Complexes of Schiff Bases and Intermediates in the Copper-Catalyzed Oxidative Heterocyclization by Atmospheric Oxygen

Article abstract of DOI:10.1021/ic034773a

After complexation with copper(II) ions, Schiff bases 1a-d may undergo an oxidative ring closure using atmospheric oxygen to give a number of imidazo[1,5-a]pyridines 2, an imidazo[1,5-a]imidazole 3, and an imidazo[5,1-a]isochinoline 4. This ligand oxidation can be performed with catalytic amounts of copper ions in the reaction. A catalytic cycle for the copper-catalyzed oxidative heterocyclization will be presented together with isolated copper complexes of Schiff bases 1a,b and intermediates 5 and 8 that were found by X-ray structure analyses which confirm this reaction scheme.

Full text of DOI:10.1021/ic034773a

Inorg. Chem. 2003, 42, 8878−8885
Complexes of Schiff Bases and Intermediates in the Copper-Catalyzed
Oxidative Heterocyclization by Atmospheric Oxygen§
,†
Martin E. Bluhm,† Michael Ciesielski,† Helmar Go1rls,‡ Olaf Walter,† and Manfred Do1ring*
Institute for Technical Chemistry (ITC-CPV), Forschungszentrum Karlsruhe, P.O. Box 3640,
76021 Karlsruhe, Germany, and Department of Inorganic Chemistry, UniVersity of Jena,
August-Bebel-Strasse 2, 07743 Jena, Germany
Received July 7, 2003
After complexation with copper(II) ions, Schiff bases 1a−d may undergo an oxidative ring closure using atmospheric
oxygen to give a number of imidazo[1,5-a]pyridines 2, an imidazo[1,5-a]imidazole 3, and an imidazo[5,1-a]isochinoline
4. This ligand oxidation can be performed with catalytic amounts of copper ions in the reaction. A catalytic cycle
for the copper-catalyzed oxidative heterocyclization will be presented together with isolated copper complexes of
Schiff bases 1a,b and intermediates 5 and 8 that were found by X-ray structure analyses which confirm this
reaction scheme.
Scheme 1. Reaction Equation of the Copper-Catalyzed Oxidative
Introduction
Formation of 2a
Previously, an ecologically compatible synthesis of new
heterobicyclic compounds was described, which can be
applied as pharmaceuticals or ligands for the development
of new homogeneous catalysts.1a,b Imidazo[1,5-a]pyridines 2,
an imidazo[1,5-a]imidazole 3, and an imidazo[5,1-a]isochi-
noline 4 were prepared from Schiff bases 1a,1c 1b, and 1c-
d1a with an oxidative ring closure reaction by atmospheric
1a-c do not disturb the catalysis. The Schiff bases 1a,b,e5
were used as reactants in reactions examined later.
The reaction equation of the copper-catalyzed formation
oxygen and catalytic amounts of copper(II) and a base (Chart
1). This method easily and rapidly yields new nitrogen-fused
heterocycles which cannot be prepared in the traditional
of the heterobicycle 2a with 1a and atmospheric oxygen
synthetic way of dehydrating amides under severe condi-
shows the transfer of altogether four electrons from two
tions.2-4 Even sensitive functional groups such as hydroxy
or amine groups at aromatic positions of the Schiff bases
imines 1a toward molecular oxygen (Scheme 1).
The catalytic reaction pathway can be described as
follows: First, the Schiff base 1 coordinates to copper(II)
* To whom correspondence should be addressed. E-mail: manfred.
(Scheme 2, 5a). After deprotonation of the coordinated
ligand, both copper(II) ions are reduced to copper(I) in a
two-electron process. A C-N bond is established between
the carbon of the imino group and a nitrogen atom of a
2-pyridyl, 2-imidazolyl, or isochinolyl group in 1 (Scheme
2, step I). This leads to the closure of nitrogen-fused
heterocycles, whereby the derivatives 2-4 are formed. As
result of the oxidation process, the number of coordinating
doering@itc-cpv.fzk.de.
† Forschungszentrum Karlsruhe.
‡ University of Jena. E-mail: goerls@xa.nlwl.uni-jena.de.
§ Dedicated to Professor Eckhard Dinjus on the occasion of his 60th
birthday.
(1) (a) Bluhm, M. E.; Ciesielski, M.; Go¨rls, H.; Do¨ring, M. Angew. Chem.,
Int. Ed. 2002, 41 (16), 2962; Angew. Chem. 2002, 114 (16), 3104. (b)
Bluhm, M.; Ciesielski, M.; Go¨rls, H.; Do¨ring, M. Chem.-Ing.-Tech.
2002, 74 (5), 556. (c) Ligtenbarg, A. G. J.; Spek, A. L.; Hage, R.;
Feringa, B. L. J. Chem. Soc., Dalton Trans. 1999, 3, 659.
