Sterically non-hindering endocyclic ligands of the bi-isoquinoline family

Article abstract of DOI:10.1039/b513222c

Bi-isoquinoline can be used as a building block to prepare a new family of non-sterically hindering chelates, including a macrocyclic system; the endocyclic nature of the ligands has been confirmed by the X-ray structure of an octahedral tris-chelate iron

Full text of DOI:10.1039/b513222c

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COMMUNICATION
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Sterically non-hindering endocyclic ligands of the bi-isoquinoline family
Fabien Durola, Jean-Pierre Sauvage* and Oliver S. Wenger
Received (in Cambridge, UK) 19th September 2005, Accepted 21st October 2005
First published as an Advance Article on the web 18th November 2005
DOI: 10.1039/b513222c
We would like to report a new family of diimine ligands which
correspond to the following prerequisites:
Bi-isoquinoline can be used as a building block to prepare a
new family of non-sterically hindering chelates, including a
macrocyclic system; the endocyclic nature of the ligands has
been confirmed by the X-ray structure of an octahedral tris-
chelate iron(II) complex, which shows that the three chelates are
easily accommodated in the coordination sphere of the metal in
spite of their crescent shape.
(i) no substituents a to the N atoms
(ii) crescent shaped allowing the inscribing of the ligand in a
ring, with endocyclic coordination.
The principle is indicated in Scheme 2.
The bi-isoquinoline-containing system is such that endocyclic
coordination will be certain and, equally important, the complexed
metal centre will be remote from any organic group of the ligand
organic backbone. In dpp (Scheme 2 (b)), the shortest C–C
distance between the phenyl rings borne by the phen nucleus at its
The incorporation of a bidentate chelate of the bipy or the phen
family (bipy: 2,29-bipyridine; phen: 1,10-phenanthroline) in a ring
in an endocyclic fashion, has been used for decades in macrocyclic
chemistry.1 It requires that the chelate be substituted at the two
positions a to the nitrogen atoms so as to ensure an endocyclic
coordination mode. If the other positions (meta or para) are used,
the coordination mode will not be controlled and exocyclic
coordination is very likely to prevail over the endocyclic mode, as
indicated in Scheme 1.
˚
˚
2 and 9 positions is around 7 A whereas it is around 11 A for the
two corresponding phenyl rings of the system represented in (b) of
Scheme 2 (attached at the 8 and 89 positions of the bi-isoquinoline
ligand).
The synthetic routes leading to the desired bi-isoquinoline
derivatives are represented in Figs. 1 and 2.
The copper(I)-templated synthesis of numerous catenanes and
rotaxanes2 relies on the dpp fragment (dpp: 2,9-diphenylphenan-
throline), whose geometry is such that, once incorporated in a ring,
endocyclic coordination is strongly favoured over any other mode
of complexation. The dpp chelate is sterically strongly hindering,
which leads to very stable tetrahedral complexes such as
[Cu(dpp)2]+. Macrocyclic ligands, incorporating non-sterically
hindering chelates, may be needed either to build new topologies
around octahedral metal centres3 or, in the field of molecular
machines,4 to make the metal more accessible to entering ligands
and thus facilitate ligand substitution.5
Isoquinoline 4, functionalized on its 3 and 8 positions, is
synthesized following an existing methodology:6 sodium diethoxy
acetate 1 is first activated with thionyl chloride and subsequently
condensed with 2-bromobenzylamine 2 in 60% yield. The resulting
amide 3 cyclizes in concentrated sulfuric acid to form 8-bromo-
isoquinolin-3-ol 4 in a so-called Pomeranz–Fritsch reaction (50 ¡
10% yield).
Activation of its alcohol function using triflic anhydride results
in the formation of triflate compound 5 in nearly quantitative yield
(95%). The latter is coupled to commercially available 4-methoxy-
phenylboronic acid in a highly selective and efficient (90% yield)
Suzuki coupling reaction7 that leads to 8-anisyl-3-triflylisoquino-
line 6. Ligand 7 is obtained in 70% yield by palladium catalyzed
homocoupling reaction8 between two triflate molecules 6. The
overall yield of the three-step synthesis of 7 from precursor 4 is
60%.
