Functionalized rhenium(V) organoimido complexes as potential radiopharmaceuticals. 2. Synthesis, structural characterization, and reactivity of N-succinimidyl ester derivatives with amines

Article abstract of DOI:10.1021/om990929w

Organoimidorhenium(V) complexes were synthesized as potential labeling agents for biologically relevant organic amines using the preconjugate approach. The bistriphenylphosphine organoimidorhenium N-succinimidyl ester complex Cl₃(PPh₃)₂Re=N-C₆H ₄CO₂N-(COCH₂)₂ (2) was synthesized and characterized by single-crystal X-ray analysis. Complex 2 was coupled in aqueous dimethylformamide solvent with a series of primary and secondary amines, amino acids, and a biotin-ethylenediamine derivative to give the corresponding amide complexes in good yields. These results demonstrate that the organoimido linkage is resistant toward hydrolysis and stable in the presence of more basic alkylamines. An unusual oxygen atom transfer reaction was observed between the byproduct N-hydroxysuccinimide and triphenylphosphine ligands when dichloromethane was used as solvent. The dithiocarbamate complexes Cl[Et₂NCS₂]₂Re=N-C₆H ₄CO₂N(COCH₂)₂ (3) and O[(Et₂NCS₂)₂Re=N-C₆H ₄-CO₂N(COCH₂)₂]2 (4) were also synthesized from 2. These complexes were unaffected by N-hydroxysuccinimide, but were not suitable for labeling due to hydrolysis of the organoimido groups under the reaction conditions.

Full text of DOI:10.1021/om990929w

Organometallics 2000, 19, 1789-1795
1789
F u n ction a lized Rh en iu m (V) Or ga n oim id o Com p lexes a s
P oten tia l Ra d iop h a r m a ceu tica ls. 2. Syn th esis, Str u ctu r a l
Ch a r a cter iza tion , a n d Rea ctivity of N-Su ccin im id yl Ester
Der iva tives w ith Am in es
J effrey B. Arterburn,* Kalla Venkateswara Rao, Donna M. Goreham,†
Marcela V. Valenzuela, and Mylena S. Holguin
Department of Chemistry and Biochemistry MSC 3C, New Mexico State University,
P.O. Box 30001, Las Cruces, New Mexico 88003
Keith A. Hall,‡ Kevin C. Ott, and J effrey C. Bryan§
CST Division, MS J 514, Los Alamos National Laboratory, Los Alamos, New Mexico 87545
Received November 24, 1999
Organoimidorhenium(V) complexes were synthesized as potential labeling agents for
biologically relevant organic amines using the preconjugate approach. The bistriphenylphos-
phine organoimidorhenium N-succinimidyl ester complex Cl3(PPh3)2RedN-C6H4CO2N-
(COCH2)2 (2) was synthesized and characterized by single-crystal X-ray analysis. Complex
2 was coupled in aqueous dimethylformamide solvent with a series of primary and secondary
amines, amino acids, and a biotin-ethylenediamine derivative to give the corresponding
amide complexes in good yields. These results demonstrate that the organoimido linkage is
resistant toward hydrolysis and stable in the presence of more basic alkylamines. An unusual
oxygen atom transfer reaction was observed between the byproduct N-hydroxysuccinimide
and triphenylphosphine ligands when dichloromethane was used as solvent. The dithiocar-
bamate complexes Cl[Et2NCS2]2RedN-C6H4CO2N(COCH2)2 (3) and O[(Et2NCS2)2RedN-C6H4-
CO2N(COCH2)2]2 (4) were also synthesized from 2. These complexes were unaffected by
N-hydroxysuccinimide, but were not suitable for labeling due to hydrolysis of the organoimido
groups under the reaction conditions.
In tr od u ction
attained through multifaceted approaches leading to a
diverse variety of candidate complexes for clinical trials.
Three general methods for producing metal biocon-
jugates are available: (1) direct labeling of biomolecules
that contain a natural ligating or reactive group such
as thiols; (2) the postconjugate approach where the
biomolecule is first attached to a modified ligand that
is then complexed with the metal; and (3) the precon-
jugate approach, where a metal complex is formed first
and then attached to the biomolecule as an intact unit.
With direct labeling it is difficult to control the site of
attachment, the structure of the biomolecule can be
disrupted, and redox changes at the metal can occur.
The postconjugate approach provides a controlled ligand
environment, but remains subject to problems during
Biomolecules labeled with organometallic and coor-
dination complexes have been developed for use as
electron-transfer mediators, as probes for the active
sites of enzymes, and for protein structural resolution
with X-ray diffraction and electron microscopy.1 The
synthesis of radiopharmaceuticals represents another
area where new technologies are necessary to overcome
the challenges associated with labeling biomolecules
with radioactive metals.2 Peptides, antibodies, and
steroids are all potential substrates for labeling with
radioactive metals such as Tc-99m and Re-186/188 for
diagnostic imaging and targeted radiotherapy, respec-
tively. The ideal radiopharmaceutical would be easy to
synthesize, exhibit stability and selective biodistribution
in vivo, and then clear the body after the clinical pro-
cedure. These stringent requirements can ultimately be
(2) (a) J urisson, S.; Berning, D.; J ia, W.; Ma, D. Chem. Rev. 1993,
93, 1137-1156. (b) Schwochau, K. Angew. Chem., Int. Ed. Engl. 1994,
33, 2258-2267. (c) Eckelman, W. C. Eur. J . Nucl. Med. 1995, 22, 249-
263. (d) Top, S.; El Hafa, H.; Vessieres, A.; Quivy, J .; Vaissermann, J .;
Hughes, D. W.; McGlinchey, M. J .; Mornon, J . P.; Thoreau, E.; J aouen,
G. J . Am. Chem. Soc. 1995, 117, 8372-8380. (e) Schubiger, P. A.;
Alberto, R.; Smith, A. Bioconj. Chem. 1996, 7, 165-179. (f) Fischman,
A. J .; Babich, J . W. Nucl. Med. Ann. 1997, 103-131. (g) Hom, R. K.;
Katzenellenbogen, J . A. Nucl. Med. Biol. 1997, 24, 485-498. (h)
Alberto, R.; Schibli, R.; Egli, A.; Schubiger, A. P.; Abram, U.; Kaden,
T. A. J . Am. Chem. Soc. 1998, 120, 7987-7988. (i) Dilworth, J . R.;
Parrott, S. J . Chem. Soc. Rev. 1998, 27, 43-55. (j) Spradau, T. W.;
Katzenellenbogen, J . A. Organometallics 1998, 17, 2009-2017. (k)
Waibel, R.; Alberto, R.; Willuda, J .; Finnern, R.; Schibli, R.; Stichel-
berger, A.; Egli, A.; Abram, U.; Mach, J . P.; Pluckthun, A.; Schubiger,
P. A. Nat. Biotechnol. 1999, 17, 897-901.
* To whom correspondence should be addressed. E-mail: jarterbu@
nmsu.edu.