(2) (a) Bower, J. D.; Ramage, G. R. J. Chem. Soc. 1955, 2834. (b)
Winterfeld, K.; Franzke, H. Angew. Chem. 1963, 22, 1101. (c)
Abushanab, E. Tetrahedron Lett. 1971, 18, 1441. (d) Edgar, M. T.;
Pettit, G. R.; Krupa, T. S. J. Org. Chem. 1979, 44, 396. (e) Tachikawa,
R.; Tanaka, S.; Terada, A. Heterocycles 1981, 15 (1), 369. (f)
Katritzky, A. P.; Rees, C. W. Compr. Heterocycl. Chem. 1984, 5, 634.
(g) Krapcho, A. P.; Powell, J. R. Tetrahedron Lett. 1986, 27 (32),
3713. (h) Renz, M.; Hemmert, C.; Donnadieu, B.; Meunier, B. Chem.
Commun. 1998, 1635.
(3) (a) Aryuzina, V. M.; Shchukina, M. N. Khim. Geterotsikl. Soedin.
1968, 3, 506. (b) Kochergin, M. P.; Lifanov, V. A. Khim. Geterotsikl.
Soedin. 1994, 4, 490.
(4) Reimlinger, H.; Vandewalle, J. J. M.; Lingier, W. R. F.; de Ruiter, E.
Chem. Ber. 1975, 108, 3771.
(5) Mousser, A.; Le Marouille, J.-Y. J. Organomet. Chem. 1986, 312,
263.
8878 Inorganic Chemistry, Vol. 42, No. 26, 2003
10.1021/ic034773a CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/22/2003

Copper-Catalyzed OxidatiWe Heterocyclization
Chart 1. Examples of Prepared Schiff Bases 1a-e and Heterocycles 2a,b, 3, and 4
Scheme 2. Catalytic Cycle for the Synthesis of 2a with Cu(II) as Catalyst and O2 as Oxidant
atoms in the formed heterocycle is reduced. The heterocycle
is then substituted by another Schiff base 1 (Scheme 2, step
II). Atmospheric oxygen regenerates the copper(II) ions
(Scheme 2, step III).
To elucidate the different steps of the copper-catalyzed
oxidative heterocyclization, X-ray diffraction studies of
copper(I) and copper(II) coordination compounds will be
presented.
isolation of copper(I) and copper(II) complexes 5a-8a.
Those complexes of the salicylaldimines of bis(2-pyridyl)-
methylamine (1a) and the heterobicycle 2a are characterized
either as intermediates or as stable compounds which exist
in equilibrium with a more reactive species. A one-pot
reaction starting with 5a directly leads to the isolated copper
complexes 7a and 8a. In this reaction the intermediate 8a is
converted again to 5a, which is used as starting material.
All isolated intermediates except for 9a may be converted
into each other. Complexes of 9 are formed only if no more
imine 1 is present for further reacting with copper. Hence,
these complexes are no intermediates of the catalysis. The
Results and Discussion
To investigate the course of this reaction, 1a was used as
model ligand. The OH substituents in 1a facilitate the
Inorganic Chemistry, Vol. 42, No. 26, 2003 8879

Bluhm et al.
Figure 2. ORTEP14 drawing of the copper(I) complex 6a with two
coordinated heterobicycles 2a. One chloride counterion is not reported in
this figure.
Figure 1. ORTEP14 drawings of the copper(II) complex 5a.
Scheme 4. Nucleophilic Attack by the Negatively Charged
Pyridine-N Atom N3 at the Imino Carbon C7
Table 1. Interatomic Distances (Å) and Angles (deg) Selected for 5a
Cu-N1
2.023(2)
1.973(2)
1.9159(15)
81.7(1)
Cu-Cl
C7-N2
2.272(1)
1.296(3)
Cu-N2
Cu-O1
N1-Cu-N2
N2-Cu-O1
O1-Cu-Cl
N1-Cu-Cl
89.9(1)
95.3(1)
92.5(1)
Scheme 3. Formation of the Heterobicycle 2a in the Copper(II)
Complex 5a
It is known that the acidity of a C-H bond in the
R-position to an imino group is markedly increased if the
imino nitrogen atom is coordinated to a copper(II) center.3
The addition of a base is not necessary in every case of the
used imine 1. Basic acceptors, such as pyridines, have the
ability to deprotonate the imino carbon-bound hydrogen
atom. Electron-withdrawing substituents also facilitate the
release of this hydrogen atom. In the case of 5a, the
conversion is possible without an additional base, but it
proceeds very slowly.
