Rhenium(I) tricarbonyl complexes with mercaptoimidazolylborate ligands bearing piperazine fragments

Article abstract of DOI:10.1039/b206603n

Reaction of an adequate borohydride salt with the functionalized mercaptoimidazoles timH^Me,pip 1 or timH^Me,CH2-pip 2 have led to Na[H₂B(tim^Me,pip)₂]3, Na[H₂B(tim^Me,CH2-pip)₂

Full text of DOI:10.1039/b206603n

View Article Online / Journal Homepage / Table of Contents for this issue
Rhenium(I) tricarbonyl complexes with mercaptoimidazolylborate
ligands bearing piperazine fragments
Raquel Garcia, Yong-Heng Xing,† António Paulo, Ângela Domingos and Isabel Santos*
Departamento de Química, ITN, Estrada Nacional 10, 2686-953 Sacavém Codex, Portugal.
E-mail: isantos@itn.pt
Received 8th July 2002, Accepted 9th September 2002
First published as an Advance Article on the web 16th October 2002
Reaction of an adequate borohydride salt with the functionalized mercaptoimidazoles timHMe,pip 1 or
timHMe,CH -pip 2have ledtoNa[H2B(timMe,pip)2] 3, Na[H2B(timMe,CH -pip)2] 4, Li[H(Ph)B(timMe)(timMe,pip)2] 6 and
2
2
Li[H(Ph)B(timMe)(timMe,CH -pip)2] 7 (timHMe = 1-methyl-2-mercaptoimidazole; timHMe,pip = 1-methyl-5-[(4-
2
(2Ј-methoxyphenyl)-1-piperazinyl)carbonyl]-2-mercaptoimidazole; timHMe,CH pip = 1-methyl-5-[(4-(2Ј-methoxy-
2
phenyl)-1-piperazinyl)methyl]-2-mercaptoimidazole). These symmetric and assymmetric functionalized
bis(mercaptoimidazolyl)borates, carrying a piperazine fragment, react readily with (NEt)4[Re(CO)3Br3] giving
[Re{κ3-H(µ-H)B(timMe,pip)2}(CO)3] 8, [Re{κ3-H(µ-H)B(timMe,CH -pip)2}(CO)3] 9, [Re{κ3-Ph(µ-H)B(timMe)(timMe,pip)}-
2
(CO)3] 10 and [Re{κ3-Ph(µ-H)B(timMe)(timMe,CH -pip)}(CO)3] 11. The organometallic complexes 8–11 are valuable
2
models for the development of specific radiopharmaceuticals for imaging serotonergic CNS receptors. The new
compounds (1–11) have been characterized by the usual analytical techniques (C, H, N analysis; IR and 1H NMR
spectroscopies), and by X-ray diffraction analysis in the case of 8.
Introduction
In recent years, it has been demonstrated that organometallic
complexes with the fac-[M(CO)3]ϩ (M = 99mTc, 186/188Re)
moieties can be applied in the labelling of biologically active
molecules, such as peptides, central nervous system (CNS)
ligands or sugar derivatives.1 However, for applying these
labelling tools adequate bifunctional chelator systems are
needed. Our research group has been exploring the utility of
poly(mercaptoimidazolyl)borates for labelling biomolecules
with the organometallic moieties fac-[M(CO)3]ϩ (M = 99mTc,
186/188Re).2 We have shown that these soft sulfur donor ligands
Fig. 1 Derivatization of bis(mercaptoimidazolyl)borates with bio-
molecules (BM) through the mercaptoimidazolyl rings.
are able to stabilize Re() or Tc() tricarbonyl complexes of the
type [M{κ3-R(µ-H)B(timMe)2}(CO)3] (M = Re, 99mTc; R = H, Me,
Ph), which display unprecedented and quite robust agostic
B–H ؒ ؒ ؒ M interactions. At non-carrier added level (99mTc),
these complexes can be prepared with high radiochemical yield
and with high specific activity, being remarkably stable under
aqueous and aerobic conditions.2 Moreover, preliminary bio-
distribution studies in mice have shown that these neutral and
lipophilic 99mTc complexes are able to cross the blood–brain
barrier.3 These features highlighted the usefulness of bis-
(mercaptoimidazolyl)borates as bifunctional chelators for the
labelling of CNS-receptor avid molecules. The coupling of
the biologically active substrates to the chelator framework can
be done using different strategies, one of them being through
the mercaptoimidazolyl rings. Using this approach, one or two
biomolecules can be coupled to the framework, in an asym-
metric or symmetric fashion, as illustrated in Fig. 1.