† Permanent address: Glaxo Wellcome Research and Development
Medicines Research Centre, Gunnels Wood Road, Stevenage, Hert-
fordshire SG1 2NY, U.K.
‡ Permanent address: Symyx Technologies, Inc., 3100 Central
Expressway, Santa Clara, CA 95051.
§ Permanent address: Chemical and Analytical Sciences Division,
Oak Ridge National Laboratory, Oak Ridge, TN 37831-6119.
(1) (a) Ryabov, A. D. Angew. Chem., Int. Ed. Engl. 1991, 30, 931-
941. (b) J aouen, G.; Vessieres, A.; Butler, I. S. Acc. Chem. Res. 1993,
26, 361-369. (c) Severin, K.; Bergs, R.; Beck, W. Angew. Chem., Int.
Ed. 1998, 37, 1634-1654.
10.1021/om990929w CCC: $19.00 © 2000 American Chemical Society
Publication on Web 03/31/2000

1790 Organometallics, Vol. 19, No. 9, 2000
Arterburn et al.
Sch em e 1
complex formation. The preconjugate approach offers
greater control through the use of a purified metal
complex, which only undergoes labeling with appropri-
ately matched functional groups on the biomolecule.
Amine side chain groups are commonly found on the
biomolecules of interest and offer convenient sites for
conjugation to a modified ligand system, due to the ease
of formation of amide bonds with various activated
carboxyl derivatives. Activated esters have been used
to attach chelating ligands,3 metal complexes,4 and
groups such as hydrazinopyridine to biomolecules.5 The
N-succinimidyl ester group is a convenient activating
group for the acylation of amines and has been employed
in the preconjugate approach to incorporate a variety
of different classes of metal complexes,6 including rhe-
nium and technetium.7
We have investigated the suitability of the multiple
bonding imido ligand for Tc and Re and recently
reported the synthesis of aryl organoimido Re(V) com-
plexes containing remotely functionalized carboxylic
acid groups 1.8 These compounds are stable to air as
solids and in solution, and Re-188 complexes can be
synthesized at tracer levels and purified by HPLC
chromatography using aqueous acetonitrile eluent. The
multiply bonded organoimido group provides a direct
covalent linkage between the organic and metal com-
ponents. With this mode of attachment it is possible to
fine-tune desirable properties of size, charge, and lipo-
philicity by varying labile ligands in the coordination
sphere, an option unavailable to chelates. Therefore we
have considered the development of organoimido com-
plexes that are remotely functionalized with active ester
analogues which would be suitable for labeling amines
by the preconjugate approach. This approach requires
that the organoimido linkage be resistant to hydrolysis
under aqueous conditions and exhibit stability in the
presence of alkylamines, which are both stronger bases
and potential ligands. We describe here the synthesis
and X-ray stucture of the activated organoimido N-
succinimidyl ester 2 and dithiocarbamate derivatives 3
and 4, and an investigation of their reactivity with
amines, amino acids, and a biotin derivative targeted
for monoclonal antibody-avidin conjugates.
(3) Eisenhut, M.; Lehmann, W. D.; Becker, W.; Behr, T.; Elser, H.;
Strittmatter, W.; Steinstrasser, A.; Baum, R. P.; Valerius, T.; Repp,
R.; Deo, Y. J . Nucl. Med. 1996, 37, 362-370.
(4) (a) Kasina, S.; Rao, T. N.; Srinivasan, A.; Sanderson, J . A.;
Fitzner, J . N.; Reno, J . M.; Beaumier, P. L.; Fritzberg, A. R. J . Nucl.
Med. 1991, 32, 1445-1451. (b) Linder, K. E.; Wen, M. D.; Nowotnik,
D. P.; Malley, M. F.; Gougoutas, J . Z.; Nunn, A. D.; Eckelman, W. C.
Bioconjugate Chem. 1991, 2, 160-170. (c) Liu, S.; Edwards, D. S.;
Looby, R. J .; Poirier, M. J .; Rajopadhye, M.; Bourque, J . P.; Carroll, T.
R. Bioconjugate Chem. 1996, 7, 196-202. (d) Giblin, M. F.; J urisson,
S. S.; Quinn, T. P. Bioconjugate Chem. 1997, 8, 347-353. (e) Ghulke,
S.; Schaffland, A.; Zamora, P. O.; Sartor, J .; Diekman, D.; Bender, H.;
Knapp, F. F.; Biersack, H. J . Nucl. Med. Biol. 1998, 25, 621-631.
(5) (a) Schwartz, D. A.; Abrams, M. J .; Hauser, M. Bioconjugate
Chem. 1991, 2, 333-336. (b) Hnatowich, D. J .; Mardirossian, G.;
Rusckowski, M.; Fogarasi, M.; Virzi, F.; Winnard, P. J . Nucl. Med.
1992, 34, 109-119. (c) Babich, J . W.; Solomon, H.; Pike, M. C.; Kroon,
D.; Graham, W.; Abrams, M. J .; Tompkins, R. G.; Rubin, R. H.;
Fischman, A. J . J . Nucl. Med. 1993, 34, 1964-1974. (d) Bridger, G. J .;
Abrams, M. J .; Padmanabhan, S.; Gaul, F.; Larsen, S.; Henson, G. W.;
Schwartz, D. A.; Longley, C. B.; Burton, C. A.; Ultee, M. E. Bioconjugate
Chem. 1996, 7, 255-264. (e) Liu, S.; Edwards, D. S.; Barrett, J . A.
Bioconjugate Chem. 1997, 8, 621-636. (f) Rose, D. J .; Maresca, K. P.;
Nicholson, T.; Davison, A.; J ones, A. G.; Babich, J .; Fischman, A.;
Graham, W.; DeBord, J . R. D.; Zubieta, J . Inorg. Chem. 1998, 37, 2701-
2716.
(6) (a) Ryabov, A. D.; Trushkin, A. M.; Baksheeva, L. I.; Gorbatova,
R. K.; Kubrakova, I. V.; Mozhaev, V. V.; Gnedenko, B. B.; Levashov,
A. V. Angew. Chem., Int. Ed. Engl. 1992, 31, 789-790. (b) Wang, Z.;
Roe, B. A.; Nicholas, K. M.; White, R. L. J . Am. Chem. Soc. 1993, 115,
4399-4400. (c) El Mouatassim, B.; Elamouri, H.; Vaissermann, J .;
J aouen, G. Organometallics 1995, 14, 3296-3302. (d) Gorfti, A.;
Salmain, M.; J aouen, G.; McGlinchey, M. J .; Bennouna, A.; Mousser,
A. Organometallics 1996, 15, 142-151. (e) Zakrzewski, J .; Klys, A.;
Bukowska-Strzyzewska, M.; Tosik, A. Organometallics 1998, 17, 5880-
5886. (f) Osella, D.; Pollone, P.; Ravera, M.; Salmain, M.; J aouen, G.