The carbanion formed at C6 increases the nucleophility
at the heterocyclic nitrogen atom N3, which facilitates a
nucleophilic attack at the imino carbon C7 (Scheme 4). In
the course of the reaction, the ligand is oxidized and the
phenolate anion is reprotonated. In this oxidation two
involved copper(II) ions are reduced to copper(I) (Scheme
2, step I).
To investigate step I of the catalytic cycle, molecular
oxygen has to be excluded. If 1a reacts with equimolar
amounts of CuCl2 and sodium hydroxide in boiling methanol
under argon, a brown reaction mixture is obtained from
which 6a crystallizes because of its low solubility. 8a is also
formed in step I, but it is dissolved in the reaction mixture.
Using orange crystals of 6a, an X-ray crystallography study
was performed (Figure 2). In the ionic 6a two imidazo[1,5-
a]pyridines chelate with four nitrogen atoms around one
copper(I) ion. Both phenoxy groups are protonated and not
used as chelating units with the copper ion. The coordination
sphere around the copper(I) ion is a distorted tetrahedron
with N-Cu-N angles ranging between 81 and 154° (Table
2). The Cu-N1 and Cu-N6 bond distances are 1.96 and
2.09 Å, respectively, which is in the normal range for those
bonds.6 Both distances between the copper ion and the
coordinated pyridine nitrogen atoms are unusually large (2.09
and 2.15 Å). A similar C-N(pyridine) bond length was found
in one of the [N-alkyl-2-pyridylmethanimine]copper(I) com-
discussion of the catalytic cycle (Scheme 2) starts with the
isolated copper(II) imine complex 5a.
For the formation of 5a a reaction with equimolar amounts
of 1a, CuCl2, and sodium hydroxide was carried out in
methanol at -60 °C. The mixture was warmed to -30 °C
and for a short period of time to -5 °C. 5a crystallized as
dark green crystals suitable for X-ray structure analysis
(Figure 1). The mononuclear complex has an essentially
undistorted square planar geometry around the copper(II) ion.
The Cu-N1 bond of 2.02 Å (Table 1) has the normal
distance found for Cu-N(pyridine) bonds in tetracoordinated
copper(II) complexes.6 The Cu-N2 (1.97 Å), Cu-O1 (1.92
Å), and Cu-Cl (2.27 Å) bond distances are in the range
expected for this coordination geometry with copper(II).
5a is the first intermediate in the copper-catalytic reaction
to the imidazo[1,5-a]pyridine 2a. It has a high thermal
stability and does not convert in the crystal state and only
slowly in solution, while heated for several hours. However,
when a base like sodium hydroxide or triethylamine is added
to a solution of methanol with 5a, the redox process starts
immediately. This suggests the increased release of the acidic
C6 hydrogen atom with a base as first step of the reaction
cascade (Scheme 3).
(6) Orpen, A. G.; Brammer, L.; Allen, F. H.; Kennard, O.; Watson, D.
G. J. Chem. Soc., Dalton Trans. 1989, S1-S83.
8880 Inorganic Chemistry, Vol. 42, No. 26, 2003

Copper-Catalyzed OxidatiWe Heterocyclization
Figure 3. ORTEP14 drawing of the copper(I) complexes 7a and 8a with two coordinated imines 1a. Half of 7a was generated by a crystallographic 2-fold
-
axis. The CuCl2 counterion of 7a and the Cl- counterion of 8a are not reported in this figure.
Table 2. Interatomic Distances (Å) and Angles (deg) Selected for 6a
Table 3. Interatomic Distances (Å) and Angles (deg) Selected for 7a
Cu-N1
1.958(3)
2.145(3)
81.2(1)
81.9(1)
120.1(1)
Cu-N4
1.993(3)
2.088(3)
109.3(1)
154.4(1)
100.0(1)
Cu1-N2
2.042(3)
134.91(15)
93.8(1)
Cu1-N3
2.015(3)
105.5(1)
93.8(1)
Cu-N3
Cu-N6
N3-Cu1-N3a
N3-Cu1-N2
N3a-Cu1-N2
N3-Cu1-N2a
N3a-Cu1-N2a
N2-Cu1-N2a
N1-Cu-N3
N4-Cu-N6
N1-Cu-N6
N3-Cu-N4
N1-Cu-N4
N3-Cu-N6
105.5(1)
128.46(15)
Table 4. Interatomic Distances (Å) and Angles (deg) Selected for 8a
plexes described by Haddleton et al.7 6a is quite stable
against molecular oxygen and, hence, does not represent any
catalytic intermediate. 6a only slowly converts into 9a in
refluxing methanol and in the presence of air. This reveals
the existence of a more labile but also more soluble
heterobicyclic copper(I) complex as catalytic intermediate
which could not be isolated yet. As proposed in Scheme 1,
6a is in equilibrium with this more reactive copper(I) species.
