One-pot three-component synthesis, structure and redox properties of ferrocenyl isoxazoles

Article abstract of DOI:10.1016/j.jorganchem.2008.10.050

A consecutive coupling-cycloaddition sequence of acid chlorides, terminal alkynes, and in situ generated nitrile oxides furnishes ferrocenyl substituted redox active isoxazoles in moderate to good yields. The structure was unambiguously assigned by X-ray

Full text of DOI:10.1016/j.jorganchem.2008.10.050

Journal of Organometallic Chemistry 694 (2009) 942–949
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
One-pot three-component synthesis, structure and redox properties
of ferrocenyl isoxazoles
Benjamin Willy a, Walter Frank b,1, Frank Rominger c,1, Thomas J.J. Müller a,
*
a Institut für Organische Chemie und Makromolekulare Chemie, Lehrstuhl für Organische Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1,
D-40225 Düsseldorf, Germany
b Institut für Anorganische Chemie und Strukturchemie, Lehrstuhl für Material- und Strukturforschung, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1,
D-40225 Düsseldorf, Germany
c Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A consecutive coupling-cycloaddition sequence of acid chlorides, terminal alkynes, and in situ generated
nitrile oxides furnishes ferrocenyl substituted redox active isoxazoles in moderate to good yields. The
structure was unambiguously assigned by X-ray structure analyses and the electronic structure was elu-
cidated by computational methods. Redox potentials of all representatives are strongly effected by the
electronic nature of the bridging isoxazoloyl moiety.
Received 19 September 2008
Received in revised form 30 October 2008
Accepted 31 October 2008
Available online 6 November 2008
Ó 2008 Elsevier B.V. All rights reserved.
Dedicated to Professor Dr. Hans-Dieter
Martin on the occasion of his 70th birthday
Keywords:
Alkynes
Cross-couplings
Cycloaddition
Ferrocene
Isoxazole
1. Introduction
[10]. Among them, ferrocene has attracted special attention as a
neutral, chemically stable and nontoxic unit in bioorganometallic
Substituted isoxazoles have become an important motif in
medicinal chemistry by virtue of their biological activity [1]. For in-
stance, they have been found to be potent, selective agonists of hu-
man cloned dopamine D4 receptors [2], they exhibit GABAA
antagonist [3], analgesic, antiinflammatory, ulcerogenic [4], COX-
2 inhibitory [5], antinociceptive [6], and anticancer [7] activity.
Therefore, many synthetic approaches have been reported for the
formation of the isoxazole core, including reactions of hydroxyl-
entities [11]. It can be easily functionalized or oxidized to give sta-
ble ferricenium salts. Many ferrocenyl compounds display interest-
ing antitumor, antimalarial, antifungal, anti-HIV and DNA-cleaving
activity [12]. Therefore, the combination of isoxazole and ferrocene
pharmacophores within the same molecule that also display inter-
esting redox properties appears to be an attractive challenge for
diversity-oriented synthesis in a one-pot fashion. As part of our
program directed to design and develop new multi-component
syntheses of heterocycles initiated by Sonogashira coupling [13],
we have focused on coupling-cycloaddition sequences [14]. Here,
we report a concise, consecutive three-component one-pot synthe-
sis of 3,4,5-trisubstituted isoxazoles with ferrocenyl substituents,
their structures and electronic properties.
amine with 1,3-dicarbonyl compounds,
a,b-unsaturated carbonyl
compounds, and ,b-unsaturated nitriles [8]. In addition, [3 + 2]
a
cycloadditions of alkynes and nitrile oxides represent an elegant
and concise access to this class of compounds [9]. Although, these
strategies are highly convergent, in many cases either strong bases
or strong mineral acids are required, or prolonged heating at ele-
vated temperatures is necessary. In addition, the observed regiose-
lectivities of the heterocyclization are often poor. Metallocenes in
their own right also exhibit a wide range of biological activity
2. Results and discussion
Sonogashira coupling [15] of acid chlorides with terminal alkynes
represents a catalytic access to alkynones [16]. Just recently, we
have established a modification, where 1 equiv. of triethylamine
as the hydrochloric acid scavenging base proves to be most favorable
for successful coupling under mild reaction conditions [17]. In turn,
the resulting alkynones readily react with aromatic nitrile oxides as
* Corresponding author. Tel.: +49 211 8112298; fax: +49 211 8114324.
E-mail address: ThomasJJ.Mueller@uni-duesseldorf.de (T.J.J. Müller).
1
X-ray structure analyses.
0022-328X/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2008.10.050

