) and quinine sulfate in
0.05 M aqueous H2SO4 (Φ = 0.53).30 Singlet excited state
lifetimes were measured by time-correlated single photon
timing (SPT) method. The results are compiled in Table 2. In
CH3CN, fluorescence spectra of 5−9 are characterized by the
presence of a band with a maximum at ∼350 nm. Spectra of 5−
8 are narrower (half intensity band with ∼3000 cm−1) than the
spectrum of 9 (half intensity band with ∼4500 cm−1). The
finding is in accordance with the typical fluorescence properties
Table 1. Quantum Yields for the Photomethanolysis
a
Reaction
a
QMP
Φ (CH3OH)
5
6
7
8
9
0.70 0.05
∼1 × 10−4
(2 1) × 10−3
0.010 0.005
0.3 0.2
a
Irradiations performed in CH3OH−H2O (4:1). Qunatum yields were
determined by use of valerophenone actinometer (Φ = 0.65).28
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Table 2. Photophysical Parameters of Naphthols 5−9
a
a
b
b
QMP
Φ (CH3CN)
Φ (CH3CN−H2O)
τ (CH3CN)/ns
τ (CH3CN−H2O)/ns
5
0.23 0.03
0.18 0.01
3.30 0.05 (40%)
6.5 0.1 (60%)
8.14 0.01
3.0 0.5 naphthol
6.1 0.5 naphtholate
6.4 0.5 naphthol
9.7 0.3 naphtholate
12.3 0.3 naphthol
4.7 0.1 naphtholate
6.3 0.1 naphthol
6
7
8
9
0.30 0.05
0.30 0.01
0.30 0.05
0.33 0.01
0.22 0.03
0.3 0.1
3.2 0.1 (4%)
10.6 0.1 (96%)
7.78 0.01
0.22 0.02
0.10 0.01
7.8 0.3 naphtholate
0.2 and 0.5 naphthol
5.7 0.2 naphtholate
4.46 0.01
a
Quantum yields of fluorescence measured by use of fluorene in CH3OH (Φ = 0.68) or quinine sulfate in 0.05 M aqueous H2SO4 (Φ = 0.53) as a
reference.30 Fluorescence lifetimes measured by time-correlated single photon timing method.
b
of 2- and 1-naphthols, respectively. The emissive state in 2-
naphthols can be characterized according to the Pratt
nomenclature31 as Lb, whereas in 1-naphthols La and Lb
states are overlapping.32 Interestingly, decay of fluorescence in
CH3CN could be fitted to single exponential function for 2-
naphthols 6 and 8, as well as for 1-naphthol 9. On the other
hand, for 5 and 7 fluorescence decay in CH3CN was best fitted
to two-exponential function.
1
1
1
Addition of H2O to the CH3CN solution of phenols or
naphthols opens a possibility for the deactivation from S1 by PT
to solvent, with concomitant quenching of fluorescence.27,33
Therefore, we performed fluorescence titration of the CH3CN
solutions of 5−9 with H2O to probe for the PT deactivation
pathways. Interestingly, on addition of H2O to the CH3CN
solution of 5−8 fluorescence increases, and only for 9 we
observed quenching (see the Supporting Information.).
However, increase of fluorescence in H2O-titration experiments
has already been reported for some adamantylphenols and
adamantyl derivatives of phenylphenols.20,21 The presumable
explanation was different solvation of the molecules by CH3CN
and H2O due to the presence of very lipophilic adamantyl
group. Although for 5−8 we have not observed quenching of
fluorescence by addition of H2O, at high concentration of H2O
PT takes place. It is demonstrated by lower quantum yields of
fluorescence at high H2O content than in neat CH3CN (Table
2) and additional bands in the fluorescence spectra at longer
wavelengths not seen in CH3CN. The bands are assigned to the
fluorescence of naphtholates formed by an adiabatic PT to the
solvent (Figure 2). For 5, 6, and 8 in CH3CN−H2O (1:4) the
naphtholate emission appears in the spectrum as a shoulder at
∼450 nm (see Figure 1 and Figures S11, S15 and S22,
Supporting Information), whereas for 7 and 9 a strong new
band can be seen at 475 and 500 nm, respectively. In particular,
in the fluorescence spectrum of 9 taken in CH3CN−H2O (1:4)
fluorescence of naphthol can be seen only as a shoulder at 375
nm, whereas fluorescence from the naphtholate dominates the
spectrum. The findings are in line with the acidity of the
investigated derivatives in S1, being much higher for 1-
naphthols (pKa = 0.4),29 than 2-naphthols (pKa ∼2.8,34 for 3-
hydroxymethyl-2-naphthol pKa = 0.7722). Furthermore, 7
bearing the ammonium moiety with a positive charge should
clearly be more acidic in the ground and excited state compared
to the alcohol 6 (positive charge stabilizes the naphthoxide
formed by PT). In addition to the steady-state fluorescence
spectra, PT to the aqueous solvent for 5−9 is indicated by SPT
measurements. In aqueous media, an additional longer-lived
decay component with a negative pre-exponential factor can be
Figure 1. Normalized fluorescence spectra of naphthols 6, 7, and 9 in
CH3CN (solid line) and CH3CN−H2O (1:4) (dashed line).
seen, contributing more at longer wavelengths. The rising
component was assigned to the naphtholate formed in the
adiabatic PT to the solvent (Table 2).
Acid−base properties in the S1 for 5−9 were investigated by
titrations with acid and base. Addition of base (NaOH) to the
CH3CN−H2O (1:4) solution of 5−9 significantly changed the
appearance of the spectra. The bands associated to the emission
of naphthol gradually disappeared, and only longer wavelength
bands at 400−600 nm from the naphtholate emission could be
seen. The finding corroborates the assignation of the long-
wavelength emission (only seen in the aqueous solvent) to
naphtholates. On the contrary, titration with acid (HClO4) in
the pH range 2.5−3.0 resulted in the quenching of fluorescence
without the change of the spectra. The relative ratio of the
emission from the naphthol and the naphtholate remained the
same (only small differences were observed in the normalized
spectra of 7). The finding indicates that the most basic site of
the molecules in S1 is not the naphtholate anion, but rather
benzylic alcohol or the carbon atoms of the naphthalene. The
Stern−Volmer plots (Φ/Φ0 vs H+ concentration) showed a
linear relationship, indicating a dynamic quenching with
quenching constants in the range kq = (1−6) × 109 dm3
mol−1 s−1 for 6−8 and somewhat higher values for 5 [kq = (1−
3) × 1010 dm3 mol−1 s−1] and 9 (kq = ∼3 × 1010 dm3 mol−1
s−1). The values of the quenching constants are in line with the
quantum efficiencies for the photomethanolysis (Table 1).
Laser Flash Photolysis (LFP). LFP was performed to
characterize QMs and other long-lived transient species in the
photochemical reactions of 5−9. The measurements were
performed in N2- and O2-purged CH3CN and CH3CN−H2O
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Figure 2. Transient absorption spectra of 5 in O2-purged CH3CN−H2O (left), and O2-purged CH3CN solution (right) taken at 350 ns after the
laser pulse (inset: decay at 350 nm).
(1:1) solutions. In principle, the difference in the transient
spectra measured in CH3CN and CH3CN−H2O could
correspond to the species formed in pathways involving PT.
In N2-purged CH3CN and CH3CN-H2O solutions of all
derivatives we observed a transient absorbing with a maximum
at 430−450 nm decaying with the rate constant k = (1−3) ×
105 s−1 (τ = 3−7 μs). The transient is quenched by O2 (in O2-
purged solution, k = (1−2) × 107 s−1, τ = 20−60 ns). Based on
the quenching by O2 and similarity with the published spectra
of naphthol triplets,35 we assign the observed transient to the
triplet−triplet absorption.
In the transient spectra of 5 obtained in O2-purged CH3CN
solution, a strong transient absorption was observed with a
maximum at 360 nm, decaying with k = 6.7 s−1 (τ = 0.15 s)
(Figure 2). The transient was not affected by O2 but
experienced a small bathochromic shift and a significant
quenching on addition of H2O. In O2-purged CH3CN−H2O
(1:1), the maximum of the transient is observed at 370 nm,
decaying with a rate k = 5.0 × 103 s−1 (τ = 0.19 ms). On the
basis of the above findings, the transient was assigned to QM5.
Further evidence which undoubtedly allowed for the
assignation of the transient were the quenching constants
(Table 3) with nucleophiles (CH3OH, ethanolamine, NaN3)
triplet (vide supra), a broad transient absorption was observed
at 500−700 nm that was not affected by O2 and decayed faster
in aqueous solution. According to the comparison with the
published spectra of naphthol radical cations,36 the transients
were tentatively assigned to the presence of radical cation 16
and solvated electron. In aqueous solvent, the phenoxyl radical
cations decay by deprotonation37 to give phenoxyl radicals.38
Therefore, more persistent transient absorption with a
maximum at 350 and 500 nm, decaying with k = (1.6−2.5)
× 104 s−1 (τ = 40−60 μs) was assigned to radical 17. The
supporting evidence for the assignation is as follows: the decay
is not affected by solvent polarity or O2, and the maximum of
the absorption is at the same wavelengths as in the published
spectra of the naphthoxyl and phenoxyl radicals.35−38 The
decay of 17 matches the rise of the most persistent transient
absorption at 330 nm (τ = 1−2 s). Freccero et al. reported
formation of QM3 characterized by the transient absorption at
310−330 nm (τ > 1 ms), which is formed by a decay of the
transient absorbing at 370 nm (τ ≈ 20 μs). In analogy, we
could tentatively assign the observed transient formed by decay
of 17 in the LFP experiments of 6 and 7 to QM6. However, we
observed the same transient absorption in the LFP experiment
́
of 8 for which a Kekule QM structure is not possible.
Therefore, with the present data, a firm assignment of the long-
lived transient absorption with the maximum at 330 nm is not
possible.
Table 3. Bimolecular Quenching Rate Constants for QM5
kq (dm3 mol−1 s−1
)
a
Since we did not detect presence of QMs formed from 6−8
in CH3CN−H2O (1:1), we carried out LFP experiment in the
acidic media. We observed that acid (pH range 2−3) catalyzes
photomethanolysis of 6 and 8 (vide supra), probably due to the
protonation of the benzyl alcohol which is more basic in S1.