molecules for the targeting of the 5-HT1A subclass of sero-
tonergic receptors.4 Herein, we describe the preparation of
1-methyl-5-[(4-(2Ј-methoxyphenyl)-1-piperazinyl)carbonyl]-2-
mercaptoimidazole 1 and 1-methyl-5-[(4-(2Ј-methoxyphenyl)-1-
piperazinyl)methyl]-2-mercaptoimidazole 2, as well as the
synthesis and characterization of the new symmetric and
asymmetric borate ligands, Na[H2B(timMe,pip)2] 3, Na[H2B-
(timMe,CH -pip)2] 4, Li[H(Ph)B(timMe)(timMe,pip)2] 6 and Li[H-
2
(Ph)B(timMe)(timMe,CH -pip)2] 7. Reactions of the starting
2
material (NEt4)2[ReBr3(CO)3] with these novel functionalized
hydroborates have been investigated and the resulting Re()
tricarbonyl complexes [Re{κ3-H(µ-H)B(timMe,pip)2}(CO)3] 8,
[Re{κ3-H(µ-H)B(timMe,CH -pip)2}(CO)3] 9, [Re{κ3-Ph(µ-H)B-
2
(timMe)(timMe,pip)}(CO)3] 10 and [Re{κ3-Ph(µ-H)B(timMe)-
(timMe,CH -pip)}(CO)3] 11 will be also reported. All of the new
2
This contribution reports our efforts on the derivatization
of bis(mercaptoimidazolyl)borate anchors with CNS receptor
avid molecules, while maintaining their ability to stabilize
organometallic complexes with the fac-[M(CO)3]ϩ (M = Tc,
Re) moieties. As a lead structure for the biologically active
fragment, we have focused on 1-(2-methoxy)arylpiperazine
derivatives, which are among the most thoroughly studied
compounds (1–11) have been fully characterized, including by
X-ray diffraction analysis in the case of 8.
Results and discussion
Synthesis and characterization of functionalized
bis(mercaptoimidazolyl)borates
As referred to above, a straightforward way to achieve the
derivatization of bis(mercaptoimidazolyl)borates is through
† Current address: Department of Chemical Engineering, Jilin Institute
of Chemical Technology, Jilin City, P. R. China.
4236
J. Chem. Soc., Dalton Trans., 2002, 4236–4241
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b206603n

View Article Online
intermediary mono(mercaptoimidazolyl)borate, containing a
1-methyl-2-mercaptomercaptoimidazolyl ring, which is further
reacted with a mercaptoimidazole bearing a piperazine moiety.
As indicated in Scheme 3, the preparation of the mono(mer-
captoimidazolyl)borate intermediate involved the reaction of
Li(PhBH3) with 1-methyl-2-mercaptoimidazole in THF, at
room temperature. The course of this reaction was followed by
11B NMR spectroscopy. After 48 h, there was complete con-
sumption of Li(PhBH3) and formation of a unique hydroborate
derivative, which has been identified as Li[H2(Ph)B(timMe)] 5 by
1H and 11B NMR spectroscopies. In CD3CN, the 11B NMR
spectrum of 5 displays a triplet centred at 35.20 ppm, confirm-
ing the linkage of two hydrogen atoms to the boron atom. The
1H NMR spectrum of 5 shows a set of resonances consistent
with the presence of one phenyl group (Ph) and one 1-methyl-2-
mercaptoimidazolyl ring (timMe): δ 7.15 (2H, d, J = 6.9 Hz, Ph);
6.99 (2H, tr, J = 6.0 Hz, Ph); 6.88 (1H, tr, J = 7.5 Hz, Ph), 6.67
(1H, d, J = 1.8 Hz, CH, timMe); 6.54 (1H, d, J = 1.8 Hz, CH,
timMe); 3.46 (3H, s, CH3, timMe).
For the synthesis of 6 and 7, Li[H2(Ph)B(timMe)] 5 was
generated in situ and then reacted with the functionalized
mercaptoimidazoles timMe,pip 1 or timMe,CH -pip 2 (Scheme 3).
2
Scheme 1
After refluxing for 2 h, the solvent was removed and the
1
crude products analysed by H NMR to confirm the presence
incorporation of the piperazine groups into the mercapto-
imidazolyl rings. To accomplish this task, we have reacted
the activated ester [(1-methyl-2-mercaptoimidazol-5-yl)-
carbonyl]succinimide5 with 1-(2-methoxyphenyl)piperazine,
as indicated in Scheme 1. This reaction led to the synthesis
of the novel 1-methyl-5-[(4-(2Ј-methoxyphenyl)-1-piperazinyl)-
carbonyl]-2-mercaptoimidazole 1 (timMe,pip), in moderate yield
(56%). Compound 1 was reduced to the respective tertiary
amine by reaction with BH3ؒSMe2 (Scheme 1).6 The reduction
ran efficiently, leading to the new derivative 1-methyl-5-[(4-(2Ј-
methoxyphenyl)-1-piperazinyl)methyl]-2-mercaptoimidazole 2
of the ligands Li[H(Ph)B(timMe)(timMe,pip)] 6 or Li[H(Ph)-
B(timMe)(timMe,CH -pip)] 7. Compounds 6 and 7 were obtained
2
in low isolated yields as their purification required successive
recrystallizations from THF/n-hexane, necessary to remove
Li[H(Ph)B(timMe)2]. This compound appears when 5 is refluxed
in THF, due to a redistribution process.
