A highly regioselective Sonogashira coupling as a key step in the preparation of the first phenanthroline with two diverse reactive groups in 3,8-positions

Article abstract of DOI:10.1021/ol006514k

(Matrix presented) The preparation of 3,8-unsymmetric phenanthrolines is described. Desymmetrization of 3,8-dibromophenanthroline was achieved after monoarylation followed by regioselective Pd-catalyzed monoalkynylation that was controlled by the methoxy

Full text of DOI:10.1021/ol006514k

ORGANIC
LETTERS
2000
Vol. 2, No. 25
3959-3962
A Highly Regioselective Sonogashira
Coupling as a Key Step in the
Preparation of the First Phenanthroline
with Two Diverse Reactive Groups in
3,8-Positions
Shi-Xia Liu, Christoph Michel, and Michael Schmittel*
Organische Chemie 1, FB 8, UniVersita¨t Siegen, Adolf-Reichwein-Strasse,
D-57068 Siegen, Germany
schmittel@chemie.uni-siegen.de
Received August 29, 2000
ABSTRACT
The preparation of 3,8-unsymmetric phenanthrolines is described. Desymmetrization of 3,8-dibromophenanthroline was achieved after
monoarylation followed by regioselective Pd-catalyzed monoalkynylation that was controlled by the methoxy group of the dimethoxyphenyl
substituent.
Metal phenanthroline complexes currently enjoy a renais-
sance because they find frequent use in exciting molecular
structures,1 such as molecular knots,2 rotaxanes,3 dendrimers,4
and catenanes,5 as well as in enantioselective and supramo-
lecular catalysts6 or so-called molecular machines.7 We are
currently utilizing our selective approach to heteroleptic
copper(I) bisphenanthroline complexes, which is based on
the use of bulky 2,9-aryl groups8 as steric blocking units
(either mesityl or 2,6-dimethoxyphenyl groups), for the
defined construction of nanocubes and nanotubes through a
highly convergent and quantitative self-assembly process.9
Having structures A and B available now (Scheme 1),10 it
would be highly desirable to connect two or more of the
analogous units C either by covalent or noncovalent linkages
in order to build artificial nanotubes D.
Scheme 1
(1) Hasenknopf, B.; Lehn, J.-M.; Kneisel, B. O.; Baum, G.; Fenske, D.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1838-1840.
(2) (a) Dietrich-Buchecker, C. O.; Guilhem, J.; Pascard, C.; Sauvage,
J.-P. Angew. Chem., Int. Ed. Engl. 1990, 29, 1154-1156. (b) Dietrich-
Buchecker, C.; Rapenne, G.; Sauvage, J.-P. Coord. Chem. ReV. 1999, 167-
176.
(3) (a) Chambron, J.-C.; Heitz, V.; Sauvage, J.-P. Bull. Soc. Chim. Fr.
1995, 132, 340-347. (b) Jime´nez, M. C.; Dietrich-Buchecker, C.; Sauvage,
J.-P.; De Cian, A. Angew. Chem., Int. Ed. 2000, 39, 1295-1298.
(4) Constable, E. C. Chem. Commun. 1997, 1073-1080.
10.1021/ol006514k CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/11/2000