Scheme 1 Situation (a) is ideally suited to endocyclic coordination
whereas (b) may lead to both endo- or exocyclic coordination.
Scheme 2 (a) The use of a dpp fragment as chelate leads to pronounced
steric hindrance once a metal centre is coordinated; (b) by using a 3,39-bi-
isoquinoline chelate substituted at the 8,89-positions, a sterically non-
hindering macrocycle should be obtained.
Laboratoire de Chimie Organo-Mine´rale, UMR 7513 du CNRS, Institut
Le Bel, Universite´ Louis Pasteur, 4 rue Blaise Pascal,
67070 Strasbourg Cedex, France. E-mail: sauvage@chimie.u-strasbg.fr;
Fax: (+33)390-241-368; Tel: (+33)390-241-364
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Deprotection of the anisyls, using pyridinium chloride at high
temperature, quantitatively affords diphenol 8. double
A
Williamson high-dilution reaction between diphenol 8 and
dibromo-linker 9 (easily obtained in a one-step reaction from
commercially available 4,49-isopropylidenediphenol, and 1,4-
dibromobutane) affords macrocycle 10 in 40% yield.
For the synthesis of ligand 16 we have used the same precursor
(4) as for chelate 7, but followed an entirely different synthetic
strategy: the alcohol function is first protected using benzoyl
chloride, and the resulting 8-bromo-isoquinoline-3-benzoyl ester
(11) is coupled to stannane 129 in 65% yield following existing
synthetic methodologies.10 Deprotection of benzoyl ester 13 in
basic solution affords 14 which is subsequently reacted with triflic
anhydride. Thereby triflate 15 is formed in nearly quantitative
yield (95%). The final step is a palladium-catalyzed coupling of two
triflate molecules 15 to one another. Under identical reaction
conditions as for chelate 7 (vide infra), we obtained ligand 16 in
70% yield. The overall yield for the five-step synthesis of 16 from 4
is 39%.11
To demonstrate that these ligands are also not sterically
hindering, we decided to make a homoleptic complex of an
octahedral transition metal with ligand 7. To our knowledge, such
homoleptic octahedral complexes, with three endocyclic ligands,
are very uncommon.
By mixing bis(tetrafluoroborate) iron(II) and ligand 7 during
two hours at room temperature in dichloromethane, and after an
anion exchange with potassium hexafluorophosphate, we easily
obtained bis(hexafluorophosphate) tris(bi-isoquinoline) iron(II) 17.
This complex affords big red crystals that allow X-ray analysis, the
corresponding crystallographic structure is shown in Fig. 3.
Interestingly, the coordination sphere of the Fe(II) centre is
perfectly octahedral in spite of the 6 anisyl groups present in the
complex, although stacking interactions are clearly observed. This
again confirms the non sterically-hindering nature of the chelate 7.
On the other hand, the two anisyl groups of each ligand are
pointing in ideal directions if one wants to construct rings.
In conclusion, the new disubstituted bi-isoquinoline ligands
described in the present communication are ideally suited to the
synthesis of octahedral transition metal complexes, their endocyclic
nature being obvious from their geometry, as shown by the X-ray
structure of complex 17.{
Fig. 1 Synthesis of a macrocycle based on a bi-isoquinoline. Reagents a:
SOCl2, Et2O, reflux, then pyridine, toluene, reflux, 60%. b: H2SO4, r.t.,
16 h, 50%. c: Tf2O, pyridine, r.t., 16 h, 95%. d: anisyl boronic acid,
Pd2dba3, PtBu3, KF, THF, r.t., 2 h, 90%. e: Zn, PdCl2dppf, KI, DMF,
90 uC, 2 h, 70%. f: pyridinium chloride, reflux, 100%. g: high dilution,
Cs2CO3, DMF, 65 uC, 40%.
F.D. thanks the CNRS and the Re´gion Alsace for a fellowship.