The functionalized mercaptoimidazoles (1 and 2) and the
corresponding symmetric (3 and 4) or asymmetric (6 and 7)
hydroborate ligands have been characterized by 1H NMR
and IR spectroscopies. The most significant feature of the IR
spectra of the hydroborate ligands is the presence of weak
and broad bands centred at frequency values spanning from
2350 to 2420 cmϪ1, which were attributed to the B–H stretching
vibrations.2 In the case of 3 and 6, their IR spectra display very
(timMe,CH -pip), which was isolated in fair yield (55 %). The
2
functionalized mercaptoimidazoles 1 and 2 were further used to
prepare symmetric and asymmetric bis(mercaptoimidazolyl)-
borates by reaction with suitable borohydrides.
intense bands centred at 1635 and 1610 cmϪ1 due to the C᎐O
᎐
The symmetric ligands Na[H2B(timMe,pip)2] 3 and Na[H2B-
stretching vibration.7 In the IR spectra of all compounds (1–7)
(timMe,CH -pip)2] 4 were synthesized by reaction of sodium
the C᎐S stretching vibration appears as a medium intense
2
᎐
borohydride with 1 and 2, respectively (Scheme 2). Both
reactions were performed under reflux, in THF solution, and
were followed by 11B NMR spectroscopy. Ligands 3 and 4 were
isolated, in a pure form, by successive recrystallizations from
THF/n-hexane.
band with frequencies between 740 and 760 cmϪ1 8
.
The 1H
NMR data obtained for compounds 1–7 are in accordance
with the respective formulations (see Experimental section).
In particular, the 1H NMR spectra of 6 and 7 show resonances
due to the protons of 2-mercaptoimidazole (timMe) and due
to the functionalized mercaptoimidazoles (timMe,pip or
For the synthesis of asymmetric bis(mercaptoimidazolyl)-
borates we devised a strategy which lies on the formation of an
timMe,CH -pip), attesting to the asymmetric character of 6 and 7.
2
Scheme 2
J. Chem. Soc., Dalton Trans., 2002, 4236–4241
4237

View Article Online
Scheme 3
The piperazinyl protons of 4 and 7, resonating at frequencies
tion of impurities being detected. The moderate isolated yields
between 2.50 and 2.96 ppm, are shielded in comparison with
the corresponding protons in 3 and 6, which appear between
2.95 and 3.75 ppm. This difference reflects the withdrawing
electronic properties of the carbonyl group directly linked to
the piperazine ring in 3 and 6.
can be justified by the loss of 8–11 during the respective purifi-
cation procedures necessary to obtain strictly pure compounds.
Complexes 8–11 are yellow microcrystalline solids, stable
towards aerial oxidation or hydrolysis, either in the solid state
or in solution.
The functionalized mercaptoimidazolylborate ligands (3, 4, 6
and 7) are quite soluble in water, being remarkably stable
towards aerial oxidation or hydrolysis, either in the solid state
or in solution. Therefore, these functionalized hydroborates
display the necessary requirements to be explored in radio-
pharmaceutical development.
The IR spectra of 8–11 display weak bands in the range 2070
to 2170 cmϪ1, assigned to ν(B–H ؒ ؒ ؒ Re), which are strongly
red-shifted compared to the B–H stretching frequencies in the
free ligands or compared to the terminal ν(B–H) in the case of
8 and 9.
The 1H NMR data obtained for complexes 8–11 are in
agreement with the proposed formulations. In particular, the 1H
NMR data indicate the presence of either functionalized or
non-functionalized mercaptoimidazolyl rings and the presence
of the piperazine moieties. In the case of 8 and 10, the 1H NMR
pattern agrees with the symmetries found in the solid state. We
should note that for complex 11, in DMSO-d6 the resonance
due to the methylenic protons bridging the piperazinyl and
mercaptoimidazolyl rings and one of the resonances due to the
piperazinyl protons merge with the residual water signal.
Unfortunately, compound 11 has a quite limited solubility in
most common deuterated solvents, and we were unable to run
the spectrum of 11 in other solvents. In agreement with the
presence of quite strong agostic B–H ؒ ؒ ؒ Re interactions, the
1H NMR spectra of 8–11 show the presence of highfield shifted
resonances due to the coordinated hydrogen atoms. These
resonances appear at Ϫ6.58 and Ϫ6.74 ppm for the symmetric
complexes (8 and 9), and at Ϫ5.41 and Ϫ5.42 ppm for the
asymmetric ones (10 and 11).
Synthesis and characterization of Re(I) tricarbonyl complexes
As depicted in Scheme 4, (NEt4)2[ReBr3(CO)3] reacts readily
The molecular structure of 8, a symmetric complex, was
confirmed by X-ray diffraction analysis. Selected bond lengths
and angles are presented in Table 1, and in Fig. 2 is shown an
ORTEP view of 8. We were also able to obtain crystals of 10
suitable for X-ray diffraction analysis, but unfortunately of
low quality. The best crystal measured did not provide a
good quality data set for accurate bond distance and angle
measurement, but the connectivity of the atoms in this asym-
metric compound was determined unambiguously (Fig. 3).
