Synthesis and structure of the first ruthenated benzodiazepines

Article abstract of DOI:10.1021/om0205288

[{RuCl(cym)}₂(μ-Cl)₂] (cym = η⁶-p-methyliso-propylbenzene) serves as precursor to synthesize the two first ruthenated benzodiazepines in which deprotonated diazepam is coordinated to a {RuCl(cym)} fragment. In complex 1, obtained by treatment with diazepam in the presence of NaBPh₄ and NEt₃, the coordination is through the imine nitrogen and an ortho carbon of the phenyl substituent. In 2, obtained by reaction of deprotonated diazepam with the metal dimer, the coordination is through the imine nitrogen and the adjacent sp³ carbon of the benzodiazepine.

Full text of DOI:10.1021/om0205288

Organometallics 2002, 21, 5437-5438
5437
Syn th esis a n d Str u ctu r e of th e F ir st Ru th en a ted
Ben zod ia zep in es
J ulio Pe´rez,*,† V´ıctor Riera,† Amor Rodr´ıguez,† and Daniel Miguel‡
Departamento de Quı´mica Orga´nica e Inorga´nica-I.U.Q.O.E.M., Facultad de Quı´mica,
Universidad de Oviedo-CSIC, Oviedo, Spain, and Departamento de Qu´ımica Inorga´nica,
Facultad de Ciencias, Universidad de Valladolid, Valladolid, Spain
Received J uly 8, 2002
Summary: [{RuCl(cym)}2(µ-Cl)2] (cym ) η6-p-methyliso-
Sch em e 1
propylbenzene) serves as precursor to synthesize the two
first ruthenated benzodiazepines in which deprotonated
diazepam is coordinated to a {RuCl(cym)} fragment. In
complex 1, obtained by treatment with diazepam in the
presence of NaBPh4 and NEt3, the coordination is
through the imine nitrogen and an ortho carbon of the
phenyl substituent. In 2, obtained by reaction of depro-
tonated diazepam with the metal dimer, the coordination
is through the imine nitrogen and the adjacent sp3
carbon of the benzodiazepine.
In tr od u ction
In addition to the well-known psychotherapeutic
properties of 1,4-benzodiazepines, benzodiazepine de-
rivatives were found to display anticancer activity.1
ment reactions.4 Is also noteworthy that the dimeric
precursor, commercially available or easily prepared in
one step from RuCl3‚H2O, does not need to be activated
by a previous bridge cleavage/chloride abstraction step.5
The structure of 1, determined by X-ray diffraction
(Figure 1), consisted of a {RuCl(cym)} fragment coor-
dinated to the imine nitrogen, N(4), and to one of the
ortho carbons of the phenyl substituents of diazepam,
C(13), defining the five-membered ring Ru-N(4)-C(5)-
C(12)-C(13). The Ru-N and Ru-C distances (2.055(4)
and 2.038(5) Å, respectively) are similar to those found
in the five-membered rings of known areneruthenium
complexes with orthometalated amines.6
Cyclometalated derivatives of benzodiazepines with
palladium and platinum were previously known;7 how-
ever, 1 is the first ruthenium complex of a benzodiaz-
epine.
As a second approach toward the synthesis of arene-
ruthenium derivatives of diazepam, we reacted the
Given the recent reports of the anticancer activity of
areneruthenium(II) complexes,2 benzodiazepine com-
plexes of areneruthenium(II) fragments, previously
unknown, are interesting synthetic targets. We have
chosen as starting material the benzodiazepine 7-chloro-
1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-
one (diazepam, commercially known as Valium). Given
the antitumor activity of metal complexes containing
cyclometalated ligands,3 we first aimed for the ortho-
metalation of diazepam. Whereas cyclometalation reac-
tions have been extensively studied with other metal
fragments, including ruthenium examples, only recently
has an effective route to cyclometalated areneruthenium
complexes been reported.4
Resu lts a n d Discu ssion
The reaction of [{RuCl(cym)}2(µ-Cl)2]5 (cym ) η6-p-
methylisopropylbenzene) with diazepam in the presence
of the base NEt3 and NaBPh4 afforded the orthometa-
lated complex 1 (Scheme 1).
In our case, the employment of a noncoordinating
solvent and room temperature avoided arene-displace-
* Corresponding author. E-mail: japm@sauron.quimica.uniovi.es.
† Universidad de Oviedo-CSIC.
‡ Universidad de Valladolid.
(1) J ames, G. L.; Goldstein, J . L.; Brown, M. S.; Rawson, T. E.;
Somers, T. C.; McDowell, R. S.; Crowley, C. W.; Lucas, B. K.; Levinson,
A. D.; Marsters, J . C. Science 1993, 260, 1937.
(2) (a) Morris, R. E.; Aird, R. E.; Murdoch, P. S.; Chen, H.;
Cummings, J .; Hughes, N. D.; Parsons, S.; Parkin, A.; Boyd, G.; J odrell,
D. I.; Sadler, P. J . J . Med. Chem. 2001, 44, 3616. (b) Chen, H.;
Parkinson, J . A.; Parsons, S.; Coxall, R. A.; Gould, R. O.; Sadler, P. J .
J . Am. Chem. Soc. 2002, 124, 3064.
(3) Flower, K. R.; Howard, V. J .; Pritchard R. C.; Warren, J . E.
Organometallics 2002, 21, 1184, and references therein.
(4) Ferna´ndez, S.; Pfeffer, M.; Ritleng, V.; Sirlin, C. Organometallic
1999, 18, 2390.
(5) Bennett, M. A.; Huang, T. N.; Matherson, T. W.; Smith, A. K.
Inorg. Synth. 1981, 21, 74.
F igu r e 1. Thermal ellipsoid (30%) plot of complex 1.
10.1021/om0205288 CCC: $22.00 © 2002 American Chemical Society
Publication on Web 10/31/2002