B. Willy et al. / Journal of Organometallic Chemistry 694 (2009) 942–949
943
OH
O
ii
iii
Fe
Fe
O
H
Cl
Fe
Fe
Cl
O
O
i
1a
O
Fe
iv
Cl
v
i
v
Fe
Fe
2b
Scheme 1. Reagents and conditions: (i) AlCl3, CH2Cl2, 0 °C, 2.5 h, 95%; (ii) KOtBu, DME, rfl., 1 h, 78%; (iii) (COCl)2, CCl4, rfl., 4 h, 98%; (iv) Ac2O, H3PO4, 100 °C, 10 min, 66%; (v)
POCl3, DMF, NaOAc, 0 °C, 2 h, 77%; (vi) NaOH, dioxane, rfl., 5 min, 95%.
1,3-dipoles in a 1,3-dipolar cycloaddition to give isoxazoles in good
to excellent yields [14]. Since aromatic nitrile oxides are usually
unstable compounds, it is necessary to generate them in situ by
dehydrochlorination of the corresponding hydroximinoyl chlorides
with a suitable base. According to literature procedures these pre-
cursors are readily available from oximes by subsequent chlorina-
tion [18]. Interestingly, triethylamine as a base is sufficiently
strong enough to achieve a mild generation of nitrile oxides that
are prone to react with the present alkynones in a one-pot fashion.
Suitable ferrocene precursors, such as ferrocenyl acid chloride
(1a) [19] and ethynylferrocene (2a) [20], are readily available from
ferrocene in three steps (Scheme 1).
Therefore, upon reacting ferrocenoyl chloride (1a) or 2-thienoyl
chloride (1b) and various terminal alkynes 2 under modified Sono-
gashira conditions for 1 h at room temperature, to furnish the ex-
pected alkynones 5, the subsequent addition of hydroximinoyl
chlorides 3 and triethylamine generating the nitrile oxides 6 gives
rise to the formation of ferrocenyl substituted isoxazoles 4 in mod-
erate to good yields as ruby red crystalline solids (Scheme 2, Table
1). Prolonged reaction times cause a slight decrease in yields in
comparison with isoxazoles without organometallic substituents
[14]. It is also noteworthy to mention that the cycloaddition step
with ferrocenyl alkynones cannot be successfully performed under
microwave heating.
nals consisting of a singlet (around d = 4.10, 5H), and two triplets
(around d = 4.40 and 4.80, each 2H). The shifts of the carbon nuclei
are readily assigned by 135-DEPT- and 2D NMR spectroscopy as
well as by increment calculations. Carbon nuclei at ring position 5
appear in the carbon NMR spectra at d 171, whereas the quaternary
resonances at ring position 4 are detected at high field around d 115
as a consequence of the polarization by the electron withdrawing
effect of the adjacent carbonyl group. Finally, the imine type reso-
nances at ring position 3 emerge at d 160. The signals at d 191 can
be unambiguously assigned to the carbonyl carbon nuclei (Chart 1).
Interestingly, compound 4c crystallizes in two crystal modifica-
tions, where for one of the modifications two independent mole-
cules are found in the unit cell (Fig. 1). Nevertheless, both crystal
modifications support the same constitution as deduced from the
spectroscopic data. Therefore, the different solid state structures
arise from conformers and their packing in a crystal lattice. Accord-
ing to the X-ray structure analysis of compounds 4a, 4c, and 4d, the
ferrocenoyl moiety is distorted from coplanarity with respect to
the isoxazole ring between 61° and 76°. However, the conforma-
tion of the ferrocene moiety in the crystal structures differs. For
4a and 4d the cyclopentadienyl rings are staggered (27.5° and
22.0°, resp.), while in the case of 4c the two Cp rings are almost
ecliptic (ꢀ2.5°). So the distortion of the Cp units is just a packing
effect in the crystal.
In agreement with theory, the 1,3-dipolar cycloaddition under ki-
netic control [21] gives rise to the formation of 4 with excellent reg-
ioselectivity. Noteventracesof theregioisomers 7 couldbe detected.
The structures were unambiguously assigned by 1H and 13C NMR
spectroscopy and later by X-ray structure analyses of the isoxazoles
4a, 4c, and 4d (Figs. 1 and 2, Table 3) (see Supplementary material).
As a consequence of the substitution pattern, no peculiar reso-
nances of the isoxazole core can be found in the proton NMR spectra.
In each case, the ferrocene protons are relocated as a set of three sig-
The UV–Vis absorption spectra of the ferrocene derivatives 4 are
characterized by the appearance of the weak absorption bands
between 404 and 491 nm that can be assigned to ferrocenyl
metal-to-ligand charge transfer bands. All ferrocenyl isoxazoles
are fluorescence silent. The absence of fluorescence is even ob-
served for the anthracene substituted derivative 4c, although,
anthracenes are known for their luminescent properties [22]. Here,
the spatial proximity to the ferrocene moiety obviously opens an
efficient channel for quenching of the fluorescence.
Electrochemical data for the ferrocene substituted isoxazoles 4
were obtained by cyclic voltammetry in dichloromethane solutions
and were recorded in the anodic region (up to +1.4 V) showing dis-
tinct reversible oxidations stemming from the redox active ferroce-
nyl substituents (Table 2, Fig. 3). In all cases the first ferrocenyl
centered oxidations are significantly shifted anodically by
85–308 mV in comparison to the parent compound ferrocene
(E0/+11/2 = 450 mV, in CH2Cl2). This can be plausibly rationalized by
the electron withdrawing nature of the carbonyl functionality that
renders the ferrocenyl part more difficult to oxidize. Isoxazole is
by three orders of magnitude less basic than its constitutional iso-
mer oxazole and, therefore, it can be considered to be a very weakly
electron donating substituent [23]. Even a ferrocenyl substituent
that is not directly bound to the carbonyl group, but to the isoxazole
core as for compounds 4f and 4g, experiences a considerable anodic
R1
2% PdCl2(PPh3)2
4% CuI
O
O
+
R2
R3
R1
Cl
R2
h,rt
1e qN Et ,T ,1
HF
3
HO
then:
O
N
N
3
4(29-79 %)
R3
Cl
1
2
1.10 eq NEt3,4h, rt
R3
N+ O-
6
coupling
1
,3-dipolar
O
R1
cycloaddition
R2
5
shift by conjugation of the carbonyl group through the
p-system
Scheme 2. One-pot three-component synthesis of isoxazoles 5 by a coupling-1,3-
dipolar cycloaddition sequence.
of the heterocycle (entries 7 and 8). In turn, the electron rich