O.S.W. acknowledges a fellowship from the Swiss National
Fig. 2 Synthesis of a long-legged bi-isoquinoline. Reagents a: benzoyl
chloride, pyridine, 0 uC. b: Pd(PPh3)2Cl2, toluene/THF (1 : 1), LiCl, reflux,
2 days, 65%. c: THF/2M KOH in H2O (1 : 1), reflux, 2 h. d: Tf2O,
pyridine, r.t., 16 h, 95%. e: Zn, PdCl2dppf, KI, DMF, 90 uC, 8 h, 70%.
Fig. 3 Crystallographic structure of complex 17.
172 | Chem. Commun., 2006, 171–173
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Notes and references
{ Crystal structure analysis of 17: C96H72F12FeN6O6P2, M = 1751.39,
˚
monoclinic, a = 15.4180(3), b = 34.4150(6), c = 17.0120(4) A, b =
3
˚
116.3621(8)u, V = 8088.0(3) A , T = 173(2) K, space group P21/n, Z = 4,
m(Mo Ka) = 0.316 mm21, 45635 collected reflections, 23640 independent
reflections [R(int) = 0.048], final R indices R1 = 0.052, wR2 = 0.1261.
CCDC 283554. For crystallographic data in CIF or other electronic format
see DOI: 10.1039/b513222c.
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300 MHz): d = 9.42 (s, 2H; H1), 8.94 (s, 2H; H4), 7.96 (d, 3J =
8.2 Hz, 2H; H5), 7.74 (t, 3J = 8.2 Hz, 2H; H6), 7.53 (d, 3J = 8.2 Hz, 2H;
H7), 7.52 (d, 3J = 8.8 Hz, 4H; Ha), 7.09 (d, 3J = 8.8 Hz, 4H; Hb), 3.91 (s,
6H; Hc) ppm. ES-MS: m/z = 469.1907 [7 + H]+ (calculated 469.1911 for
C32H25N2O2). 10: 1H-NMR (CD2Cl2, 400 MHz, COSY-ROESY): d =
9.38 (s, 2H; H1), 8.37 (s, 2H; H4), 7.94 (d, 3J = 8.4 Hz, 2H; H5), 7.76 (t,
3J = 8.2 Hz, 2H; H6), 7.58 (d, 3J = 8.3 Hz, 2H; H7), 7.46 (d, 3J = 8.8 Hz,
4H; Ha), 7.16 (d, 3J = 8.9 Hz, 4H; Ha9), 7.08 (d, 3J = 8.8 Hz, 4H; Hb),
6.81 (d, 3J = 9.0 Hz, 4H; Hb9), 4.26 (t, 3J = 6.3 Hz, 4H; Ha), 3.99 (t, 3J =
6.2 Hz, 4H; Hd), 1.99 (m, 8H; Hb,c), 1.59 (s, 6H; Hc9) ppm. ES-MS:
m/z = 777.3761 [10 + H]+ (calculated 777.3687 for C53H49N2O4). 16:
1H-NMR (CDCl3/CF3COOD 5%, 300 MHz): d = 9.72 (s, 2H; H1),
9.07 (s, 2H; H4), 8.35 (d, 3J = 5.1 Hz, 4H; H5,7), 8.12 (t, 3J = 5.1 Hz, 2H;
H6), 7.83 (d, 3J = 8.4 Hz, 4H; Ha), 7.67 (d, 3J = 8.7 Hz, 4H; Hc), 7.60 (d,
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3
3J = 8.4 Hz, 4H; Hb), 7.07 (d, J = 8.7 Hz, 4H; Hd), 3.93 (s, 6H; He)
ppm. ES-MS: m/z = 621.2529 [16 + H]+ (calculated 621.2537 for
C44H33N2O2). 17: 1H-NMR (CD2Cl2, 300 MHz): d = 8.89 (s, 6H; H1),
8.10 (d, 3J = 8.4 Hz, 6H; H5), 7.87 (s, 6H; H4), 7.84 (t, 3J = 8.4 Hz, 6H;
H6), 7.45 (d, 3J = 7.3 Hz, 6H; H7), 6.62 (d, 3J = 8.8 Hz, 12H; Ha), 6.31 (d,
3J = 8.8 Hz, 12H; Hb), 3.58 (s, 18H; Hc) ppm. ES-MS: m/z = 730.2431
[17]2+ (calculated 730.2428 for C96H72FeN6O6).
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