Hence, it was anticipated that LFP experiments carried out in
CH3CN−H2O (1:1) solution at pH 2 should give rise to the
transients that are associated to cations or QMs formed via
cationic intermediates. Furthermore, LFP experiments were
performed in 2,2,2-trifluoroethanol (TFE) which is acidic, but
less nucleophilic than H2O, wherein QMs20,21,39 and cations40
generally have longer lifetimes. However, in the transient
absorption spectra of 6 and 7 in CH3CN−H2O (1:1) at pH 2
we detected similar transients as in the neutral CH3CN−H2O
that were assigned to the naphthoxyl radical. In the transient
absorption spectra of 6 and 8 recorded in O2-purged TFE,
naphthoxyl radicals were also detected, decaying slower (k = 6.5
× 103 s−1, τ = 150 μs) than the analogous transient species
observed in CH3CN−H2O. However, in O2-purged TFE
solution of 8 we detected the presence of a transient absorbing
CH3OH
(8.0 0.6) × 103
(1.08 0.05) × 105
(1.1 0.2) × 105
(3.7 0.5) × 106
85 10
a
b
ethanolamine
ethanolamine
b
NaN3
a
ethyl vinyl ether
a
b
Measurement performed in CH3CN. Measurement performed in
CH3CN−H2O (1:1).
and ethyl vinyl ether, which are in agreement with the
published constants for QMs.11c,22 However, Popik et al.
reported that photolysis of 1 gave rise to a benzoxete absorbing
at 370 nm which decayed (τ = 12−13 μs), giving QM1 (τ = 4−
8 ms, Amax = 330 nm).22 We have not detected any
intermediate in the QM formation; the transient was formed
within the laser pulse, indicating that the corresponding
benzoxete was not formed or that it has a shorter lifetime
than 20 ns.
The transient spectra obtained by LFP of naphthols 6−8
were more complex than those of 5. Besides the signal of the
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at 350−450 nm, decaying with the rate k = (7−8) × 106 s−1 (τ
= 125−140 ns). According to the comparison with the spectra
of naphthylmethyl cations,40 the transient was assigned to the
zwitterionic QM8. In addition, the transient was quenched by
ethanolamine. However, because of the overlap with the signal
of the triplet, a precise quenching rate constant could not be
estimated.
Scheme 4
Transient absorption spectra of 9 were different from the
spectra of 5−8. Addition of H2O to the CH3CN solution
induced significant change of the spectrum with appearance of
rather a strong absorption band at >600 nm, decaying in O2-
purged solution with a biexponential law (k = 6.0 × 104 s−1, τ =
17 μs and k = 1.1 × 103 s−1, τ = 0.9 ms). The long wavelength
absorption band was not affected by O2 or N2O, indicating that
it does not correspond to triplets, radicals, or solvated electrons.
In TFE solution, the LFP gave rise to the same appearance of
the transition spectra (Figure 3), however, decaying slower,
operation of an intrinsic ESIPT delivering QM5 that reacts with
methanol (or other nucleophiles) giving adducts. Estimated
quenching constants for the reaction of QM5 with nucleophiles
by LFP are higher than reported by Popik for the parent
naphthol system22 but in line with those reported by
Freccero11d for QMs derived from BINOLs. On addition of
H2O to the CH3CN solution, the intramolecular H-bond
between the phenol OH and the alcohol is partly perturbed, the
ESIPT quantum yields are lowered, and the fluorescence is
enhanced. In H2O, in addition to ESIPT, a PT to solvent takes
place delivering naphtholate, as demonstrated by fluorescence
measurements. Furthermore, a H2O-mediated PT may also
ultimately deliver QM5 that reacts with nucleophiles or H2O.
Excitation of derivatives 6−8 to the S1 cannot give rise to
ESIPT due to a larger distance between the phenolic OH and
the alcohol group R (Scheme 5) or absence of the basic site in
7. Therefore, the fluorescence quantum yield of the CH3CN
solution of 6−8 is higher than the one of 5. Population of the
S1 state in CH3CN does not lead to the formation of QMs.
Instead, a photoionization takes place delivering radical-cations
16 and solvated electron, as suggested by the LFP measure-
ments. Photoionization and formation of naphthoxyl radicals
may account to the formation of high-weight material and
spectral changes observed on photolyses in CH3CN and
CH3CN−H2O in UV−vis cuvettes. Naphthoxyl radical cations
are very acidic,36−38 so 16 decays in the presence of proton-
accepting solvent by PT giving naphthoxyl radicals 17 that were
detected by LFP. In case of 6, radical 17 may undergo
homolytic cleavage of the OH· to give QM6. Homolytic
cleavage of radicals is a well-documented reaction, for example,
in the Norrish type-I41 or photo-Kolbe reactions.42 Further-
more, formation of QMs in the electron-transfer reactions has
already been reported by Freccero et al.43 This pathway may
account to minor formation of 6c on irradiation of 6 in
CH3OH (Φ for methanolysis is only 1 × 10−4). The reason for
such a low overall quantum yield is probably back-electron
transfer after photoionization giving starting material 6−8. In
aqueous solvent, PT to H2O clusters takes place giving
naphtholates.27,33 Incorporation of the ammonium salt in the
molecule results in stronger acidity of the phenolic OH in 7
(compared to 6) which is demonstrated in fluorescence spectra,
by stronger contribution of the naphtholate emission, and
higher quantum yield of the photomethanolysis reaction.
Deprotonation of the phenolic OH in S1 coupled with the
elimination of H2O or ammonia from 6 and 7, respectively,
delivers QM6. Similarly, solvent-assisted PT and dehydration
gives rise to zwitterionic QM8 from 8. Due to low quantum
yield of formation, QM6 was not detected by LFP, but QM8
Figure 3. Transient absorption spectra of 9 in O2-purged TFE.
with k = 9.0 × 104 s−1, τ = 11 μs, and k = 40 s−1, τ = 25 ms.
Furthermore, the transients could be quenched by ethanol-
amine and sodium azide (Table 4). Consequently, we assigned
the short-lived transient (τ = 11 μs) to the zwitterion Zw9 and
long-lived (τ = 25 ms) to QM9.
Table 4. Bimolecular Quenching Rate Constants (kq (dm3
mol−1 s−1)) for QM9 and Zw9
QM9
ZW9
a
ethanolamine
(2.6 0.5) × 103
(1.1 0.1) × 107
∼1 × 109
b
NaN3
a
b
Measurement performed in TFE. Measurement performed in
CH3CN−H2O (1:1).
Reaction Mechanisms. Excitation of 2,3-substituted
naphthalene derivative 5 to S1 leads to an efficient ESIPT
wherein the phenolic OH is transferred to the alcohol group
along the intramolecular H-bond trajectory. The ESIPT is
coupled with dehydration, delivering QM5 (Scheme 4).
Because of the efficient ESIPT, the quantum yield of
fluorescence for 5 is lower than for the other investigated
derivatives. Formation of QM5 and subsequent reactions with
nucleophiles probably do not require presence of a protic
solvent. That is demonstrated by LFP measurements
performed in neat CH3CN, wherein the transient assigned to
QM5 was detected. Furthermore, quantum efficiency of the
photomethanolysis does not depend on the addition of H2O or
pH of the solution (in the range 2−10), in agreement with the
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Scheme 5
Scheme 6
Scheme 7
was detected in the TFE solution. Reaction of QM6 and QM8
with nucleophiles gives adducts or photosolvolysis products.
Photoexcitation of 9 to S1 in aprotic solvent cannot give rise
to ESIPT, similar to 6−8. Therefore, for the formation of QM9
(Scheme 6), addition of a protic solvent is required to mediate
the deprotonation of the naphthol OH and protonation of the
benzyl alcohol which is coupled with a dehydration. Since 1-
naphthols are more acidic than the corresponding 2-naphthol
derivatives, less protic solvent is required for the formal solvent-
assisted PT and formation of QM9. Hence, already a small
addition of H2O (up to 5%) significantly propels the
photosolvolysis reaction in CH3OH, and pH (in the range
2−10) has no effect on the quantum efficiency. QM9 has been
detected by LFP in CH3CN−H2O and its kinetics with
ethanolamine and NaN3 determined. Interestingly, QM9 reacts
∼3 times faster with NaN3 than QM5, but the quenching rate
constant with ethanolamine is about 100 times smaller. The
estimated quenching constants are in line with those previously
reported for sterically congested QMs.21 Obviously, structure of
the QMs influences largely their reactivity with nucleophiles. In
addition to photosolvolysis, 9 undergoes solvent-assisted PT
wherein carbon atom of the naphthalene is the basic site. This
PT process gives zwitterion Zw9 that does not react with
nucleophiles but undergoes tautomerization to the starting
material. LFP in TFE gave rise to a short-lived transient (τ = 11
μs) that was tentatively assigned to Zw9. On irradiation in
CH3CN−D2O formation of Zw9 leads to deuteration of the
position 8 of the naphthalene ring. Competition of photo-
solvolysis and solvent-assisted PT leading to deuteration of
carbon atoms has already been reported.21a,25
Attempts to synthesize naphthol derivatives 10 and 11 gave
the corresponding QM10 and QM11, suggesting that QMs are
characterized by similar stability as naphthols. According to
B3LYP/6-311G, the energy gain in the hydration reaction of
QM10 and QM11 is only 13.84, and 30.71 kJ/mol,
respectively, whereas hydration of QM5 is highly exergonic
(ΔE = −138.60 kJmol−1). Therefore, QM10 and QM11 do not
react with H2O even under acidic conditions. However, in the
presence of concd H2SO4 under very acidic conditions, they
undergo cleavage to naphthol and adamantanone. In addition,
H
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a
Table 5. IC50 Values (in μM)
cell lines
MCF-7
HCT116
H 460
b
b
b
compd
not irradiated
irradiated
not irradiated
irradiated
not irradiated
irradiated
5
6
7
8
9
≥100
≥100
≥100
5
1
≥100
19
≥100
18
17
11 0.1
39
3
16
12
34
2
1
1
19
12
23
3
2
6
16
11
18
24
3
1
2
4
1
1
2
10
6
5
1
45 10
25
29 12
20
36 25
2.0 0.1
2.0 0.1
45 35
39 16
1.0 0.4
3.0 0.1
1
8
QM10
2.0 0.2
2.0 0.1
≥100
QM11
c
Trioxsalen
19
2
0.2 0.02
34
6
0.24 0.1
0.1 0.1
a
b
IC50; the concentration that causes 50% growth inhibition. Irradiated 3 × 1 min at 300 nm with six lamps. In the calculation of IC50, the treated
and irradiated cells were compared with only irradiated control cells so that 25% inhibition of growth caused by 300 nm light does not influence the
reported result. Trioxsalen IUPAC name: 2,5,9-trimethyl-7H-furo[3,2-g]chromen-7-one
c
protonation of the carbonyl moiety of QM11 gives carbocation
that undergoes rearrangement to less sterically hindered
protoadamantyl cation 11’+ that reacts with phenol in the
intramolecular reaction giving 14 (Scheme 7). Rearrangement
of the adamantyl cation to the protoadamantyl skeleton has
been intensively studied,44 as well as reactions of protonated
QMs.18,45 However, to the best of our knowledge the lack of
reactivity of protonated QMs with H2O has not yet been
reported. The unusual stability of QM10 and QM11, compared
to the previously studied QMs may be rationalized by loss of
aromaticity in only one benzene ring of the naphthalene
moiety, high-resonance stabilization of the carbocations
obtained by protonation, and steric effect of the adamantane
hindering the attack of nucleophiles to QMs or the
carbocations.
