Total synthesis and radiolabelling of an efficient rt-PA inhibitor: [11C] (Z,Z)-BABCH. A first route to [11C] labelled amidines

Article abstract of DOI:10.1039/b009850g

A rapid route for the synthesis of radiolabelled t-PA_stop 8, an efficient serine protease inhibitor, is described. (E,E)-2,7-Bis(4-iodobenzylidene)cycloheptan-1-one 2a was obtained in high yields (>90%) from cycloheptanone and 4-iodobenzaldehyde, with the unprecedented use of CsOH or by microwave irradiation using catalytic amounts (<20%) of bis(methoxyphenyl) telluroxide (BMPTO). These methods are general and have been successfully applied to the high yielding preparation of other aldol adducts such as 2b and 2c. The two step transformation of (E,E) 2a into the asymmetric (Z,Z)-2-(4-cyanobenzylidene)-7-(4-iodobenzylidene)cycloheptan-1-one 5 has been optimized. The radiochemical yield for the radiolabelling of 5 with K[¹¹CN] followed by palladium catalysis to give the labelled bisnitrile 7 was 80-90%. A series of experiments with various methods is reported and the first procedure for the preparation of [¹¹C]amidines from the corresponding [¹¹C]bisnitriles with N-acetylcysteine is presented; the radiochemical yield, based on analytical liquid chromatography was 80% for the radioamidination. [¹¹C]t-PA_stop was isolated in a radiochemical yield ranging from 50 to 60% in 55 min overall and with a radiochemical purity higher than 95%.

Full text of DOI:10.1039/b009850g

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Total synthesis and radiolabelling of an efficient rt-PA inhibitor:
[11C] (Z,Z)-BABCH. A first route to [11C] labelled amidines
Fabrice Siméon, Franck Sobrio, Fabienne Gourand and Louisa Barré*
1
Centre Cycéron, GDM-TEP, LRA 10V-UPRES EA 2609, Université de Caen - CEA/DSV, 15,
Boulevard Henri Becquerel, BP 5229, F-14074, Caen, France
Received (in Cambridge, UK) 7th December 2000, Accepted 20th February 2001
First published as an Advance Article on the web 13th March 2001
A rapid route for the synthesis of radiolabelled t-PAstop 8, an efficient serine protease inhibitor, is described. (E,E)-2,7-
Bis(4-iodobenzylidene)cycloheptan-1-one 2a was obtained in high yields (>90%) from cycloheptanone and 4-
iodobenzaldehyde, with the unprecedented use of CsOH or by microwave irradiation using catalytic amounts (<20%)
of bis(methoxyphenyl) telluroxide (BMPTO). These methods are general and have been successfully applied to the
high yielding preparation of other aldol adducts such as 2b and 2c. The two step transformation of (E,E) 2a into the
asymmetric (Z,Z)-2-(4-cyanobenzylidene)-7-(4-iodobenzylidene)cycloheptan-1-one 5 has been optimized. The
radiochemical yield for the radiolabelling of 5 with K[11CN] followed by palladium catalysis to give the labelled
bisnitrile 7 was 80–90%. A series of experiments with various methods is reported and the first procedure for the
preparation of [11C]amidines from the corresponding [11C]bisnitriles with N-acetylcysteine is presented; the
radiochemical yield, based on analytical liquid chromatography was 80% for the radioamidination. [11C]t-PAstop was
isolated in a radiochemical yield ranging from 50 to 60% in 55 min overall and with a radiochemical purity higher
than 95%.
Introduction
The serine proteases are a family of proteins in which most
members exert their proteolytic activity after arginine residue
cleavage. These proteins have been studied extensively in rela-
tion to coagulation and thrombolysis (for a review see Carme-
liet et al.1). In addition to their existence in the blood, several of
these proteases have been localized within the central nervous
system (CNS).2,3 In the brain, the CNS serine proteases most
studied are the plasminogen activators: tissue type-plasminogen
activator (t-PA) and urokinase type-plasminogen activator
(u-PA) which are thought to play a critical role in the homeo-
stasis of the central nervous system. By its enzymatic activity,
t-PA regulates the balance between the accumulation and the
degradation of the extracellular matrix and it is involved in
many physiological functions ranging from synaptic outgrowth
during peri-natal development to plasticity in the adult brain.
Results and discussion
The (E,E)-BABCH symmetric molecule was first prepared in a
one step procedure from 4-amidinobenzaldehyde and cyclohept-
anone in low yields (10%).7 This synthesis was recently studied
by Shaw’s group,8 who showed that (E,E), (E,Z) and (Z,Z)-
BABCH isomers exhibited different affinity against human
factor Xa (FXa); the Ki/nM values were 17000, 200 and 0.66
respectively.4 This experimental evidence is provided to support
assignment of 1 as the bioactive olefin isomer in the BABCH
series.
