Simplified synthesis of 1,1′[14C]-methylene-di (2-naphthol). A radiochemical and kinetic approach

Article abstract of DOI:10.1002/jlcr.838

The synthesis of the 1,1′[¹⁴C]-methylene-di-(2-naphthol) 2, as the radiolabeled probe of a possible interaction between the β-amyloid fibrils and the di-naphthol mojety in the Alzheimer's disease, is reported. Very simple radiochemical procedure, starting from [ ¹⁴C]paraformaldehyde, produced 8.66 MBq of compound 2 at the specific radioactivity of 1.22 TBq/mol. A mechanistic and kinetic approach allowed the comprehension of the right experimental conditions. The stability of compound 2 in acetonitrile solution was investigated, denoting a significative decomposition process through the transient formation of the 1,2-naphthyne intermediate. Copyright

Full text of DOI:10.1002/jlcr.838

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2004; 47: 543–556.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.838
Research Article
Simplified synthesis of 1,10[14C]-methylene-di
(2-naphthol). A radiochemical and kinetic approach
Giancarlo Angelini1,*, Ornella Ursini1, Patrizia Minetti2, Diana Celona2 and
Francesco De Angelis3
1 Istituto di Metodologie Chimiche C.N.R., Area della Ricerca di Roma (Montelibretti)
C.P. 10, I-00016 Monterotondo Stazione, Roma, Italy
2 Sigma Tau Industrie Farmaceutiche Riunite, Via Pontina km.30,400, I-00040 Pomezia,
Roma, Italy
3 Dipartimento di Chimica, Universita’ dell’Aquila, Coppito, I-67010 L’Aquila, Italy
Summary
The synthesis of the 1,10[14C]-methylene-di-(2-naphthol) 2, as the radiolabeled probe
of a possible interaction between the b-amyloid fibrils and the di-naphthol mojety in
the Alzheimer’s disease, is reported. Very simple radiochemical procedure, starting
from [14C]paraformaldehyde, produced 8.66 MBq of compound 2 at the specific
radioactivity of 1.22 TBq/mol. A mechanistic and kinetic approach allowed the
comprehension of the right experimental conditions. The stability of compound 2 in
acetonitrile solution was investigated, denoting a significative decomposition process
through the transient formation of the 1,2-naphthyne intermediate. Copyright #
2004 John Wiley & Sons, Ltd.
Key Words: Alzheimer’s disease; 1,10[14C]-methylene-di-(2-naphthol); 2-naphthol
hydroxymethylation; 1,2-naphthyne
Introduction
Alzheimer’s disease (AD) is one of the most common progressive neurode-
generative diseases that affect elderly people. The presence of amyloid plaques
and neuronal cytoskeleton alterations is the most common evidence of AD.
The b-amyloid (bA) peptide is composed of 39–43 amino acids, and is able to
form fibrils. Significant evidence suggests that fibrillary plaques are mainly
*Correspondence to: G. Angelini, Istituto di Metodologie Chimiche C.N.R., Area della Ricerca di
Roma (Montelibretti) C.P. 10, I-00016 Monterotondo Stazione, Roma, Italy. E-mail: giancarlo.
angelini@imc.cnr.it
Copyright # 2004 John Wiley & Sons, Ltd.
Received 24 November 2003
Revised 27 April 2004
Accepted 30 April 2004