Antiproliferative Investigation. To investigate the
antiproliferative effect of QMs we performed testing of
compounds on three human cancer cell lines HCT 116
(colon), MCF-7 (breast), and H 460 (lung). The testing was
performed on 5−9 in the presence and absence of 300 nm
irradiation, as well as on QM10 and QM11 without the
irradiation. In addition, we performed a control experiment
wherein the cells were only irradiated at 300 nm, but without
the treatment with compounds, as well as a positive control
experiment wherein the cells were treated with trioxsalen that is
known to exhibit antiproliferative activity on photoactivation
(see the Supporting Information).16,24 After 72 h of incubation
the cell growth rate was evaluated by performing the MTT
assay46 which detects dehydrogenase activity in viable cells.
Compounds 6−9 as well as QM10 and QM11 showed an
antiproliferative effect to all cell lines in the micromolar
concentration range without exposure to light (Table 5). QMs
exhibited activity in approximately 10 times lower concen-
tration than 6−9. The antiproliferative effect of 6−9 was very
similar and cannot be correlated with the molecular structure,
lipophylicity, or solubility in H2O. On the contrary, naphthol 5
exhibited very low activity on the cells that were kept in dark.
Irradiations of cells (3 × 1 min at 300 nm with six lamps)
resulted in significant enhancement of the activity, reaching
almost the one of the trioxsalen, but only on the MCF-7 cell
line. Enhancement of the antiproliferative action with
compound 5 can be correlated with the highest efficiency of
the QM formation in the investigated series (see Table 1).
Although we cannot give an explanation for the observed
selectivity on the MCF-7 cell line, the selective antiproliferative
action of the photogenerated QMs has already been reported
by us21 and Freccero.16,24 The observed enhancement of the
activity of 5 on exposure to light, and selective action to only
one cancer cell line classifies it as a potential lead for further
investigations.
CONCLUSION
■
New (2-adamantyl)naphthol derivatives 5−9 were synthesized
and their ESIPT, and solvent-assisted PT reactivity was
investigated. All derivatives undergo photosolvolysis via QM
intermediates. QM5 formed from 5 in the S1 via ESIPT and
dehydration was characterized by LFP and its rate constants
with nucleophiles determined. Incorporation of the adamantyl
moiety results in different reactivity pattern compared to the
nonsusbtituted structure. Naphthols 6−8 in S1 undergo
photoionization and formation of naphthoxyl radicals. Photo-
solvolysis via QM6 and zwitterion QM8 takes place in a protic
solvent but with significantly lower overall quantum efficiency.
Naphthol 9 in S1 in a protic solvent undergoes photosolvolysis
via QM9 and solvent-assisted PT to carbon atom of the
naphthalene giving zwitterion Zw9. QM9 has been charac-
terized by LFP. Determined quenching rate constants for QM9
with nucleophiles reveal very different reactivity patterns. In
addition to photogenerated QMs, two stable naphthalene QM
derivatives QM10 and QM11 were synthesized and fully
characterized. QM10 and QM11 do not react with H2O but
undergo acid-catalyzed fragmentation or rearrangement. The
results indicate importance of preparing new QM derivatives
and studying their reactivity to fully understand their chemistry
before the ultimate use in biology and medicine. Antiprolifer-
ative activity of 5−9 was investigated on three human cancer
cell lines HCT 116 (colon), MCF-7 (breast), and H 460
(lung). Exposure of cells treated with 5 to 300 nm irradiation
leads to enhanced antiproliferative effect on MCF-7 cell line,
classifying 5 (or QM5) as a potential lead for further
antiproliferative studies.
EXPERIMENTAL SECTION
■
General Procedure for the Preparation of Compounds 12a
and 12b. A solution of bromonaphthol (1110 mg, 5.0 mmol) and
benzyl bromide (0.9 mL, 7.5 mmol) in DMF (15 mL) was treated with
K2CO3 (1380 mg, 10.0 mmol), and the resulting mixture was heated at
60 °C for 2 h. After cooling and filtration, the mixture was evaporated.
The residue was dissolved in ethyl acetate (50 mL), and the organic
solution was washed with 1 M HCl (3 × 25 mL) and brine (2 × 20
mL), dried over unhydrous MgSO4, filtered, and evaporated. The
I
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residue was chromatographed on silica gel using dichloromethane/
hexane (1:1) as eluent to afford the pure compounds.
ν/cm−1 3537 (s), 2900 (s). 2854 (m), 1454 (m), 1215 (s), 1176 (s),
979 (m), 760 (m) cm−1; 1H NMR (CDCl3, 600 MHz) δ/ppm 7.89 (s,
1H), 7.76 (d, 1H, J = 8.2 Hz), 7.67 (d, 1H, J = 8.0 Hz), 7.38−744 (m,
5H), 7.31−7.36 (m, 2H), 7.25 (s, 1H), 5.24 (s, 2H), 3.64 (s, 1H), 2.83
(br s, 2H), 2.48−2.56 (m, 2H), 1.77−1.98 (m, 6H), 1.73 (br s, 2H),
1.60−1.65 (m, 2H); 13C NMR (CDCl3, 150 MHz) δ/ppm 155.5 (s),
136.3 (s), 134.5 (s), 133.1 (s), 128.8 (d), 128.6 (s), 128.2 (d), 128.0
(d), 127.9 (d), 127.3 (d), 126.4 (d), 126.0 (d), 124.1 (d), 107.7 (d),
76.9 (s), 70.3 (t), 38.1 (t, 2C), 35.7 (d, 2C), 35.5 (t), 33.1 (t, 2C), 27.5
(d), 27.0 (d); HRMS (MALDI) calcd for C27H28O2 (+Na+) 407.1981,
found 407.1988.
2-Benzyloxy-3-bromonaphthalene (12a). Compound 12a was
prepared in 78% yield according to the general procedure from 2-
bromo-3-hydroxynaphthalene (1 g, 4.5 mmol) and benzyl bromide
(0.8 mL, 6.7 mmol): mp 83−84 °C; IR (KBr) ν/cm−1 3029 (vw),
1
1587 (m), 1379 (s), 1247 (s), 1020 (s), 727(s); H NMR (CDCl3,
300 MHz) δ/ppm 8.06 (s, 1H), 7.63−769 (m, 2H), 7.49−7.54 (m,
2H), 7.29−7.45 (m, 5H), 7.18 (s, 1H), 5.23 (s, 2H); 13C NMR
(CDCl3, 75 MHz) δ/ppm 152.6 (s), 136.4 (s), 133.4 (s), 132.3 (d),
129.5 (s), 128.6 (d), 127.9 (d), 126.9 (d), 126.7 (d), 126.6 (d), 124.6
(d), 113.9 (s), 108.3 (d), 70.7 (t).
2-(2-Hydroxy-2-adamantyl)-6-methoxynaphthalene (6a).
The Grignard reagent was prepared from 2-bromo-6-methoxynaph-
thalene (2.40 g, 10 mmol) and magnesium (264 mg, 11 mmol) and
reacted with 2-adamantanone (1.5 g, 10 mmol) to afford 3.2 g of the
crude product that was purified on a column of silica gel using CH2Cl2
as eluent to give the product (2.50 g, 81%) in the form of colorless
crystals: mp 162−163 °C; IR (KBr) ν/cm−1 3562 (s), 2931 (s), 2903
2-Benzyloxy-7-bromonaphthalene (12b). Compound 12b was
prepared in 86% yield from 2-bromo-7-hydroxynaphthalene (556 mg,
2.5 mmol) and benzyl bromide (0.36 mL, 3.0 mmol) as described in
the general procedure: mp 117−119 °C; IR (KBr) ν/cm−1 3050 (wv),
1
1624 (s), 1500 (s), 1170 (s), 1003 (m), 845 (s), 735 (s); H NMR
(CDCl3, 300 MHz) δ/ppm 7.87 (d, 1H, J = 1.7 Hz), 7.71 (d, 1H, J =
8.9 Hz), 7.62 (d, 1H, J = 8.7 Hz), 7.32−7.50 (m, 6H), 7.22 (dd, 1H, J
= 2.3 Hz, J = 8.9 Hz), 7.10 (d, 1H, J=2.4 Hz), 5.16 (s, 1H); 13C NMR
(CDCl3, 75 MHz) δ/ppm 157.5 (s), 136.6 (s), 135.8 (s), 129.4 (d),
129.3 (d), 128.8 (d) 128.7 (d), 128.1 (d), 127.5 (d), 127.4 (s), 127.0
(d), 120.6 (s), 119.5 (d), 106.4 (d), 70.1 (t).