The synthesis of a labelled analogue of 1 requires the prepar-
ation of a precursor that can react rapidly with a selected
carbon-11 reagent. With this aim, we have selected the [11C]
cyanation route from (Z,Z)-2-(4-cyanobenzylidene)-7-(4-
t-PAstop (Z,Z)-bis(amidinobenzylidene)cycloheptanone
1
((Z,Z)-BABCH) is a synthetic antagonist of t-PA characterized
by its ability to interact with one of t-PAs catalytic sites.4
Experimental evidence showed that t-PAstop could link with t-PA
by forming a salt bridge with some of the constituent amino
acids of the protease such as aspartic or glutamic acid.5 The
role of the very basic amidine in the catalytic pockets of the
serine enzymes seems crucial and the formation of more than
one salt bridge is likely to contribute significantly to the affinity
and the potency of this family of inhibitors.6
iodobenzylidene)cycloheptanone
Scheme 1.
5 prepared as shown in
To improve our understanding of the role of t-PA in the CNS
in vivo, it seemed reasonable to develop a radioligand that could
be used in positron emission tomography (PET).
Chemistry
During the aldol reaction, cycloheptanone showed a weak
reactivity compared to cyclopentanone and cyclohexanone; the
relative rate of enol formation decreasing drastically with the
increasing ring size.9 Classically, the aldol reaction may be
catalyzed by acids or bases, the latter being more frequently
employed in spite of the fact that a method has been described
with the use of bis(4-methoxyphenyl) telluroxide (BMPTO)10,11
as catalyst.
In this paper, we propose a total synthesis of [11C] (Z,Z)-
BABCH. The use of this labelled compound should be helpful
to evaluate in vivo the amount of t-PA in the cerebral par-
enchyma following acute brain injury. Such data could repre-
sent an important new tool for the measurement of neuronal
pain and an efficient strategy for the treatment of acute cerebral
injury in humans.
690
J. Chem. Soc., Perkin Trans. 1, 2001, 690–694
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b009850g

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Table 1 Preparation of 2 (E,E) (a–c) with various bases
observed that non-negligible amounts of (Z,Z) 3 and some
(E,Z) 4 diarylidenecycloheptanones were present in solution.
These isomers were more soluble in the aqueous ethanolic
solutions than the corresponding (E,E) 2a. We have observed
that the E,E : E,Z : Z,Z ratio during the preparation of 2a
was 8 : 0.5 : 1 (yield of E,E = 77%) and that an additional 7%
of the monosubstituted derivative was isolated with an
E : Z = 9.5 : 0.5 ratio. However, the optimum yields were
reached with CsOH (81%) where only traces of isomers 3 and 4
could be detected (<2%) and 5% of the E monoarylidene
compound.
Thus the use of the conditions described above, i.e. alkaline
bases and polar solvents, made more favourable the formation
of isomers and by-products even in the absence of light. The
results obtained when using 20% BMPTO in refluxing toluene
for 24 hours, were better than with any base (Table 2) and a
major advantage of this procedure was the use of stoichio-
metric conditions (2.0 : 1 aldehyde : ketone ratio). The most
significant improvement in the yields by this procedure was due
essentially to a total conversion into (E,E)-diarylidene deriva-
tives (e.g. 2a = 90%) without any trace of monoarylidene (E or
Z) nor other by-products. Finally, it appeared that the use of
microwave irradiation12 did not increase the yields notably, but
the reaction times, for maximum completion, were from 15 to
20 min whereas the classical heating needed a 24 hour period.
Similar improvement in the yields has been obtained in the
cross-aldol reaction for the preparation of 2b and 2c from 4-
cyano and 4-bromobenzaldehyde respectively either with CsOH
or BMPTO (Table 1, Table 2).
Basea
MeONa
NaOH
KOH
CsOH
2a
2b
2c
29
25
—
49
25
59
77
40
70
81
75
85
a In a boiling ethanolic aqueous solution, except for MeONa which was
in methanol.
Table 2 Synthesis of 2 (E,E) (a–c) with BMPTO using microwave
(MW) and classical heating
Compounds
∆, 24 h, yield (%)a
MW, 15 minb yield (%)
2a
2b
2c
90
79
88
92
78c
90
a In toluene. b In acetonitrile—DMSO. c 20 min irradiation.