Bioconjugate Chem. 1999, 10, 607-612.
Resu lts a n d Discu ssion
Syn th esis a n d Ch a r a cter iza tion of Or ga n oim id o
Su ccin im id yl Ester s 2-4. Iminophosphoranes are
known to react with rhenium(V) oxo complexes to form
arylimidorhenium(V) complexes and triphenylphos-
phine oxide.9 The bis-triphenylphosphine organoimi-
dorhenium N-succinimidyl ester complex Cl3(PPh3)2-
RedN-C6H4CO2N(COCH2)2 (2) was prepared in 91%
yield by heating the rhenium(V) oxo complex ReOCl3-
(PPh3)2 in benzene for 1 h with the iminophosphorane
derived from N-succinimidyl-4-azidobenzoate (Scheme
1).10 No precautions to dry the solvent or exclude air
were required. The complex exhibits a single 31P{1H}
NMR signal at δ -23.7 for the equivalent trans triphen-
ylphosphine ligands. The complex was fully character-
ized by H and 13C NMR and elemental analysis. The
1
FT-IR absorbances of the ester and imide carbonyl
groups occur at 1770 and 1743 cm-1, respectively. The
complex exhibits a characteristic UV-vis absorbance at
λ ) 336 nm, ꢀ ) 14 030 in CH2Cl2 and is easily
(7) (a) Salmain, M.; Gunn, M.; Gorfti, A.; Top, S.; J aouen, G.
Bioconjugate Chem. 1993, 4, 425-433. (b) Salmain, M.; Gorfti, A.;
J aouen, G. Eur. J . Biochem. 1998, 258, 192-199. (c) Spradau, T. W.;
Katzenellenbogen, J . A. Bioconjugate Chem. 1998, 9, 765-772. (d) Top,
S.; Lehn, J . S.; Morel, P.; J aouen, G. J . Organomet. 1999, 583, 63-68.
(e) Top, S.; Morel, P.; J aouen, G. Inorg. Chem. Commun. 1999, 2, 7-9.
(8) Arterburn, J . B.; Fogarty, I.; Hall, K. A.; Ott, K. C.; Bryan, J . C.
Angew Chem., Int. Ed. Engl. 1996, 35, 2877-2879.
(9) (a) Chatt, J .; Dilworth, J . R. J . Chem. Soc., Chem. Commun.
1972, 549. (b) Goeden, G. V.; Haymore, B. L. Inorg. Chem. 1983, 22,
157-167.
(10) Yip, C. C.; Yeung, C. W. T.; Moule, M. L. Biochemistry 1980,
19, 70-76.

Re(V) Organoimido Complexes
Organometallics, Vol. 19, No. 9, 2000 1791
C1 organoimido bond angle of 171.4(4)° are typical of
multiple bonded rhenium(V) monoimido complexes
(1.69-1.75 Å, 156-180°).11 The Re-Cl and Re-P dis-
tances are similar to those reported for the closely
related complex [Re(NPh)Cl3(PPh3)2].12 The N-succin-
imidyl ester carbonyl group of 2 is situated remotely
from the coordination environment of the metal and is
not perturbed by it.
The monomeric dithiocarbamate complex Cl[Et2-
NCS2]2RedN-C6H4CO2N(COCH2)2 (3) was prepared in
84% yield by heating a solution of 2 with tetraethylthi-
1
uramdisulfide in acetone for 1 h (Scheme 1).13 The H
NMR spectra of 3 in CDCl3 at 22 °C shows a single
triplet for the four methyl groups and a multiplet for
the inequivalent CH2 groups due to slow rotation about
the C-N bond of the dithiocarbamate ligands. The ethyl
groups in 3 give rise to two 13C NMR peaks at δ 12.42
and 45.16. The FT-IR spectra show strong absorbances
at 1531 and 997 cm-1 associated with the C-N and C-S
bonds of the dithiocarbamate ligand. The absorbances
for the ester and imide carbonyls of 3 appeared at 1769
and 1741 cm-1 and are very close to the corresponding
carbonyl groups of complex 2. Complex 3 exhibits a UV-
vis absorbance in CH2Cl2 at 418 nm, ꢀ ) 4710 that is
easily distinguished from the oxo complex Cl[Et2NCS2]2-
RedO, which absorbs at 344 nm.
F igu r e 1. ORTEP drawing (50% probability ellipsoids) of
Cl3 (P P h 3 )2 RedN -C6 H 4 CO2 N (COCH 2 )2 ‚(CH 2 Cl2 )1 . 4 3
-
(EtOH)0.57. Hydrogen atoms and disordered lattice mol-
ecules are omitted.
Ta ble 1. Su m m a r y of Cr ysta llogr a p h ic Da ta
chemical formula
temp (K)
C49.57H44.28Cl5.86N2O4.57P2Re
203
space group
cryst dimens (mm)
a, Å
P1h (No. 2)
0.18 × 0.23 × 0.68
12.703(3)
The tetrakis(dithiocarbamate) µ-oxo-dirhenium com-
plex O[(Et2NCS2)2RedN-NC6H4CO2N(COCH2)2]2 (4) was
prepared in 73% yield by treating 3 with sodium
carbonate in 0.1% v/v aqueous acetone and heating for
b, Å
14.250(3)
c, Å
14.930(3)
R, deg
100.04(3)
105.40(3)
101.23(3)
triclinic
2, 1197.0
1.60
2.88
1
1 h (Scheme 1).13 The H NMR spectra of 4 in CDCl3 at
â, deg
γ, deg
22 °C shows a single triplet for the four methyl groups
and a multiplet for the CH2 groups of the dithiocarbam-
ate ligand. The FT-IR spectra of 4 shows strong absor-
bances of the dithiocarbamate ligand at 1500 and 1072
cm-1 and also an absorbance at 684 cm-1 due to the
bridging µ-oxo Re-O-Re group. The absorbance of the
ester carbonyl in 4 is shifted to 1780 cm-1, an increase
of +10 cm-1 compared with complexes 2 and 3. This
shift indicates the apparently greater electron-with-
drawing effect of the bridging oxo group in comparison
with the chloride ligand, which influences the remote
conjugated carbonyl through the phenylimido group.
Complex 4 showed a UV-vis absorbance at 444 nm in
CH2Cl2; however this absorbance exhibited a nonlinear
dependence on concentration. Similar deviations from
the Beer-Lambert law have been observed in the
electronic spectra of related oxo-bridged organoimido
molybdenum dimers and were attributed to an equilib-
rium disproportionation reaction.14 The corresponding
oxo dimer O[(Et2NCS2)2RedO]2 absorbs at 388 nm in
CH2Cl2 and is easily distinguished from the organoimido
complex 4.
cryst syst
Z, volume (Å3)
density (calcd) (g/cm3)
abs coeff (mm-1
)
transmission factors
θ range for data collection (deg)
limiting indices
0.592, 0.719
2.0-25.0
-15 e h e 0, -16 e k e 16,
-17 e l e 17
8965
no. of reflns collected
no. of indepdt reflns, Rint
Ra
8537, 0.029
0.034
a
R ) (∑|[Fobs - Fcalc]|)/(∑Fobs).