1
(s), 2852 (m), 1606 (m), 1479 (m), 1194 (m), 852 (m); H NMR
(CDCl3, 300 MHz) δ/ppm 7.86 (d, 1H, J = 1.1 Hz), 7.68−7.76 (m,
2H), 7.63 (dd, 1H, J = 1.8 Hz, J = 8.8 Hz), 7.09−7.16 (m, 2H), 3.90
(s, 3H, OCH3), 2.66 (br s, 2H), 2.47 (br s, 1H), 2.43 (br s, 1H), 1.92
(br s, 1H), 1.68−1.80 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ/ppm
157.7 (s), 140.4 (s), 136.6 (s), 129.6 (d), 128.8 (s), 127.2 (d), 124.2
(d), 124.1 (d), 118.6 (d), 105.3 (d), 75.6 (s), 55.2 (q), 37.6 (t), 35.7
(d, 2C), 34.9 (t, 2C), 32.9 (t, 2C), 27.4 (d), 26.9 (d); HRMS
(MALDI) calcd for C21H24O2 (+H+ − H2O) 291.1743, found
291.1731.
General Procedure for the Grignard Reaction. The reaction
was carried out under N2 inert atmosphere in a two-neck, round-
bottom flask (100 mL) equipped with a condenser and a dropping
funnel. Magnesium (10 mmol) which was freshly activated prior to the
reaction was placed in the flask and suspended in THF (10 mL). In
the dropping funnel was placed a THF solution (20 mL) of
bromonaphthol (10 mmol). A few drops of the solution were added
to the suspension in the flask, and the reaction was initiated by adding
a crystal of iodine and heating. The remaining solution in the funnel
was added over 30 min at rt. After the addition was completed,
reaction mixture was refluxed until all magnesium reacted (1−1.5 h).
The solution of the Grignard reagent was cooled to rt, and a THF
solution (20 mL) of 2-adamantanone (10 mmol) was added dropvise
during 1 h. After addition was completed, the reaction mixture was
refluxed for 4 h and stirred at rt overnight. The next day, to the
reaction mixture was added a saturated solution of ammonium
chloride (100 mL), the layers were separated, and the aqueous layer
was additionally acidified with 1 M HCl until all solid dissolved. The
acidified aqueous layer was extracted with diethyl ether (3 × 30 mL),
and the organic extracts were combined and dried over anhydrous
MgSO4. After filtration and removal of the solvent, the crude product
was obtained that was additionally purified by chromatography on
silica gel using CH2Cl2 as eluent.
2-(2-Hydroxy-2-adamantyl)-7-methoxynaphthalene (8a).
The Grignard reagent was prepared from 2-bromo-7-methoxynaph-
thalene (1.00 g, 4.2 mmol) and magnesium (130 mg, 5.4 mmol) and
reacted with 2-adamantanone (740 mg, 4.9 mmol) to afford 1.4 g of
the crude product that was purified on a column of silica gel using
CH2Cl2 as eluent to give the product (1.15 g, 88%) in the form of
colorless crystals: mp 135−136 °C; IR (KBr) ν/cm−1 3522 (s), 2904
1
(s), 2845 (m), 1632 (m), 1464 (m), 1211 (m), 829 (m); H NMR
(CDCl3, 300 MHz) δ/ppm 7.86 (s, 1H), 7.77 (d, 1H, J = 8.6 Hz), 7.70
(d, 1H, J = 9.6 Hz), 7.53 (dd, 1H, J = 1.6 Hz, J = 8.6 Hz), 7.10−7.15
(m, 2H), 3.91 (s, 3H, OCH3), 2.68 (br s, 2H), 2.53 (br s, 1H), 2.48
(br s, 1H), 1.92 (br s, 1H), 1.70−1.80 (m, 10H); 13C NMR (CDCl3,
75 MHz) δ/ppm 157.6 (s), 143.2 (s), 134.5 (s), 128.7 (d), 128.1 (d),
128.0 (s), 123.3 (d), 121.3 (d), 118.7 (d), 106.1 (d), 75.7 (s), 55.2
(q), 37.6 (t), 35.7 (d, 2C), 34.9 (t, 2C), 32.9 (t, 2C), 27.3 (d), 26.9
(d); HRMS (MALDI) calcd for C21H24O2 (+H+ − H2O) 291.1743,
found 291.1744.
2-Benzyloxy-7-(2-hydroxy-2-adamantyl)naphthalene (8b).
The Grignard reagent was prepared from 2-benzyloxy-7-bromonaph-
thalene (12b, 1.44 g, 4.6 mmol) and magnesium (140 mg, 5.8 mmol)
and reacted with 2-adamantanone (690 mg, 4.6 mmol) to afford 1.66 g
of the crude product that was purified on a column of silica gel using
CH2Cl2 as eluent to give the product (1.32 g, 75%) in the form of
colorless crystals: mp 195−197 °C; IR (KBr) ν/cm−1 3554 (m), 3440
2-(2-Hydroxy-2-adamantyl)-3-methoxynaphthalene (5a).
The Grignard reagent was prepared from 2-bromo-3-methoxynaph-
thalene (970 mg, 4.1 mmol) and magnesium (119 mg, 4.9 mmol) and
reacted with 2-adamantanone (736 mg, 4.9 mmol) to afford 1.5 g of
the crude product that was purified on a column of silica gel using
CH2Cl2 as eluent to give the product (1.10 g, 87%) in the form of
colorless crystals: mp 208−210 °C; IR (KBr) ν/cm−1 3554 (s), 2902
(s), 2842 (m), 1630 (m), 1448 (m), 1217 (m), 1176 (m), 1001 (m),
1
(m), 2902 (s), 1629 (s), 1217 (s), 835 (s); H NMR (CDCl3, 600
MHz) δ/ppm 7.83 (d, 1H, J = 1.9 Hz), 7.77 (d, 1H, J = 8.7 Hz), 7.71
(d, 1H, J = 9.6 Hz), 7.53 (dd, 1H, J = 8.7 Hz, J = 1.9 Hz), 7.46−7.49
(m, 2H), 7.37−7.41 (m, 2H), 7.31−7.35 (m, 1H), 7.20−7.23 (m, 2H),
5.17 (s, 2H), 2.67 (s, 2H), 2.46 (s, 1H), 2.45 (s, 1H), 1.92 (s,1H),
1.70−1.80 (m, 9H); 13C NMR (CDCl3, 150 MHz) δ/ppm 156.9 (s),
143.3 (s), 136.9 (s), 134.6 (s), 128.9 (d), 128.6 (d), 128.3 (s), 128.2
(d), 128.0 (d), 127.5 (d), 123.5 (d), 121.5 (d), 119.2 (d), 107.7 (d),
75.8 (s), 70.1 (t), 37.7 (t), 35.8 (d, 2C), 35.0 (t, 2C), 33.0 (t, 2C), 27.5
(d), 27.0 (d); HRMS (MALDI) calcd for C27H28O2 (+Na+) 407.1981,
found 407.1982.
1
742 (m); H NMR (CDCl3, 300 MHz) δ/ppm 7.86 (s, 1H), 7.76 (d,
1H, J = 8.0 Hz), 7.69 (d, 1H, J = 8.0 Hz), 7.42 (dt, 1H, J = 1.2 Hz, J =
8.0 Hz), 7.34 (dt, 1H, J = 1.2 Hz, J = 8.0 Hz), 7.17 (s, 1H), 3.97 (s,
3H, OCH3), 3.56 (s, 1H, OH), 2.78 (br s, 2H), 2.55 (br s, 2H), 1.60−
2.08 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ/ppm 156.4 (s), 134.2
(s), 133.0 (s), 128.3 (s), 127.9 (d), 127.6 (d), 126.2 (d), 125.8 (d),
123.8 (d), 106.4 (d), 76.7 (s), 55.0 (q), 37.9 (t), 35.5 (d, 2C), 35.3 (t,
2C), 33.1 (t, 2C), 27.3 (d), 26.9 (d); HRMS (MALDI) calcd for
C21H24O2 (+H+ − H2O) 291.1743, found 291.1742.
2-Benzyloxy-3-(2-hydroxy-2-adamantyl)naphthalene (5b).
The Grignard reagent was prepared from 2-benzyloxy-3-bromonaph-
thalene (12a, 640 mg, 2.0 mmol) and magnesium (60 mg, 2.5 mmol)
and reacted with 2-adamantanone (300 mg, 2.0 mmol) to afford 696
mg of the crude product that was purified on a column of silica gel
using CH2Cl2 /hexane 7:3 and 9:1 as eluent to give the product (550
mg, 72%) in the form of colorless crystals: mp 182−183 °C; IR (KBr)
1-Benzyloxy-5-(2-hydroxy-2-adamantyl)naphthalene (9b).
The Grignard reagent was prepared from 1-benzyloxy-5-bromonaph-
thalene47 (12c, 468 mg, 1.5 mmol) and magnesium (50 mg, 2 mmol)
and reacted with 2-adamantanone (225 mg, 1.5 mmol) to afford 530
mg of the crude product that was purified on a column of silica gel
using hexane/diethyl ether (9:1) as eluent to give the product (321 mg
56%) in the form of colorless crystals: mp 155−157 °C; IR (KBr) ν/
J
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cm−1 3545 (m), 2893 (s), 2849 (m), 1256 (m), 1227 (m), 793 (s); 1H
NMR (CDCl3, 600 MHz), δ/ppm 8.40 (d, 1H, J = 8.91 Hz), 8.35 (d,
1H, J = 8.27 Hz), 7.68 (dd, 1H, J = 7.32 Hz, J = 0.79 Hz), 7.49−
7.54(m, 2H), 7.28−7.44 (m, 5H), 6.85 (d, 1H, J = 7.47 Hz), 5.22 (s,
2H), 2.62 (br s, 1H), 2.64 (br s, 1H), 1.89−1.97 (m, 2H, with a
discernible singlet at 1.90), 1.65−1.80 (m, 6H); 13C NMR (CDCl3,
150 MHz) δ/ppm 155.0 (s), 140.2 (s), 137.4 (s), 132.8 (s), 128.7 (d),
128.0 (d), 127.8 (s), 127.5 (d), 125.9 (d), 124.6 (d), 123.8 (d), 122.4
(d), 120.7 (d), 104.7 (d), 78.2 (s), 70.3 (t), 38.0 (t), 27.8 (d), 27.1
(d); HRMS (MALDI) calcd for C27H28O2 (−e−) 384.2095, found
384.2096.
2-(2-Hydroxy-2-adamantyl)-3-hydroxynaphthalene (5).
