Labeling of organic biomolecules with ethynylferrocene

Article abstract of DOI:10.1039/b300191a

The Sonogashira coupling reaction of ethynylferrocene with adenine, uracil, tyrosine and steroid derivatives was studied; with the exception of tyrosine it was proved to be a good route for the attachment of ferrocene to these representative biomolecules. In addition the transformation of alkynyl uracil to furanopyrimidone derivative was investigated and the formation of the furanopyrimidone ring was confirmed by an X-ray crystallographic analysis carried out on product 16.

Full text of DOI:10.1039/b300191a

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Labeling of organic biomolecules with ethynylferrocene
Evdoxia Coutouli-Argyropoulou,*a Maria Tsitabani,a Georgios Petrantonakis,a Aris Terzisb and
Catherine Raptopouloub
a Department of Chemistry, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece.
E-mail: evd@chem.auth.gr; Fax: ϩϩ310997679; Tel: ϩϩ310997733
b Institute of Materials Science, NCSR “Demokritos”, 15310 Aghia Paraskevi, Attiki, Greece.
E-mail: aterzis@ims.demokritos.gr; Fax: ϩϩ0106519430; Tel: ϩϩ0106503346
Received 7th January 2003, Accepted 4th March 2003
First published as an Advance Article on the web 26th March 2003
The Sonogashira coupling reaction of ethynylferrocene with adenine, uracil, tyrosine and steroid derivatives was
studied; with the exception of tyrosine it was proved to be a good route for the attachment of ferrocene to these
representative biomolecules. In addition the transformation of alkynyl uracil to furanopyrimidone derivatives was
investigated and the formation of the furanopyrimidone ring was confirmed by an X-ray crystallographic analysis
carried out on product 16.
used to a rather limited extent.8 To the best of our knowledge,
Introduction
in regard to biomolecule labeling only its reaction with iodode-
oxyuridine has been reported,5e in which besides the expected
alkyne derivative a cyclization product was also obtained.
In connection with our previous studies on ferrocene chem-
istry,9 in this paper we examine the Sonogashira coupling reac-
tions of ethynylferrocene with some representative organic
biomolecules.
Nowadays, the detection of biomolecules in the nanogram and
subnanogram region is routinely performed with methods
based mainly on enzyme and luminescent labels,1 which are
replacing the traditional radioactive labels. During the last
decade electrochemical biosensors have attracted high and
continuously increasing interest as another alternative for the
analytical determination of biomolecules.2 In this regard ferro-
cene and its derivatives are attractive electrochemical probes,
because they are stable with convenient synthetic chemistry
and they possess reversible and tunable redox properties.3,4
Especially, ferrocene labeled oligonucleotides have emerged as
important versatile tools for the development of bioelectronic
gene-sensing systems.5
The reaction of choice for the formation of the covalent
bond between the label and the biomolecule is often the
Sonogashira coupling reaction6,7 of terminal label-substituted
alkynes with suitably derivatised biomolecules. The use of
Sonogashira coupling allows low polarity covalent bonds to be
formed without the participation of polar functional groups
necessary in a nucleophilic substitution or electrophilic addi-
tion type of reaction. For ferrocene labeling the most appropri-
ate alkyne seems to be ethynylferrocene since it lacks any other
functionalities, it is straight and positions the label remote from
essential functional groups on the biomolecule. Furthermore,
using ethynylferrocene the label is connected with a carbon–
carbon bond without the intervention of enzyme-sensitive
ester or amide groups, which are the most common connecting
links for ferrocene labeling.3,4 Despite these good prospects,
Sonogashira coupling reactions of ethynylferrocene have been
Results and discussion
As representative biomolecules for the purposes of our study
we have chosen uracil, adenine, amino acid and steroid deriv-
atives. Compounds 1–6 (Scheme 1) were readily prepared and
their Sonogashira coupling with ethynylferrocene 8 was stud-
ied. Also, for reasons of comparison, the reaction with the acti-
vated triflate 7 was examined. For the substituted uracils and
adenines we have used C-5 pyrimidine and C-8 purine substi-
tuted derivatives. The C-5 pyrimidine and C-8 purine positions
are usually the position of choice for labeling of nucleic bases
since they are not involved in the Watson–Crick base pairing;
furthermore C-5 substituted pyrimidines and C-8 substituted
purines are compatible with polymerase enzymes.5c,5h,5i
The Sonogashira approach for the reaction between a ter-
minal alkyne and an aryl or vinyl halide includes a catalytic
amount of Pd or Pd complexes, copper iodide and an excess
of amine.6c Different conditions have been employed for this
reaction depending on the reactivity of the halide and the
alkyne. Although PdL2 has been postulated as a common
intermediate with both Pd and Pd catalysts, considerable dif-
ferences have been observed in their reactivity and selectivity
Scheme 1
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 8 2 – 1 3 8 8
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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over several substrates. For our coupling experiments we have
used both Pd and Pd catalysts employing two methods:
method A) Pd(PPh3)4–CuI–NEt3; method B) Pd(PPh3)2Cl2–
CuI–NHPri2. A potential problem in palladium coupling of
alkynes with an organic electrophile is the formation of the
homocoupled alkyne in preference to the cross-coupled prod-
uct. Thus despite the inert atmosphere applied, the formation
of alkyne dimers is usually observed in this kind of reaction.7c,7d
In our case compound 9 (Scheme 2), the dimerization product
of ethynylferrocene, was also detected in all reactions studied.
After testing several reaction temperatures and reaction times
we have found as the optimum conditions to minimize its form-
ation the use of lower temperature (room temperature) and
longer reaction times (24 h). Furthermore ethynylferrocene
was used in a moderate excess (1.5 equiv.) and it was added
gradually during the course of the reaction.
i
᎐
Scheme 4 i) Fc–C᎐CH, Pd(PPh3)2Cl2, CuI, NHPr 2, DMF, rt, 24 h.
᎐
reaction with Pd catalyst afforded 14 in lower yield (58%) and a
significant amount of compound 16.