Ta ble 2. Selected Bon d Len gth s (Å) a n d An gles
(d eg) for 2
bond distances
bond angles
Re-N1
1.721(4)
2.440(1)
2.411(1)
2.524(2)
2.518(2)
1.380(6)
1.211(6)
Re-N-C1
171.4(4)
175.3(1)
85.4(1)
93.9(1)
89.7(1)
90.0(1)
90.4(1)
Re-Cl1
Re-Cl2
Re-P1
Re-P2
N1-C1
O1-C7
P1-Re-P2
Cl2-Re-Cl3
Cl1-Re-N
Cl1-Re-P1
Cl1-Re-P2
Cl1-Re-Cl2
distinguished from the oxo complex ReOCl3(PPh3)2,
which absorbs at 272 nm.
Sta bility Stu d ies of Or ga n oim id o Su ccin im id yl
Ester s 2-4. The characteristic UV-vis absorbances of
the organoimido complexes were useful for monitoring
the stability of the organoimido bond toward hydrolysis
in solution. For the developmental stage of this project,
The structure of the complex 2 (Figure 1) consists of
an octahedral arrangement of mer-cis-oriented chloride
ligands, trans-triphenylphosphine ligands, and the im-
ido ligand. This ligand arrangement around the rhe-
nium is similar to that of previously reported phenylim-
ido complexes and is consistent with spectroscopic data
for the complex in solution. A summary of crystal-
lographic data is reported in Table 1. Selected bond
lengths and angles are reported in Table 2. The Re-N
bond length of 1.721(4) Å and the nearly linear Re-N-
(11) Wigley, D. E. Prog. Inorg. Chem. 1994, 42, 239-482.
(12) (a) Forsellini, E.; Casellato, U.; Graziani, M. C.; Carletti, M.
C.; Magon, L. Acta Crystallogr. C 1984, 40, 1795-1797. (b) Wittern,
U.; Strahle, J .; Abram, U. Z. Naturforsch. 1995, 50b, 997-1003.
(13) Rowbottom, J . F.; Wilkinson, G. J . Chem. Soc., Dalton Trans.
1972, 826-830.
(14) Devore, D. D.; Maatta, E. A. Inorg. Chem. 1985, 24, 2846-2849

1792 Organometallics, Vol. 19, No. 9, 2000
Arterburn et al.
the stability of the complexes over the course of a 3 h
time period was taken as representative of the necessary
time for preparing, administering, and imaging a po-
tential organoimido radiopharmaceutical. Solutions of
all three of the organoimido complexes in CH2Cl2 or
CDCl3 were stable for several days at room temperature,
exhibiting no change in either their absorbance spectra
or their 1H NMR. The complex 2 was not soluble in
water alone, but dilute solutions (10-5 M) in 10% DMF/
H2O were prepared by first dissolving the complex in
DMF and then diluting with H2O. The complex 2
decomposed slowly in the aqueous media, exhibiting
30% hydrolysis after 3 h. The simple oxo complex
ReOCl3(PPh3)2 resulting from hydrolysis of the orga-
noimido bond was observed by UV-vis, and correspond-
ing amounts of the aniline H2NC6H4CO2N(COCH2)2
were isolated. Hydrolysis of the succinimide ester group
was not observed during the 3 h time period. The
monomeric chloro dithiocarbamate complex 3 rapidly
dimerized in 10% DMF/H2O to form 4. This reaction is
similar to the preparative dimerization that is carried
out in aqueous acetone in the presence of base and
precludes the formation of monomeric complexes from
3 in the presence of H2O.13 The µ-oxo dimer complex 4
was very stable in the aqueous DMF and exhibited no
hydrolysis of the organoimido bond after 3 h, as evi-
denced by NMR and UV-vis.
absorbance due to the coordinated PPh3 ligands at 264
nm decreased in intensity and was completely replaced
by the appearance of OPPh3 after 1 h. The absorbance
at 342 nm shifted slightly to 362 nm, suggesting the
possible existence of a phosphine oxide complex with
an intact organoimido bond. The addition of water
eliminated the absorbance at 362 nm and caused
decomposition of the complex along with hydrolysis of
the organoimido group to produce the aniline derivative
H2NC6H4CONHCH(CH3)2, which was isolated from the
reaction mixture in 68% yield after silica gel chroma-
tography (eq 2). Attempts to isolate the putative phos-
phine oxide complex from these reactions and prepara-
tions carried out with exclusion of O2 and H2O were
unsuccessful. The PPh3 ligands in complex 5a were not
displaced by the addition of excess OPPh3. The low
amide coupling yields of 5a with isopropylamine in
CH2Cl2 can therefore be attributed to oxidation of the
coordinated phosphine ligands by HON(COCH2)2, which
is released after each coupling event, followed by hy-
drolysis of the imido bond, which occurs faster in
complexes containing phosphine oxide ligands. The
oxygen atom transfer chemistry to the coordinated PPh3
from N-hydroxysuccinimide in CH2Cl2 was unexpected
and to the best of our knowledge unprecedented in the
literature, although various other N-oxides are recog-
nized as thermodynamically favorable oxidants toward
oxidation of PPh3.15
The yield of the coupling reaction was significantly
improved by changing the solvent to DMF, and complex
2 reacted with a series of amines to produce the
corresponding amide complexes 5a -i, Table 3. In a
typical reaction, complex 2 was treated with 10 equiv
of the amine in DMF (0.025 M) at 25 °C for 10 min,
followed by the addition of water to precipitate the
amide products. Two factors contributed to the dramatic
success of this procedure: the enhanced rate of amide
formation in DMF and the ability to precipitate the
products with H2O, which concentrated the HON-
(COCH2)2 in the aqueous phase, thereby preventing it
from oxidizing bound PPh3 ligands of the metal prod-
ucts. The yields of the organoimido amide products from
primary and secondary amines using this procedure
varied from 67% to 78%. Complexes 5a , 5d , 5e, and 5f
were recrystallized from CH2Cl2, and the solids retained
some CH2Cl2 solvent, which was not removed by drying
in vacuo and was evident in the NMR spectra and
elemental analyses of these compounds. The ethyl ester
hydrochloride salts of alanine and cysteine were coupled
under similar conditions in the presence of added
triethylamine, producing amides 5g,h in 67% and 74%
yields, respectively. The success of the coupling reaction
Rea ctivity of N-Su ccin im id yl Ester
2 w ith
Am in es. The amine coupling reactions of 2 were
initially conducted with isopropylamine using CH2Cl2
as solvent (eq 1). In this reaction the nucleophilic amine
undergoes acylation with the succinimidyl ester complex
2 to produce the amide product 5a and 1 equiv of
N-hydroxysuccinimide HON(COCH2)2. Because the ul-
timate goal was to develop practical amine labeling
agents, no efforts were taken to dry solvents and
reagents or to exclude air from the reactions. The amide
product 5a was isolated by precipitation with hexanes
after concentrating the solvent. The complex 5a was
characterized by 1H and 13C NMR and elemental
analysis. The FT-IR of 5a shows the absorbance of
the amide CdO group at 1639 cm-1. The isolated yields
of product 5a from repeated experiments in CH2Cl2
were consistently below 30% and were accompanied by
large amounts of triphenylphosphine oxide (OPPh3),
succinimide HN(COCH2)2, and the hydrolyzed amide
H2NC6H4CONHCH(CH3)2. The yields of product 5a
were not improved when this reaction was repeated
using anhydrous CH2Cl2 under an atmosphere of argon.