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B. Willy et al. / Journal of Organometallic Chemistry 694 (2009) 942–949
Table 1
Coupling-1,3-dipolar cycloaddition synthesis of isoxazoles 4.
Entry
1
Acid chloride 1
Alkyne 2
Hydroximinoyl chloride 3
3a: R3 = 4-MeOC6H4
Isoxazole 4 (yield, %)b
Alkynone 5 (yield, %)
5a (–)
1a: R1 = ferrocenyl
2a: R2 = Me3Si
Fe
O
OCH3
Si
O
N
4a (79)
2
1a
2a
3b: R3 = 4-O2NC6H4
5a (33)
Fe
O
NO2
Si
O
N
4b (29)
3
1a
2a
3c: R3 = 10-anthranyl
5a (–)
Fe
O
Si
O
N
4c(62)
4
5
6
1a
1a
1a
2b: R2 = 4-MeO2CC6H4
3a
3a
3a
5b (37)
5c (24)
5d (25)
Fe
O
O
H3CO
O
OCH3
N
4d (51)
2c: R2 = 10-methyl phenothiazin-3-
yl
Fe
S
O
OCH3
N
O
N
4e (51)
2d: R2 = ferrocenyl
Fe
O
OCH3
Fe
N
O
4f (47)
7
1b: R1 = 2-thienyl
2d
3a
5d (41)
S
O
OCH3
Fe
O
N
4g (53)
phenothiazinyl moiety in ring position 5 in compound 4e is a remote
donor to diminish the electron withdrawing power of the carbonyl
group (entry 6). Hence, the oxidation of the ferrocenyl substituent
is only shifted anodically by 85 mV vs. ferrocene.
In addition, isoxazoles 4e and 4f contain two redox active
moieties, i.e. a 10-methyl phenothiazinyl (4e) and ferrocenyl
substituent (4f) in close spatial proximity. Expectedly, two revers-
ible oxidation waves can be found in the corresponding cyclic