To investigate the role of various parameters (stoichiometry,
nature of the base or catalyst) and to determine the nature of
the products in the cross-aldol reaction with cycloheptanone
and various substituted benzaldehydes, a series of experiments
has been designed (Scheme 2). The reactions were conducted
either in boiling aqueous ethanolic solution with an aldehyde–
ketone–base ratio ranging from 3 to 3.2 : 1 : 2, with the use
of MOH (M = Na, K, Cs) for one hour (Table 1) or with
BMPTO using classical heating and microwave irradiation
(Table 2).
Our experiments showed that the nature of the basic agent is
of essential importance. In fact, it appeared to us that the reac-
tion of cycloheptanone and 4-iodobenzaldehyde with MeONa,
NaOH or even KOH afforded mainly the expected (E,E)-
diarylidenecycloheptanone accompanied by the (Z,Z) and
(E,E) analogues, and variable amounts of a complex mixture of
the respective monoarylidenecycloheptanone isomers with
other inextricable compounds. For example, with the use of
KOH, in a complete study of the mother liquors, we have
Photoisomerisation conditions have been considered to pro-
duce (Z,Z) isomer 3 from (E,E) 2a as starting material. Thus,
short irradiation of a methanolic solution of 2a with a high
pressure mercury lamp produced isomers 3 and 4, which were
separated by chromatography and identified as the (Z,Z) and
(Z,E) isomers respectively. The three bisiodobenzylidene iso-
mers could be differentiated and assigned from their charac-
teristic NMR spectra in such a way that 2a and 3 exhibited
1
symmetric signals in H and 13C NMR while 4 appeared as an
asymmetric structure. The upfield chemical shifts of the vinylic
protons (δ(E,E) = 7.29 ppm and δ(Z,Z) = 6.58 ppm) were consistent
Scheme 1
Scheme 2
J. Chem. Soc., Perkin Trans. 1, 2001, 690–694
691

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with related compounds containing the same double configur-
ation.13 A kinetic study by HPLC showed that the photoiso-
merisation reached a 45% 3, 50% 4 and 5% 2a equilibrium
after 20–30 min irradiation.
could be a more efficient method for cyanation. K11CN was
formed in situ from H11CN by addition of KOH powder in dry
THF and compound 7 was obtained in 80–90% radiochemical
yield in 20 min overall (from the end of irradiation) using
Pd(PPh3)4 as catalyst.
The preparation of 5 via a monocyanation reaction is a
crucial step since the nitrilation of aromatic molecules con-
taining more than one halogen atom usually leads to poly-
nitriles.14 This kind of reaction has been well studied15 but
there are only a few examples of syntheses which leave one out
of several halogens unaltered.16 Various cyanation procedures
with KCN using organometallic catalysts have been described
in the literature.17 However, in our hands, any attempt to
realise a monocyanation of the bisiodobenzylidene 3 with
KCN and palladium catalyst (tetrakis(triphenylphosphine)-
palladium(0) or palladium acetate) led essentially to bisnitriles
as major products in addition to unreacted bishalogen com-
pounds. In some cases, some intermolecular coupling product
and deshalogenated compound have been detected in small
quantities (<3%); no effort has been made to optimize these
results. The very significant reactivity of palladium catalysts
observed during the cyanation reaction, led us to consider this
step in the classical Rosenmund reaction conditions. Thus,
when copper cyanide was allowed to react with a two-fold ratio
of bisiodobenzylidenes 3 in acetonitrile or hexamethylphos-
phorous triamide (HMPTA), the monocyanated derivative 5
was isolated in 35% yield; the use of refluxing degassed DMF,
under nitrogen, raised the yields to 51%. The by-products
detected under these conditions were the unreacted bisiodo-
benzylidene 5 (30%), and the biscyanated derivative (15%). No
isomerisation was observed when the reaction was performed in
the absence of light. A similar procedure applied to compound
2a, led to 6 in 59% yield. Isomers 5 and 6 have been identified
The labelling of t-PAstop required the development of a new
route leading to [11C] labelled amidines. In classical chemistry,
amidines are efficiently produced from nitriles via frequently
multistep processes, that proceed in moderate to poor yields.21a,b
However, although a procedure for [14C] radioamidination has
been described22 previously, to our knowledge, no previous
author has until now described a [11C] radioamidination
procedure.