544
G. ANGELINI ET AL.
formed by aggregates of the bA peptide which, on its turn, is a metabolic
product of a transmembrane glycoprotein present in nervous system tissues,
the so-called amyloid precursor protein (APP). Proteolytic processing of the
APP by the action of different secretes,1 in fact, splits APP into several
fragments, one of them being the bA peptide.
The pathologic properties of this peptide, such as neurotoxicity and
resistance to proteolytic degradation, depend on the ability of bA to form
b-sheet structures which rapidly collape into amyloid fibrils.2 Recent
etiopathogenesis studies demonstrate, in fact, the significant role of the
insoluble b-amyloid fibrils and plaques3 in AD affected patients. It is
thus conceivable that, under the molecular point of view, inhibition of
the b-sheet formation as well as of the bA peptide self aggregation, or even the
possibility to degrade the amyloid plaques, could represent an important
therapeutic target.4
As a part of our research in this field, we are involved in the study of
molecules possibly able to prevent the bA aggregation process and fibrils
formation: one of these, the 1,10-methylene-di-(2-naphthol), is the object of a
recently published patent.5 The di-naphthol frame itself, in our project, is also
used as a scaffold suitable for the assembly of new functionalities.5
Under a different point of view, the possibility of a binding between the di-
naphthol molecule itself and the b-amyloid fibrils suggests the use of this
molecule as a molecular label for the evaluation of amyloidic deposits in the
cerebral tissue of AD patients or, even, for the AD diagnosis. In this context,
the autoradiographic techniques appear to be the methods of choice. In this
paper, the synthesis of the 1,10[14C]-methylene-di-(2-naphthol) as a radiola-
beled probe is described, together with a comprehensive study of the cold
reaction for the optimization of the radiolabeling conditions. Due to the
ability of di-naphthol to bind to b 1-42 it could be also possible, by using the
labeled molecule, to evaluate its binding in competition with other non labeled
compounds, putative intercalators during the b-amyloid aggregation process.
As to the radiochemical synthesis, which is to be performed at high specific
radioactivity, it has to be carried out in a simple way and its performance
must fit with the best yield of the product.6–9 In this context an important
point of the radiosynthetic procedure is the isolation and purification
of the product. The usual radioactivity of 14C employed in a radiochemical
process carried out at the maximum specific radioactivity, means massive
amounts of products of only a few milligrams or less. Any purification
process determines, as a negative consequence, the loss of consistent amounts
of the product.
An efficient, fast and clean procedure moves through synthetic steps which
allow to avoid any purification of the product. This means the complete
consuming of the reagents and the absence of any by-products and
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 543–556

A RADIOCHEMICAL AND KINETIC APPROACH
545
decomposition products as well. All these reaction features are not always easy
to introduce in the same synthetic procedure but, in most of the cases,
preliminary mechanistic and kinetic studies promote the design of simple,
effective and clean procedures.
The synthesis of dimeric compounds such as methylene-di-naphthyl or
phenyl derivatives is a well-known procedure which uses hydroxymethylation
of the aromatic compound in the acidic medium as the first reaction step.10–12
In particular, the presence of an extra hydroxyl group on the aromatic ring
favors the reaction even if the formation of several naphthoquinone
derivatives has also been described.13 The 1,10-methylene-di-(2-naphthol),
whose anthelmintic activity and antinflammatory properties have been studied
more than 20 years ago,14–16 has been also recently employed as an
intermediate compound for the preparation of heat-resistant polyesters.17
Its synthesis is reported in literature17–19 but, despite the high production
yields, the experimental procedures are characterized by drastic conditions
(long reaction time and high temperature) which do not match our synthetic
requirements. Oliver et al.20 have also prepared 1,10-methylene-di-(2-naphthol)
labeled with 14C at C-8 of both aromatic rings and, in a different synthesis, at
the methylene carbon, starting from 2-[8-14C]naphthol and [14C]formaldehyde,
respectively. However in the former case, they obtained the product labeled on
the naphtalene moieties only with a limited yield, probably due to the high
reaction temperature. In the latter case the product was labeled at the
methylene position (in accordance with our own project) but the specific
radioactivity is very low, due to the low radio labeling value of the starting
[14C]formaldehyde they used.
We propose, herein, a very simple radiochemical procedure for the synthesis
of 1,10[14C]-methylene-di-(2-naphthol) 2, starting from 2-naphthol and
[14C]paraformaldehyde at very high specific radioactivity. Indications for its
preparation in a simply efficient way came from the study of the reaction
mechanism and of the kinetic parameters.
Results and discussion
A reaction mechanism for the synthesis of 1,10-methylene-di-(2-naphthol),
which comprises two steps, can be conceivably depicted as follows (Scheme 1):
(i) thermal depolymerization of paraformaldehyde (T>908C) to formalde-
hyde;
(ii) in situ protonation of formaldehyde;
(iii) first step: electrophilic aromatic substitution and formation of
1-hydromethyl-2-naphthol (intermediate 1);
(iv) second step: in situ protonation of 1 and electrophilic aromatic
substitution to produce 1,10-methylene-di-(2-naphthol) 2.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 543–556