linearly the phenanthroline to open up a multitude of potential
applications, e.g., in material chemistry for tunable fluoro-
phores.12
Scheme 2
In principle, several ways to prepare unsymmetric 3,8-
disubstituted 1,10-phenanthrolines should be feasible. How-
ever, since regioselective aromatic halogenation at the
phenanthroline core using two different halogens is still an
unsolved problem, a synthetic procedure was searched
allowing for the preparation of unsymmetric 3,8-disubstituted
1,10-phenanthrolines starting from 3,8-dibromo-1,10-phenan-
throline (2). In a first attempt, we sought to effect mono-
lithiation of 2 (Scheme 3). However, when 2 was reacted
Scheme 3
As a prerequisite for the preparation of D (Scheme 2), we
need linear bis- or oligophenanthrolines containing both the
steric blocking units (see Scheme 1) and two different
reactive functionalities at the 3,8-positions of the phenan-
throline core. A search in the Beilstein database reveals that
basically all 3,8-unsymmetric phenanthrolines follow the
pattern 3-R (R ) Hal, alkyl, aryl, C(dO)R′) and 8-H. An
exception is 3-tert-butyl-8-methylphenanthroline,11 but that
is not a suitable candidate for linear extension. Herein, we
want to describe the difficulties we encountered in preparing
3,8-unsymmetric phenanthroline ligands and finally detail a
convenient and brief synthetic access to the unsymmetric
phenanthroline 1. Our approach constitutes the first prepara-
with lithium (2 equiv) only a small amount of 3-bromo-8-
lithiophenanthroline (3) was obtained (18%). Moreover,
reactivity of 3 vs ethyl formate to furnish 4 was too low for
an efficient trapping of the lithiated species.
Another attempt was to react 2 with trimethylsilylacetylene
(1 equiv) in the presence of PdCl2(PPh3)2, but to our surprise
only the symmetric ligand 5 (26%) was formed in addition
to some unreacted starting material (Scheme 4). This finding
Scheme 4
tion of an unsymmetric phenanthroline with two diverse
reactive groups in the 3,8-positions allowing for extending
(5) (a) Dietrich-Buchecker, C.; Frommberger, B.; Lu¨er, I.; Sauvage, J.-
P.; Vo¨gtle, F. Angew. Chem., Int. Ed. Engl. 1993, 32, 1434-1437. (b)
Amabilino, D. B.; Ashton, P. R.; Reder, A. S.; Spencer, N.; Stoddart, J. F.
Angew. Chem., Int. Ed. Engl. 1994, 33, 433-437. (c) Fujita, M. Chem.
Soc. ReV. 1998, 27, 417-426.
(6) (a) Frontiers in Supramolecular Organic Chemistry and Photochem-
istry; Schneider, H.-J., Du¨rr, H., Eds.; VCH: Weinheim, 1991. (b) Dietrich,
B.; Viout, P.; Lehn, J.-M. Macrocyclic Chemistry; VCH: Weinheim, 1993.
(c) Davies, R. R.; Kuang, H.; Qi, D.; Mazhary, A.; Mayaan, E.; Distefano,
M. D. Bioorg. Med. Chem. Lett. 1999, 9, 79-84. (d) Gallo, E.; Ragaini,
F.; Cenini, S.; Demartin, F. J. Organomet. Chem. 1999, 586, 190-195.
(7) Sauvage, J.-P. Acc. Chem. Res. 1998, 31, 611-619.
(8) (a) Schmittel, M.; Ganz, A. Chem. Commun. 1997, 999-1000. (b)
Schmittel, M.; Ganz, A.; Fenske, D.; Herderich, M. J. Chem. Soc., Dalton
Trans. 2000, 353-359.
(9) Schmittel, M.; Michel, C.; Ganz, A.; Herderich, M. J. Prakt. Chem.
1999, 341, 228-236.
can be explained because of the low solubility of 2. As the
first alkynylation increases drastically the solubility, the
subsequent alkynylation to furnish 5 is an efficient homo-
geneous phase reaction. To avoid this problem, we reacted
2 with equal amounts of trimethylsilylacetylene and prop-
argyl alcohol again under Sonogashira coupling conditions.
(10) Schmittel, M.; Michel, C. Unpublished results.
(11) Belser, P.; Bernhard, S.; Guerig, U. Tetrahedron 1996, 52, 2937-
2944.
(12) Joshi, H. S.; Jamshidi, R.; Tor, Y. Angew. Chem., Int. Ed. 1999,
38, 2722-2725.
3960
Org. Lett., Vol. 2, No. 25, 2000