Taking into account the radiochemical constraints described
previously for the preparation of [11C]radiopharmaceuticals, we
examined a series of methods for radioamidination. Three
procedures have been selected and tested in radiochemistry:
the Pinner23 synthesis, the Garigipati24 process and Lange’s
method.25
First, we tried to adapt the Pinner reaction to [11C]radio-
chemistry, however, such a two-step reaction cannot be effi-
ciently simplified due to the inevitable passage from strong acid
to strong basic conditions. Thus, the addition of 7 to 2 M HCl
in absolute ethyl alcohol led, in 10 min at 0 ЊC, to the formation
of only 30% of an intermediate. All attempts to purify this
intermediate or to prepare the corresponding amidine by using
a 2 M NH3 solution failed. To overcome these difficulties we
have focused on the one-pot processes suitable for direct
amidination.
A one-step procedure for amidination has been reported by
Garigipati using aluminium amide reagents such as AlMe-
(Cl)NH2 in toluene. In our hands, application of similar condi-
tions in the course of a radiochemical synthesis, led to the
complete transformation of the radiolabelled 7 into an
undetermined compound complexed in an inextricable white
and bulky mass of aluminium salts. The expected amidine
could not be liberated from that mixture in a short time.
Recently, a catalytic one step process for direct amidination
has been described by Lange and co-workers with N-
acetylcysteine (NAC).25 This synthesis is favoured by the ability
of thiolate salts to react strongly with various nitriles26 and give
a reactive iminothioether intermediate.
We applied this procedure to our radiochemical process and,
addition of NAC to 7 within a solution of anhydrous NH4Cl in
methanol, with 8 minutes at reflux, allowed us to obtain 8 in
51% radiochemical yield. The use of a concentrated NH3
solution in methanol permitted us to optimize this reaction and
the cysteinate salt of 8 was isolated in 80% radiochemical yield
(Scheme 4). The structure of the [11C] t-PAstop cysteine salt 8
was verified by radioHPLC with coinjection of non-radioactive
reference material.
We are currently developing a fully automated version for
the radioamidination of t-PAstop or any other target molecule.
Amidine groups, which can be conveniently obtained, from
labelled nitriles are common among biologically active sub-
stances. Their [11C] labelling would represent an interesting
route for the study of various psychiatric or pathological
disorders27 because the amidine functional group is present in
structures with important properties such as blood coagulation
factors,28 antidepressants,29 antipsychotic30 or even antipara-
sitic agents.31
1
by H, 13C and COSY NMR as asymmetric structures with
two double bonds in the same configuration either E or Z.
These configurations were ascertained by comparison with the
corresponding structures of isomerically pure bisiodo and
biscyanobenzylidenes.
Radiochemistry
Due to the very short half-life of many radioelements (for
example, t1/2 11C = 20.4 min), the preparation of radiopharma-
ceuticals labelled for use in PET (positron emission tom-
ography) implies the tuning of very particular procedures. The
number of radiochemical steps needs to be reduced as much as
possible (one to two steps with [11C]) and the delay for every
process should not exceed one period (t1/2) leaving time enough
for a workup and the purification of the labelled compound.
Labelled hydrocyanic acid H11CN, was produced according
to classical conditions18 and trapped efficiently by freezing it in
a glass vial at Ϫ20 ЊC. Cu11CN could be obtained from H11CN
by heating with a solution of copper() sulfate and sodium
metabisulfite. Application of the radiochemical equivalent pro-
cedure19 to the Rosenmund reaction led to 7 in 46% radio-
chemical yield and any attempt to optimize this result failed
(Scheme 3). In our case and in view of the first results obtained
Conclusions
In this paper, we describe some new high yielding procedures
for the preparation of aldol adducts for a series of cyclo-
heptanones; the unprecedented use of CsOH or the efficient
catalyst BMPTO under microwaves are simple methods to
produce the expected (E,E) bisaldol compounds with very high
purity. With the aim of preparing new radiotracers, a first effi-
Scheme 3
with Cu11CN, we considered that the use of palladium catalysts
with K11CN, according to the recent published procedures,20
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J. Chem. Soc., Perkin Trans. 1, 2001, 690–694

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removed by filtration and rinsed thoroughly with 30 mL alco-
hol, 10 mL of 3% acetic acid and 20 mL water. The residue
obtained was recrystallized in high volumes of boiling ethanol
to give pure 2a as white crystals (1.86 g, 81%), mp 138–140ЊC
(Found: C, 46.6; H, 3.5. Calc. for C21H18I2O: C, 46.7; H, 3.4%);
δH (250.13 MHz; CDCl3; Me4Si) 1.95 (m, 4H, CH2CH2C), 2.65
(m, 4H, CH2CH2C), 7.17 (d, 4H, J 8.28, CHarCI), 7.29 (s, 2H),
7.73 (d, 4H, J 8.41, CHarC); δC (62.9 MHz; CDCl3; Me4Si) 28.4,
29.1, 94.6, 131.5, 135.1, 135.7, 138.1, 142.7, 199.3; m/z 540 (M+,
100%), 413 (21), 326 (27), 241 (24); νmax/cmϪ1 2920, 1672 (C᎐O),
᎐
1620, 1098, 500 (C–I).