Compound 10 crystallizes from dichloromethane as pale
yellow crystals in the monoclinic P21/c space group, with cell
Scheme 4
with ligands 3, 4, 6, or 7, affording the rhenium tricarbonyl
complexes 8–11 in fair isolated yields (45–58%), after adequate
work-up. The follow-up of these reactions by 1H NMR in
CD3OD revealed that the starting material is converted into
complexes 8–11 almost quantitatively, with only minor forma-
4238
J. Chem. Soc., Dalton Trans., 2002, 4236–4241

View Article Online
Table 1 Selected bond lengths (Å) and angles (Њ) for 8
involved in the agostic interaction B–H ؒ ؒ ؒ Re. The contribu-
tions of both B–H hydrogen atoms were included in calculated
positions, constrained to ride on their boron atom. Never-
theless, the B ؒ ؒ ؒ Re distance of 2.79(2) Å is clearly consistent
with the presence of an agostic B–H ؒ ؒ ؒ Re interaction in 8, as
would be expected from the spectroscopic properties of this
complex. The B ؒ ؒ ؒ Re distance, the average Re–C [1.90(1) Å]
and Re–S [2.478(4) Å] distances in 8 are comparable to the
values that we have previously reported for the correspondent
distances in the non-functionalized complexes [Re{κ3-R(µ-H)-
B(timMe)2}(CO)3] (R = H, Me, Ph).2 In respect to the functional-
ized dihydrobis(mercaptoimidazolyl)borate, the intraligand
bond distances and angles are normal; both six-membered
piperazinyl rings are in a chair conformation, avoiding in
such a way any intramolecular repulsive interaction with the
coordinated mercaptoimidazolyl rings.
Re–C(1)
Re–S(1)
C(1)–O(1)
C(11)–S(1)
1.89(2)
2.478(4)
1.15(2)
Re–C(2)
Re–B
C(2)–O(2)
1.90(2)
2.79(2)
1.14(2)
1.704(11)
C(1)–Re–C(2)
C(1)–Re–S(1)
C(2)–Re–S(1*)a
89.2(6)
92.2(5)
177.4(4)
C(2)–Re–C(2*)a
C(2)–Re–S(1)
90.9(9)
91.3(5)
86.5(2)
S(1)–Re–S(1*)a
a Equivalent atoms generated by the symmetry operation x, Ϫy ϩ 0.5, z.
Concluding remarks
Bis(mercaptoimidazolyl)borate ligands were successfully
functionalized, in a symmetric or asymmetric fashion, with
piperazine fragments which are part of a known antagonist
(WAY 100 635) of the 5-HT1A subtype serotonergic receptors.
The incorporation of the biologically active fragment did not
disturb the coordination capabilities of the borate ligands
towards the fac-[Re(CO)3]ϩ moiety,2 and several novel Re() tri-
carbonyl complexes, 8–11, with these functionalized ligands
have been prepared. Complexes 8–11, as indicated by spectro-
scopic data, contain a remarkably robust agostic B–H ؒ ؒ ؒ Re
interaction, which remains intact even in coordinating solvents
such as water, methanol, tetrahydrofuran and dimethyl
sulfoxide. These compounds can be seen as adequate surrogate
molecules of 99mTc complexes potentially relevant in the
development of specific radiopharmaceuticals for the targeting
of 5-HT1A serotonergic receptors. 99mTc radiopharmaceuticals
for in vivo imaging of 5-HT1A receptors have a well recognized
clinical interest, as these biological structures are implied in a
series of neurological diseases. However, so far, none of the
evaluated 99mTc complexes have proved to be adequate for
imaging the receptors in vivo.4 Interestingly, the use of func-
tionalized mercaptoimidazolylborates offers the opportunity
of exploring the so-called bivalent approach, which relies on
the use of two pharmacophores linked through a spacer in a
single ligand.9 This approach is one of the strategies currently
being explored by medicinal chemists to design selective CNS
receptor subtype ligands,10 but remains unexplored in the field
of radiopharmaceutical chemistry. Despite increasing the size
of the 99mTc complexes, the bivalent approach is expected to
be helpful in identifying more selective 99mTc radiopharmaceu-
ticals for the targeting of CNS receptors.
Fig.
2
ORTEP view of [Re{κ3-H(µ-H)B(timMe,pip)2}(CO)3] 8.
Vibrational ellipsoids are drawn at the 20% probability level.
Relative binding affinity (RBA) measurements of the sym-
metric or asymmetric rhenium complexes (8–11) are currently
under way. These measurements are expected to assess whether
the bivalent approach can enhance the binding affinity and
selectivity to the 5-HT1A receptors. The introduction of dif-
ferent length spacers between the mercaptoimidazolyl and
piperazinyl rings is also being explored, in order to evaluate the
influence on the affinity and selectivity of the symmetric or
asymmetric complexes.
Fig. 3 ORTEP view of [Re{κ3-Ph(µ-H)B(timMe)(timMe,pip)}(CO)3] 10.
Vibrational ellipsoids are drawn at the 20% probability level.
parameters a = 10.393(2) Å, b = 15.497(2) Å, c = 19.900(3) Å, β
= 101.777(13)Њ, V = 3137.6(9) Å3, Z = 4, Dc = 1.695 g cmϪ3
.