After the heterobicycle has been released from the metal
ion of the intermediate which is in equilibrium with 6a, a
heterocyclic imine coordinates to the copper(I) ion (Scheme
2, step II). The tridentate imine 1a coordinates better to the
copper(I) center than the formed heterobicycle 2a, which is
bidentate. The intermediate 8a is also formed in this reaction
step. 8a is in equilibrium with a thermodynamically more
stable species 7a. To isolate the relevant copper(I)-imine
complexes 7a and 8a, 5a was reacted with 1a in the presence
of small amounts of NaOH under argon. The conversion of
5a into 6a and, thus, into 7a and 8a already happens at room
temperature (steps I and II, Scheme 2). This gives a brown
and very air sensitive solution. During removal of some
solvent and cooling of the solution, crystals were obtained
of 7a and 8a with additional small amounts of 6a. 7a is also
formed directly with 1a and CuCl. 7a and 8a were isolated
and structurally characterized (Figure 3). Both complexes
are very similar to each other but show a different behavior
in their reactivity toward molecular oxygen and in their
solubility properties. While the copper(I) complex 7a obtains
CuCl2- as coordinating anion, it is Cl- and the formation of
neutral CuCl in 8a. Both compounds 7a and 8a contain a
copper(I) atom coordinated to two imines 1a each. The angle
around the copper(I) ion is distorted tetrahedrally, while the
Cu1-N1
2.023(7)
2.074(8)
144.9(3)
109.1(3)
91.7(3)
Cu1-N4
2.107(8)
1.985(8)
91.2(3)
109.6(3)
107.5(3)
Cu1-N2
Cu1-N5
N1-Cu1-N5
N2-Cu1-N5
N1-Cu1-N2
N4-Cu1-N5
N1-Cu1-N4
N2-Cu1-N4
angle N1-Cu1-N5 is larger (144.9 deg) in 8a compared to
the angle N3-Cu1-N3a (134.9 deg) in 7a (Tables 3 and
4). The Cu1-N4 bond in 8a is expanded (2.107 Å), while
the Cu1-N5 bond is shorter (1.958 Å) compared with the
Cu1-N bonds (2.015-2.042 Å) in 7a. The expansion and
the lower shielding of the copper ion in 8a explain the much
higher reactivity toward molecular oxygen and a better
solubility in organic solvents. Like 6a, both phenoxy groups
are protonated in 7a and 8a and not used as chelating units
with the copper ion (Scheme 2). 7a and 8a prove the
coordination of imines to copper(I) in the catalysis. The 1H
spectrum of 8a shows a broader set of imine signals
compared to the noncoordinated ligand 1a, which suggests
a kinetically labile coordination of the imine to the copper-
(I) ion.
In step III molecular oxygen oxidizes copper(I) to copper-
(II), while both phenoxy substituents in the ligand are
deprotonated. A total of 2 equiv of 8a react with oxygen
under release of two molecules of water to the intermediate
5a. A yellow-brown methanolic solution of 8a immediately
turns green with atmospheric oxygen, and crystals of 5a are
formed while cooling the closed flask. 7a reacts much more
slowly with molecular oxygen to 5a. Like 5a, 8a may well
be considered as important intermediate of the catalysis. The
catalytic cycle starts from the beginning with the formation
of 5a.
The formation of 9a is possible only when all imine
molecules of 1a have reacted to the heterobicycle 2a. Then,
2a coordinates to copper(II) ions which have been oxidized
(7) Haddleton, D. M.; Duncalf, D. J.; Kukulj, D.; Crossman, M. C.;
Jackson, S. G.; Bon, S. A. F.; Clark, A. J.; Shooter, A. J. Eur. J.
Inorg. Chem. 1998, 1799.
Inorganic Chemistry, Vol. 42, No. 26, 2003 8881

Bluhm et al.
Table 6. Interatomic Distances (Å) and Angles (deg) Selected for 9b
Cu-N1
2.057(2)
1.932(2)
2.005(2)
1.943(2)
80.1(1)
86.7(1)
156.0(1)
94.7(1)
S-N4
S-O1
S-O2
1.596(3)
1.457(2)
1.450(2)
Cu-N3
Cu-N4
Cu-O3
N1-Cu-N3
N3-Cu-N4
N1-Cu-N4
N1-Cu-O3
N3-Cu-O3
N4-Cu-O3
O1-S-N4
O2-S-N4
172.1(1)
100.2(1)
105.5(1)
112.7(1)
Table 7. Interatomic Distances (Å) and Angles (deg) Selected for 5e
Figure 4. ORTEP14 drawing of the binuclear copper(II) complex 9a. Half
of 9a was generated by a crystallographic inversion center.