The furanopyrimidone derivative 15 is a rather expected
byproduct since Sonogashira coupling with 5-iodouracil sub-
strates is known to give often as byproducts substantial
amounts of furano[2,3-d]pyrimidin-2-ones formed by cycliz-
ation of the initial alkyne derivatives.5e,7a,7c,7f Concerning the
mechanism of the cyclization Yu and coworkers5e proposed a
base initiated cyclization in contrast to the results of Robins
and Barr who suggested a metal catalysed cyclization.7a In
order to clarify the conditions for the transformation of 14 to
15 we also carried out some blank experiments. Thus triethyl-
amine and CuI were sequentially added to a solution of 14 in
DMF. After each addition the solution was allowed to stay at
room temperature for 24 h and then was heated to 50 ЊC for 6 h.
As monitored by TLC, substantial formation of 15 and total
consumption of 14 were observed only after heating with both
triethylamine and CuI, although traces of 15 were observed
even in the test sample at room temperature without any
catalyst.
Compounds 16, 17 are unexpected products since formation
of analogous derivatives has not been reported in Sonogashira
coupling of uracil substrates. At first, compound 15 was con-
sidered to be a possible precursor of both. Thus coupling of 15
with ethynylferrocene could give 16, whereas homocoupling
could lead to 17. However blank experiments performed with
both 14 and 15 showed that 16 and 17 are formed only from 14.
Thus to a solution of ethynylferrocene and 14 or 15 in DMF
were added sequentially triethylamine and CuI and the reac-
tions were monitored by TLC. After each addition the reaction
mixture was allowed to stay at room temperature for 24 h and
then was heated to 50 ЊC for 6 h. Only in the reaction starting
from 14 and after the addition of CuI 16 and 17 were formed,
whereas after heating 14 was totally consumed.
Scheme 2
The reaction of ethynylferrocene 8 with bromoadenine deriv-
ative 1, prepared from 9-octyladenine, proceeded without com-
plications with both PdCl2(PPh3)2 and Pd(PPh3)4 catalysts to
give the expected alkyne derivative 11. Pd catalyst under condi-
tions B was proved to be more suitable, affording 11 (Scheme 3)
in higher yield (82%) than Pd (50%). Analogous behaviour was
shown by the nucleoside 2, which gave under conditions B the
alkyne derivative 12 in 80% yield (Scheme 4).
᎐
Scheme 3 i) Br2, CH3CO2Na, 50 ЊC, 48 h; ii) Fc–C᎐CH, Pd(PPh3)4,
᎐
i
᎐
CuI, NEt3, DMF or Fc–C᎐CH, Pd(PPh3)2Cl2, CuI, NHPr 2, DMF, rt,
᎐
24 h.
The reaction of ethynylferrocene 8 with the uracil derivative
3, prepared by alkylation of iodouracil, was more complicated
(Scheme 5). Thus with Pd it gave the expected alkyne derivative
14 as the main product (80% yield) and in low yields com-
pounds 15, 16 and 17 (10%, 3% and 5% respectively). The
Probably a common precursor of all of 15, 16, 17 is the anion
II formed in basic conditions by cyclization of the oxy anion of
uracil I (Scheme 6). Thus II gives 15 by back proton transfer,
whereas coupling with ethynylferrocene or homocoupling gives
16 and 17 respectively with mechanisms analogous to that
᎐
Scheme 5 i) (CH3)3SiSi(CH3)3, (NH4)2SO4, reflux, 15 h and then CH3(CH2)6CH2Br, DMF, 80 ЊC, 24 h; ii) Fc–C᎐CH, Pd(PPh3)4, CuI, NEt3, DMF or
᎐
i
᎐
Fc–C᎐CH, Pd(PPh3)2Cl2, CuI, NHPr 2, DMF, rt, 24 h.
᎐
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 8 2 – 1 3 8 8
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Table 1 sp2 Carbon chemical shifts of 15, 16, 17
Chemical shifts, δ
Compound
C-2
C-4
C-4a
C-5
C-6
C-7a
15
16
17
155.2
155.3
155.1
137.5
137.9
138.9
108.5
108.8
106.8
94.7
96.3
100.0
157.6
159.5
154.3
171.7
170.4
171.1
the corresponding ketone as a vinylic triflate, is expected to be
more reactive than 5. Indeed compound 6 reacted with the
ethynylferrocene 6 employing both methods A and B and gave
the coupling product 20 in 87% and 65% yields respectively
(Scheme 8).
Scheme 6
postulated for the homocoupling of alkynes.6e The driving force
for the cyclization step and the subsequent transformations is
probably the high electrophilic character of the ferrocene
moiety-adjacent carbon atom of the triple bond.
In contrast to 3, the fully protected nucleoside 4, prepared
from iodouridine, in which cyclization is not possible, reacted
with ethynylferrocene under conditions A to give the expected
alkyne derivative 19 in satisfactory yield (76%) without the
formation of analogous byproducts (Scheme 7).
᎐
᎐
Scheme 8 i) Fc–C᎐CH, Pd(PPh ) , CuI, NEt , DMF or Fc–C᎐CH,
᎐
3
4
3
᎐
Pd(PPh3)2Cl2, CuI, NHPri2, DMF, rt, 24 h.
In order to extend the scope of Sonogashira coupling of
ethynylferrocene with triflates we examined the reaction of
4-nitrophenol triflate 7, an activated aromatic triflate. Electron
withdrawing substituents on the aromatic ring are expected to
enhance the coupling reaction since they increase the reactivity
towards oxidative addition to Pd which is considered to be the
first stage of the reaction and resembles aromatic nucleophilic
substitution. As expected, nitrophenol triflate 7 reacted readily
with ethynylferrocene employing method A to give 21 in 90%
yield (Scheme 9).
᎐
Scheme 7 i) BzCl, pyridine, 0 ЊC, 24 h; ii) Fc–C᎐CH, Pd(PPh3)4, CuI,
᎐
NEt3, DMF, rt, 24 h.
᎐
As another target molecule the protected tyrosine triflate 5
was examined for labeling with ethynylferrocene. The attach-
ment of the ferrocene moiety to amino acids is of high interest
not only for the purposes of labeling but also for the under-
standing of electron transfer processes in peptide assem-
blies.4a,4b,4c On the other hand, due to their facile preparation
from carbonyl compounds and phenols trifluoromethane-
sulfonates (triflates) have been widely used in the last ten years
instead of halides in cross-coupling reactions with organo-
metallics, exhibiting the same reactivity with bromides.10 How-
ever, reaction of 5 with alkyne 8 using method A or B failed to
give any coupled product. Recently, tyrosine triflates have been
reported to be coupled with alkynes under palladium catalysis
at 70 ЊC.7e So, in a series of experiments the reaction was
repeated with increases in the reaction temperature (up to 70
ЊC) and the amount of catalyst (up to 1 equiv.) without success.