From 2-(2-hydroxy-2-adamantyl)-3-methoxynaphthalene (5a, 650
mg, 2.1 mmol) and solution of BBr3 (1 M, 8 mL), the reaction gave
630 mg of the crude product that was purified by column filled with
silica gel by use of CH2Cl2 and CH2Cl2−EtOAc to afford 400 mg
(64%) of the pure product in a form of colorless crystals: mp 226−228
°C; IR (KBr) ν/cm−1 3485 (s), 3105 (s), 2902 (s), 2854 (m), 1633
1
(m), 1225 (s), 995 (s), 746 (s); H NMR (DMSO-d6, 600 MHz) δ/
ppm 9.69 (s, 1H, OH), 7.85 (s, 1H), 7.80 (d, 1H, J = 8.1 Hz), 7.63 (d,
1H, J = 8.1 Hz), 7.36 (t, 1H, J = 8.1 Hz), 7.25 (t, 1H, J = 8.1 Hz), 7.16
(s, 1H), 5.07 (s, 1H, OH), 2.76 (br s, 2H), 2.50 (br s, 1H, covered by
DMSO), 2.47 (br s, 1H), 1.80−1.85 (m, 3H), 1.72−1.80 (m, 3H),
1.67 (br s, 2H), 1.57 (d, 2H, J = 11.6 Hz); 13C NMR (DMSO-d6, 150
MHz) δ/ppm 154.7 (s), 133.8 (s), 133.1 (s), 127.9 (d), 127.4 (s),
126.8 (d), 125.9 (d), 125.0 (d), 122.7 (d), 110.5 (d), 75.9 (s), 37.6 (t),
35.0 (t, 2C), 34.8 (d, 2C), 32.7 (t, 2C), 26.8 (d), 26.4 (d); HRMS
(MALDI) calcd for C20H22O2 (+H+ − H2O) 277.1587, found
277.1600.
2-(2-Hydroxy-2-adamantyl)-6-hydroxynaphthalene (6).
From 2-(2-hydroxy-2-adamantyl)-6-methoxynaphthalene (6a, 1.50 g,
4.8 mmol) and a solution of BBr3 (1 M, 15 mL), the reaction gave 1.5
g of the crude product that was purified by crystallization from ethyl
acetate to afford 880 mg (62%) of the pure product in a form of
colorless crystals: mp 196−198 °C; IR (KBr) ν/cm−1 3456 (m), 3238
(m), 2902 (s), 2854 (m), 1604 (m), 1217 (m), 997 (m), 871 (m); 1H
NMR (DMSO-d6, 300 MHz) δ/ppm 9.63 (s, 1H, OH), 7.80 (br s,
1H), 7.74 (d, 1H, J = 8.6 Hz), 7.63 (d, 1H, J = 8.8 Hz), 7.53 (dd, 1H, J
= 1.2 Hz, J = 8.8 Hz), 7.01−7.08 (m, 2H), 4.57 (s, 1H, OH), 2.57 (br
s, 2H), 2.44 (br s, 1H), 2.40 (br s, 1H), 1.82 (br s, 1H), 1.45−1.65 (m,
9H); 13C NMR (DMSO-d6, 75 MHz) δ/ppm 155.1 (s), 140.3 (s),
133.3 (s), 129.6 (d), 127.6 (s), 125.8 (d), 124.7 (d), 124.0 (d), 118.3
(d), 108.2 (d), 73.6 (s), 37.5 (t), 34.9 (d, 2C), 34.5 (t, 2C), 32.6 (t,
2C), 27.0 (d), 26.6 (d); HRMS (MALDI) calcd for C20H22O2 (+H+ −
H2O) 277.1587, found 277.1599.
1-Benzyloxy-4-(2-hydroxy-2-adamantyl)naphthalene (10b).
The Grignard reagent was prepared from 1-benzyloxy-4-bromonaph-
thalene48 (12d, 850 mg, 2.7 mmol) and magnesium (100 mg, 4.2
mmol) and reacted with 2-adamantanone (408 mg, 2.7 mmol) to
afford 1.0 g of the crude product that was purified on a column of silica
gel using CH2Cl2/hexane 3:1 as eluent to give the product (609 mg,
58%) in the form of colorless crystals: mp 152−153 °C; IR (KBr) ν/
cm−1 3570 (s), 3444 (s), 2906 (s), 2854 (w), 1596 (w), 1363 (w),
1
1088 (w), 764 (m); H NMR (CDCl3, 600 MHz) δ/ppm 8.78−8.81
(m, 1H), 8.39−8.48 (m, 1H), 7.52−7.57 (m, 3H, with a discernible
doublet at 7.55, J = 8.3 Hz), 7.41−7.49 (m, 4H), 7.35−7.38 (m, 1H),
6.79 (d, 1H, J = 8.3 Hz), 5.26 (s, 2H), 2.67 (br s, 1H), 2.65 (br s, 1H),
1.95 (br s, 1H), 1.85 (s, 1H), 1.70−1.82 (m, 6H); 13C NMR (CDCl3,
150 MHz) δ/ppm 153.9 (s), 137.0 (s), 132.8 (s), 132.6 (s), 128.5 (d),
127.8 (d), 127.5 (d), 127.3 (s), 127.2 (d), 125.2 (d), 125.1 (d), 124.4
(d), 122.6 (d), 103.1 (d), 77.8 (s), 69.9 (t), 37.9 (t), 27.7 (d), 26.9
(d); HRMS (MALDI) calcd for C27H28O2 (+Na+) 407.1981, found
407.1977.
1-(2-Adamantylidene)naphthalen-2(1H)-one (QM11). The
reaction was carried out in a three-neck flask (100 mL) equipped
with a N2 inlet and a septum. The flask was charged with dry THF (30
mL) and n-BuLi (4 mL, 2.5 M solution in hexane). The mixture was
cooled to 0 °C. To the cooled solution of BuLi, by use of a syringe,
was added a solution of 1-bromo-2-hydroxynaphthalene (1.0 g, 4.5
mmol) in THF (10 mL). After being stirred for 5−10 min at 0 °C, the
reaction mixture was cooled to −78 °C, and solution of 2-
adamantanone (0.67 g, 4.5 mmol) in THF (10 mL) was added
dropvise. After being stirred at −78 °C for 1 h, the reaction mixture
was allowed to reach rt overnight. The next day, saturated aqueous
solution of NH4Cl (50 mL) was added, and extractions with diethyl
ether (3 × 50 mL) were carried out. The extracts were dried over
anhydrous MgSO4. After filtration and evaporation of the solvent 1.5 g
of the crude product was obtained that was purified on a column of
silica gel using CH2Cl2 to afford 600 mg (48%) of the pure product in
the form of yellow crystals: mp 158−160 °C; IR (KBr) ν/cm−1 2908
2-(2-Hydroxy-2-adamantyl)-7-hydroxynaphthalene (8).
From 2-(2-hydroxy-2-adamantyl)-7-methoxynaphthalene (8a, 650
mg, 2.1 mmol) and solution of BBr3 (1 M, 8 mL), the reaction gave
660 mg of the crude product that was purified by crystallization from
ethyl acetate to afford 390 mg (63%) of the pure product in a form of
colorless crystals: mp 250−252 °C; IR (KBr) ν/cm−1 3515 (s), 3240
1
(s), 2914 (s) 1629 (m), 1211 (s), 1003 (m); H NMR (DMSO-d6,
300 MHz) δ/ppm 7.66−7.74 (m, 3H), 7.40 (d, 1H, J = 8.8 Hz), 7.11
(d, 1H, J = 2.2 Hz), 7.03 (dd, 1H, J = 2.2 Hz, J = 8.7 Hz), 2.58 (br s,
2H), 2.44 (br s, 1H), 2.40 (br s, 1H), 1.82 (br s, 1H), 1.56−1.72 (m,
9H), OH signals were not seen; 13C NMR (DMSO-d6, 75 MHz) δ/
ppm 155.2 (s), 143.8 (s), 134.6 (s), 128.6 (d), 127.3 (d), 126.5 (s),
122.5 (d), 121.2 (d), 118.2 (d), 109.1 (d), 73.7 (s), 37.5 (t), 34.9 (d,
2C), 34.4 (t, 2C), 32.6 (t, 2C), 27.0 (d), 26.6 (d); HRMS (MALDI)
calculated for C20H22O2 (+H+ − H2O) 277.1587, found 277.1582.
General Procedure for the Removal of the Benzyl Group.
The benzyl derivative (1 mmol) was dissolved in a mixture of THF
(10 mL) and methanol (0.5 mL) and placed in a vessel for
hydrogenation. Palladium catalyst (5% Pd/C, 40 mg) and pyridine (20
μL) were added. The reaction mixture was hydrogenated in a Paar
apparatus under pressure of 49 psi (3 atm) for 4−48 h, and followed
by TLC, until all benzyl derivative was transformed to naphthol. The
reaction mixture was filtered to remove the catalyst, and the solvent
was removed on a rotary evaporator. The crude product was purified
on a column filled with silica gel by use of CH2Cl2 or hexane/diethyl
ether mixture (3:2) as eluent.
Hydrogenation of 2-Benzyloxy-3-(2-hydroxy-2-adamantyl)-
naphthalene (5b). 2-Benzyloxy-3-(2-hydroxy-2-adamantyl)-
naphthalene (5b, 270 mg, 0.70 mmol) was dissolved in a mixture of
THF, CH3OH, and pyridine (10 mL, 0.5 mL, and 20 μL, respectively)
and hydrogenated during 34 h to furnish 200 mg (97%) of the pure
product 5.
Hydrogenation of 2-Benzyloxy-7-(2-hydroxy-2-adamantyl)-
naphthalene (8b). 2-Benzyloxy-7-(2-hydroxy-2-adamantyl)-
naphthalene (8b, 342 mg, 0.9 mmol) was dissolved in a mixture of
THF, CH3OH, and pyridine (10 mL, 0.5 mL, and 20 μL, respectively)
1
(s), 2847 (m), 1639 (s), 1556 (m), 837 (m); H NMR (DMSO-d6,
600 MHz) δ/ppm 7.48−7.52 (m, 2H), 7.30−7.37 (m, 3H), 6.22 (d,
1H, J = 9.8 Hz), 4.10 (br s, 1H), 3.43 (br s, 1H), 1.94−2.02 (m, 6H),
1.84−1.90 (m, 4H), 1.77 (d, 2H, J = 12.2 Hz); 13C NMR (DMSO-d6,
75 MHz) δ/ppm 192.2 (s), 165.4 (s), 141.2 (d), 133.9 (s), 130.4 (s),
125.6 (d), 128.2 (d), 128.0 (d), 127.8 (d), 127.6 (s), 127.0 (d), 39.7
(t), 39.3 (t), 36.0 (t), 34.5 (d), 31.4 (d), 26.9 (d, 2C); HRMS
(MALDI) calcd for C20H20O (+H+) 277.1587, found 277.1595.