Cu1-N1
2.108(3)
2.205(3)
1.968(3)
1.789(2)
86.6(1)
Cu1-O1
2.049(2)
1.853(2)
3.376(1)
2.842(1)
84.1(1)
Cu1-N2
Cu2-O6
Cu2-N3
Cu2-N4
N1-Cu1-N2
N3-Cu2-N4
O1-Cu1-N2
O1-Cu1-N1
Cu1-Na
Cu2-Na
O6-Cu2-N4
O6-Cu2-N3
Cu1-Na-Cu2
101.2(1)
102.2(1)
170.7(1)
174.6(1)
112.9
Scheme 5. Heterobicycle Which Cannot Be Formed with Imine 1e
Figure 5. ORTEP14 drawing of the copper(II) complex 9b.
(II) ion. The molecular geometry around the copper ion is
distorted square planar. Like in 9a, the complex 9b has a
similarly short Cu-N(imidazo) bond length (1.93 Å; Table
6). 9b also is a product of the reaction of 1b with copper(II)
ions. If all imines 1b have been reacted in the catalysis, no
ligand replacement in step II (Scheme 2) can occur.
Table 5. Interatomic Distances (Å) and Angles (deg) Selected for 9a
Cu1-N1
2.056(2)
1.924(2)
1.929(2)
80.3(1)
97.1(1)
93.0(1)
164.4(1)
88.6(1)
92.6(1)
Cu1-Cl1
2.276(1)
2.723(1)
3.480(2)
98.8(1)
172.6(1)
94.8(1)
87.7
Cu1-N2
Cu1a-Cl1
Cu1-O1
Cu1a-Cu1
N1-Cu1-N2
N1-Cu1-Cl1
N1-Cu1-Cl1a
N1-Cu1-O1
N2-Cu1-O1
O1-Cu1-Cl1
O1-Cu1-Cl1a
N2-Cu1-Cl1
N2-Cu1-Cl1a
Cu1-Cl1-Cu1a
Cl1-Cu1-Cl1a
In contrast to 1a, 1e does not react to a heterobicycle. In
5e the imine ligand 1e has two methylene groups between
the pyridine substituent and the imino group (Table 7). The
formation of a carbanion under basic conditions in 5e is less
favorable compared to 5a because of a lower CH acidity
and loss of resonance stabilization through the pyridine ring.
No C-N bond can be established between the carbon of the
imino group and a nitrogen atom of the 2-pyridyl ring. A
four-electron process would be necessary for the oxidation
of 1e, which was not observed in the oxidative heterocy-
clization described. Scheme 5 shows the not achieved
formation of the heterocycle.
92.3
by molecular oxygen to give the characterized complex 9a.
If 5a is heated in methanol in the presence of air for several
hours, the product 9a is formed. Crystals suitable for X-ray
crystallography are obtained while cooling the reaction
mixture of refluxing 1a, CuCl2, and NaOH in the presence
of air (Figure 4). In the bimetallic complex 9a both copper-
(II) ions have a distorted square pyramidal geometry. Two
chlorides act as bridging ligands. Whereas the Cu-N(pyri-
dine) length (2.06 Å; Table 5) is the distance commonly
found for those bonds, the Cu-N(imidazo) distance (1.92
Å) is relatively short. The Cu-O1, Cu-O1a (1.93 Å) and
Cu-Cl1, Cu-Cl1a (2.28 Å) bond distances are in the range
expected for this coordination geometry with copper(II).6
The attempts to oxidatively heterocyclize 1e lead to the
formation of two copper complexes with 1e, which were
structurally characterized. The imine 1e forms a copper(II)
complex 5e in methanol, whereby two complex spheres each
are bridged by one sodium ion (Figure 6). Three acetate
molecules with their oxygen atoms form the bridge between
sodium and copper ions, and one methanol molecule forms
the bond to the central sodium ion. Both copper ions are
coordinated in a slightly distorted square planar coordination
sphere. Nevertheless, 5e is not stable in solution and
rearranges by ligand exchange to the copper(II) complex 10
and copper(II) acetate. In 10 the imine 1e is coordinated with
two molecules to one copper(II) center (Table 8). Conse-
quently, another molecule of the ligand 1e is used to complete
the coordination sphere around the copper ion (Figure 6).
The Cu-N bond lengths (2.00 Å) and the Cu-O distances
The imine 1b that bears a toluenesulfonyl amino group
instead of the o-hydroxy group reacts in a way similar to
1a. In the presence of O2 and sodium hydroxide, 1b reacts
with copper(II) acetate to the copper(II) complex 9b, which
contains the imidazo[1,5-a]pyridine 2b as chelating ligand
(Figure 5). The X-ray structure was determined using crystals
of 9b, which have been obtained by recrystallization from
methanol. In contrast to 9a, a mononuclear complex 9b is
formed and the coordination number of the copper is 4 only.