The alkyne dimer 9 was isolated in all cases as the only identifi-
able product. Probably the stability of alkyne 8 cannot stand
the higher temperature demands of the reaction. The failure of
the reaction of 5 with 8 under the applied conditions can be
explained on the basis of the relative reactivity scales in
Sonogashira couplings. The relative reactivity of halides is I >
Br ∼ OTf > Cl whereas with respect to an sp2 centre the reactiv-
ity is vinylic > heteroaromatic > aromatic. In accordance with
these reactivity scales ethynylferrocene reacted under mild con-
ditions with heteroaromatic bromides as the adenine derivatives
1 and 2 and failed to react with aromatic triflates.
Scheme 9 i) Fc–C᎐CH, Pd(PPh3)4, CuI, NEt3, DMF, rt, 24 h.
᎐
The spectral and analytical data of all new compounds are in
accordance with the proposed structures. The differentiation of
the two isomeric uracil derivatives 14 and 15 was mainly based
on their 1H NMR spectra. The 1H NMR spectrum of 14
exhibits a chemical shift at δ 8.97 corresponding to the NH
proton, whereas in the spectrum of 15 this peak is missing and
there is a peak at δ 6.25 consistent with a vinyl proton. For
compound 16 both MS and NMR data suggest the coupling of
1
one uracil with two ferrocene moieties. In the H NMR spec-
trum NH and vinyl hydrogen chemical shifts are missing,
whereas there is a peak at δ 7.79 very close to the value 7.73
observed in 15 for 4-H. The main evidence for the assignment
of structure 17 comes from its MS spectrum where the molecu-
lar ion peak at m/z 862 suggests that 17 is an oxidative dimer of
14 or 15. In the 1H NMR and 13C NMR spectra there is only a
set of peaks for the ferrocene and uracil moieties indicating a
symmetric dimer, whereas the absence of NH and vinyl hydro-
gen chemical shifts in the 1H NMR spectrum is consistent with
a furanopyrimidone structure dimerized from the 5-position.
The broadenings of some chemical shifts in both 1H NMR and
13C NMR of 17 are attributed to dynamic effects due to the
hindered rotation around the C5–C5Ј bond. The existence of
the common furanopyrimidine ring in compounds 15, 16 and
17 is further supported by the close similarity observed in their
sp2 carbon chemical shifts as depicted in Table 1.
The steroid derivative 6 was also examined as another inter-
esting biomolecule for labeling. Its triflate, easily prepared from
Finally the structure of compound 16 was unambiguously
confirmed by the results of a crystallographic X-ray analysis.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 8 2 – 1 3 8 8
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was extracted with a 10% NaHSO3 solution (3 × 20 cm3) and a
saturated NaHCO3 solution (2 × 20 cm3). After the organic
layer was dried and evaporated under reduced pressure the resi-
due was purified by column chromatography on silica using
ethyl acetate as eluent to give the bromo derivative 1 (1.02 g,
77%) as a beige solid Rf 0.74 (ethyl acetate). Mp 140–142 ЊC
(Found: C, 48.0; N, 21.0; H, 6.1. Calc. for C13H20BrN5: C, 47.9;
N, 21.5; H, 6.2%); νmax(Nujol)/cmϪ1 3270, 3100 (NH2), 1650
(C᎐N); δ 0.87 (3 H, t, J 6.4, CH3), 1.26 (10 H, m, CH2CH2-
᎐
H
(CH2)5CH3), 1.84 (2 H, m, CH2CH2(CH2)5CH3), 4.20 (2 H, t,
J 7.3, CH2CH2(CH2)5CH3), 6.32 (2 H, br s, NH2), 8.31 (1 H, s,
2-H); δC 14.2 (CH3), 22.5, 26.5, 29.0, 29.4 and 31.7 (CH2-
(CH2)6CH3), 44.5 (CH2(CH2)6CH3), 119.9 (C-5), 127.2 (C-8),
151.2 (C-4), 152.8 (C-2), 154.3 (C-6); m/z 325 (Mϩ, 16%), 246.
5-Iodo-1-octyluracil 3
A mixture of 5-iodouracil (0.5 g, 2.1 mmol), 1,1,1,3,3,3-hexa-
methyldisilazane (1.3 cm3, 6.3 mmol) and (NH4)2SO4 (0.008 g,
0.06 mmol) was heated at reflux for 15 h under an argon atmos-
phere. The solution was then concentrated by rotary evaporator
and to the residue were added DMF (3 cm3) and bromooctane
(0.6 g, 3.1 mmol). The resulting solution was heated at 80 ЊC for
24 h. Ice–water (30 cm3) was then added and the mixture was
stirred for 30 min and then extracted with dichloromethane
(2 × 40 cm3). After the organic phase was dried and evaporated
the residue was purified by column chromatography on silica
with hexane–ethyl acetate (3 : 1) as eluent to give 3 (0.36 g, 50%)
as a pale yellow solid Rf 0.33 (hexane–ethyl acetate 3 : 1). Mp
151–154 ЊC (Found: C, 41.3; N, 8.2; H, 5.3. Calc. for
C12H19IN2O2: C, 41.2; N, 8.0; H, 5.5%); νmax(Nujol)/cmϪ1 3120
Fig. 1 The molecular structure of compound 16. The Cp ring defined
by C16–C20 is disordered over two orientations; only one is shown in
the ORTEP diagram above. Average selected bond distances (Å): Fe(1)–
Cp(1) = 2.038(6) Å, Fe(1)–Cp(2) = 2.031(6) Å, Fe(2)–Cp(3) = 2.037(6)
Å, Fe(2)–Cp(4) = 2.053(6) Å (Cp(1), Cp(2), Cp(3) and Cp(4) are defined
by the atoms C(1)–C(5), C(6)–C(10), C(11)–C(15) and C(16)–C(20)
respectively).
An ORTEP diagram showing the atomic labeling is given in
Fig. 1.