In similar conditions, the use of NaOH or KOH afforded
after chromatography lower yields of 2a (see Table 1) and two
main by-products corresponding to the mono benzylidene
derivatives (E)-2-(4-iodobenzylidene)cycloheptan-1-one33 and
(Z)-2-(4-iodobenzylidene)cycloheptan-1-one. The latter was
recrystallized in methyl alcohol to give golden crystals, mp
98 ЊC (Found: C, 51.3; H, 4.7. Calc. for C14H15IO: C, 51.55; H,
4.6%); δH (250.13 MHz; CDCl3; Me4Si) 1.78 (m, 6H), 2.41 (d,
2H, J 9.19, CH CO), 2.56 (d, 2H, J 10.13, CH C᎐C), 6.39 (s,
᎐
2
2
1H), 6.98 (d, 2H, J 8.35, CHarCI), 7.60 (d, 2H, J 8.45, CHarC);
δC (62.9 MHz; CDCl3; Me4Si) 24.8, 30.2, 31.1, 35.7, 43.7, 93.6,
130.5, 135.5, 135.9, 137.8, 145.6, 204.9; m/z 326 (M+, 17%), 284
(100), 216 (15), 200 (12); νmax/cmϪ1 2920, 1680 (C᎐O), 1606
᎐
(C᎐C), 1280, 1000, 560 (C–I), 530.
᎐
General procedure for the preparation of 2a using BMPTO
By thermal heating: cycloheptanone (0.242 g, 2.154 mmol),
4-iodobenzaldehyde (1 g, 4.308 mmol) and bis(methoxyphenyl)
telluroxide (0.154 g, 0.431 mmol) were placed in a 25 mL flask
with 6 mL of dry toluene and refluxed for 24 h. The cold
mixture was evaporated and chromatographed on silica gel
(cyclohexane–AcOEt 95 : 5) to give 1.05 g 2a (90%) as white
crystals. By microwave heating: this procedure was performed
in a similar manner using a Prolabo Synthewave 402, with 2 mL
of CH3CN–DMSO (9 : 1) as solvent and the reactants were
irradiated at 150 W for 15 min. After cooling, the mixture was
purified as described above to give 2a in 92% yield.
Scheme 4
cient method for radioamidination has been described and the
presented procedure is rapid, mild, general and conducted in a
one-pot process suitable for automation. In this way, prepar-
ation of [11C] t-PAstop 8 has been successfully realized in 55 min
with a radiochemical yield of 55% and with a radiochemical
purity superior to 95%. Work is now in progress to evaluate
these new tracers on animal models presenting an ischemia.
Experimental
1H NMR and 13C NMR spectra were recorded with a “Bruker
AC 250” spectrometer (at 250.13 MHz and 62.89 MHz respec-
tively) in CDCl3, with respect to tetramethylsilane as an internal
standard, δ are given in ppm and J in Hz. Conventional
abbreviations are used. The FT infra-red spectra were recorded
with a “Perkin Elmer 16 PC” spectrometer as liquid films and ν
are given in cmϪ1. Mass spectra were obtained at 70 eV. Elem-
ental analyses were performed at the Institut Supérieur de la
Matière et du Rayonnement, UMR CNRS 6507, Université de
Caen. Melting points were determined on a Kofler bank and
are uncorrected. Flash chromatography was performed using
230–400 mesh silica gel. 4-Iodobenzaldehyde32 was prepared
according to a previously described procedure. All commercial
reagents were purchased from Aldrich Co. and used without
further purification, except 4-cyanobenzaldehyde which was
from Accros Chemicals. The 11C was produced by the
14N(p,α)11C nuclear reaction using a baby cyclotron (CGR Mev
325) at the CYCERON Center of Caen. Samples of pure tPAstop
have been prepared according to procedures previously
described.5,7
(Z,Z)-2,7-Bis(4-iodobenzylidene)cycloheptan-1-one (3)
0.5 g of 2a was suspended in 70 mL of 95% ethanol under dry
nitrogen in a quartz flask. The mixture was stirred and irradi-
ated at 150 W during 25 minutes. Isomerization was followed by
HPLC and stopped when a 45–50% 3
4 equilibrium was
reached. Evaporation of the solvent followed by reversed phase
chromatography (MeOH–H2O 75 : 25) gave 0.21 g of 3 as a pale
yellow powder, mp 124–126 ЊC (Found: C, 46.7; H, 3.4. Calc.