As can be seen in Fig. 2, 8 is a butterfly-shaped molecule that
displays a crystallographic imposed mirror plane containing
one of the CO ligands, the rhenium and boron atoms. The
Re atom is in a slightly distorted octahedral coordination
environment, one of the triangular faces being occupied by the
three CO ligands. The remaining coordination positions are
occupied by the thione sulfur atoms and by the hydrogen atom
involved in the agostic B–H ؒ ؒ ؒ Re interaction, the dihydrobis-
(mercaptoimidazolyl)borate acting as a tridentate (κ3-HS2)
donor ligand. The same coordination environment was found
for complex 10 (Fig. 3). The X-ray structural analysis of 8
did not allow the direct localization of the hydrogen atom
Experimental
General procedures
The synthesis of the functionalized mercaptoimidazoles and of
the corresponding hydroborate ligands were carried out under a
nitrogen atmosphere using standard Schlenk techniques, while
the synthesis of the rhenium complexes was performed under
air. Tetrahydrofuran and CH2Cl2 were dried and distilled
according to described procedures. All other solvents and
J. Chem. Soc., Dalton Trans., 2002, 4236–4241
4239

View Article Online
chemicals were used as purchased. The starting material
(NEt4)2[ReBr3(CO)3],11 the organoborohydride Li(PhBH3)12
and [(1-methyl-2-mercaptoimidazol-5-yl)carbonyl]succinimide
(timMe,NHS)5 were prepared by the literature methods. 1H NMR
spectra were recorded on a Varian Unity 300 MHz spec-
51%). νmax/cmϪ1: 2350w (B–H), 750m (C᎐S). δ (CD CN): 6.86–
᎐
H 3
6.91 (8 ϩ 2H, m, CH and Ph), 3.78 (6H, s, O–CH3), 3.48 (6H, s,
N–CH3), 3.34 (4H, s, N–CH2), 2.96 (8H, br, N–CH2), 2.51 (8H,
br, N–CH2).
1
trometer; H chemical shifts were referenced with the residual
Li[H(Ph)B(timMe)(timMe,pip)2] 6
solvent resonances relative to Me4Si, and 11B NMR chemical
shifts were referenced externally with sodium borohydride. IR
spectra were recorded as KBr pellets on a Perkin-Elmer 577
spectrometer. C, H and N analyses were performed on an
EA110 CE Instruments automatic analyser. It was not possible
to obtain accurate C, H, N analyses for 3, 4, 6 and 7, although
1H NMR analysis indicated that we had obtained pure
compounds.
To a solution of Li(PhBH3) (200 mg, 2.04 mmol) in THF was
added dropwise a solution of 2-mercapto-1-methylimidazole
(233 mg, 2.04 mmol) in THF, and the reaction mixture was
stirred at room temperature for 48 h. After this time, solid
timMe,pip (679 mg, 2.04 mmol) was added to the reaction mixture
and the resulting suspension was refluxed for 2 h. After cooling
to room temperature, the reaction mixture was filtrated and the
filtrate was concentrated to one third of its original volume.
Upon addition of n-hexane, compound 6 precipitated as a
microcrystalline white solid. Further purification of 6 was
achieved by successive recrystallizations from THF/n-hexane
1-Methyl-5-[(4-(2Ј-methoxyphenyl)-1-piperazinyl)carbonyl]-2-
mercaptoimidazole (timMe,pip) 1
To a suspension of the activated ester timMe,NHS (1.940 g, 7.59
mmol) in THF was added, dropwise and at 0 ЊC, a solution of
2-methoxyphenylpiperazine (1.606 g, 8.35 mmol) (10% molar
excess) in THF. The reaction mixture was allowed to warm to
room temperature and was stirred for 24 h. After this time,
compound 1 precipitated from the reaction mixtures and was
recovered by filtration, followed by washing with 10% NaHCO3
(20 ml) and water (20 ml). After drying under vacuum, com-
pound 1 was obtained as a microcrystalline white solid (1.410 g,
56%). Found: C, 56.1; H, 6.6; N, 16.3. C16H20N4O2S requires:
(0.134 g, 12%). νmax/cmϪ1: 2400w (B–H), 1610s (C᎐O), 750m
᎐
(C᎐S). δ (CD3CN): 6.84–7.14 (1 ϩ 9H, m, CH ϩ Ph), 6.70
᎐
H
(1H, d, JH–H = 2.1 Hz, CH), 6.57 (1H, d, JH–H = 2.1 Hz, CH),
3.80 (3H, s, –OCH3), 3.75 (4H, m, N–CH2), 3.56 (3H, s,
N–CH3), 3.45 (3H, s, N–CH3), 2.94 (4H, m, N–CH2).
Li[H(Ph)B(timMe)(timMe,CH -pip)2] 7
2
Starting from 0.140 g (1.43 mmol) of Li(PhBH3), 0.164 g
(1.44 mmol) of 2-mercapto-1-methylimidazole, and 0.455 g
(1.43 mmol) of timMe,CH -pip, compound 7 was prepared and
2
C, 57.8; H, 6.0; N, 16.9%. νmax/cmϪ1: 1585vs (C᎐O), 760m
᎐
recovered as described above for 6 (0.075 g, 10%). νmax/cmϪ1
:
(C᎐S). δH (CD3CN): 6.91–6.94 (5H, m, CH ϩ Ph), 3.77 (3H, s,
᎐
2420w (B–H), 750m (C᎐S). δ (CD3CN): 6.88–7.13 (9H, m,
᎐
H
O–CH3), 3.73 (4H, m, N–CH2), 3.53 (3H, s, N–CH3), 3.02 (4H,
m, N–CH2).