In conclusion, we have shown that, with the exception of
the aromatic triflate 5 the Sonogashira coupling reaction of
ethynylferrocene with organic biomolecules bearing aromatic
or vinylic halogens or triflates provides an efficient entry for
their labeling with the sensitive electrochemical probe of ferro-
cene without the intervention of ester or amide groups. The
reactions proceed smoothly at room temperature providing a
significant practical advantage to those that require elevated
temperatures. Furthermore the transformation of alkynyl
uracil was investigated and the formation of the furanopyrimid-
one ring was unambiguously proved.
(NH), 1660 (C᎐O); δH 0.81 (3 H, t, J 6.4, CH3), 1.22 (10 H, m,
᎐
CH2CH2(CH2)5CH3), 1.62 (2 H, m, CH2CH2(CH2)5CH3), 3.69
(2 H, t, J 6.4, CH2CH2(CH2)5CH3), 7.61 (1 H, s, 6-H), 10.16
(1 H, s, NH); δC 13.9 (CH3), 22.4, 26.2, 28.9, 30.0 and 31.5
(CH2(CH2)6CH3), 49.1 (CH2(CH2)6CH3), 67.4 (C-5), 149.0
(C-6), 150.1 (C-2) and 160.9 (C-4)); m/z 350 (Mϩ, 18%), 223
(100, M Ϫ I).
3-Benzoyl-2Ј,3Ј,5Ј-tri-O-benzoyl-5-iodouridine 4
Benzoyl chloride (0.2 cm3, 1.7 mmol) was added to a solution of
5-iodouridine 18 (0.1 g, 0.29 mmol) in pyridine (1 cm3) under
cooling and the reaction solution was allowed to remain in the
refrigerator for 24 h. Then it was decanted into ice–water
(5 cm3) and extracted with chloroform (2 × 10 cm3). The
organic phase was dried, evaporated and chromatographed on
silica with hexane–ethyl acetate (3 : 1) to afford 4 (0.2 g, 88%) as
a white solid Rf 0.22 (hexane–ethyl acetate 3 : 1). Mp 180–182
ЊC (Found: C, 56.5; N, 3.4; H, 3.4. Calc. for C37H27IN2O10: C,
Experimental
Mps are uncorrected and were determined on a Kofler hot-
stage microscope. IR spectra were recorded on a Perkin-Elmer
297 spectrometer. 1H NMR spectra were recorded at 300 MHz
on a Bruker 300 AM spectrometer and 13C NMR spectra at
75.5 MHz on the same spectrometer and are quoted relative to
tetramethylsilane as internal reference, in deuteriochloroform
solutions, unless otherwise stated. J Values are given in Hz.
Mass spectra were performed on a VG-250 spectrometer with
ionisation energy maintained at 70 eV. Microanalyses were per-
formed on a Perkin-Elmer 2400-II element analyser. Column
chromatography was carried out on Merck Kieselgel (particle
size 0.063–0.200 mm) and solvents were distilled before use.
Pyridine, NEt3 and NHPri2 were dried with KOH, distilled and
stored over molecular sieves 4 Å. DMF was dried with CaH2,
distilled under reduced pressure and stored over molecular
sieves 4 Å. Ethynylferrocene was obtained from ferrocene-
carboxaldehyde according to a previously described method.11
The known compounds 2,12a 5,12b 6,12c 7,12d 1012e were also
prepared according to the literature procedures.
56.5; N, 3.6; H, 3.5%); νmax(Nujol)/cmϪ1 1700 (C᎐O, ester), 1655
᎐
(C᎐O, amide); δ 4.72–4.85 (3 H, m, 4Ј-H and 5Ј-H), 5.77 (1 H,
᎐
H
apparent t, ΣJ 12.2, 2Ј-H), 5.92 (1 H, dd, J2Ј,3Ј 5.8, J3Ј,4Ј 3.2,
3Ј-H), 6.38 (1 H, d, J 6.4, 1Ј-H), 7.30–7.66 (12 H, m, Ph-H),
7.89 (4 H, t, Ph-H), 7.98 (1 H, s, 6-H), 8.03 (2 H, d, J = 7, Ph-H),
8.15 (2 H, d, J = 7, Ph-H); δC 63.8 (C-5Ј), 69.4 (C-5), 71.5 (C-3Ј),
74.0 (C-2Ј), 81.1 (C-4Ј), 87.7 (C-1Ј), 128.2, 128.5, 128.55, 128.6,
128.65, 129.0, 129.05, 129.1, 129.7, 129.8, 129.9, 130.6, 130.9,
133.8, 133.9 and 135.1 (C-Ph), 143.6 (C-6), 149.1 (C-2), 158.4
(C-4), 165.3, 165.5, 166.1 and 167.1 (C᎐O).
᎐
General procedure for the coupling reactions
Method A. To a stirred suspension of the halide or triflate
(0.2 mmol), Pd(PPh3)4 (0.022 g, 0.02 mmol) and CuI (0.008 g,
0.04 mmol) in DMF (2 cm3) deoxygenated with Ar were added
sequentially ethynylferrocene 8 (0.042 g, 0.2 mmol) and tri-
ethylamine (0.4 cm3) and the reaction mixture was stirred at rt
for 12 h under Ar. TLC showed full consumption of the alkyne.
Then a second portion of 8 (0.021 g, 0.1 mmol) was added and
the stirring was continued for another 12 h. The solvent was
8-Bromo-9-octyladenine 1
Bromine (2.08 g, 13 mmol) was added to a solution of 9-octyl-
adenine 10 (1 g, 4.05 mmol) and CH3CO2Na (1.56 g, 19.02
mmol) in glacial acetic acid (12 cm3) and the reaction mixture
was heated at 50 ЊC for 48 h. After that ethyl acetate (30 cm3)
was added, the precipitated salts were filtered off and the filtrate
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 8 2 – 1 3 8 8
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removed under reduced pressure and the residue separated by
column chromatography on silica.