for C21H18I2O: C, 46.7; H, 3.4%); δH (250.13 MHz; CDCl3;
Me4Si) 1.91 (m, 4H, CH2CH2C), 2.53 (m, 4H, CH2CH2C), 6.58
(s, 2H), 7.03 (d, 4H, J 8.28, CHarCI), 7.55 (d, 4H, J 8.45,
CHarC); δC (62.9 MHz; CDCl3; Me4Si) 32.3, 36.8, 94.2, 131,
134.9, 135.7, 137.6, 143.6, 200.0; m/z 540 (M+, 46%), 413 (54),
288 (20), 242 (40), 191 (100); νmax/cmϪ1 3036, 1672 (C᎐O),
᎐
1620, 1098, 1038, 566 (C–I). (E,Z)-2,7-Bis(4-iodobenzyl-
idene)cycloheptan-1-one (4) was isolated in the same manner
as 3 as pale yellow crystals, mp 126–128 ЊC (Found: C, 46.5; H,
3.3. Calc for C21H18I2O: C, 46.7; H, 3.4%); δH (250.13 MHz;
CDCl3; Me4Si) 1.90 (m, 4H, CH2CH2C), 2.46 (m, 2H,
CH2CH2C), 2.72 (m, 2H, CH2CH2C), 6.47 (s, 1H), 6.96 (d, 2H,
J 8.32, CHarCI), 7.13 (d, 2H, J 8.29, CHarCI), 7.36 (s, 1H), 7.58
(d, 2H, J 8.17, CHarC), 7.73 (d, 2H, J 8.37, CHarC); δC (62.9
MHz; CDCl3; Me4Si) 28.3, 30.1, 32.4, 36.3, 93.6, 95.1, 130.6,
130.6, 131.6, 135.4, 135.8, 136.5, 137.9, 138.1, 139.8, 146.2,
General procedure for the preparation of (E,E)-2,7-bis(4-iodo-
benzylidene)cycloheptan-1-one (2a) using CsOH
Cycloheptanone (0.48 g, 4.31 mmol) and 4-iodobenzaldehyde
(3 g, 12.93 mmol) were suspended in 20 mL absolute ethanol.
This was followed by the dropwise addition of CsOH (1.29 g,
8.62 mmol) in aqueous ethanolic solution (5 mL) with constant
stirring. The solution was heated at reflux for one hour, then the
precipitate was allowed to deposit during 12 hours at room
temperature in the absence of light. The solid precipitate was
200.3; m/z 540 (M+, 28%), 413 (26), 217 (100), 165 (73); νmax
/
cmϪ1 2926, 2850, 1674 (C᎐O), 1032, 560 (C–I).
᎐
(Z,Z)-2-(4-Cyanobenzylidene)-7-(4-iodobenzylidene)-
cycloheptan-1-one (5)
In a 25 mL two-necked round-bottomed flask, 3 (0.6 g, 1.11
J. Chem. Soc., Perkin Trans. 1, 2001, 690–694 693

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mmol) and CuCN (0.04 g, 0.45 mmol) were mixed in 12 mL of
degassed DMF. The solution was heated at reflux for 24 hours,
then the mixture was cooled and the DMF was evaporated to
dryness under vacuum with toluene. The residue was taken up
in dichloromethane and filtered through Celite. The resulting
brown solution was chromatographed on silica gel to give 5
(0.25 g, 51%) as a pale yellow powder (Found: C 60.1; H, 4.0; N,
3.3. Calc for C21H18I2O: C, 60.15; H, 4.1; N, 3.2%); δH (250.13
MHz; CDCl3; Me4Si) 1.92 (m, 4H, CH2CH2C), 2.55 (m, 4H,
CH2CH2C), 6.62 (s, 1H), 6.64 (s, 1H), 7.03 (d, 2H, J 8.28,
CHarCI), 7.33 (d, 2H, J 8.12, CHarCN), 7.49 (d, 2H, J 8.43,
CHarC), 7.53 (d, 2H, J 8.43, CHarC); δC (62.9 MHz; CDCl3;
Me4Si) 32.2, 32.4, 36.7, 36.8, 94.4, 111.5, 119.2, 129.7, 131.0,
132.3, 133.7, 135.5, 135.7, 137.6, 141.0, 143.0, 146.1, 199.3; m/z
Schäfer for helpful comments concerning the techniques of
purification and amidination with N-acetylcysteine. The
authors are grateful to M. V. Lakshmikantham for his helpful
comments concerning the preparation of telluroxide catalysts.