General Procedure for the Removal of the Methyl Groups
from Naphthols with BBr3. The reaction was carried out under N2
atmosphere in a three-neck, round-bottom flask (250 mL) equipped
with a septum and a syringe. In the flask was placed methoxynaph-
thalene derivative (10 mmol) dissolved in dry CH2Cl2 (100 mL) and
the solution cooled to 0 °C by ice bath. To the cold solution, by use of
a syringe, was added dropwise a solution of BBr3 in CH2Cl2 (1 M, 30
mL) during 1 h. After the addition was completed, the stirring was
continued 1 h at 0 °C and at rt overnight. The next day, to the reaction
mixture was added cold water (100 mL), the layers were separated,
and the aqueous layer was extracted with CH2Cl2 (50 mL) and ethyl
acetate (3 × 50 mL). The combined organic extracts were dried over
anhydrous MgSO4, solid was removed by filtration, and solvent was
removed on a rotary evaporator. The obtained crude product was
purified on a column filled with silica gel by use of CH2Cl2 and
CH2Cl2−EtOAc (4:1) as eluent.
K
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and hydrogenated during 48 h to furnish 256 mg (97%) of the crude
product. Obtained crude product was purified on a column filled with
silica gel by use of CH2Cl2 with THF (0→10%) as eluent giving 160
mg (60%) of the pure product 8.
afford 259 mg of the crude amine. The solid was washed with hexane
and ethyl acetate and used in the next step without purification. The
amine was dissolved in dry ethyl ether (50 mL) and purged with HCl
during 30 min, whereupon a colorless precipitate formed. The
precipitate was filtered through a sinter funnel, washed with ether and
CH2Cl2, and dried in vacuum to afford pure product (56 mg, 19%):
colorless crystals; mp 256−258 °C; IR (KBr) ν/cm−1 3196 (m), 3036
(m), 2920 (s), 1605 (m), 1508 (m), 1198 (m); 1H NMR (DMSO-d6,
300 MHz) δ/ppm 9.92 (s, 1H), 8.12 (br s, 3H), 7.98 (br s, 1H), 7.75−
7.85 (m, 2H), 7.56−7.62 (m, 1H), 7.11−7.16 (m, 2H), 2.86 (br s,
2H), 2.34 (br s, 1H), 2.29 (br s, 1H), 1.63−1.97 (m, 10H); 13C NMR
(DMSO-d6, 75 MHz) δ/ppm 156.1 (s), 134.1 (s), 132.6 (s), 129.9
(d), 127.3 (s), 126.4 (d), 126.3 (s), 124.0 (d), 119.0 (d), 108.2 (d),
61.2 (s), 37.2 (t), 33.3 (t, 2C), 31.8 (d, 2C), 31.0 (t, 2C), 26.3 (d),
25.8 (d); HRMS (MALDI) calcd for C20H24ClNO (+H+ − NH4Cl)
277.1587, found 277.1579.
Reaction of QM in the Presence of Acid: General Procedure.
A mixture of QM11 or QM10 (83 mg, 0.3 mmol), CH3CN (8 mL),
H2O (2 mL), and H2SO4 (2 drops) was refluxed for 3 days. After
being cooled to rt, the reaction mixture was poured into cold water,
the layers were separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 20 mL). The combined organic extracts were dried over
anhydrous MgSO4. The solution was filtered and the solvent was
removed on a rotary evaporator to furnish a crude mixture of products
that was chromatographed on silica gel using hexane/ether (3:2) as
eluent.
Hydrogenation of 1-Benzyloxy-5-(2-hydroxy-2-adamantyl)-
naphthalene (9b). 1-Benzyloxy-5-(2-hydroxy-2-adamantyl)-
naphthalene (9b, 176 mg, 0.46 mmol) was dissolved in a mixture of
THF, CH3OH, and pyridine (10 mL, 0.5 mL, and 20 μL, respectively)
and hydrogenated during 4 h to furnish 140 mg of the crude product
that was purified on a column of silica gel by use of hexane/ether 3:2
to afford pure product 9 (111 mg, 82%): mp 218−220 °C; IR (KBr)
ν/cm−1 3518 (m), 3230 (s), 2914 (s), 1599 (m), 1279 (s), 783 (s);1H
NMR (CD3OD, 600 MHz) δ/ppm 8.26 (d, 1H, J = 8.8 Hz), 8.17 (d,
1H, J = 8.5 Hz), 7.65 (d, 1H, J = 7.4 Hz), 7.32 (dd, 1H, J = 8.2, J = 7.5
Hz), 7.16 (dd, 1H, J = 8.8, J = 7.5 Hz), 6.75 (d, 1H, J = 7.5 Hz), 2.70
(s, 1H), 2.69 (s, 1H), 1.87 (br s,1H), 1.62−1.81 (m, 6H); 13C NMR
(CD3OD, 150 MHz) δ/ppm 154.7 (s), 141.4 (s), 134.4 (s), 128.3 (s),
126.7 (d), 125.3 (d), 123.8 (d), 122.9 (d), 120.6 (d), 108.0 (d), 78.7
(s), 39.2 (t), 29.3 (d), 28.6 (d); HRMS (MALDI) calcd for C20H22O2
(+Na+) 317.1512, found 317.1512.
Hydrogenation of 1-Benzyloxy-4-(2-hydroxy-2-adamantyl)-
naphthalene (10b). 1-Benzyloxy-4-(2-hydroxy-2-adamantyl)-
naphthalene (10b, 520 mg, 1.35 mmol) was dissolved in THF (50
mL) and hydrogenated during 48 h at 48 psi. The obtained crude
product was purified on a column filled with silica gel by use of THF
(0→10%) in CH2Cl2 as eluent. Pure compound was identified as
QM10 (311 mg 83%).
QM10 furnished after column chromatography starting QM10 (42
mg, 0.15 mmol), adamantan-2-one (22 mg, 0.15 mmol), and α-
naphthol (21 mg, 0.15 mmol).
4-(2-Adamantylidene)naphthalene-1(4H)-one (QM10): yel-
low crystals; mp 152−153 °C; IR (KBr) ν/cm−1 2918 (s), 2850
1
(m), 1630 (s), 1595 (s), 1540 (s), 1305 (m), 958 (w), 756 (m); H
QM11 furnished after column chromatography protoadamantane
derivative 14 (18 mg, 0.06 mmol), starting QM11 (5 mg, 0.02 mmol),
adamantan-2-one (25 mg, 0.17 mmol), and β-naphthol (26 mg, 0.18
mmol).
NMR (DMSO-d6, 600 MHz) δ/ppm 8.14 (d, 1H, J = 10.3 Hz), 8.04
(dd, 1H,J = 7.8 Hz, J = 1.4 Hz), 7.71 (d, 1H, J = 7.8 Hz), 7.64 (dt, 1H,
J = 1.3 Hz, J = 8.0 Hz), 7.51 (dt, 1H, J = 0.9 Hz, J = 7.4 Hz), 6.3 (d,
1H, J = 10.3 Hz), 3.73 (s, 1H), 3.61 (s, 1H), 1.85 − 2.17 (m. 12H);
13C NMR (DMSO-d6, 150 MHz) δ/ppm 183.9 (s), 168.3 (s), 139.4
(d), 135.6 (s), 132.0 (s), 130.6 (d), 127.6 (d), 127.2 (d) 125.7 (d),
123.8 (d), 123.0 (s), 39.7 (t, 2C), 39.5 (t, 2C), 37.2 (d), 35.9 (t), 35.3
(d), 27.7 (d, 2C); HRMS (MALDI) calcd for C20H20O2 (+ H+)
277.1587, founded 277.1583.
3-(H-endo)-2-Oxahexacyclo[9.8.0.15,9. 17,10.03,10.012,17]-
unicosa-11,13,15,17,19-pentaene (14): colorless crystals; mp
118−119 °C; IR (KBr) ν/cm−1 2939 (s), 1585 (m), 1454 (m),
1
1252 (s), 976 (s) 812 (s), 752 (m); H NMR (CDCl3, 600 MHz) δ/
ppm 8.02 (d, 1H, J = 8.1 Hz), 7.78 (d, 1H, J = 8.1 Hz), 7.61 (d, 1H, J
= 8.6 Hz), 7.37−742 (m, 1H), 7.24−7.29 (m, 1H), 7.15 (d, 1H, J = 8.6
Hz), 4.85 (d, 1H, J = 9.5 Hz), 3.16−3.21 (m, 1H), 2.5 (br s, 1H),
2.27−2.35 (m, 2H), 2.17−2.23 (m, 1H), 2.07−2.12 (m, 1H), 1.97−
2.04 (m, 2H), 1.83−1.89 (m, 1H), 1.64−1.69 (m, 2H), 1.49−1.55 (m,
2H); 13C NMR (CDCl3, 150 MHz) δ/ppm 157.8 (s), 130.3 (s), 130.2
(s), 129.3 (d), 128.6 (s), 128.3 (d), 126.0 (d), 122.5 (d), 121.6 (d),
112.7 (d), 89.6 (d), 53.3 (s), 43.9 (t), 43.07 (t), 43.05 (d), 37.9 (t),
36.5 (d), 35.3 (t), 34.0 (t), 26.7 (d); HRMS (MALDI) calcd for
C20H20O 276.1509, found 276.1519.