The imidazo[1,5-a]pyridine 2b acts as a tridentate chelating
ligand and an acetate oxygen atom is attached to the copper-
8882 Inorganic Chemistry, Vol. 42, No. 26, 2003

Copper-Catalyzed OxidatiWe Heterocyclization
Figure 6. ORTEP14 drawings of the copper(II) complexes 5e (two imine units, acetate, and methanol molecules shown with filled bonds) and 10.
Table 8. Interatomic Distances (Å) and Angles (deg) Selected for 10
Conclusion
Cu-N2
2.00(1)
92.3(5)
Cu-O1
1.88(1)
87.7(5)
It was possible to investigate in detail the single steps of
the copper-catalyzed heterocyclization with the oxidation of
1a to 2a. The isolated copper(II) and copper(I) complexes
of 5a, 6a, 7a, and 8a characterized by X-ray structure
N2-Cu-O1
N2-Cu-O1
(1.88 Å) are in the normal range for this square planar
coordination geometry in 10.
Table 9. Crystallographic Data
5a
5e
6a
7a
empirical formula
fw
C18H14ClCuN3O‚CH3OH
419.35
C35H39Cu2N4NaO9
809.77
C36H26ClCuN6O2
673.62
C18H15ClCuN3O
388.32
temp (K)
λ (Å)
cryst system
space group
a (Å)
b (Å)
c (Å)
R (deg)
â (deg)
γ (deg)
V (Å3)
183
0.710 73
triclinic
P1h
7.7047(4)
8.5429(4)
14.3676(4)
89.319(3)
77.905(3)
80.714(4)
912.34(7)
2
1.527
13.62
R1 ) 0.0316
wR2 ) 0.0776
R1 ) 0.0404
wR2 ) 0.0824
183
200
200
0.710 73
monoclinic
P21/n
8.2228(2)
21.5194(6)
20.9198(5)
90
99.002(2)
90
3656.2(2)
4
1.471
12.33
R1 ) 0.0388
wR2 ) 0.111
R1 ) 0.0416
wR2 ) 0.117
0.710 73
monoclinic
P21/c
11.6733(5)
20.0909(9)
12.9625(6)
90
90.366(1)
90
3040.0(2)
4
1.472
8.51
R1 ) 0.0512
wR2 ) 0.1092
R1 ) 0.1446
wR2 ) 0.1382
0.710 73
monoclinic
C2/c
13.5373(12)
14.9827(13)
18.4163(16)
90
111.1590(10)
90
3483.5(5)
8
1.481
14.16
R1 ) 0.0437
wR2 ) 0.1018
R1 ) 0.1076
wR2 ) 0.1173
Z
F
calcd (g cm-3
)
µ (cm-1
)
R [I > 2σ(I)]a
R (all data)a
8a
9a
9b
10
empirical formula
fw
C38H36ClCuN6O4.70
750.92
C18H12ClCuN3O3
417.31
C28H26CuN4O5S
594.13
C28H28CuN4O2
516.08
temp (K)
λ (Å)
cryst system
space group
a (Å)
b (Å)
c (Å)
R (deg)
â (deg)
γ (deg)
V (Å3)
200
183
183
183
0.710 73
monoclinic
P21/c
14.730(4)
18.355(6)
15.654(5)
90
112.018(5)
90
3924(2)
0.710 73
orthorhombic
Pccn
17.5223(6)
20.5783(7)
9.5807(2)
90
0.710 73
monoclinic
P21/c
14.5787(4)
16.3295(4)
11.1576(3)
90
100.825(1)
90
2608.94(12)
4
1.513
9.65
R1 ) 0.0378
wR2 ) 0.1001
R1 ) 0.0547
wR2 ) 0.1193
0.710 73
monoclinic
P21/c
10.0403(3)
25.0150(10)
10.6396(4)
90
118.139(2)
90
2356.38(15)
4
90
90
3454.60(18)
4
1.605
Z
4
F
calcd (g cm-3
)
1.271
6.72
R1 ) 0.1132
wR2 ) 0.2943
R1 ) 0.3175
wR2 ) 0.3931
1.455
9.61
µ (cm-1
)
14.42
R [I > 2σ(I)]a
R1 ) 0.0307
wR2 ) 0.0826
R1 ) 0.0379
wR2 ) 0.0983
R (all data)a
2
2
a R1 ) [Σ||Fo| - |Fc||]/Σ|Fo|, wR2 ) [[Σw(|Fo2 - Fc |)2]/[Σw(Fo )]]1/2, w ) 1/[(σFo)2 + (aP)2]. The value of aP was obtained from structure refinement.
Inorganic Chemistry, Vol. 42, No. 26, 2003 8883

Bluhm et al.