References
1 P. Carmeliet and D. Collen, Curr. Opin. Lipidol., 1997, 8, 118.
2 S. E. Tsirka, A. D. Rogove and S. Strickland, Nature, 1996, 384, 123.
3 Y. F. Wang, S. E. Tsirka, S. Strickland, P. E. Stieg, S. G. Soriano and
S. A. Lipton, Nat. Med. N. Y., 1998, 4, 633.
4 C.-K. Hu, U. Kohnert, J. Stürzebecher, S. Fischer and M. Llinas,
Biochemistry, 1996, 35, 3270.
5 K. J. Shaw, W. J. Guilford, J. L. Dallas, S. K. Koovakkaat,
M. A. McCarrick, A. Liang, D. R. Light and M. M. Morrissey,
J. Med. Chem., 1998, 41, 3551.
6 G. Wagner, Folia Haematol. (Leipzig), 1982, 109, 67.
7 G. Wagner, H. Vieweg and H. Horn, Pharmazie, 1977, 32, 141.
8 J. L. Dallas, W. J. Guilford, S. K. Koovakkat, M. M. Morrissey and
K. J. Shaw, US Pat. 5,633,381, 1997.
9 H. Shechter, M. J. Collis, R. Dessy, Y. Okuzumi and A. Chen, J. Am.
Chem. Soc., 1962, 84, 2905.
10 (a) M. Akiba, M. V. Lakshmikantham, K.-Y. Jen and M. P. Cava,
J. Org. Chem., 1984, 49, 4819; (b) L. Engman and M. P. Cava,
Tetrahedron Lett., 1981, 22, 5251.
11 M. Zheng, L. Wang, J. Shao and Q. Zhong, Synth. Commun., 1997,
27, 351.
12 E. L. Gall, F. Texier-Boullet and J. Hamelin, Synth. Commun., 1999,
29, 3651.
440 (M+, 90.5%), 439 (22), 313 (100), 243 (69); νmax/cmϪ1 2922,
᎐
2220 (C᎐N), 1728, 1666 (C᎐O), 1014, 560 (C–I).
᎐
᎐
(E,E)-2-(4-Cyanobenzylidene)-7-(4-iodobenzylidene)cyclo-
heptan-1-one (6)
Compound 6 was obtained from 2a by a similar procedure,
yielding 59% of white crystals (Found: C, 60.2; H, 4.1; N, 3.1.
Calc for C21H18I2O: C, 60.15; H, 4.1; N, 3.2%); δH (250.13 MHz;
CDCl3; Me4Si) 1.96 (m, 4H, CH2CH2C), 2.66 (m, 4H,
CH2CH2C), 7.16 (d, 2H, J 8.24, CHarCI), 7.33 (s, 1H), 7.34
(s, 1H), 7.51 (d, 2H, J 8.32, CHarCN), 7.68 (d, 2H, J 8.37,
CHarC), 7.74 (d, 2H, J 8.43, CHarC); δC (62.9 MHz; CDCl3;
Me4Si) 28.3, 28.5, 29.2, 30.1, 94.8, 112.0, 119.0, 130.2, 131.5,
132.6, 133.9, 135.5, 135.8, 138.1, 140.9, 142.0, 145.1, 199.3; m/z
13 Z. Aizenshtat, M. Hausmann, Y. Pickholtz, D. Tal and J. Blum,
J. Org. Chem., 1977, 42, 2386.
14 C. D. Weiss, J. Org. Chem., 1962, 27, 2964.
15 G. P. Ellis and T. M. Romney-Alexander, Chem. Rev., 1987, 87, 779.
16 J. Krepelka, I. Vancurova and J. Holubek, Collect. Czech. Chem.
Commun., 1981, 46, 1523.
439.8 (M+, 100%), 412 (5.5), 313 (81), 242.5 (46); νmax/cmϪ1
᎐
2922, 2220 (C᎐N), 1728, 1666 (C᎐O), 1228, 562 (C–I).
᎐
᎐
17 (a) T. Sakamoto and K. Ohsawa, J. Chem. Soc., Perkin Trans. 1,
1999, 2323; (b) D. M. Tschaen, R. Desmond, A. O. King, M. C.
Fortin, B. Pipik, S. King and T. R. Verhoeven, Synth. Commun.,
1994, 24, 887.
18 R. Iwata, T. Ido, T. Takahashi, H. Nakanishi and S. Iida, Appl.
Radiat. Isot., 1987, 38, 97.