546
G. ANGELINI ET AL.
Temp.
PARAFORMALDEHYDE
HCHO formaldehyde
+
H
+
O−H
C
H
H
First step
k1
+
OH
+ [CH2OH]+
Multi-hydroxymethyl-2-Naphthol
collateral reaction
OH
1
CH2OH
+
+
H
H
k2
OH
OH
Second step
5
4
3
6
7
2
OH
8
1
collateral reaction
Multi-(2-hydroxy-Naphthyl)
methane derivatives
CH2
+ [CH2OH]+
+
8
1
OH
2
3
OH
7
6
3
5
4
2
Scheme 1.
Due to the high propensity of intermediate 1 and product 2 as well to be
further hydroxy-methylated, also collateral reactions have to be considered.21
As a consequence, a mixture of multi (2-hydroxy-naphthyl)-methane
derivatives 3 has been evidenced.
The importance of these collateral reactions depends on the following
factors:
(i) the free formaldehyde concentration;
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 543–556

A RADIOCHEMICAL AND KINETIC APPROACH
547
(ii) the concentration of 2-naphthol;
(iii) the reaction temperature;
(iv) the reaction time.
Considering that the 2-naphthol and formaldehyde concentrations must be
linked by the stoichiometry ratio of 2:1, their absolute values have not any
direct influence on the collateral reactions. Conversely, these reactions are kept
to an acceptable level if prolonged reaction times and high reaction
temperature are be avoided. The by-products of series 3 and their precursors
are quite negligible when the reaction is carried out at T51008C and within 1 h
time. These strict reaction conditions, the low reaction temperature in
particular, determine the incomplete depolymerization of paraformaldehyde.
Accordingly, the free formaldehyde which evolved was roughly estimated at
about 50% of the starting paraformaldehyde. This defect of formaldehyde
does limit the complete hydroxy-methylation 2-naphthol to form intermediate
1 and, as a consequence, a defect of 2-naphthol itself was employed, in order to
ensure its complete consumption.
Accordingly, a thorough study was undertaken in order to find the best
experimental conditions, as far as the correct ratio between the free
formaldehyde and the 2-naphthol concentrations is concerned, at a reaction
temperature which was accurately kept below 1008C (see Table 1).
Some kinetic considerations can facilitate the comprehension of the
synthetic process. As reported in Table 1, intermediate 1 is never isolated in
appreciable amounts, with
d½intermediate 1ꢀ
¼ 0 ¼ k1½CH2OHþꢀ½2-naphtholꢀ
dt
ꢁ k2½intermediate 1ꢀ½2-naphtholꢀ
ð1Þ
the only exception of entry 5, where a large defect of 2-naphthol is employed.
Its instantaneous concentration can be considered very low and constant
during the reaction course. Under this condition the steady-state approxima-
tion is conceivable.22 As a consequence, the reaction rate of the first step is
quite similar to the second one. It follows that:
k1½CH2OHþꢀ ¼ k2½intermediate 1ꢀ
ð2Þ
Clearly both the reaction rates depend on the concentration of 2-naphthol
but, by considering the instantaneous concentration of intermediate 1 always
lower than the protonated formaldehyde, it follows that k2 is higher than k1 .
From a qualitative point of view, we can conclude that
(i) the second step can be sufficiently fast also if the 2-naphthol concentra-
tion is low;
(ii) under the same conditions the first step is very slow.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 543–556