The isolated product 5a was found to be stable in the
presence of excess isopropylamine in CH2Cl2 solution
for at least 6 h.
A control experiment was performed to evaluate the
stability of 5a in the presence of HON(COCH2)2, the
reaction byproduct of amide formation. A 10-2 M solu-
tion of the amide complex 5a in CH2Cl2 was treated with
2 equiv of HON(COCH2)2, and the UV-vis spectrum
was monitored during the course of the reaction. The
(15) Holm, R. H.; Donahue, J . P. Polyhedron 1993, 12, 571-589.

Re(V) Organoimido Complexes
Organometallics, Vol. 19, No. 9, 2000 1793
Ta ble 3. Cou p lin g of 1° a n d 2° Am in es w ith 2a
amine product-amide
entry
yield (%)
70
1
2
3
4
isopropylamine
5a : R′ ) H
R ) -CH(CH3)2
2-amino-3-methylbutane
phenethylamine
benzylamine
5b: R′ ) H
69
67
72
R ) -CH(CH3)CH(CH3)2
5c: R′ ) H
R ) -CH2CH2-C6H5
5d : R′ ) H
R ) -CH2-C6H5
5
6
7
8
9
pyrrolidine
morpholine
5e: R ) R′ ) N(CH2CH2)2
5f: R′ ) R ) N(CH2CH2)2O
5g: R′ ) H, R ) -CH(CH3)CO2CH2CH3
5h : R′ ) H, R ) CH(CH2SH)CO2CH2CH3
5i: R′ ) H
70
78
67
74
49
alanine ethyl ester hydrochlorideb
cysteine ethyl ester hydrochlorideb
6b
R ) -(CH2)2NHC(O)biotin
a
b
Reactions were carried out in DMF, and the product was precipitated with water. Triethylamine (2 mmol) was added in the reaction
mixture.
in the presence of the free sulfhydryl group of cysteine
is particularly notable considering the strong potential
for ligation of this group. Solutions of the cysteine
complex 5h did exhibit slow decomposition after several
hours at ambient temperature, which presumably could
be initiated by intermolecular ligand substitution reac-
tions involving the sulfhydryl group.
There has been a great deal of interest in preparing
labeled biotin derivatives for use in radioimmunodetec-
tion and radioimmunotherapy.16 In the pretargeting
approach, monoclonal antibody-avidin conjugates are
allowed to localize at their target site, followed by
treatment with a radiolabeled biotin derivitive, which
is then selectively accumulated due to the high binding
affinity of avidin for biotin. The ethylenediamine de-
rivative of biotin 6 was prepared following the literature
procedure.17 The coupling reaction of 2 with 6 was
performed in DMF as described above and afforded the
biotin-amide derivative 5i in 49% isolated yield (eq 3).
The amide coupling proceeded to completion; however
decided to investigate analogous organoimido complexes
containing nonoxidizable ligands. Organoimidorhenium-
(V) dithiocarbamate complexes are well-known and can
be prepared directly from the phosphine complexes.9b,13,18
The replacement of chloride ligands is an additional
important structural difference in these types of com-
plexes. Solutions of complexes 3 and 4 in CH2Cl2 and
1
CDCl3 were monitored by UV-vis and H NMR, respec-
tively, and found to be stable in the presence of excess
N-hydroxysuccinimide for at least 3 days at ambient
temperature. The dimerization of the chloro complex 3
in the presence of H2O was described previously, and
reactions of 3 with excess isopropylamine in CH2Cl2
containing trace amounts of water resulted in the
formation of the bridging µ-oxo dimer O[ReO(S2CNEt2)2]2
and the hydrolyzed aniline derivative H2NC6H4CO-
NHCH(CH3)2. The dimeric succinimide ester complex
4 reacted with isopropylamine in CH2Cl2 with traces of
H2O to give only low yields of the desired amide product
and was also accompanied by larger amounts of the
hydrolysis product O[ReO(S2CNEt2)2]2. When the reac-
tion of 4 with isopropylamine was performed in 10%
DMF/H2O, none of the desired bis-organoimido µ-oxo
dimer O[RedN-C6H4CONHCH(CH3)2(S2CNEt2)2]2 was
isolated; only the hydrolyzed aniline and µ-oxo dimer
O[ReO(S2CNEt2)2]2 were obtained. These results con-
trast with the general stability of complex 4 in aqueous
DMF alone, but may simply reflect the enhanced
nuleophilicity of water in the presence of an alkylamine
base. Thus, while the organoimido dithiocarbamate
complexes were unaffected by N-hydroxysuccinimide,
these complexes were subject to the more severe prob-
lem of hydrolysis of the imido bond in the presence of
amines.
the lower isolated yield in this case can be attributed
to the solubility characteristics of the biotin moiety in
5i, which adversely affected the precipitation of the
complex. The complex was characterized by 31P{1H}, 1H,
and 13C NMR.
Rea ctivity of Dith ioca r ba m a te Com p lexes 3 a n d
4. Recognizing the problems associated with oxidation
of the phosphine ligands by N-hydroxysuccinimide, we
Con clu sion s
A series of organoimido complexes possessing re-
motely functionalized succinimidyl ester groups were
synthesized. The organoimidorhenium(V) N-hydroxy-
succinimidyl ester phosphine complex 2 is an effective
labeling agent for alkylamines when the reactions are
carried out in aqueous DMF solution. A series of pri-
mary and secondary amines, amino acids, and a biotin-
ethylenediamine derivative were successfully coupled
with 2 to give the corresponding amides in good yields.
(16) (a) Koch, P.; Macke, H. R. Angew. Chem., Int. Ed. Engl. 1992,
31, 1507-1509. (b) J eong, J . M.; Kinuya, S.; Paik, C. H.; Saga, T.; Sood,
V. K.; Carrasquillo, J . A.; Neumann, R. D.; Reynolds, J . C. Nucl. Med.
Biol. 1994, 21, 935-940. (c) Goodwin, D. A.; Meares, C. F.; Osen, M.
J . Nucl. Med. 1998, 39, 1813-1818.
(17) Garlick, R. K.; Giese, R. W. J . Biol. Chem. 1988, 263, 210-
215.