Ph), 6.69 (1H, d, JH–H = 2.1 Hz, CH), 6.46 (1H, JH–H = 2.1 Hz,
CH), 6.38 (1H, s, CH), 3.79 (3H, s, –OCH3), 3.54 (3H, s,
N–CH3), 3.47 (3H, s, N–CH3), 3.34 (2H, s, CH2), 2.97 (4H, m,
N–CH2), 2.50 (4H, m, N–CH2).
1-Methyl-5-[(4-(2Ј-methoxyphenyl)-1-piperazinyl)methyl]-2-
mercaptoimidazole (timMe,CH -pip) 2
2
To a suspension of 1 (1.196 g, 3.60 mmol) in CH2Cl2 was added
dropwise 11 ml of 1.0 M BH3ؒSMe2 in CH2Cl2, and the mixture
was stirred for 24 h at room temperature. The reaction mixture
was cooled in ice, and methanol was added dropwise until gas
evolution ceased. After removal of the solvent under vacuum,
10 ml of methanol was added to the crude mixture and the
resulting solution was refluxed for 1 hour. Methanol was
evaporated and the crude product was purified by silica-gel
flash chromatography using THF/n-hexane (50:50) as eluent.
Removal of the solvent from the collected fractions gave a white
residue, which was washed with n-hexane. The insoluble
material was dried under vacuum to afford compound 2 as a
microcrystalline white solid (0.629 g, 55%). Found: C, 59.0; H,
6.6; N, 16.2. C16H22N4OS requires: C, 60.4; H, 6.9; N, 17.6%).
νmax/cmϪ1 740 m (C᎐S). δ (CD3CN) 6.87–6.93 (4H, m, Ph),
General procedure for the synthesis of complexes 8–11
To a solution of (NEt4)2[Re(CO)3Br3] (0.100 g, 0.13 mmol)
in methanol was added a methanolic solution of the desired
ligand, in a 1:1 molar ratio, and the mixtures were allowed to
react for 2 h at room temperature. Complexes 8 and 11 precipi-
tated from the respective reaction mixtures, and were recovered
by filtration followed by washing with small portions of metha-
nol. Complexes 9 and 10 were recovered by recrystallization
from dichloromethane/n-hexane, after removal of methanol.
[Re{ꢀ3-H(ꢁ-H)B(timMe,pip)2}(CO)3] 8
Yield: 0.055 g, 45%. Found: C, 44.7; H, 4.4; N, 11.9. C35H40B-
N8O7S2Re requires: C, 44.4; H 4.2; N 11.9%. νmax/cmϪ1: 2450w
᎐
(B–H), 2070w (Re ؒ ؒ ؒ B–H), 1910vs and 2020vs (C᎐O), 1630s
᎐
᎐
H
6.63 (1H, s, CH), 3.79 (3H, s, O–CH3), 3.54 (3H, s, N–CH3),
(C᎐O), 770m (C᎐S). δ (DMSO-d ): 7.70 (2H, s, CH), 6.82–6.96
᎐ ᎐
H 6
3.39 (2H, s, CH2), 2.98 (4H, br, N–CH2), 2.54 (4H, br, N–CH2).
(8H, m, Ph), 3.72 (6H, s, –OCH3), 3.70 (8H, br, N–CH2), 3.55
(6H, s, N–CH3), 2.97 (8H, m, N–CH2), Ϫ6.71 (1H, br,
Re ؒ ؒ ؒ H–B).
Na[H2B(timMe,pip)2] 3
A suspension of NaBH4 (0.100 g, 2.64 mmol) and timMe,pip
(1.753 g, 5.28 mmol) in THF was refluxed for 24 h. After
cooling at room temperature the reaction mixture was filtered
to remove any insoluble material, and the filtrate was concen-
trated under vacuum; upon addition of n-hexane compound
3 precipitated as a white microcrystalline solid (0.970 g,
53%). νmax/cmϪ1: 2410w (B–H), 1635s (C᎐O), 760m (C᎐S).
δH (acetone-d6): 7.40 (2H, s, CH), 6.87–6.96 (8H, m, Ph), 3.78
(6H, s, –OCH3), 3.58 (8H, m, N–CH2), 3.44 (6H, s, N–CH3),
2.95 (8H, m, N–CH2).
[Re{ꢀ3-H(ꢁ-H)B(timMe,CH -pip)2}(CO)3] 9
2
Yield: 0.055 g, 46%. Found: C, 46.2; H, 5.4; N, 11.7. C35H44B-
N8O5S2Re requires: C, 45.8; H, 4.8; N, 12.2%. νmax/cmϪ1: 2430w
(B–H), 2150w and 2070w (Re ؒ ؒ ؒ B–H), 2020vs and 1910vs
(C᎐O), 750m (C᎐S). δ (CD CN): 6.80–6.95 (2 ϩ 8H, m, CH ϩ
Ph), 3.73 (6H, s, –OCH3), 3.55 (6H, s, N–CH3), 3.37 (4H, m,
N–CH2), 2.94 (8H, m, N–CH2), 2.50 (8H, m, N–CH2), Ϫ6.58
(1H, br, Re ؒ ؒ ؒ H–B).