5438 Organometallics, Vol. 21, No. 24, 2002
Notes
g, 0.35 mmol), NaBPh4 (0.24 g, 0.70 mmol), and NEt3 (0.24
mL, 1.72 mmol) in CH2Cl2 (20 mL). After 3.5 days stirring,
solvent evaporation in vacuo, extraction of the residue (CH2-
Cl2, 10 mL), filtration (silica gel), in vacuo concentration (to 5
mL), and layering with hexane (20 mL) afforded, after 2 days
at -20 °C, red crystals. Yield: 0.39 g, 81%. Anal. Calcd for
C
26H26Cl2N2ORu: C, 56.32; H, 4.72; N, 5.05. Found: C, 56.50;
1
H, 4.57; N, 5.38. H NMR (CDCl3): δ 8.24-7.10(m, 7H, Ph);
5.72(t(7), 2H, C6H4); 5.53(d(5), 1H, C6H4); 5.24(d(12), 1H, CH2
diazepam); 4.91(d(5), 1H, C6H4); 4.60(d(12), 1H, CH2 diaze-
pam); 5.70(qAB, 4H, C6H4); 3.39(s, 3H, CH3 diazepam); 2.34-
(m, 1H, CH(iPr)); 2.12(s, 3H, CH3 C6H4); 0.97(d(7), CH3(iPr));
0.66(d(7), CH3(iPr)). 13C{1H} NMR (CDCl3): 189.1(s, Cortho);
175.8(s, CdN); 169.5(s, CO); 143.8, 141.4, 139.8, 136.1, 131.4,
130.3, 130.1, 129.8, 129.5, 129.40(s, Ph diazepam); 107.1(s,
C(C6H4)), 100.8(s, C(C6H4)); 93.2, 92.9, 80.6, 77.5(s, CH(C6H4));
65.9(s, CH2 diazepam); 38.4(s, CH3 diazepam); 31.0(s, CH3-
(iPr)); 23.2(s, CH3(iPr)); 20.6(s, CH(iPr)); 19.0(s, CH3 (C6H4)).
X-ray quality crystals of the ethanol hemisolvate were obtained
by crystallization of this material from toluene/ethanol.
Syn th esis of 2. To a solution of the carbanion resulting
from the C(3) metalation of diazepam (0.20 g, 0.70 mmol) in
THF (10 mL) was added a solution of [{RuCl(cym)}2(µ-Cl)2]
(0.21 g, 0.35 mmol) at -78 °C. After stirring (1.5 days), solvent
evaporation in vacuo, extraction of the residue (CH2Cl2, 10
mL), filtration (silica gel), in vacuo concentration (to 5 mL),
and layering with hexane (20 mL) afforded, after 2 days at
F igu r e 2. Thermal ellipsoid (30%) plot of complex 2.
Sch em e 2
-20 °C, red crystals. Yield: 0.30 g, 77%. Anal. Calcd for C26H26
-
Cl2N2ORu: C, 56.32; H, 4.72; N, 5.05. Found: C, 56.09; H,
1
4.90; N, 5.22. H NMR (CDCl3): δ 8.1-7.3(m, 8H, Ph); 5.55-
(t(6), 2H, C6H4); 5.11(d(6), 1H, C6H4); 4.88(d(5), 1H, C6H4); 3.78-
(s, 1H, CH diazepam); 3.31(s, 3H, CH3 diazepam); 2.22(m, 1H,
CH(iPr)); 1.82(s, 3H, CH3(C6H4); 1.08(d(7), CH3(iPr)); 1.02(d(7),
CH3(iPr)). 13C{1H} NMR (CDCl3): 177.1(s, CdN); 165.3(s, CO);
143.1, 134.9, 132.2, 131.7, 129.8, 128.9, 128.6, 123.6(s, Ph
diazepam); 101.6(s, C(C6H4)); 94.5(s, C(C6H4)); 84.5, 83.8, 83.2,
82.1(s, CH(C6H4)); 39.8(s, CH diazepam); 37.5(s, CH3 diaze-
pam); 29.8(s, CH3 (iPr)); 22.3(s, CH3 (iPr)); 22.1(s, CH(iPr));
19.6(s, CH3 (C6H4)).
Cr ysta l d a ta for 1: C27H29Cl2N2O1.5Ru, M ) 577.49, mono-
clinic, space group P21/n, a ) 18.3046(16) Å, b ) 14.0908(12)
Å, c ) 19.5929(6) Å, â ) 96.667(2)°, Z ) 8, V ) 5019.4(8) Å3,
F ) 1.528 g/cm-3; T ) 299(2) K; λ ) 0.71073, 32284 reflections
measured, 7256 unique (Rint ) 0.0689), R1 ) 0.0434 and wR2
) 0.1004.
carbanion resulting from the C(3) lithiation of diaze-
pam8 with [{RuCl(cym)}2(µ-Cl)2], as depicted in Scheme
2. C(3)-metalated diazepam has been employed for the
synthesis of a gold complex, resulting in coordination
of the benzodiazepine ligand through only that carbon