(18) Soe, K. N.; Ichimura, A.; Kitagawa, T. Inorg. Chim. Acta 1993,
207, 21-25.

1794 Organometallics, Vol. 19, No. 9, 2000
Arterburn et al.
0.1% v/v aqueous acetone (20 mL) was added sodium carbonate
(400 mg), and the mixture was heated at reflux for 2 h. The
reaction mixture was filtered and concentrated in vacuo, and
the crude product was isolated by addition of hexanes to a
dichloromethane solution and purified by recrystallization
from hexanes/CH2Cl2 to give the product 4 (70 mg, 73%
yield): UV-vis (CH2Cl2) λ ) 244, 268, 348, 444 nm; FT-IR
These results demonstrate the stability of the orga-
noimido linkage against competing hydrolysis to the oxo
and in the presence of more basic alkylamines. When
CH2Cl2 solvent was used, the amide formation was
slower, and oxidation of the PPh3 ligands by the released
N-hydroxysuccinimide caused decompostion of the or-
ganoimido complexes. The dithiocarbamate complexes
3 and 4 were unaffected by N-hydroxysuccinimide, but
the organoimido groups were not stable under the
reaction conditions with alkylamines and hydrolysis to
the oxo complexes was observed. The problem of PPh3
oxidation of 2 could potentially be avoided by preparing
other activated carboxylic acid derivatives such as the
pentachlorophenol or nitrophenol esters. The stability
of the organoimido bond is dramatically affected by the
nature of the ancillary ligands, and further efforts will
attempt to develop systems with enhanced stability and
water solubility.
1
1780, 1744, 1500, 1072, 684 cm-1; H NMR δ 7.88 (d, J ) 8.7
Hz, 4H), 7.28 (d, J ) 8.2 Hz, 4H), 3.95-3.55 (m, 16H), 2.87 (s,
8H), 1.37 (t, J ) 7.0 Hz, 24H); 13C NMR δ 239.47, 169.27,
164.24, 130.99, 124.55, 118.70, 43.70, 25.53, 12.63.
Syn th esis of Cl3(P h 3P )2RedN-C6H4CONHCH(CH3)2 (5a).
Isopropylamine (50 µL, 1 mmol) was added to a solution of 2
(105 mg, 0.1 mmol) in DMF (4 mL) and stirred at 25 °C for 10
min. Water (36 mL) was added while stirring vigorously to
precipitate the complex. The product was filtered, washed with
water and hexanes, and then recrystallized from dichlo-
romethane by adding hexanes to give the green solid 5a (70
mg, 70% yield): UV-vis (CH2Cl2) λ ) 234, 264, 346 nm (ꢀ )
13000); FT-IR 1639, 1525, 1435, 1093, 745, 694, 521 cm-1; 1H
NMR δ 7.85-7.70 (m, 12H), 7.38-7.15 (m, 20H), 6.88 (d, J )
8.4 Hz, 2H), 5.76 (m, 1H), 4.23 (m, 1H), 1.26 (d, J ) 6.4 Hz,
6H); 13C NMR δ 163.62, 158.19, 135.33, 133.29, 132.17, 131.67,
130.70, 128.22, 121.76, 42.81, 23.13; 31P{1H} NMR δ -21.05
(s). Anal. Calcd for C46H42Cl3N2OP2Re‚0.5CH2Cl2: C, 53.86; H,
4.15; N, 2.70. Found: C, 53.89; H, 4.09; N, 2.77.
Exp er im en ta l Section
Gen er a l P r oced u r es. Reagents were purchased from
Aldrich or Acros and used as received. Trichlorooxobis(tri-
phenylphosphine)rhenium(V) was prepared according to the
literature procedure.19 1H NMR and 13C NMR spectra were
recorded at 200 and 50 MHz, respectively, using CDCl3 as
solvent and internally referenced to TMS. 31P{1H} NMR
spectra were obtained at 161.9 MHz, referenced to an internal
capillary containing 85% H3PO4(aq) (δ ) 0). IR spectra were
recorded as KBr pellets using a Perkin-Elmer 1720 X FT-IR
spectrometer. UV-vis spectra were recorded using a Hewlett-
Packard 8452A diode array spectrophotometer. Elemental
analyses were performed by Desert Analytics, Tucson, AZ.
Syn th esis of Cl3(P P h 3)2RedN-C6H4CO2N(COCH2)2 (2).
Triphenylphosphine (1.57 g, 6 mmol) was added to a solution
of N3C6H4CO2N(COCH2)2 (780 mg, 3.0 mmol) in benzene (200
mL) and stirred for 20 min at 25 °C, and trichlorooxobis-
(triphenylphosphine)rhenium(V) (2.50 g, 3.0 mmol) was then
added and the mixture heated to reflux for 1 h. The volatiles
were removed in vacuo, and the product was recrystallized
from dichloromethane by the addition of hexanes, filtered, and
washed with Et2O and hexanes to give a green solid, 2 (2.865
g, 91% yield): UV-vis (CH2Cl2) λ ) 234, 266, 298 (ꢀ ) 16 400),
336 nm (ꢀ ) 14 030); FT-IR 1770, 1743, 1197, 745, 694, 521
cm-1; 1H NMR δ 7.88-7.72 (m, 12H), 7.52 (d, J ) 8.6 Hz, 2H),
Syn th esis of Cl3(P h 3P )2RedN-C6H4CONHCH(CH3)CH-
(CH3)2 (5b). The procedure described for the synthesis of 5a
was repeated using 2 (105 mg, 0.10 mmol) and 2-amino-3-
methylbutane (87 mg, 1.00 mmol) to give the green solid 5b
(70 mg, 69% yield): UV-vis (CH2Cl2) λ ) 234, 264, 346 nm (ꢀ
) 11 437); FT-IR 1655, 1536, 1435, 1093, 745, 694, 521 cm-1
;
1H NMR δ 7.88-7.68 (m, 12H), 7.40-7.10 (m, 20H), 6.88 (d, J
) 7.4 Hz, 2H), 5.75 (m, 1H), 4.02 (m, 1H), 1.80 (m, 1H), 1.17
(d, J ) 6.6 Hz, 3H), 0.95 (d, J ) 6.0 Hz, 6H); 13C NMR δ 165.22,
157.61, 134.73, 131.51, 131.09, 130.09, 127.59, 127.11, 121.20,
50.71, 32.86, 18.51, 17.36; 31P{1H} NMR δ -19.46.
Syn th esis of Cl3(P h 3P )2RedN-C6H4CONH(CH2)2P h (5c).