᎐
᎐
᎐
H
3
᎐
᎐
[Re{ꢀ3-Ph(ꢁ-H)B(timMe)(timMe,pip)}(CO)3] 10
Na[H2B(timMe,CH -pip)2] 4
2
Yield: 0.050 g, 48%. Found: C, 43.0; H, 3.1; N, 10.7. C29H30B-
The preparation and recovery of 4 was carried out as described
above for 1. Starting from 0.026 g (0.69 mmol) of NaBH4, com-
pound 4 was obtained in the form of a white solid (236 mg,
N6O5S2Re requires: C, 43.3; H, 3.7; N, 10.5%. νmax/cmϪ1: 2170w
᎐
(Re ؒ ؒ ؒ B–H), 2020vs and 1910vs (C᎐O). δ (CD3CN): 7.32–
7.38 (5H, m, Ph), 7.14 (1H, d, JH–H = 2.1 Hz, CH), 6.80–6.96
᎐
H
4240
J. Chem. Soc., Dalton Trans., 2002, 4236–4241

View Article Online
Table 2 Crystallographic data for 8
See http://www.rsc.org/suppdata/dt/b2/b206603n/ for crystal-
lographic data in CIF or other electronic format.
Chemical formula
Mol. wt.
Crystal system
Space group
a/Å
C35H40BN8O7S2ReؒC4H8OؒH2O
1036.00
Orthorhombic
Pnma
Acknowledgements
18.068(3)
27.733(4)
9.1500(1)
4584.9(1)
4
1.501
2.800
2096
This work has been partially supported by the FCT (POCTI/
2001/QUI/42939) and by the Commission of the European
Communities (COST action B12). R. G. and Y. H. X. thank
the FCT for a PhD research grant and Post-doctoral Grant,
respectively.
b/Å
c/Å
V/Å3
Z
Dc/g cmϪ3
µ/mmϪ1
F(000)
References
Index ranges
Ϫ21 ≤ h ≤ 1
Ϫ1 ≤ k ≤ 32
Ϫ10 ≤ l ≤ 1
2.3–25.0
1 R. Alberto, R. Schibli, A. Egli, P. A. Schubiger, U. Abram and
T. A. Kaden, J. Am. Chem. Soc., 1998, 120, 7987; A. Hoepping, M.
Reisgys, P. Brust, S. Seifert, H. Spies, R. Alberto and B. Johannsen,
J. Med. Chem., 1998, 41, 4429; R. Alberto, R. Schibli, A. Egli,
P. A. Schubiger, U. Abram, H.-J. Pietzsch and B. Johannsen, J. Am.
Chem. Soc., 1999, 121, 6076; A. Egli, R. Alberto, L. Tannahill,
R. Schibli, U. Abram, A. Schaffland, R. Waibel, D. Tourwé,
L. Jeannin, K. Iterbeke and P. A. Schubiger, J. Nucl. Med., 1999, 40,
1913; R. Waibel, R. Alberto, J. Willuda, R. Finnern, R. Schibli,
A. Stichelberger, A. Egli, U. Abram, J.-P. Mach, A. Plueckthun
and P. A. Schubiger, Nat. Biotechnol., 1999, 17, 897; R. Schibli,
R. La Bella, R. Alberto, E. G. Garayoa, K. Ortner, U. Abram and
P. A. Schubiger, Bioconjugate Chem., 2000, 11, 345; H.-J. Pietzsch,
A. Gupta, M. Reisgys, A. Drews, S. Seifert, R. Syhre, H. Spies,
R. Alberto, U. Abram, P. A. Schubiger and B. Johannsen, Bio-
conjugate Chem., 2000, 11, 414; J. Wald, R. Alberto, K. Ortner
and L. Candreia, Angew. Chem., Int. Ed., 2001, 40, 3062; J. Petrig,
R. Schibili, C. Dumas, R. Alberto and P. A. Schubiger, Chem. Eur.
J., 2001, 7, 1868.
2 R. Garcia, A. Paulo, A. Domingos, I. Santos, K. Ortner and
R. Alberto, J. Am. Chem. Soc., 2000, 122, 11240; R. Garcia,
A. Paulo, A. Domingos and I. Santos, J. Organomet. Chem., 2001,
632, 41; R. Garcia, A. Domingos, A. Paulo, I. Santos and
R. Alberto, Inorg. Chem., 2002, 41, 2422.
3 R. Garcia, A. Paulo, L. Gano, I. Santos, unpublished results.
4 J. Passchier and A. van Waarde, Eur. J. Nucl. Med., 2001, 28,
113; B. Johannsen and H.-J. Pietzsch, Eur. J. Nucl. Med., 2002, 29,
263.
θ Range/Њ
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F 2
Final R1a [I > 2σ(I)]/wR2b
Large diff. peak/hole/e ÅϪ3
4585
4125 (Rint = 0.0472)
3351/20/281
1.062
0.0700/0.1487
1.194/Ϫ0.945
a R1 = Σ||Fo| Ϫ |Fc||/Σ|Fo|. b wR2 = [Σ(w(Fo2 Ϫ Fc2)2)/Σ(w(Fo )2)]0.5
.
2
(1 ϩ 4H, m, CH ϩ Ph), 6.77 (1H, d, JH–H = 2.1 Hz, CH), 3.81
(3H, s, O–CH3), 3.69 (4H, m, N–CH2), 3.62 (3H, m, N–CH3),
3.58 (3H, s, N–CH3), 2.97 (4H, m, N–CH2), Ϫ5.41 (1H, br,
Re ؒ ؒ ؒ H–B).