548
G. ANGELINI ET AL.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 543–556

A RADIOCHEMICAL AND KINETIC APPROACH
549
Accordingly, appreciable amounts of 2-naphthol remain unreacted during
the scheduled reaction time. In order to ensure the complete consumption
of 2-naphthol, this has to be present in the reaction mixture as a minor
component with respect to the free formaldehyde. Following these requisites,
the correct [2-naphthol]/[paraformaldehyde] ratio was approximately esti-
mated as equal to 0.8, which turns out to be 1.6 [2-naphthol]/[paraformalde-
hyde] by considering the partial paraformaldehyde depolymerization: 50% at
T51008C. The absence of the 2-naphthol and of the by-products of series 3 in
the products mixture allows to avoid any time-consuming chromatographic
process for the purification of 2; it is also worth noting that its chemical yield
in entry 13 (Table 1) is very high (97.2%). In this way, the synthetic procedure
is very fast and can be easily used also for the preparation of the [11C]-analog
of 2. This study has been already undertaken and will represent our ultimate
goal.
The negative drawback of the overall procedure is the incomplete
consumption of paraformaldehyde (and formaldehyde as a consequence),
which turns out in a low level of the total radioactivity transferred to the
product. Conversely, the di-naphthol derivative 2 can be isolated without the
intervention of any purification step. The chemical yield of 2 is calculated with
respect to the starting phenol, which is the reagent present in defect.
Table 1 reports the results obtained in a number of experiments for the
synthesis of 1,10-methylene-di-(2-naphthol) 2. Different reaction parameters
have been taken into account, which showed to play important and specific
roles. First of all, high reaction temperature (equal or higher than 1208C) and
long reaction time (120 min) resulted in a massive paraformaldehyde
decomposition (more than 80%) and quite high yields in the formation of 2.
The presence of consistent amounts of by-products, like multi-hydroxymethy-
lated compounds and multi-2-hydroxynaphthyl coupling by-products, had to
be considered (entries 1 and 2). The control of these side reactions leading to
oligomerization compounds was achieved by lowering the temperature and
shortening the reaction times to get, finally, their complete disappearance
(entries 3–13).
Another important parameter is the R-value, which determines the
distribution of the reagents. R is defined as the ratio between 2-naphthol
and paraformaldehyde starting concentrations. The reaction stoichiometry
should give an R-value equal to 2 but, by operating at this level (entries 2–4),
the negative consequence is the presence of unreacted 2-naphthol in the
reaction mixture. A valid explanation for this behavior can be found either in
the kinetic development of the process (where k2>k1) or in the applied
relatively low temperature (51008C) which is not sufficient for the complete
paraformaldehyde decomposition. Conversely, 2-naphthol was totally con-
sumed in entries 5 and 6, where R approaches the unit value. Under these last
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 543–556

550
G. ANGELINI ET AL.
conditions the effective concentration of free formaldehyde is about 50% with
respect to the nominal paraformaldehyde amount used, thus implying that the
operative value of R approximates 2, according to the stoichiometry necessary
for the complete consumption of 2-naphthol.
As to 1-hydroxymethyl-2-hydroxynaphthalene (intermediate 1), this is a
minor product under all the experimental conditions, thus confirming its
nature of transient, low concentration intermediate, as the kinetic treatment of
the reaction suggests.
Different considerations can be drawn from the analyses of the tests carried
out by using a microwave oven as the energy source, in the temperature range
of 100–1708C, depending on the irradiation power. First of all, at very short
reaction times (5–20 min) high yields of 2 were obtained (entries 7–11). This
result could be of paramount importance if 2 is to be produced with a short life
radioisotopic label (i.e. 11C). Moreover under these conditions, paraformalde-
hyde depolymerization takes place very efficiently (more than 80% undergoes
decomposition), thus generating a high free formaldehyde concentration.
However, the fast and rapid heating promoted by the microwave radiation
takes to a partial loss of formaldehyde, which leads to the survival of
appreciable amounts of 2-naphthol. Also, consistent amounts of by-products
are produced. These events convinced us to carry out the radiochemical
synthesis according to the conventional way, with a total reaction time of
120 min (entries 12 and 13), and using the experimental conditions of entry 5
as a reference. A second addition of a paraformaldehyde aliquot after the first
60 min of reaction allowed the complete consumption of 2-naphthol. This
addition, performed with ‘cold paraformaldehyde’, induced further depoly-
merization of the radioactive residual paraformaldehyde, thus contributing to
the increase of the yield of 2 without detriment to the specific radioactivity.
Following this procedure, an almost quantitative transformation of the
starting 2-naphthol was obtained while the level of the impurities was not
appreciable. The 1,10[14C]-methylene-di- (2-naphthol) 2 was isolated at the
specific radioactivity of 1.22 TBq/mol (total radioactivity=8.66 MBq). Only
limited amount of the radioactive intermediate 1 was recovered, at the specific
radioactivity of 0.74 TBq/mol and a total radioactivity of 296 KBq.
In Table 2 several tests are reported, very useful to elaborate some kinetic
considerations. These tests have been carried out at 908C, by employing a large
excess of paraformaldehyde (164.3 mmol as the nominal starting value) with
respect to 2-naphthol (42.2 mmol). The reaction mixtures have been checked
after 5 and 12 min. Clearly, these reaction conditions do not appear to be
useful for radiosynthetic purposes (the amount of radioactive starting
paraformaldehyde is too high and the formation of 2 is too low), but they
allow to follow the two steps reaction pathway, by the isolation of large
quantities of intermediate 1.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 543–556