19 M. Ponchant, F. Hinnen, S. Demphel and C. Crouzel, Appl. Radiat.
Isot., 1997, 48, 755.
20 Y. Andersson, M. Bergström and B. Långström, Appl. Radiat. Isot.,
1994, 45, 707.
21 (a) G. Tennant, in Comprehensive Organic Chemistry, ed. D. Barton
and W. D. Ollis, Pergamon Press, Oxford, 1979, vol. II; (b)
J. A. Gauter, M. Miocque and C. C. Farnoux, in The Chemistry
of Amidines and Imidates, Vol. 1, ed. S. Patai; John Wiley & Sons,
New York, 1975, p. 283.
22 A. Allentoff, G. Ciszewska, B. Markus, H. Pfefferkorn, T. Ray,
L. Jones and T. Duelfer, Synthesis and Application of Isotopically
Labelled Compounds, eds. J. R. Heys and D. G. Melillo, John Wiley
& Sons, New York, 1998, p. 185.
(Z,Z)-2-(4-[11C]Cyanobenzylidene)-7-(4-cyanobenzylidene)-
cycloheptan-1-one (7)
K[11C]CN was produced in situ by adding a THF solution of 2
M KOH (100 µL) to trapped H[11C]CN. The mixture was
heated to 90 ЊC and evaporated to dryness under a flux of
helium. To this was added a solution of 5 (4 mg) with
Kriptofix® 2.2.2 (2 mg) in THF (100 µL). 1.2 mg of
tetrakis(triphenylphosphine)palladium(0) (99%) was dissolved
in THF (100 µL) and added to the mixture of reagents and the
substitution reaction was carried out at 90 ЊC for 10 min.
Radio TLC was achieved with a sample of the mixture in
cyclohexane–AcOEt 60 : 40 (Rf = 0.48). An aliquot was taken
and analyzed by HPLC employing the following conditions:
µBondapak C-18, MeOH–H2O 85 : 15, flow 2 mL minϪ1
wavelength 254 nm. The retention time for 7 was 9.1 min.
,
23 A. Pinner and F. Klein, Ber. Dtsch. Chem. Ges., 1877, 10, 1889.
24 R. S. Garigipati, Tetrahedron Lett., 1990, 31, 1969.
25 U. E. W. Lange, B. Schäfer, D. Baucke, E. Buschmann and H. Mack,
Tetrahedron Lett., 1999, 40, 7067.
26 M. W. Partridge and W. F. Short, J. Chem. Soc., 1947, 390.
27 J. Stanek, G. Caravatti, J. Frei, P. Furet, H. Mett, P. Schneider and
U. Regenass, J. Med. Chem., 1993, 36, 2168.
28 For example, J. Hauptmann and F. Markwardt, Biochem.
Pharmacol., 1977, 26, 325.
29 K. Sindelar, Z. Sedivy, M. Hrubantova, M. Valchar, J. Metysova and
M. Protiva, Collect. Czech. Chem. Commun., 1988, 53, 381.
30 A. Thurkauf, A. Hutchison, J. Peterson, L. Cornfield, R. Meade, K.
Huston, K. Harris, P. C. Ross, K. Gerber and T. V. Ramabhadran,
J. Med. Chem., 1995, 38, 2251.
(Z,Z)-2-(4-[11C]Amidinobenzylidene)-7-(4-amidinobenzylidene)-
cycloheptan-1-one (8)
Compound 7 in THF was evaporated to dryness under a flux of
helium. A methanolic solution of N-acetylcysteine (4 mg),
NH4OAc (4 mg) and NH3 (7 M, 30 µL) dissolved was added
and the mixture was heated to 80 ЊC for 8 min. An aliquot
was taken and analysed by HPLC employing the following
conditions: Waters Symmetry C-18, acetonitrile : H2O : TFA
20 : 80 : 0.1, flow 2 mL minϪ1, wavelength 254 nm and the
retention time for 8 was 5.5 min.
31 P. M. S. Chauhan, R. N. Iyer, D. S. Bhakuni, V. Shankhdhar,
P. Y. Guru and A. B. Sen, Indian J. Chem., Sect. B Org. Chem. Incl.
Med. Chem., 1988, 27, 38.
32 S. H. Yang, C. S. Li and C. H. Cheng, J. Org. Chem., 1987, 52, 691.
33 A. C. Huitric and W. D. Kumler, J. Chem. Soc, 1956, 1147.
Acknowledgements
This work was supported by a grant from the Commissariat
agrave l’Energie Atomique. The authors wish to thank Professor
694
J. Chem. Soc., Perkin Trans. 1, 2001, 690–694