6-Ferrocenyl-3-octylfuro[2,3-d]pyrimidin-2(3H)-one 15
This compound was obtained as an orange solid Rf 0.21 (hex-
ane–ethyl acetate 1 : 1). Mp 225 ЊC (under dec.) (Found: C,
66.5; N, 6.8; H, 6.25. Calc. for C24H28FeN2O2: C, 66.7; N, 6.5;
H, 6.5%); νmax(Nujol)/cmϪ1 1690–1660 (C᎐O and C᎐N); δ 0.88
Method B. To a stirred suspension of the halide or triflate
(0.2 mmol), Pd(PPh3)2Cl2 (0.010 g, 0.013 mmol) and CuI (0.008
g, 0.04 mmol) in DMF (2 cm3) were added sequentially ethynyl-
ferrocene 8 (0.042 g, 0.2 mmol) and diisopropylamine (1 cm3)
and the reaction mixture was stirred at rt for 12 h under Ar.
TLC showed full consumption of the alkyne. Then a second
portion of 8 (0.021 g, 0.1 mmol) was added and the stirring
was continued for another 12 h. The solvent was removed
under reduced pressure and the residue separated by column
chromatography on silica.
᎐
᎐
H
(3 H, t, J 7.1, CH3), 1.29 (10 H, m, CH2CH2(CH2)5CH3), 1.82
(2 H, m, CH2CH2(CH2)5CH3), 3.97 (2 H, t, J 7.2, CH2CH2-
(CH2)5CH3), 4.15 (5 H, s, Fc-H), 4.41 (2 H, apparent s, Fc-H),
4.72 (2 H, apparent s, Fc-H), 6.25 (1 H, s, 5-H), 7.73 (1 H, s,
4-H); δC 14.0 (CH3), 22.6, 26.6, 29.1, 29.15, 29.2 and 31.7
(CH2(CH2)6CH3), 52.3 (CH2(CH2)6CH3), 66.5, 69.9, 70.0 and
72.6 (C-Fc), 94.7 (C-5), 108.5 (C-4a), 137.5 (C-4), 155.2 and
157.6 (C-2 and C-6), 171.7 (C-7α); m/z 432 (Mϩ, 85%).
8-(2-Ferrocenylethynyl)-9-octyladenine 11
6-Ferrocenyl-5-(2-ferrocenylethynyl)-3-octylfuro[2,3-d]-
pyrimidin-2(3H)-one 16
From the reaction of the alkyne 8 with the substrate 1 the title
compound was obtained (45 mg, 50% using method A or 75
mg, 82% using method B) by column chromatography (eluent:
2% NEt3 in hexane–ethyl acetate, 1 : 1) as a red-orange solid Rf
0.3 (hexane–ethyl acetate 1 : 1). Mp 168–170 ЊC (Found: C,
65.8; N, 15.15; H, 6.1. Calc. for C25H29FeN5: C, 65.9; N, 15.4; H,
This compound was obtained as a red solid Rf 0.45 (hexane–
ethyl acetate 1 : 1). Mp 180–182 ЊC (Found: C, 67.3; N, 4.6; H,
5.95. Calc. for C36H36Fe2N2O2: C, 67.5; N, 4.4; H, 5.7%);
νmax(Nujol)/cmϪ1 1660 (C᎐O); δH 0.88 (3 H, t, J 6.6, CH3), 1.29
᎐
6.4%); νmax(Nujol)/cmϪ1 3310, 3100 (NH ), 2200 (C᎐C), 1640
(10 H, m, CH2CH2(CH2)5CH3), 1.56 (2 H, m, CH2CH2-
(CH2)5CH3), 4.02 (2 H, t, J 7.3, CH2CH2(CH2)5CH3), 4.22 (5 H,
s, Fc-H), 4.31 (5 H, s, Fc-H), 4.34 (2 H, t, J 1.8, Fc-H), 4.51
(2 H, t, J 1.8, Fc-H), 4.58 (2 H, t, J 1.8, Fc-H), 5.14 (2 H, t,
J 1.8, Fc-H), 7.79 (1 H, s, 4-H); δC 14.0 (CH3), 22.6, 26.6, 29.0,
29.1, 29.2 and 31.7 (CH2(CH2)6CH3), 52.4 (CH2(CH2)6CH3),
64.6, 67.4, 69.3, 70.0, 70.1, 70.5, 71.4, 71.9 (C-Fc), 75.1 (C-5α),
93.25 (C-5β), 96.3 (C-5), 108.8 (C-4a), 137.9 (C-4), 155.3 (C-2),
159.5 (C-6), 170.4 (C-7α); m/z 640 (Mϩ, 16%).
᎐
᎐
2
(C᎐N); δ 0.85 (3 H, t, J 6.7, CH3), 1.26–1.38 (10 H, m,
᎐
H
CH2CH2(CH2)5CH3), 1.94 (2 H, m, CH2CH2(CH2)5CH3), 4.28
(7 H, m, CH2CH2(CH2)5CH3 and Fc-H), 4.37 (2 H, t, J 1.9,
Fc-H), 4.62 (2 H, t, J 1.9, Fc-H), 5.86 (2 H, br s, NH2), 8.39
(1 H, s, 2-H); δC 14.0 (CH3), 22.6, 26.7, 29.1, 29.7 and 31.7
(CH2(CH2)6CH3), 43.8 (CH2(CH2)6CH3), 61.9, 69.9, 70.3 and
72.0 (C-Fc), 74.9 (C-8α), 96.2 (C-8β), 119.7 (C-5), 135.8 (C-8),
149.9 (C-4), 153.2 (C-2), 154.6 (C-6); m/z 455 (Mϩ, 65%).