A RADIOCHEMICAL AND KINETIC APPROACH
551
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 543–556

552
G. ANGELINI ET AL.
On the grounds of the data reported in Table 2, the following considerations
can be proposed:
(i) After 300 s of reaction, the average formation rate of intermediate 1
(8.67 ꢂ 10ꢁ5 mmol/s) is about two times that of the product 2
(3.87 ꢂ 10ꢁ5 mmol/s). The same is the result after 720 s. Obviously, under
these particular conditions it is not conceivable to expect similar reaction
rates for both the first and the second steps, as the steady-state
approximation for intermediate 1 would suggest. In fact, the large excess
of free formaldehyde which is generated would guarantee a consistent
formation of intermediate 1, whose concentration clearly does not remain
constant as the reaction goes on.
(ii) Considering the high concentration of free formaldehyde during the
whole observation time, an average rate for the first step much greater
than the second one should be expected. This suggests that k2 is well
greater than k1.
(iii) A rough estimation of k2 can be derived from the data relevant to the
second part of the reaction, considering the elapsed time of further 420 s.
Here, the residual quantity of 2-naphthol and free formaldehyde are,
respectively, 0.0046 and 0.0562 mmol, and the differential average rate for
the first and the second steps are both decreased of about one order of
magnitude if compared with the relevant values determined after 300 s.
The lowering of these values strictly follows the massive decrease
observed for 2-naphthol concentration, denoting its first-order depen-
dence for the first and the second step rates. However during the elapsed
time of 420 s, the average rates for the first and the second reaction steps
are so slow and similar to each other that we can consider them as
constant along the observation time. At this condition, the steady-state
approximation for intermediate 1 is reached. Considering that the free
formaldehyde amount remains nearly constant (at around 0.054 mmol),
and that the same can be assumed for the intermediate 1 (at around
0.0145 mmol), we can estimate, by applying Equation (2), a k2/k1 ratio
greater than 2.
Belyanin et al.23 reported an interesting decomposition reaction of 1,10-
methylene-di-(2-naphthol) 2 when heated in benzene with paraformaldehyde
and boric acid. The final product is a characteristic spirodimer. Along the
course of our experiments, we have never observed this particular reaction,
probably because of to the soft reaction conditions we have employed.
Another decomposition process, however, clearly emerged. Although the 1,10-
methylene-di-(2-naphthol) 2, when isolated, is totally stable, as it is in
completely anhydrous solution of acetonitrile, we observed that in diluted wet
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 543–556

A RADIOCHEMICAL AND KINETIC APPROACH
553
acetonitrile solution, once exposed to visible light it thoroughly decomposes.
Three decomposition products formed in this, reasonably radical, process
(Scheme 2): the first one is represented by intermediate 1 itself, which contains
all the radioactivity initially located in 2; the other two, present in quite similar
amounts, once isolated and analyzed by GC-MS as well as mono and
bidimensional 1H NMR, revealed to be the two alkynyl derivatives of benzene,
1,2-diethynylbenzene and 1,3-butadiynylbenzene, which do not contain any
radioactivity at all. It is thus conceivable to suppose the transient formation of
the 1,2-naphthyne intermediate.24–27
OH
OH
O
H
H
visible light
CH2
CH2
O
Aqueous CH3CN
OH
H
2
- H2O
OH
1
CH2OH
Scheme 2.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 543–556