The procedure described for the synthesis of 5a was repeated
using 2 (50 mg, 0.05 mmol) and phenethylamine (50 µL, 0.50
mmol) to give the green complex 5c (35 mg, 67%): UV-vis
(CH2Cl2) λ ) 232, 264, 344 nm (ꢀ ) 10 598); FT-IR 1665, 1541,
1093, 747, 694, 521 cm-1; 1H NMR δ 7.90-7.70 (m, 12H), 7.45-
7.15 (m, 23H), 7.08 (d, J ) 8.4 Hz, 2H), 6.82 (d, J ) 8.4 Hz,
2H), 5.96 (m, 1H), 3.67 (q, J ) 6.7 Hz, 2H), 2.92 (t, J ) 6.7
Hz, 2H); 13C NMR δ 166.48, 158.10, 139.12, 135.30, 132.08,
131.69, 131.15, 130.65, 129.23, 128.21, 127.87, 127.19, 121.77,
41.75, 35.87; 31P{1H} NMR δ -19.83 (s).
7.35-7.20 (m, 18H), 6.88 (d, J ) 8.6 Hz, 2H), 2.91 (s, 4H); 13
C
NMR δ 169.36, 160.49, 135.21, 132.22, 131.73, 131.17, 130.78,
128.22, 123.20, 121.31, 26.07; 31P{1H} NMR δ -23.66 (s). Anal.
Calcd for C47H38Cl3N2O4P2Re: C, 53.80; H, 3.65; N, 2.67.
Found: C, 53.73; H, 3.65 N, 2.66.
Syn th esis of Cl3(P h 3P )2RedN-C6H4CONHCH2P h (5d ).
The procedure described for the synthesis of 5a was repeated
using 2 (105 mg, 0.1 mmol) and benzylamine (110 µL, 1 mmol),
and the crude product was recrystallized by slow diffusion of
ethanol into a dichloromethane solution to give the green
complex 5d (75 mg, 72% yield): UV-vis (CH2Cl2) λ ) 234, 264,
Syn th esis of Cl[(Et)2NCS2]2RedN-C6H4CO2N(COCH2)2
(3). A mixture of 2 (300 mg, 0.28 mmol) and tetraethylthi-
uramdisulfide (170 mg, 0.57 mmol) was heated at reflux in
dry acetone (20 mL) under argon for 1 h, during which time
the solution became dark green. The volume was reduced to 5
mL, and the flask was cooled in an ice bath to crystallize the
complex. The complex was filtered and washed with cold
acetone and Et2O to give 3 (150 mg, 84% yield): UV-vis (CH2-
Cl2): λ ) 234, 272, 296 (ꢀ ) 24 045), 418 nm (ꢀ ) 4710); FT-IR
344 nm (ꢀ ) 13 398); FT-IR 1656, 1093, 745, 694, 521 cm-1
;
1H NMR δ 7.82-7.73 (m, 12H), 7.40-7.30 (m, 5H), 7.26-7.17
(m, 20H), 6.86 (d, J ) 8.4 Hz, 2H), 6.35 (t, J ) 5.2 Hz, 1H),
4.58 (d, J ) 5.2 Hz, 2H); 13C NMR δ 166.30, 158.27, 138.19,
135.20, 133.97, 132.66, 132.06, 131.64, 130.63, 129.31, 128.56,
120.17, 121.75, 44.71; 31P{1H} NMR δ -21.29 (s). Anal. Calcd
for C50H42Cl3N2O2P2Re-0.25CH2Cl2: C, 56.74; H, 3.98. Found:
C, 56.92; H, 3.60.
1
1769, 1741, 1531, 1073, 997 cm-1; H NMR δ 7.99 (d, J ) 8.6
Hz, 2H), 7.54 (d, J ) 8.6 Hz, 2H) 3.95-3.65 (m, 8H), 2.89 (s,
4H), 1.38 (t, J ) 7.1 Hz, 12H); 13C NMR δ 239.88, 168.95,
161.12, 131.51, 123.81, 122.79, 45.16, 25.50, 12.42. Anal. Calcd
for C21H28ClN4O4S4Re: C, 33.61; H, 3.76; N, 7.47. Found: C,
33.37; H, 3.74; N, 7.41.
Syn th esis of Cl3(P h 3P )2RedN-C6H4CON(CH2)4 (5e). The
procedure described for the synthesis of 5a was repeated using
2 (50 mg, 0.05 mmol) and pyrrolidine (50 µL, 0.50 mmol), and
the crude product was recrystallized by slow diffusion of
ethanol into a dichloromethane solution to give the green
complex 5e (35 mg, 70% yield) and recrystallized from dichlo-
romethane and ethanol: UV-vis (CH2Cl2) λ ) 232, 264, 344
Syn th esis of O[((Et)2NCS2-)2RedN-C6H4CO2N(CO-
CH2)2]2 (4). To a solution of complex 3 (100 mg, 0.13 mmol) in
nm (ꢀ ) 10 486); FT-IR 1628, 1092, 745, 694, 521 cm-1
;
1H
(19) J ohnson, N. P.; Lock, C. J . L.; Wilkinson, G. Inorg. Synth. 1967,
9, 145-148.
NMR δ 7.85-7.65 (m, 12H), 7.30-7.15 (m, 18H), 6.93 (d, J )

Re(V) Organoimido Complexes
Organometallics, Vol. 19, No. 9, 2000 1795
8.0 Hz, 2H), 6.86 (d, J ) 8.0 Hz, 2H), 3.58 (t, J ) 6.4 Hz, 2H),
3.22 (t, J ) 6.4 Hz, 2H), 2.05-1.82 (m, 4H); 13C NMR δ 168.65,
156.85, 135.31, 132.16, 131.66, 131.20, 130.60, 128.14, 121.64,
49.82, 46.73, 26.81, 24.79; 31P{1H} NMR δ -21.00 (s). Anal.
Calcd for C47H42Cl3N2OP2Re‚0.5CH2Cl2: C, 54.39; H, 4.10; N,
2.67. Found: C, 54.55; H, 4.13; N, 2.66.
green complex 5i (107 mg, 49%): UV-vis (CH2Cl2) λ ) 232,
264, 342 nm (ꢀ ) 7045); FT-IR 1705, 1655, 1544, 1435, 1093,
747, 694, 521 cm-1; 1H NMR (CDCl3+CD3OD) δ 7.88-7.68 (m,
12H), 7.48-7.22 (m, 20H), 6.88 (d, J ) 8.0 Hz, 2H), 4.55-4.40
(m, 1H), 4.35-4.22 (m, 1H), 3.58-3.32 (m, 4H), 3.20-2.65 (m,
3H), 2.23 (t, J ) 8 Hz, 2H), 1.85-1.25 (m, 4H); 13C NMR
(CDCl3+CD3OD) δ 175.71, 167.42, 157.95, 135.06, 133.79,
131.87, 131.42, 130.57, 128.66, 128.07, 121.67, 62.25, 60.50,
55.73, 40.99, 40.58, 39.21, 35.87, 28.33, 25.66; 31P{1H} NMR
δ -20.85 (s).
Syn th esis of Cl3(P h 3P )2RedN-C6H4CON(CH2CH2)2O (5f).