2-(2-Azido-2-adamantyl)-6-hydroxynaphthalene (13). A two-
neck flask (50 mL) was charged with sodium azide (130 mg, 2.0
mmol) and CHCl3 (6 mL). The obtained suspension was cooled in a
salt−ice bath, and by use of a syringe, and TFA (375 μL, 5 mmol) was
slowly added. After 10 min of stirring, a suspension of alcohol 6 (294
mg, 1.0 mmol) in CHCl3 (5 mL) was added. The reaction mixture was
stirred at −5 °C for 4 h and at rt overnight. To the reaction mixture
was added aqueous ammonia (10 mL, 15%), and the layers were
separated. The aqueous layer was extracted with CHCl3 (2 × 10 mL),
The combined extracts were dried over anhydrous MgSO4, the
solution was filtered, and solvent was removed on a rotary evaporator
to furnish crude azide that was purified on a column of silica gel by use
20% EtOAc in CH2Cl2 as as eluent to afford pure product (287 mg,
90%) in a form of pale yellow crystals: mp 134−135 °C; IR (KBr) ν/
Photochemical Experiments: General Method. In a quartz
vessel was placed a CH3OH or CH3OH−H2O (3:1 or 4:1) solution
(100 mL, c ∼10−3 M) of naphthalene derivatives 5−9 (20−100 mg)
and the solution irradiated in a Rayonet reactor using 16 lamps (1
lamp −8 W, with the output at 254 or 300 nm) for 1 min to 1 h. Prior
to, and during the irradiation, the solution was continuously purged
with a stream of Ar and cooled by a coldfinger condenser. After
irradiation, CH3OH was removed on a rotary evaporator and the
residue (if irradiated in CH3OH−H2O) extracted with EtOAc (3 × 75
mL). Extracts were dried over anhydrous MgSO4, filtered and solvent
was removed on a rotary evaporator. The residue was chromato-
graphed on a TLC using CH2Cl2−EtOAc (30%) as eluens.
1
cm−1 3446 (s), 2920 (m), 2089 (m), 1635 (w), 1238 (w); H NMR
(CDCl3, 600 MHz) δ/ppm 7.82 (d, 1H, J = 1.8 Hz), 7.76 (d, 1H, J =
8.9 Hz), 7.72 (d, 1H, J = 8.9 Hz), 7.54 (dd, 1H, J = 1.8 Hz, J = 8.9 Hz),
7.14 (d, 1H, J = 2.5 Hz), 7.11 (dd, 1H, J = 2.5 Hz, J = 8.9 Hz), 5.04 (s,
1H), 2.75 (s, 2H), 2.37 (s, 1H), 2.34 (s, 1H), 1.97 (br s, 1H), 1.72−
1.86 (m, 9H); 13C NMR (CDCl3, 150 MHz) δ/ppm 154.0 (s), 135.5
(s), 134.0 (s), 130.5 (d), 128.8 (s), 127.3 (d), 124.9 (d), 124.3 (d),
118.2 (d), 109.3 (d), 37.8 (t), 34.2 (t), 33.5 (t), 33.4 (d), 27.5 (d),
26.9 (d); HRMS (MALDI) calcd for C20H21N3O (+Na+) 342.1577,
found 342.1577.
2-(2-Amino-2-adamantyl)-6-hydroxynaphthalene Hydro-
chloride (7). A two-neck flask (100 mL) equipped with a condenser
was charged with an absolute ethanol solution (10 mL) of azide 13
(287 mg, 0.9 mmol). To the solution was added a suspension of
freshly activated Raney Ni (∼2.5 g). The suspension was heated at
∼70 °C overnight. The next day, the reaction mixture was filtered to
remove the Raney Ni, and the ethanol solution was evaporated to
Irradiation of 5 (15 mg, 0.051 mmol) in CH3OH (100 mL) for 15
min gave after evaporation of the methanol crude mixture that was
pure enough for the characterization.
2-Hydroxy-3-(2-methoxy-2-adamantyl)naphthalene (5c): mp
148−150 °C; IR (KBr) ν/cm−1 3305 (s), 2901 (s), 2854 (m), 1637
(m), 1504 (m), 1458 (m), 1290 (m), 1163 (m), 1041 (m), 872 (m),
742 (m); 1H NMR (CDCl3, 600 MHz) δ/ppm 8.32 (s, 1H, OH), 7.80
(s, 1H), 7.73 (dd, 1H, J = 0.6 Hz, J = 8.0 Hz), 7.66 (dd, 1H, J = 0.6 Hz,
J = 8.0 Hz), 7.39 (dt, 1H, J = 1.2 Hz, J = 8.0 Hz), 7.29 (dt, 1H, J = 1.2
Hz, J = 8.0 Hz), 7.24 (s, 1H, covered by CDCl3), 3.04 (s, 3H, OCH3),
2.73 (br s, 2H), 2.54 (br s, 1H), 2.51 (br s, 1H), 2.23 (dd, 1H, J = 2.0
L
dx.doi.org/10.1021/jo3002479 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
Hz, J = 12.0 Hz), 2.04 (ddd, 1H, J = 2.8 Hz, J = 2.9 Hz, J = 12.8 Hz),
1.90 (br s, 1H), 1.83 (br s, 1H), 1.70−1.74 (m, 2H), 1.69 (ddd, 1H, J
= 2.6 Hz, J = 2.8 Hz, J = 12.8 Hz), 1.64 (ddd, 1H, J = 2.6 Hz, J = 2.8
Hz, J = 12.8 Hz), 1.59 (ddd, 1H, J = 2.6 Hz, J = 2.8 Hz, J = 12.8 Hz),
1.35 (d, 1H, J = 12.8 Hz); 13C NMR (CDCl3, 125 MHz) δ/ppm 154.1
(s), 134.1 (s), 129.4 (d), 128.8 (s), 127.7 (d), 127.6 (s), 126.3 (d),
125.8 (d), 123.2 (d), 111.9 (d), 83.8 (s), 48.7 (q), 37.6 (t), 36.2 (t),
35.3 (d), 34.2 (t), 33.1 (t), 32.5 (t), 30.7 (d), 27.1 (d), 26.7 (d);
HRMS (MALDI) calcd for C21H24O2 (+K+) 347.1408, found
347.1394.
Irradiation of 6 (30 mg, 0.10 mmol) in CH3OH (100 mL) for 1 h
gave after evaporation of the methanol crude mixture that contained
15% of the product (according to NMR). Separation attempt on TLC
using CH2Cl2−EtOAc (5%) afforded the starting material.
The pure product 6c was obtained by stirring 6 (50 mg) in CH3OH
(50 mL) in the presence of H2SO4 (200 mg) overnight. After the
conversion was completed, as indicated by HPLC analysis, to the
solution NaHCO3 was added (1.0 g), and stirring was continued over
1 h. The mixture was filtered and the solvent evaporated. The
remaining solid was extracted by ethyl acetate to afford the pure
product (35 mg, 65%).
2-Hydroxy-6-(2-methoxy-2-adamantyl)naphthalene (6c): mp
195−197 °C; IR (KBr) ν/cm−1 3232 (m), 2930 (s), 2856 (m), 1639
(m), 1290 (m), 1047 (m), 893 (m); 1H NMR (DMSO-d6, 300 MHz)
δ/ppm 7.82 (s, 1H), 7.78 (d, 1H, J = 8.5 Hz), 7.65 (d, 1H, J = 8.6 Hz),
7.47 (d, 1H, J = 8.6 Hz), 7.04−7.10 (m, 2H), 2.70 (br s, 2H), 2.68 (s,
3H, OCH3), 2.28 (br s, 1H), 2.24 (br s, 1H), 1.85 (br s, 1H), 1.55−
1.80 (m, 9H), OH signal was not observed; 13C NMR (DMSO-d6, 75
MHz) δ/ppm 155.7 (s), 134.4 (s), 133.7 (s), 129.7 (d), 127.0 (s),
126.5 (d), 125.9 (d), 125.1 (d), 118.6 (d), 108.2 (d), 79.3 (s), 47.5
(q), 37.2 (t), 34.2 (d, t, 4C), 32.4 (t, 2C), 27.1 (d), 26.3 (d); HRMS
(MALDI) calcd for C21H24O2 (+Na+) 331.1668, found 331.1676.
Irradiation of 8 (40 mg, 0.10 mmol) in CH3OH (100 mL) for 15
min gave after evaporation of the methanol crude mixture that
contained 30% of the product (according to NMR). Attempt of
separation on a TLC using CH2Cl2−EtOAc (5%) afforded the starting
material.
The pure product 8c was obtained by stirring 8 (50 mg) in CH3OH
(50 mL) in the presence of H2SO4 (200 mg) overnight. After the
conversion was completed, as indicated by HPLC analysis, to the
solution was added NaHCO3 (1.0 g), and stirring was continued over
1 h. The mixture was filtered and the solvent evaporated. The
remaining solid was extracted by ethyl acetate to afford the pure
product (35 mg, 65%).
2.1 Hz); 13C NMR (CDCl3, 150 MHz) δ/ppm 151.6 (s), 136.8 (s),
133.1 (s), 128.5 (d), 126.0 (s), 124.3 (d), 123.1 (d), 121.5 (d), 120.3
(d), 107.8 (d), 82.8 (s), 48.3 (q), 37.9 (t), 37.2 (d), 36.0 (t), 34.0 (t),
33.6 (t), 32.9 (t), 31.4 (d), 27.8 (d), 27.0 (d); HRMS (MALDI) calcd
for C21H24O2 (+K+) 347.1408, found 347.1399.
Irradiation in the Presence of Ethanolamine. Naphthol derivative
5 (50 mg, 0.17 mmol) was dissolved in CH3CN−H2O (3:1, 100 mL).
To the solution was added ethanolamine (150 mg, 2.45 mmol). The
solution was purged with Ar for 30 min and irradiated in a Rayonet
reactor at 254 nm for 5 min. After the irradiation, H2O (100 mL) was
added, and the extractions with ethyl acetate (3 × 75 mL) were carried
out. The extracts were dried over anhydrous MgSO4, the solution was
filtered, and the solvent was removed on a rotary evaporator. The
residue was chromatographed on a TLC using CH2Cl2/ethyl acetate
(20%) as eluent to afford pure product 15 (34 mg, 59%) in a form of
yellowish crystals.