6-Ferrocenyl-5-(6-ferrocenyl-3-octyl-2-oxo-2,3-dihydrofuro[2,3-
d]pyrimidin-5-yl)-3-octylfuro[2,3-d]pyrimidin-2(3H)-one 17
8-(2-Ferrocenylethynyl)-2Ј,3Ј,5Ј-tri-O-acetyladenosine 12
From the reaction of the alkyne 8 with the substrate 2 the title
compound was obtained (96 mg, 80%, using method B) by
column chromatography (eluent hexane–ethyl acetate 5 : 1 and
then ethyl acetate) as an orange solid Rf 0.48 (ethyl acetate). Mp
106–108 ЊC (Found: C, 55.4; N, 11.3; H, 4.8; Calc. for C28H27-
FeN5O7: C, 55.9; N, 11.65; H, 4.5%); νmax(Nujol)/cmϪ1 3320,
This compound was obtained as a red solid Rf 0.09 (hexane–
ethyl acetate 1 : 1). Mp 250 ЊC (under dec.) (Found: C, 66.6; N,
6.7; H, 6.05. Calc. for C48H54Fe2N4O4: C, 66.8; N, 6.5; H, 6.3%);
νmax(Nujol)/cmϪ1 1650 (C᎐O); δH 0.87 (6 H, t, J 7.1, CH3), 1.23
᎐
(20 H, m, CH2CH2(CH2)5CH3), 1.63 (4 H, m, CH2CH2-
(CH2)5CH3), 3.71 (2 H, br, CH2CH2(CH2)5CH3), 3.96 (2 H, br,
CH2CH2(CH2)5CH3), 4.23 (10 H, s, Fc-H), 4.42 (6 H, m, Fc-H),
4.84 (2 H, apparent s, Fc-H), 7.24 (2 H, s, 4-H); δC 14.0 (CH3),
22.5, 26.4, 28.9, 29.15, 29.1 and 31.7 (CH2(CH2)6CH3), 52.2
(CH2(CH2)6CH3), 67.6, 68.2, 70.1, 71.7 (C-Fc), 100.0 (C-5),
106.8 (C-4a), 138.9 (C-4), 154.3 and 155.1 (C-2 and C-6), 171.1
(C-7α); m/z 862 (Mϩ, 7%).
᎐
3160 (NH ), 2200 (C᎐C), 1720–1660 (C᎐O, C᎐N); δ 2.05 (3 H,
᎐
᎐
᎐
2
H
s, CH3), 2.12 (3 H, s, CH3), 2.16 (3 H, s, CH3), 4.31–4.43 (9 H,
m, Fc-H, 4Ј-H and 5Ј-Ha), 4.56 (1 H, dd, J5Ј-Ha,5Ј-Hb 11.0, J4Ј,5Ј-Hb
2.9, 5Ј-Hb), 4.67 (2 H, m, Fc-H), 5.83 (2 H, br s, NH2), 5.95
(1 H, apparent t, ΣJ 11.5, 3Ј-H), 6.28–6.34 (2 H, m, 1Ј-H and
2Ј-H), 8.37 (1 H, s, 2-H); δC 20.5, 20.55 and 20.7 (CH3), 62.9 and
63.1 (C-5Ј and C-Fc), 70.1, 70.4, 72.2, 72.3 and 72.4 (C-3Ј, C-2Ј
and C-Fc), 74.0 (C-8α), 80.0 (C-4Ј), 87.4 (C-1Ј), 97.4 (C-8β),
128.8 (C-5), 130.9 (C-8), 149.4 (C-4), 150.8 (C-2), 153.3 (C-1),
3-Benzoyl-2Ј,3Ј,5Ј-tri-O-benzoyl-5-(ferrocenylethynyl)uridine 19
169.3, 169.4 and 170.6 (C᎐O, ester); m/z 601 (Mϩ, 13%).
᎐
From the reaction of the alkyne 8 with the substrate 4 the title
compound was obtained (130 mg, 76%, using method A) by
column chromatography (eluent hexane–ethyl acetate 3 : 1) as
an orange solid Rf 0.63 (hexane–ethyl acetate 3 : 1). Mp 92–94
ЊC (Found: C, 67.45; N, 3.1; H, 4.3. Calc. for C49H36FeN2O10: C,
Reaction of ethynylferrocene 8 with 5-iodo-1-octyluracil 3
After using method A or B the reaction mixture was separated
on a silica column with hexane–ethyl acetate (2 : 1) as eluent to
give in order of elution: 14 (69 mg, 80%), 16 (4 mg, 3%), 15
(9 mg, 10%) and 17 (5 mg, 5%) using method A; 14 (50 mg,
58%) and 16 (19 mg, 15%) using method B.
67.75; N, 3.2; H, 4.2%); νmax(Nujol)/cmϪ1 2200 (C᎐C), 1700
᎐
᎐
(C᎐O, ester), 1660 (C᎐O, amide); δ 4.19 (7 H, m, Fc-H), 4.34
᎐
᎐
H
(1 H, apparent s, Fc-H), 4.38 (1 H, apparent s, Fc-H), 4.75–4.79
(3 H, m, 4Ј-H and 5Ј-H), 5.77 (1 H, apparent t, ΣJ 11.6, 2Ј-H),
5.92 (1 H, dd, J2Ј,3Ј 5.5, J3Ј,4Ј 3.7, 3Ј-H), 6.37 (1 H, d, J 6.1, 1Ј-H),
7.25–7.62 (12 H, m, Ph-H), 7.83 (1 H, s, 6-H), 7.87 (2 H, d,
J = 7.9, Ph-H), 7.91 (2 H, d, J = 7.9, Ph-H), 7.97 (2 H, d, J = 7.9,
Ph-H), 8.05 (2 H, d, J = 8.5, Ph-H); δC 63.8 (C-5Јand C-Fc),
68.9, 70.1 and 71.4 (C-Fc), 71.6 (C-3Ј), 74.0 (C-2Ј), 75.1 (C-5α),
81.0 (C-4Ј), 88.2 (C-1Ј), 94.5 (C-5β), 102.6 (C-5), 126.2, 128.2,
128.3, 128.5, 128.6, 128.8, 128.9, 129.1, 129.6, 129.8, 129.9,
130.6, 131.1, 133.6, 133.8 and 135.2 (C–Ph), 140.1 (C-6), 148.4
5-(2-Ferrocenylethynyl)-1-octyluracil 14
This compound was obtained as a yellow solid Rf 0.63 (hexane–
ethyl acetate 1 : 1). Mp 125–127 ЊC (Found: C, 66.45; N, 6.2;
H, 6.4. Calc. for C24H28FeN2O2: C, 66.7; N, 6.5; H, 6.5%);
νmax(Nujol)/cmϪ1 3150 (NH), 2210 (C᎐C), 1670 (C᎐O); δ 0.89
᎐
᎐
᎐
H
(3 H, t, J 6.4, CH3), 1.29 (10 H, m, CH2CH2(CH2)5CH3), 1.68
(2 H, m, CH2CH2(CH2)5CH3), 3.76 (2 H, t, J 6.4, CH2CH2-
(CH2)5CH3), 4.24 (7 H, m, Fc-H), 4.49 (2 H, apparent s, Fc-H),
7.45 (1 H, s, 6-H), 8.97 (1 H, s, NH); δC 14.1 (CH3), 22.6, 26.3,
29.0, 29.05, 29.1 and 31.7 (CH2(CH2)6CH3), 49.2 (CH2-
(CH2)6CH3), 64.2, 68.9, 70,0 and 71.0 (C-Fc), 75.9 (C-5α), 93.2
(C-5β), 100.7 (C-5), 145.8 (C-6), 149.7 (C-2), 161.6 (C-4); m/z
432 (Mϩ, 11%).