554
G. ANGELINI ET AL.
Experimental
Specific procedure for the synthesis of 1,10[14C]-methylene-di-(2-naphthol) 2
(Entries 12 and 13 of the Table 1. The procedure is also valid for the other
entries of the same table).
In a small, tight screw cap mini-vial (1.8 ml), equipped with a magnetic
stirrer, 2.1 mg (0.0146 mmol) of 2-naphthol and 0.378 mg (0.0118 mmol) of
[14C]-paraformaldehyde (American Radiolabelled Chemical Inc., specific
radioactivity 1.48 GBq/mmol) were weighted.
Acetic acid (0.2 ml) was added and the mini-vial was heated at
908C for 60 min. A sample of 2 ml of the obtained light-red solution
was added to 50 ml of a 1:1 mixture of ethyl acetate/acetonitrile. This
solution was analyzed by a HPLC chromatographic system (5 mm
C18 Phenomenex ‘LUNA’ 250 ꢂ 4.6 mm column, isocratic elution
50% water–acetonitrile at 1.0 ml/min) equipped with the UV-detector
Rainin (l=254 nm) and the Berthold mod. 503 radiochemical flow
monitor.
To complete the consuming of the 2-naphthol, a further addition of ‘cold’
paraformaldehyde (0.1 mg, 3.33 mmol) was done. The solution was heated for
60 min at 908C. The HPLC analysis confirmed the nearly quantitative
formation of 1,10[14C]-methylene-di-(2-naphthol) 2.
Acetic acid was then evaporated by a gentle flux of nitrogen at
room temperature, and the radioactive product
2
was recovered
as a gray solid (7.1 mmol at the specific radioactivity of 1.22 TBq/mol,
chemical yield: 97.2% with respect to 2-naphthol; radiochemical yield:
49.6% with respect to [14C]-paraformaldehyde. The latter becomes
close to 98% if the partial depolymerization of paraformaldehyde is
considered).
1H NMR spectrum was performed at 600.13 MHz on a Bruker Avance 600
spectrometer in the following conditions: room temperature, c.=5 mg in 0.7 ml
of CDCl3.
1D spectrum (TD=32K; Nscans=64; Sweep=16 ppm; 908 pulse=10 ms;
Relaxation delay=6 s), COSY and COSYLR parameters used with gradients
(TD in F2 1K; Nscans=4; TD in F1 512K). The proton spectrum consists of 8
signals, all with the same intensity and attributed as follows (proton
identification refers to the numeration of compound 2 in Scheme 1):
8.22 ppm, doublet, 2 protons (n. 5); 7.81 ppm, doublet, 2 protons (n. 8);
7.67 ppm, doublet, 2 protons (n. 4); 7.45 ppm, triplet, 2 protons (n. 6);
7.34 ppm, triplet, 2 protons (n. 7); 7.06 ppm, doublet, 2 protons (n. 3);
6.07 ppm, broad singlet, 2 protons (–OH); 4.82 ppm, singlet, 2 protons (–CH2).
Peak assignment was assisted by 2D COSY and 2D long range COSY maps.
No other resonances were found.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 543–556