[Re{ꢀ3-Ph(ꢁ-H)B(timMe)(timMe,CH -pip)}(CO)3] 11
2
Yield: 0.060 g, 58%. Found: C, 43.5; H, 4.3; N, 10.6. C29H32B-
N6O4S2Re requires: C, 44.1; H, 4.1; N, 10.7%. νmax/cmϪ1: 2130w
᎐
(Re ؒ ؒ ؒ B–H), 2030vs and 1900vs (C᎐O). δ (DMSO-d6): 7.48
᎐
H
(1H, d, JH–H = 2.1 Hz, CH), 7.38–7.32 (3H, m, Ph), 7.21 (2H, m,
Ph), 6.98 (1H, d, JH–H = 2.1 Hz, CH), 6.95 (1H, s, CH), 6.91–
6.84 (4H, m, Ph), 3.74 (3H, s, O–CH3), 3.59 (3H, s, N–CH3),
3.56 (3H, s, N–CH3), 2.92 (4H, br, N–CH2), Ϫ5.42 (1H, br,
Re ؒ ؒ ؒ H–B).
5 E. Palma, J. D. G. Correia, A. Domingos and I. Santos, Eur. J. Inorg.
Chem., 2002, 2402.
6 H.L.C. Brown, Y. M. Choi and S. Narasimhan, J. Org. Chem., 1982,
47, 3153.
X-Ray crystallographic analysis
7 L. J. Bellamy, The Infra-red Spectra of Complex Molecules, Volume
2, Chapman and Hall, London, 1975, p. 241.
8 G. G. Lobbia, C. Pettinari, C. Santini, N. Somers, B. W. Skelton and
A. H. White, Inorg. Chim. Acta, 2001, 319, 15.
9 M. Mammen, S.-K. Choi and G. M. Whitesides, Angew. Chem., Int.
Ed., 1998, 37, 2755.
A yellowish crystal of 8 was obtained by recrystallization from
THF/n-hexane and fixed inside a thin-walled glass capillary.
Data were collected at room temperature on an Enraf-Nonius
CAD4-diffractometer with graphite-monochromatized Mo-Kα
radiation, using a ω–2θ scan mode. Unit cell dimensions were
obtained by least-squares refinement of the setting angles
of 25 reflections with 16.5 < 2θ < 29.6Њ. A summary of the
crystallographic data is given in Table 2. Data were corrected
for Lorentz and polarization effects and for absorption by
empirical corrections based on Ψ scans.13 The heavy atom
positions were located by Patterson methods using SHELXS-
86.14 The remaining atoms were located by successive difference
Fourier maps and refined by least-squares refinements on F 2
using SHELXL-93.15 A THF solvent molecule of crystalliza-
tion was located in the Fourier difference map. A remaining
residual peak was assigned as an oxygen atom of a water
molecule. All the non-hydrogen atoms were refined with aniso-
tropic thermal motion parameters and the contributions of the
hydrogen atoms were included in calculated positions (except
those of the water molecule). Atomic scattering factors and
anomalous disperson terms were as in SHELXL-93.15 The
drawings were made with ORTEP-3,16 and all the calculations
were performed on a DEC α 3000 computer.
10 S. Halazy, M. Perez, C. Fourrier, I. Pallard, P. J. Pauwels, C. Palmier,
G. W. John, J. P. Valentin, R. Bonnafous and J. Martinez, J. Med.
Chem., 1996, 39, 4920; A. P. Tamiz, J. Zhang, M. Zhang,
C. Z. Wang, K. M. Johnson and A. P. Kozikowski, J. Am. Chem.
Soc, 2000, 122, 5393; A. P. Tamiz, B. Bandyopadhyay, J. Zhang,
J. L. Flippen-Anderson, M. Zhang, C. Z. Wang, K. M. Johnson,
S. Tella and A. P. Kozikowski, J. Med. Chem., 2001, 44, 1615;
P. S. Portoghese, J. Med. Chem., 2001, 44, 2259; W. G. Rajeswaran,
Y. Cao, X.-P. Huang, M. E. Wroblewski, T. Colclough, S. Lee,
F. Liu, P. I. Nagy, J. Ellis, B. A. Levine, K. H. Nocka and W. S.
Messer, J. Med. Chem., 2001, 44, 4563.
11 R. Alberto, A. Egli, U. Abram, K. Hegetschweiler, V. Gramlich and
P. A. Schubiger, J. Chem. Soc., Dalton Trans., 1994, 2815.
12 B. Singaram, T. E. Cole and C. H. Brown, Organometallics, 1984, 3,
774.
13 C. K. Fair, MOLEN, Enraf-Nonius, Delft, The Netherlands,
1990.
14 G. M. Sheldrick, SHELXS-86: Program for the Solution of Crystal
Structure, University of Göttingen, Germany, 1986.
15 G. M. Sheldrick, SHELXL-93: Program for the Refinement of
Crystal Structure, University of Göttingen, Germany, 1993.
16 L. Farrugia, J. Appl. Crystallogr., 1997, 32, 565.
CCDC reference number 189597.
J. Chem. Soc., Dalton Trans., 2002, 4236–4241
4241