Preparation of 6a. Under argon, a methanolic solution (30 mL)
of equimolar amounts of 1.45 g (5 mmol) of 1a, 0.67 g (5 mmol)
of CuCl2, and 0.20 g (5 mmol) of sodium hydroxide was heated
under reflux for 3 h. After the solution had been cooled to room
temperature, a brown solid precipitated. Yellow crystals of 6a
suitable for X-ray structure determination were obtained by
recrystallization of the crude product from methanol under argon.
analyses confirm the suggested reaction mechanism in
Scheme 2. The isolated complexes 5a and 8a were success-
fully converted into each other according to the catalytic
cycle. This proves the significance of this reaction mecha-
nism. The catalysis starts with the copper(II) complex 5a.
5a can only react after the coordinated imine 1a is depro-
tonated close to the imine group. This explains the reaction-
accelerating effect of strong bases such as sodium hydroxide,
including the fact that such imines can react only where the
deprotonation is structurally favored. The oxidative dehy-
drogenation takes place after the deprotonation to give
copper(I) complexes of the heterobicycle 2a. Because of its
low solubility, 6a was isolated. A rapid ligand exchange
occurs under the reaction conditions existing in the catalysis,
forming copper(I) complexes of the imine 1a. 7a and 8a both
were isolated and characterized. The high sensitivity of 8a
to molecular oxygen suggests that this step of the catalysis
is responsible for the coordination and activation of oxygen.
The oxidation of 8a with air leads to the starting material
5a. This shows the importance of 8a as intermediate in the
catalytic cycle. The elementary steps of oxygen activation
at the copper center and the steps of the oxidative hetero-
cyclization remain unclear. Kinetic investigations with
isolated intermediates are in progress and will be reported
in due course.
Preparation of 7a. Under argon, a mixture of equimolar amounts
of 1.73 g (6 mmol) of 1a in 40 mL of methanol and a solution of
0.25 g (6 mmol) of CuCl in acetonitrile and hexane was heated
under reflux for 15 min. After the solution had been cooled to room
temperature, it was layered with diethyl ether and stored for 1 day.
Brown-red crystals of 7a precipitated, which were suitable for X-ray
structure determination.
Preparation of 8a. Under argon, a mixture of 2.2 g (4.5 mmol)
of 5a, 1.30 g (4.5 mmol) of 1a, and 0.018 g (0.45 mmol, 0. 1 equiv)
of NaOH in 30 mL of methanol was stirred for 2 h at ambient
temperature. The obtained brown solution was stored at -20 °C
for 15 h. Then a small amount of 6a was removed by filtration
under argon. The filtrate was concentrated to approximately 20 mL
in vacuo. The solution was cooled slowly, whereby yellow crystals
of 8a were obtained which were suitable for X-ray structure
analysis. After decanting from the solid, the mother liquor was
concentrated to 10 mL. While the solution was cooling to -25 °C
overnight, pure 8a crystallized. 1H NMR (200 MHz, MeOH-d4): δ
) 8.83 (s, br., 1H), 8.31 (s, br., 2H), 7.95 (m, 2H), 7.82 (m, 2H),
7.43 (m, 1H), 7.29 (m, 3H), 6.81 (m, 2H), 6.22 (s, 1H). 13C NMR
(50.3 MHz, MeOH-d4): δ ) 170.0, 161.6, 159.1, 150.8, 139.8,
134.5, 133.3, 125.6, 125.3, 120.5, 120.3, 117.7, 77.9.
Experimental Section
Preparation of 1b. A solution of 1 g (5.5 mmol) of bis(2-
pyridyl)methylamine was added dropwise to a solution of 1.5 g
(5.5 mmol) of toluene-4-sulfonic acid (2-formylanilide)8 in 7 mL
of ethanol. Then the mixture was refluxed for 1 h. The dark solution
was cooled to -25 °C, as a result of which 1b precipitated. Yield:
Preparation of 9a. Method A. A methanolic solution of
equimolar amounts of 1a, CuCl2, and sodium hydroxide was heated
in the presence of air for 1 h. The binuclear copper(II) complex 9a
was formed in the reaction. 9a crystallized directly from the reaction
mixture under cooling.
1
1 g (2.2 mmol, 40%). Mp: 135 °C. H NMR (200 MHz, CDCl3):
Method B. The copper(I) complex 6a was heated in methanol
in the presence of air for 8 h. Cooling of the methanolic solution
yielded crystals of 9a.
δ ) 13.20 (s, 1H), 8.57 (m, 3H), 6.61-8.16 (m, 14H), 5.89 (s,
1H), 2.30 (s, 3H). 13C NMR (50.3 MHz, CDCl3): δ ) 165.4, 160.4,
149.4, 143.3, 139.4, 137.1, 136.8, 133.7, 131.9, 129.4, 128.5, 127.0,
126.1, 122.6, 122.5, 122.2, 120.7, 117.7, 81.6, 21.4. EI+-MS [m/z
(%)]: 443 (100), [M + H]+.