(C-2), 159.9 (C-4), 165.2, 165.5, 166.1 and 167.5 (C᎐O).
᎐
3-(2-Ferrocenylethynyl)cholesta-3,5-diene 20
From the reaction of the alkyne 8 with the substrate 6 the title
compound was obtained (100 mg, 87%, using method A, or
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 8 2 – 1 3 8 8
1386

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187; A. Mayer and S. Neuenhofer, Angew. Chem., Int. Ed., 1994, 33,
75 mg, 65%, using method B) by column chromatography
(eluent hexane–ethyl acetate 5 : 1) as an orange solid Rf 0.83
(hexane–ethyl acetate 5 : 1). Mp 134–136 ЊC (Found: C, 81.4; H,
1044; A. P. de Silva, H. Q. N. Gunaratne, T. Gunnlaugsson, A. J. M.
Huxley, C. P. McCoy, J. T. Rademacher and T. E. Rice, Chem. Rev.,
1997, 97, 1515.
9.3. Calc. for C39H52Fe: C, 81.2; H, 9.1%); νmax(Nujol)/cmϪ1
2 D. G. Georganopoulou, R. Carley, D. A. Jones and M. G. Boutelle,
Faraday Discuss. Chem. Soc., 2000, 116, 291; F. A. Armstrong
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G. Aloisi, L. Becucci, A. Dolfi, M. R. Moncelli and F. T.
Buoninsengi, J. Electroanal. Chem., 2001, 504, 1; M. Trojanowicz,
Fresenius’ Z. Anal. Chem., 2001, 371, 246; J. Wang, Electroanalysis,
2001, 13, 983; D. R. Thevenot, K. Toth, R. A. Durst and G. S.
Wilson, Anal. Lett., 2001, 34, 635; E. Bakker and M. Telting-Diaz,
Anal. Chem., 2002, 74, 2781.
3 A. Togni and T. Hahashi, Ferrocenes, VCH: Weinheim, 1995.
4 (a) H.-B. Kraatz, J. Lusztyk and G. D. Enright, Inorg. Chem.,
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(c) E. Butkus, D. Tauraite, J. Barauskas, Z. Talaikyte and
V. Razumas, J. Chem. Res. (S), 1998, 722; (d ) A. Hess, O. Brosch,
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885; ( f ) O. Brosch, T. Weyhermuller and N. Metzler-Nolte, Eur. J.
Inorg. Chem., 2000, 323; (g) A. Hess, J. Sehnert, T. Weyhermuller
and N. Metzler-Nolte, Inorg. Chem., 2000, 39, 5437; (h) Y. Xu and
H.-B. Kraatz, Tetrahedron Lett., 2001, 42, 2601; (i) J. Sehnert,
A. Hess and N. Metzler-Nolte, J. Organomet. Chem., 2001, 637–639,
349.
5 (a) T. Ihara, Y. Maruo, S. Takenaka and M. Takagi, Nucleic Acids
Res., 1996, 24, 4273; (b) R. C. Mucic, M. K. Herrlein, C. A. Mirkin
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H. Konto, M. Abe, T. Suzuki and S. Takenaka, Anal. Biochem.,
1997, 250, 122; (d ) E. Buchi, L. De Napoli, G. Di Fabio, A. Messere,
D. Montesarchio, A. Romanelli, G. Piccialli and M. Varra,
Tetrahedron, 1999, 55, 14435; (e) C. J. Yu, H. Yowanto, Y. Wan,
T. J. Meade, Y. Chong, M. Strong, L. H. Donilon, J. F. Kayyem,
M. Gozin and G. F. Blackburn, J. Am. Chem. Soc., 2000, 122, 6767;
( f ) A. E. Beilstein and M. W. Grinstaff, Chem. Commun., 2000,
509; (g) C. J. Yu, H. Wang, Y. Wan, H. Yowanto, J. C. Kim,
L. H. Donilon, C. Tao, M. Strong and Y. Chong, J. Org. Chem.,
2001, 66, 2937; (h) A. Anne, B. Blanc and J. Moiroux, Bioconjugate
Chem., 2001, 12, 396; (i) A. E. Beilstein and M. W. Grinstaff,
J. Organomet. Chem., 2001, 637–639, 398; (j) S. A. Brazill,
P. H. Kim and W. G. Kuhr, Anal. Chem., 2001, 73, 4882; (k) C. J. Yu,
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11155.
᎐
2190 (C᎐C); δ 0.64 (3 H, s, CH3), 0.79–2.35 (38 H, m), 4.12
᎐
H
(2 H, t, J 1.8, Fc-H), 4.14 (5 H, s, Fc-H), 4.34 (2 H, t, J 1.8,
Fc-H), 5.45 (1 H, m, 6-H), 6.24 (1 H, s, 4-H); δC 12.0, 18.7, 19.1,
21.0, 22.6, 22.8, 23.8, 24.2, 27.2, 28.0, 28.2, 31.8, 32.1, 33.7,
34.6, 35.8, 36.2, 39.5, 39.8, 48.2, 56.2 and 56.9 (sp3 C), 66.0,
68.6, 69.9 and 71.2 (C-Fc), 87.7 and 87.9 (C-3α and C-3β),
117.7, 125.7, 134.5 and 141.6 (C-3, C-4, C-5 and C-6); m/z 576
(Mϩ, 38%).