A RADIOCHEMICAL AND KINETIC APPROACH
555
Conclusion
It was possible to find the appropriate experimental conditions for a simple
and soft synthesis of 1,10[14C]-methylene-di-(2-naphthol) 2 by using the
indications deriving from the mechanism and from the reaction kinetic, as
evidenced in Scheme 1. In particular, the reported procedure allows the
complete consumption of the starting compound (2-naphthol) and also to
eliminate the formation of any by-product. The recovery of product 2 turned
out to be very easy. An extensive decomposition of product 2 was observed
once diluted in acetonitrile solution and exposed to light. The intermediacy of
1,2-naphthyne was supposed along this last process.
Acknowledgements
The authors are thankful to Dr Annalaura Segre and Mrs Ida Bernabei for
their involvement in NMR determinations and synthetic procedures,
respectively.
References
1. Wolfe MS. J Med Chem 2001; 44 (13): 2039–2060.
Thorsett ED, Latimer LH. Curr Opin Chem Biol 2000; 4: 377–382.
2. Teplow DB. Int J Exp Clin Invest 1998; 5: 121–142.
3. Soto C. Mole Med Today 1999; 5: 343–350.
4. McKeon-O’Malley C, Saunders AJ, Bush AI, Tanzi RE. Emerg Ther Targ 1998;
2 (2):157–179.
Sabbagh MN, Galasko D, Thal LJ. Alzhheimer’s Dis Rev 1997; 3: 1–19.
5. Sigma Tau Patent PCT WO 2002000603. Use of pamoic acid or one of its
derivatives, or one of its analogues, for the preparation of a medicament for the
treatment of diseases characterised by deposits of amyloid aggregates.
6. Iannone F, Ursini O. J Radioanal Nucl Chem 2002; 251: 363–368.
7. Angelini G, Lilla G, Sparapani C, Ursini O, Rossi E, Segre AL, McAllister MA,
Tidwell TT. Appl Radial Isot 1994; 45: 386.
8. Angelini G, Lilla G, Sparapani C, Ursini O, Rossi E, Segre AL, McAllister MA,
Tidwell TT. Can J Chem 1992; 70: 1221–1228.
9. Angelini G, Carnevaletti F, Piccinini F. J Label Compd Radiopharm 1992; 31: 289.
10. Hofmann JE, Schriesheim A. Alkylation of aromatic with aldehydes and ketones.
In Friedel-Crafts and related reactions, Olah GA (ed). Wiley: New York, 1964;
597–640.
11. Okido S. Patent Application: JP 19680318, 1972.
12. Parulekar MH, Bhatt HA, Potnis SP. J Indian Chem Soc 1972; 49: 1201–1207.
13. Wurm G. Patent Application: DE 80-3035279, 1982.
14. Tandan SK, Vijjan VK. Indian Drugs 1982; 19: 156–157.
15. Poupelin JP, Saint-Ruf G, Foussard-Blanpin O, Narcisse G, Uchida-Ernouf G,
Lacroix R. Eur J Med Chem 1978; 13: 67–71.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 543–556

556
G. ANGELINI ET AL.
16. Poupelin JP, Saint-Ruf G, Lacroix R, Narcisse G, Foussard-Blanpin O, Uchida-
Ernouf G. Eur J Med Chem 1978; 13: 381–385.
17. Mirci LE. Patent Application : RO 92-149221, 1992.
18. Casiraghi G, Casnati G, Pochini A, Puglia G, Ungaro R, Sartori G. Synthesis
1981; 2: 143–146.
19. Casiraghi G, Casnati G, Cornia M, Pochini A, Puglia G, Sartori G, Ungaro R.
J Chem Soc, Perkin Trans 1978; 4: 318–321.
20. Oliver JE, Lamb CN, Smith RH. Jr., J Agric Food Chem 1983; 31(6): 1178–1183.
21. Arduini A, Pavan F, Pochini A, Ungaro R, Corno C. Tetrahedron 1990; 46:
3613–3620.
22. Laidler JK. Chemical Kinetics (3rd ed), Harper & Row Publishers: New York,
1987.
23. Belyanin ML, Filimonov VD, Raldugin VA, Krasnov EA. Russ Chem Bull 2001;
50: 914–916.
24. Sato T, Niino H, Yabe A. J Photochem PhotoBiol A: Chem 2001; 145: 3–10.
25. Sato T, Niino H, Yabe A. J Phys Chem A 2001; 105: 7790.
26. Gribble GW, Perni RB, Onan KD. J Org Chem 1985; 50: 2934.
27. Chen YL, Zhang HK, Wong WY, Lee WM. Tetrahedron Lett 2002; 43:
2259–2262.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 543–556