The procedure described for the synthesis of 5a was repeated
using 2 (105 mg, 0.10 mmol) and morpholine (88 µL, 1.00
mmol), and the precipitated product was recrystallized by slow
diffusion of ethanol into a dichloromethane solution to give
the green complex 5f (80 mg, 78%): UV-vis (CH2Cl2) λ ) 234,
264, 344 nm (ꢀ ) 13 922); FT-IR 1636, 1093, 746, 694, 521
cm-1; 1H NMR δ 7.85-7.65 (m, 12H), 7.30-7.15 (m, 18H), 6.88
(d, J ) 8.0 Hz, 2H), 6.81 (d, J ) 8.0 Hz, 2H), 3.99 (m, 2H),
3.80-3.50 (m, 4H), 3.25 (m, 2H); 13C NMR δ 169.39, 156.93,
135.33, 132.22, 131.73, 131.17, 130.62, 128.16, 121.85, 61.12,
X-r a y Str u ctu r e Deter m in a tion of Cl3(P P h 3)2RedN-
C6H4CO2N(COCH2)2‚(CH2Cl2)1.43(EtOH)0.57. Complex 2 was
crystallized by slow diffusion of ethanol into a CH2Cl2 solution
of 2 at room temperature to give green, rod-shaped crystals of
the complex 2‚(CH2Cl2)1.43‚(EtOH)0.57. A suitable crystal was
suspended in viscous mineral oil, mounted on a glass fiber,
and cooled to -70 °C. Data collection was performed by a
Siemens R3m/V diffractometer operating in the θ-2θ scan
mode with graphite-monochromated Mo KR radiation (λ )
0.710 73 Å) as previously described.20 Intensities were cor-
rected for Lorentz and polarization effects, and empirical
absorption corrections were applied based on a set of ψ scans.
The structure was solved by direct methods using Siemens’
SHEXTL PLUS structure package. The unit cell and lack of
systematic absences indicated a Laue symmetry of triclinic and
the space group P1h. Two solvent molecules are included in the
asymmetric unit, with one exhibiting complex disorder. This
site refined adequately for 57% occupancy by EtOH and 43%
occupancy by CH2Cl2, disordered over three positions. The
structure was refined with full-matrix least-squares, and all
non-hydrogen atoms in 2 and the ordered CH2Cl2 were refined
anisotropically. The positions of the hydrogen atoms were
calculated (C-H ) 0.95 Å) and allowed to ride isotropically
on their respective carbons atoms during refinement. Refine-
ment of the data converged with a goodness-of-fit of 1.20 and
final residuals (for 7463 data with F > 4σF) of R ) 3.44% and
Rw ) 4.19%. Crystallographic data are presented in Table 1;
selected bond distances and angles are given in Table 2.
48.64; 31P{1H} NMR δ -21.36 (s). Anal. Calcd for C47H42
-
Cl3N2O2P2Re‚0.5CH2Cl2: C, 53.57; H, 4.04; N, 2.63. Found: C,
53.16; H, 3.92; N, 2.64.
Syn th esis of Cl3(P h 3P )2RedN-C6H4CONHCH(CH3)CO2Et
(5g). Triethylamine (300 µL, 2.00 mmol) was added to a
solution of alanine ethyl ester hydrochloride (303 mg, 2.00
mmol) in DMF (4 mL), and the solution was stirred for 15 min.
A solution of complex 2 (210 mg, 0.20 mmol) in DMF (4 mL)
was then added, and the mixture was stirred for 10 min. Water
(72 mL) was added, and the precipitated product 5g was
isolated by filtration and was subsequently recrystallized by
addition of hexanes to a CH2Cl2 solution (140 mg, 67% yield):
UV-vis (CH2Cl2) λ ) 232, 264, 342 nm (ꢀ ) 12 000); FT-IR
1
1737, 1666, 1092, 750, 693, 521 cm-1; H NMR δ 7.85-7.68
(m, 12H), 7.35-7.15 (m, 20H), 6.87 (d, J ) 8.4 Hz, 2H), 6.84
(d, J ) 7.2 Hz, 1H), 4.70 (m, 1H), 4.25 (q, J ) 7.0 Hz, 2H),
1.51 (d, J ) 6.8 Hz, 3H), 1.32 (t, J ) 7.0 Hz, 3H); 13C NMR δ
172.90, 165.28, 157.90, 134.70, 131.54, 131.11, 130.70, 130.09,
127.59, 121.19, 61.77, 48.63, 18.38, 14.01; 31P{1H} NMR δ
-21.50 (s). Anal. Calcd for C48H44Cl3N2OP2Re: C, 54.83; H, 4.22;
N, 2.66. Found: C, 54.83; H, 4.18; N, 2.79.
Syn th esis of Cl3(P h 3P )2RedN-C6H4CONHCH(CH2SH)-
CO2Et (5h ). The procedure described for the synthesis of 5g
was repeated using the cysteine ethyl ester hydrochloride (370
mg, 2.00 mmol), DMF (3 mL), triethylamine (300 µL, 2.00
mmol), 2 (210 mg, 0.20 mmol), DMF (3 mL), and water (54
mL). The product was recrystallized from dichloromethane and
hexanes to give the green complex 5h (160 mg, 74% yield):
UV-vis (CH2Cl2) λ ) 234, 264, 336 nm (ꢀ ) 14 870); FT-IR
Ack n ow led gm en t. J .B.A. thanks the USAMRC
Breast Cancer Research Program DAMD17-97-1-7120
and ACS-PRF for financial support. M.V.V. and M.S.H.
were supported by NIH-MBRS undergraduate fellow-
ships.
Su p p or tin g In for m a tion Ava ila ble: Complete tabula-
tions of crystallographic data, bond lengths and angles, atomic
coordinates, and thermal parameters, a completely labeled
ball-and-stick diagram, and copies of 1H, 13C{1H}, and 31P{1H}
NMR spectra for complexes 4, 5b, 5c, 5h , and 5i. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
1737, 1665, 1093, 746, 694, 521 cm-1; H NMR δ 7.82-7.70
(m, 12H), 7.35-7.15 (m, 20H), 6.88 (d, J ) 8.0 Hz, 2H), 4.99
(m, 1H), 4.35-4.25 (m, 3H), 3.20-3.05 (m, 2H), 1.34 (t, J )
7.6 Hz, 3H); 31P{1H} NMR δ -21.23 (s).
Syn th esis of Cl3(P h 3P )2RedN-C6H4CONH(CH2)2NH-
Biotin (5i). The procedure described for the synthesis of 5g
was repeated with 6 (108 mg, 0.38 mmol), DMF (6 mL),
triethylamine (86 µL, 0.57 mmol), complex 2 (200 mg, 0.19
mmol), DMF (6 mL), and water (108 mL). The product was
recrystallized from dichloromethane and hexanes to give the
OM990929W
(20) Bryan, J . C.; Burrell, A. K.; Miller, M. M.; Smith, W. H.; Burns,
C. J .; Sattelberger, A. P. Polyhedron 1993, 12, 1769-1777.