4-(2-Ferrocenylethynyl)-1-nitrobenzene 21
From the reaction of the alkyne 8 with the substrate 7 the title
compound was obtained (60 mg, 90%, using method A) by
column chromatography (eluent hexane–ethyl acetate 10 : 1) as
a dark red solid Rf 0.73 (hexane–ethyl acetate 10 : 1). Mp 144–
145 ЊC (Found: C, 65.4; N, 4.2; H, 4.1. Calc. for C18H13FeNO2:
C, 65.3; N, 4.2, H, 4.0%); νmax(Nujol)/cmϪ1 2165 (C᎐C); δH 4.26
᎐
᎐
(5 H, s, Fc-H), 4.32 (2 H, t, J 1.8, Fc-H), 4.55 (2 H, t, J 1.8,
Fc-H), 7.60 (2 H, d, J 8.5, 3-H), 8.19 (2 H, J 8.5, 2-H); δC 63.7,
69.5, 70.1 and 71.8 (C-Fc), 84.4 and 95.2 (C-4α and C-4β),
123.6, 131.1, 131.8 and 146.4 (C–Ar); m/z 331 (Mϩ, 100%).
Crystal structure determination of compound 16†
A yellow/orange crystal of compound 16 (0.03 × 0.20 ×
0.60 mm) was mounted in air. Diffraction measurements were
made on a P21 Nicolet diffractometer upgraded by Crystal
Logic using graphite monochromated Cu radiation. Unit cell
dimensions were determined and refined by using the angular
settings of 25 automatically centered reflections in the range 22
< 2θ < 54Њ. Intensity data were recorded using a θ–2θ scan to
2θmax = 121Њ, with scan speed 1.5Њ minϪ1 and scan range 2.6Њ
plus α1α2 separation. Three standard reflections monitored
every 97 reflections showed less than 3% variation and no decay.
Lorentz, polarization and ψ-scan absorption corrections were
applied using Crystal Logic software. The structure was solved
by direct methods using SHELXS-8613a and refined by full-
matrix least-squares techniques on F 2 with SHELXL-93.13b All
non-hydrogen atoms were refined anisotropically. The Cp ring
defined by the atoms C(16)–C(20) was found disordered and
refined anisotropically in two orientations with occupation
factors 0.53 and 0.47 respectively. Thus, no hydrogen atoms for
that Cp ring were included in the refinement. The rest of the
hydrogen atoms were located by difference maps and were
refined isotropically.
6 (a) K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett.,
1975, 4467; (b) K. Sonogashira, in Comprehensive Organic Synthesis,
eds. B. M. Trost and I. Fleming, Pergamon Press, New York, 1991,
vol. 3, p. 521; (c) C. Amatore and A. Jutand, Acc. Chem. Res., 2000,
33, 314.
7 (a) M. J. Robins and P. J. Barr, J. Org. Chem., 1983, 48, 1854;
(b) F. W. Hobbs, Jr, J. Org. Chem., 1989, 54, 3420; (c) M. J.
Robins, R. S. Vinayak and S. G. Wood, Tetrahedron Lett., 1990, 31,
3731; (d ) G. T. Crisp and B. L. Flynn, J. Org. Chem., 1993, 58,
6614; (e) G. T. Crisp and J. Gore, Tetrahedron, 1997, 53, 1523;
( f ) C. McGuigan, C. J. Yarnold, G. Jones, S. Velázquez, H. Baruchi,
A. Brancale, G. Andrei, R. Snoeck, E. De Clercq and J. Balzarini,
J. Med. Chem., 1999, 42, 4479; (g) E. Trévisiol, E. Defrancq,
J. Lhomme, A. Laayoun and P. Cros, Tetrahedron, 2000, 56, 6501;
(h) E. Trévisiol, E. Defrancq, J. Lhomme, A. Laayoun and P. Cros,
Eur. J. Org. Chem., 2000, 211; (i) E. S. Kumarasinghe, M. A.
Peterson and M. J. Robins, Tetrahedron Lett., 2000, 41, 8741;
(j) F. Seela, E. Feiling, J. Cross, F. Hillenkamp, N. Ramzaeva,
H. Rosemeyer and M. Zulauf, J. Biotechnol., 2001, 86, 269; (k) R. H.
E. Hudson, G. Li and J. Tse, Tetrahedron Lett., 2002, 43, 1381;
(l ) N. Esho, B. Davies, J. Lee and R. Dembinski, Chem. Commun.,
2002, 332.
Crystal data
C36H36Fe2N2O2, M = 640.37, monoclinic, a = 16.192(5), b =
10.689(4), c = 17.644(6) Å, β = 91.95(2)Њ, V = 3052(2) Å3, T =
298 K, space group P21/c, Z = 4, µ(Cu-Kα) = 7.892 mmϪ1, 4701
reflections measured, 4538 unique (Rint = 0.0391), 4238 reflec-
tions used in all calculations. The final wR(F 2) was 0.2006 (all
data), the final R = 0.0600 for 2594 reflections with I > 2σ(I ).
8 R. P. Hsung, J. R. Babcock, C. E. D. Chidsey and L. R. Sita,
Tetrahedron Lett., 1995, 36, 4525; H. Fink, N. J. Long, A. J. Martin,
G. Opromolla, A. J. P. White, D. J. Williams and P. Zanello,
Organometallics, 1997, 16, 2646; K. R. J. Thomas, J. T.
Lin and Y. S. Wen, Organometallics, 2000, 19, 1008; C. J. McAdam,
B. H. Robinson and J. Simpson, Organometallics, 2000, 19, 3644;
W.-Y. Wong, G.-L. Lu, K.-F. Ng, C.-K. Wong and K.-H. Choi,
J. Organomet. Chem., 2001, 637–639, 159; S. Kocher and H. Lang,
J. Organomet. Chem., 2001, 637–639, 198.
† CCDC reference number 200800. See http://www.rsc.org/suppdata/
ob/b3/b300191a/ for crystallographic files in .cif or other electronic
format.
Acknowledgements
We are grateful to The Hellenic General Secretariat for
Research and Technology for financial support of this work.
9 E. Coutouli-Argyropoulou, A. Kelaidopoulou, C. Sideris and
G. Kokkinidis, J. Electroanal. Chem., 1999, 477, 130; E. Coutouli-
Argyropoulou, I. Sabbas and S. Konarski, J. Heterocycl. Chem.,
2000, 37, 1055; N. G. Argyropoulos and E. Coutouli-Argyropoulou,
J. Organomet. Chem., 2002, 654, 117.
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