atom.9 In contrast, 2 (for which the crystal structure
has been determined by X-ray diffraction; see Figure
2) features a ligand resulting from deprotonation of
diazepam coordinated to a {RuCl(cym)} fragment through
C(3) and the imine nitrogen N(4). Therefore, 1 and 2
are isomers.
Due to the vicinal position of the C(3) and N(4) atoms,
a three-membered ring (metallaaziridine or metallaaza-
cyclopropane) is present in the structure of complex 2.
Three-membered rings of this kind are known with early
transition metals;10 however, this is the first example
within a ruthenium complex.11 Furthermore, this is a
unprecedented coordination mode for a metalated ben-
zodiazepine derivative.
Cr ysta l d a ta for 2: C26H26Cl2N2ORu, M ) 554.46, ortho-
rhombic, space group Pbca, a ) 13.541(4) Å, b ) 18.168(6) Å,
c ) 24.862(8) Å, Z ) 8, V ) 6116(3) Å3, F ) 1.204 g/cm-3; T )
295(2) K; λ ) 0.71073, 37625 reflections measured, 4408
unique (Rint ) 0.0938), R1 ) 0.0767 and wR2 ) 0.2126.
Su p p or tin g In for m a tion Ava ila ble: Tables giving posi-
tional and thermal parameters and bond distances and bond
angles for 1 and 2. This material is available free of charge
via the Internet at http://pubs.acs.org.
OM0205288
Exp er im en ta l Section
General conditions were given elsewhere.12
(10) (a) Bazinet, P.; Yap, G. P. A.; Richeson, D. S. Organometallics
2001, 20, 4129. (b) Go´mez, M.; Go´mez-Sal, M. P.; J ime´nez, G.; Mart´ın,
A.; Royo, P.; Sa´nchez-Nieves, I. Organometallics 1996, 15, 3579. (c)
Alcalde, M. I.; Go´mez-Sal, M. P.; Royo, P. Organometallics 1999, 18,
546. (d) Sa´nchez-Nieves, I.; Royo, P.; Pellinghelli, M. A.; Tiripicchio,
A. Organometallics 2000, 16, 3161.
(11) Several examples of N-C-Ru rings not involving imine moi-
eties are known: (a) Staal, L. H.; Polm, L. H.; Balk, R. W.; van Koten,
G.; Vrieze, K.; Brouwers, A. M. F. Inorg. Chem. 1980, 19, 3343. (b)
Adams, R. D.; Babin, J . E.; Tanner, J . Organometallics 1988, 7, 765.
(c) Adams, R. D.; Babin, J . E.; Tanner, J . Organometallics 1988, 7,
2027. (d) Mauthner, K.; Slugovc, C.; Mereiter, K.; Schmid, R.; Kirchner,
K. Organometallics 1997, 16, 1956. For a ruthenated 2-phenylpyridine
see: Guary, Y.; Sabo-Etienne, S.; Chaudret, B. J . Am. Chem. Soc. 1998,
120, 4228.
Syn th esis of 1. Under dinitrogen, diazepam (0.20 g, 0.70
mmol) was added to a solution of [{RuCl(cym)}2(µ-Cl)2] (0.21
(6) Hansen, H. D.; Maitra, K.; Nelson, J . H. Inorg. Chem. 1999, 38,
2150.
(7) (a) Cinellu, M. A.; Ganadu, M. L.; Minghetti, G.; Cariati, F.;
Demartin, F.; Manassero, M. Inorg. Chim. Acta 1988, 143, 197. (b)
Cinellu, M. A.; Gladiali, S.; Minghetti, G.; Stoccoro, S.; Demartin, F.
J . Organomet. Chem. 1991, 401, 371. (c) Stoccoro, S.; Cinellu, M. A.;
Zucca, A.; Minghetti, G.; Demartin, F. Inorg. Chim. Acta 1994, 215,
17.
(8) Reitter, B. E.; Sachdeva, Y. P.; Wolfe, J . F. J . Org. Chem. 1981,
46, 3945.
(9) Minghetti, G.; Zucca, A.; Cinellu, M. A.; Stoccoro, S.; Manassero,
M.; Sansoni, M. J . Organomet. Chem. 1998, 553, 405.
(12) Mene´ndez, C.; Morales, D.; Pe´rez, J .; Riera, V.; Miguel, D.
Organometallics 2001, 20, 2775.