2-[2-(2-Hydroxyethylamino)-2-adamantyl]-3-hydroxynaph-
thalene (15): mp 134−135 °C; IR (KBr) ν/cm−1 3381 (m), 2914 (s),
28587 (m), 1631 (m), 1454 (m), 738 (m); 1H NMR (DMSO-d6, 600
MHz) δ/ppm 11.60 (br s, 1H), 7.79 (d, 1H, J = 7.3 Hz), 7.78 (s, 1H),
7.61 (d, 1H, J = 8.0 Hz), 7.35 (ddd, 1H, J = 1.1 Hz, J = 7.3 Hz, J = 8.0
Hz), 7.23 (ddd, 1H, J = 1.1 Hz, J = 7.3 Hz, J = 8.0 Hz), 7.07 (s, 1H),
4.60 (br s, 1H), 3.34−3.40 (m, 2H), 2.76 (br s, 1H), 2.62 (br s, 1H),
2.50−2.54 (m, 2H), 2.37 (d, 1H, J = 13.0 Hz), 2.25 (d, 1H, J = 13.0
Hz), 1.85−1.95 (m, 3H), 1.76 (br s, 1H), 1.65−1.72 (m, 3H), 1.62
(dd, 1H, J = 13.0 Hz, J = 2.0 Hz), 1.57 (dd, 1H, J = 13.0 Hz, J = 3.0
Hz), 1.26 (d, 1H, J = 12.8 Hz); 13C NMR (DMSO-d6, 75 MHz) δ/
ppm 155.6 (s), 133.3 (s), 131.1 (s), 128.9 (d), 127.8 (d), 127.0 (s),
125.8 (d), 125.1 (d), 122.4 (d), 110.5 (d), 62.4 (s), 60.4 (t), 42.8 (t),
37.9 (t), 34.9 (t), 34.1 (t), 33.7 (d), 31.9 (t), 31.8 (t), 30.1 (d), 27.0
(d), 26.2 (d); HRMS (MALDI) calculated for C22H27NO2 (+Na+)
360.1934, found 360.1933.
Irradiation in CH3CN−D2O. To a solution of 9 (5 mg, 0.017 mmol)
in CH3CN (12 mL) was added D2O (3 mL). The solution was purged
with Ar for 30 min and irradiated in a Luzchem reacator at 300 nm (8
lamps) for 20 min. After the irradiation, H2O (30 mL) was added, and
the extractions with EtOAc (3 × 25 mL) were carried out. The extracts
were dried over anhydrous MgSO4. After filtration and evaporation of
the solvent, the crude mixture was analyzed by NMR and MS: MS
(ESI) 37% D, 7% 2D.
Quantum Yields for the Photomethanolysis Reaction.
Solutions of 5−9 in CH3OH−H2O (4:1) as well as a solution of
valerophenone in CH3CN−H2O (1:1) were freshly prepared and their
concentrations adjusted to have absorbances 0.4−0.8 at 254 nm. After
adjustment of the concentration and measurement of the correspond-
ing UV−vis spectra the solutions were filled in quartz cuvettes (15
mL), purged with a stream of N2 (20 min each), and sealed with a
septum. The cuvettes were irradiated at the same time in a Luzchem
reactor equipped with a merry-go-round and two lamps with the
output at 254 nm for 0.5, 1, 2, 5, 10, and 15 min. After each irradiation,
the samples were taken from the cuvettes by use of a syringe and
analyzed by HPLC. Quantum yields for the methanolysis were
calculated using valerophenone actinometer (formation of acetophe-
none in aqueous media, Φ = 0.65 0.03).28
Antiproliferative Investigation. Cells (HCT 116, MCF-7, and H
460) were cultured as monolayers and maintained in Dulbecco’s
modified Eagle medium (DMEM) supplemented with 10% fetal
bovine serum (FBS), 2 mM L-glutamine, 100 U/mL of penicillin, and
100 μg/mL of streptomycin in a humidified atmosphere with 5% CO2
at 37 °C. The cells were inoculated in parallel on two 96-well
microtiter plates on day 0, at 1.5 × 104 cells/mL (HCT 116 and H
460), and at 2 × 104 cells/mL (MCF-7). Test agents were added in
10-fold dilutions (10−8 to 10−4 M) on the next day and incubated for a
further 72 h. Working dilutions were freshly prepared on the day of
testing. One of the plates was left in the dark, while the other was
irradiated in a Luzchem reactor (6 lamps 300 nm, 1 min) 4, 28, and 52
h after the addition of the compounds. After 72 h of incubation, the
cell growth rate was evaluated by performing the MTT assay46 which
detects dehydrogenase activity in viable cells. The absorbance (A) was
2-Hydroxy-7-(2-methoxy-2-adamantyl)naphthalene (8c): mp
118−120 °C; IR (KBr) ν/cm−1 3417 (m), 2908 (s), 2852 (m), 1630
1
(m), 1448 (m), 1207 (m); H NMR (DMSO-d6, 300 MHz) δ/ppm
7.70 (d, 1H, J = 8.6 Hz), 7.67 (d, 1H, J = 8.6 Hz), 7.66 (br s, 1H), 7.29
(dd, 1H, J = 1.5 Hz, J = 8.6 Hz), 7.11 (d, 1H, J = 2.3 Hz), 7.06 (dd,
1H, J = 2.3 Hz, J = 8.6 Hz), 2.68 (s, 3H, OCH3), 2.67 (br s, 2H), 2.27
(br s, 1H), 2.23 (br s, 1H), 1.84 (br s, 1H), 1.55−1.75 (m, 9H), OH
signal was not observed; 13C NMR (DMSO-d6, 75 MHz) δ/ppm
156.8 (s), 137.8 (s), 134.3 (s), 128.4 (d), 127.4 (d), 126.3 (s), 124.8
(d), 121.1 (d), 119.3 (d), 109.2 (d), 79.4 (s), 47.6 (q), 37.2 (t), 34.2
(d, t, 4C), 32.4 (t, 2C), 27.1 (d), 26.3 (d); HRMS (MALDI) calcd for
C21H24O2 (+Na+) 331.1668, found 331.1668.
Irradiation of 9 (40 mg, 0.14 mmol) in CH3OH−H2O (9:1, 100
mL) for 15 min gave after evaporation of the solvent crude mixture
that was purified on a TLC using CH2Cl2 to afford 30 mg (72%) of the
pure product.
1-Hydroxy-5-(2-methoxy-2-adamantyl)naphthalene (9c):
156−158 °C; IR (KBr) ν/cm−1 3294 (m), 2916 (s), 2858 (m),
1
1595 (m), 1269 (m), 783 (m); H NMR (CDCl3, 600 MHz) δ/ppm
8.43 (dd, 1H, J = 0.6 Hz, J = 8.8 Hz), 8.18 (dt, 1H, J = 8.3 Hz, J = 1.0
Hz), 7.62 (d, 1H, J = 7.1 Hz), 7.40 (dd, 1H, J = 7.1 Hz, J = 8.3 Hz),
7.21 (dd, 1H, J = 7.3 Hz, J = 8.8 Hz), 6.76 (dd, 1H, J = 0.6 Hz, J = 7.3
Hz), 3.12 (br s, 1H), 2.89 (s, 3H, OCH3), 2.92 (br s, 1H), 2.71 (d, 1H,
J = 12.2 Hz), 2.64 (d, 1H, J = 12.2 Hz), 2.36−2.42 (m, 2H), 1.90−1.98
(m, 2H), 1.68−1.80 (m, 3H), 1.58 (dq, 1H, J = 12.1 Hz, J = 2.5 Hz),
1.47 (dq, 1H, J = 13.1 Hz, J = 3.0 Hz), 1.09 (dq, 1H, J = 13.1 Hz, J =
M
dx.doi.org/10.1021/jo3002479 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
measured on a microplate reader at 570 nm. Each test was performed
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ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental procedures, data obtained by fluores-
cence measurements, LFP, B3LYP calculations, H and 13C
1
NMR spectra, and crystallographic data (collection and
structure refinement data, details on crystal structures CCDC
nos. 865242−865244). This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) (a) Engholm, M.; Koch, T. H. J. Am. Chem. Soc. 1989, 111,
8291−8293. (b) Gaudiano, G.; Frigerio, M.; Bravo, P.; Koch, T. H. J.
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AUTHOR INFORMATION
■
Corresponding Author
*Tel: +385 1 4561 141. Fax: + 385 1 4680 195. E-mail:
nbasaric@irb.hr.
́
Johnson, D. S.; Cai, H.; Mesini, P.; Garbaccio, R. M.; Jin, Q.; Kitos, P.
́
A. J. Am. Chem. Soc. 1997, 119, 4987−4998. (c) Boger, D. L.; Santillan,
A., Jr.; Searcey, M.; Jin, Q. J. Am. Chem. Soc. 1998, 120, 11554−11557.
(16) Doria, F.; Richter, S. N.; Nadai, M.; Colloredo-Mels, S.; Mella,
M.; Palumbo, M.; Freccero, M. J. Med. Chem. 2007, 50, 6570−6579.
(17) Wan, P.; Barker, B.; Diao, L.; Fisher, M.; Shi, Y.; Yang, C. Can. J.
Chem. 1996, 74, 465−475.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(18) (a) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2000,
122, 9854−9855. (b) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem.
Soc. 2001, 123, 8089−8094. (c) Chiang, Y.; Kresge, A. J.; Zhu, Y. J.
Am. Chem. Soc. 2002, 124, 717−722. (d) Chiang, Y.; Kresge, A. J.;
Zhu, Y. J. Am. Chem. Soc. 2002, 124, 6349−6356.
These materials are based on work financed by the National
Foundation for Science, Higher Education and Technological
Development of the Republic of Croatia (HRZZ Grant No.
02.05/25), the Ministry of Science Education and Sports of the
Republic of Croatia (Grant No. 098-0982933-2911), the
Natural Sciences and Engineering Research Council
(NSERC) of Canada, and the University of Victoria.
(19) Nakatani, K.; Higashida, N.; Saito, I. Tetrahedron Lett. 1997, 38,
5005−5008.
̌
́ ̌ ́ ́
N.; Zabcic, I.; Mlinaric-Majerski, K.; Wan, P. J. Org.
(20) Basaric,
Chem. 2010, 75, 102−116.
(21) (a) Basaric, N.; Cindro, N.; Hou, Y.; Zabci
Majerski, K.; Wan, P. Can. J. Chem. 2011, 89, 221−234. (b) Basaric,
N.; Cindro, N.; Bobinac, D.; Mlinaric-Majerski, K.; Uzelac, L.; Kralj,
M.; Wan, P. Photochem. Photobiol. Sci. 2011, 10, 1910−1925.
(c) Basaric, N.; Cindro, N.; Bobinac, D.; Mlinaric-Majerski, K.;
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c, I.; Mlinaric-
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