group. Accordingly, the commercially available 2-bromo-
1,3-dimethoxybenzene was first treated with n-BuLi to
generate the corresponding aryllithium which then underwent
nucleophilic aromatic substitution at 217 followed by oxida-
tive workup with MnO2 to afford the target phenanthroline
6 in a satisfying yield. Subsequent palladium-catalyzed
coupling reaction of phenanthroline 6 and trimethylsily-
lacetylene occurred regioselectively at the 3-position.
Purification of 7 was readily achieved, allowing us to
assign rigorously the substitution pattern on the basis of
characteristic chemical shifts in the DEPT NMR spectrum.
It should be noted that variations of the molar ratio of
trimethylsilylacetylene/6 and of reaction time exerted a
notable effect on the outcome of this transformation (Table
1). The highest yield (55%) was received in an experiment
Scheme 5
Table 1. Sonogashira Coupling of Phenanthroline 6 and
Trimethylsilylacetylene
entry
reaction time (day)
molar ratioa
7, % yield
1
2
3
4
5
6
2
2
2
2
4
1
1.2:1
1.5:1
2:1
2.5:1
1.5:1
1.5:1
15
55
38
19
28
45
a Molar ratio of trimethylsilylacetylene and phenanthroline 6.
with a 1.5:1 ratio and 2 d reaction time. It is important to
note that no bisfunctionalization was observed. We assume
that after oxidative addition complexation of the Pd metal
center by the methoxy group, as depicted in 9, is a key
stabilization motif for achieving the high regioselectivity,
in line with models in the literature of oxa- and azapalla-
dacycles.16
However, only phenanthrolines 5 and 2 and no 3,8-
unsymmetric phenanthroline were detected.
With the difficulties encountered in the above reaction,
we realized that despite the ample use of Pd(0)-catalyzed
reactions13 there is a remarkable shortage of reports address-
ing regioselective bond formation.14 For example, the role
of adjacent groups in controling regioselectivity, e.g., in
polybrominated arenes,15 has not been studied sufficiently
to provide a conceptual framework for reliable predictions.
As we searched specifically for a 3,8-unsymmetric phenan-
throline with bulky aryl groups in the 2,9-position, we finally
reasoned that one should first desymmetrize 2 through
monoarylation. The aryl substituent should then be used to
guide the regioselective functionalization at the 3-position
through the intermediacy of oxapalladacycles or azapalla-
dacycles.16
A second aromatic substitution at 7 with 2,6-dimethoxy-
phenyllithium provides phenanthroline 8 in 68% yield, and
subsequent hydroxide-induced desilylation finally leads to
the target phenanthroline 1 in 80% yield.
All phenanthrolines 7, 8, and 1 are 3,8-unsymmetrically
substituted phenanthrolines, whose functionalities along the
axis of the ligand in the 3- and 8-position can independently
be manipulated for further linear extensions using Sono-
gashira coupling protocols. For example, after desilylation
of 7 with KOH in methanol/THF and subsequent reaction
Indeed, the successful preparation of 1 (Scheme 5) is based
on (a) the selective monoarylation of 2 with 2,6-dimethoxy-
phenyllithium followed by (b) a regioselective Sonogashira
coupling with trimethylsilylacetylene making use of the
coordinating properties of the methoxy groups at the aryl
(13) (a) De Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994,
33, 2379-2411. (b) Crisp, G. T. Chem. Soc. ReV. 1998, 27, 427-436.
(14) Horn, K. A. Chem. ReV. 1995, 95, 1317-1350.
(15) (a) Eickmeier, C.; Junga, H.; Matzger, A. J.; Scherhag, F.; Shim,
M.; Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1997, 36, 2103-2108.
(b) Bach, T.; Kru¨ger, L. Eur. J. Org. Chem. 1999, 2045-2057.
(16) (a) Mateo, C.; Cardenas, D. J.; Fernandez Rivas, C.; Echavarren,
A. M. Chem. Eur. J. 1996, 2, 1596-1606. (b) Gies, A.-E.; Pfeffer, M.;
Sirlin, C.; Spencer, J. Eur. J. Org. Chem. 1999, 1957-1061.
(17) (a) Tzalis, D.; Tor, Y.; Failla, S.; Siegel, J. S. Tetrahedron Lett.
1995, 36, 3489-3490. (b) Dietrich-Buchecker, C.; Jime´nez, M. C.; Sauvage,
J.-P. Tetrahedron Lett. 1999, 40, 3395-3396.
Org. Lett., Vol. 2, No. 25, 2000
3961

with 1,4-diiodobenzene in a Sonogashira coupling, the
corresponding linear bisphenanthroline was afforded.18
Industrie is gratefully acknowledged. S.X.L. is indebted to
the Alexander-von-Humboldt Stiftung for a scholarship.
Supporting Information Available: Full experimental
details and characterization data for 1 and 6-8. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Generous financial support from the
DFG (Schm 647/5-2) and the Fonds der Chemischen
(18) Liu, S. X. Unpublished results.
OL006514K
3962
Org. Lett., Vol. 2, No. 25, 2000