Preparation of 5a. Method A. A methanolic solution (30 mL)
of equimolar amounts of 1.45 g (5 mmol) of 1a, 0.67 g (5 mmol)
of CuCl2, and 0.20 g (5 mmol) of sodium hydroxide was prepared
at -60 °C under formation of a green suspension. The mixture
was warmed to -30 °C to give a green solution. After 3 h, 5a
crystallized as a dark green solid. The methanolic suspension of
the crude complex was warmed to -5 °C for 20 min and slowly
cooled again. This procedure was repeated three times, thus leading
to large compact crystals of 5a.
Preparation of 9b. A methanolic solution of equimolar amounts
of 1b, copper(II) acetate, and sodium hydroxide was heated in the
presence of air for 2 h. The binuclear copper(II) complex 9b was
formed in the reaction. 9b crystallized directly from the reaction
mixture under cooling.
Preparation of 10. Under argon, a methanolic solution of
equimolar amounts of 1e, CuCl2, and sodium hydroxide was heated
under reflux for 3 h. After the solution had been cooled to room
temperature, a brown solid precipitated. Brown crystals of 10
suitable for X-ray structure determination were obtained by
recrystallization of the crude product from methanol under argon.
Method B: Oxidation of 8a with Air (Reconversion to 5a).
Under argon, 1 g (1.5 mmol) of 8a was dissolved in 40 mL of
methanol. A small amount of a nondissolved solid was removed
by filtration. The yellow-brown filtrate was stirred under air for 3
min at ambient temperature whereby the color changed to deep-
green. Then the solution was transferred into a closed vessel and
stored for 3 days at -25 °C. Green crystals of 5a suitable for X-ray
structure determination were obtained.
Crystal Structure Determination. The intensity data for the
compounds were collected by a Nonius KappaCCD and a Siemens
Smart 1000 CCD diffractometer (compounds 6a, 7a, and 8a) using
graphite-monochromated Mo KR radiation. Data were corrected
for Lorentz and polarization effects but not for absorption.9,10
(8) Chernova, N. I.; Ryabokobylko, Y. S.; Brudz, Y. G.; Bolotin, B. M.
Zh. Neorg. Khim 1971, 1680.
Preparation of 5e. A methanolic solution of equimolar amounts
of 1e, copper(II) acetate, and sodium hydroxide was stirred at 0
°C in the presence of air for 2 h. The binuclear copper(II) complex
5e was formed in the reaction. 5e crystallized directly from the
reaction mixture.
(9) COLLECT, Data Collection Software; Nonius BV: Delft, The
Netherlands, 1998.
(10) Otwinowski, Z.; Minor, W. Processing of X-ray Diffraction Data
Collected in Oscillation Mode. In Methods in Enzymology, Vol. 276,
Macromolecular Crystallography; Carter, C. W., Sweet, R. M., Eds.;
Academic Press: San Diego, CA, 1997; Part A, pp 307-326.
8884 Inorganic Chemistry, Vol. 42, No. 26, 2003

Copper-Catalyzed OxidatiWe Heterocyclization
The structures were resolved by direct methods (SHELXS11) and
refined by full-matrix least-squares techniques against Fo2 (SHELXL-
9712) (Table 9). For the compounds 5a,e (not for the methyl groups),
6a, 7a (only for the O1-H), and 8a, the hydrogen atoms were
localized by difference Fourier synthesis and refined isotropically.
The hydrogen atoms of the other structures were included at the
calculated positions with fixed thermal parameters. The quality of
the data for compound 10 is too bad. We will only publish the
conformation of the molecule and the crystallographic data. The
data shall not be deposited in the Cambridge Crystallographic Data
Centre.
All non-hydrogen atoms were refined anisotropically.12 XP
(Siemens Analytical X-ray Instruments, Inc.) was used for structure
representations.
(11) Sheldrick, G. M. Acta Crystallogr. Sect. A 1990, 46, 467-473.
(12) Sheldrick, G. M. SHELXL-97; University of Go¨ttingen: Go¨ttingen,
Germany, 1993.
(13) CCDC 197824, 197825, 197827, and 197828 (5a, 5e, 9a, 9b), CCDC
221808 (6a), CCDC 199953 (7a), and CCDC 212673 (8a) contain
the supplementary crystallographic data for this paper. These data can
be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving-
.html (or from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, U.K.; fax (+44) 1223-336-033 or
e-mail deposit@ccdc.cam.ac.uk).
IC034773A
(14) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
Inorganic Chemistry, Vol. 42, No. 26, 2003 8885