B. Willy et al. / Journal of Organometallic Chemistry 694 (2009) 942–949
945
Fig. 1. ORTEP plot of isoxazole 4c modification 1 (left); fit for structure 4c as obtained from both crystal modifications (modification 1: dashed bonds; modification 2: black
and hollow bonds; the fit was made by superimposition of the five atoms of the isoxazole core) where the modification 2 displays two independent molecules in the unit cell
(right).
Fig. 2. ORTEP plots of isoxazoles 4a (left) and 4d (right, cocrystallized CDCl3 was omitted for clarity).
R1
a through space interaction of the two inequivalent ferrocenyl
units might influence their separate oxidation behavior.
O
3
R2
R1
4
R2
R3
R3
Therefore, the electronic structure of the frontier orbitals was
investigated by computational methods. Based upon a starting
geometry from the X-ray structure analysis of 4a, calculations were
carried out using the B3LYP functional [24] and the 6-311 G++ SDD
basis set for geometry optimization. As expected, the results
clearly indicate, that the HOMO is localized on the ferrocenyl frag-
ment (Fig. 4). The minimal energy difference to HOMO À 1 sug-
gests that the highest occupied molecular orbitals are almost
degenerate. HOMO À 2 is significantly lower in energy and it is
predominantly localized on the anisyl isoxazole moiety, where as
HOMO À 3 is represented by the ferrocenoyl part. The LUMO is
delocalized over the isoxazole core and the ferrocenoyl substituent
(Fig. 4).
Applying the same methodological protocol, the diferrocenyl
substituted isoxazole 4f was also computed. Pairwise, the highest
occupied molecular orbitals indicate an energetic degeneracy of
HOMO and HOMO À 1 on one hand and HOMO À 2 and HOMO À 3
on the other hand (Fig. 5). The energy gap between both pairs of
orbitals is relatively small and indicate that the first one electron
oxidations should display a relatively small separation. This is in
good agreement with the recorded cyclovoltammetric data. Hence,
the first oxidation should occur on the more electron rich ferrocene
at ring position 5 of the isoxazole followed by the second oxidation
5
O
N
O
O
N
4
7
Chart 1.
Table 2
Redox potentials of the isoxazoles 4 (recorded in CH2Cl2 at 20 °C, 0.1 M nBu4NPF6, Pt
as working electrode, Ag/AgCl as reference electrode, and Pt as counter electrode).
0/+1
+1/+2
Entry
Isoxazole 4
E
1/2
(mV)
E
(mV)
1/2
1
2
3
4
5
6
7
8
Ferrocene
450
698
725
758
745
535
601
749
–
–
–
–
4a
4b
4c
4d
4e
4f
–
764
722
–
4g
voltammograms (entries 6 and 7, Fig. 3 right). In the case of the dif-
errocenyl substituted system 4f the question lies at hand whether

946
B. Willy et al. / Journal of Organometallic Chemistry 694 (2009) 942–949
Table 3
X-ray structure data collection and refinement parameters for 4a, 4c (modifications 1 and 2), and 4d.
4a
4c (modification 1)
4c (modification 2)
4d
Empirical formula
M (g/mol)
Temperature (K)
Wavelength
Crystal system
Space group
Z
C24H25FeNO3Si
459.40
291(2)
0.71073 Å
Monoclinic
Ia
C31H27FeNO2Si
529.48
200(2)
C31H27FeNO2Si
529.48
200(2)
C29H23FeNO5 Á 0.5CDCl3
521.34
291(2)
0.71073 Å
Monoclinic
P21/c
0.71073 Å
Triclinic
0.71073 Å
Triclinic
ꢀ
ꢀ
P1
P1
4
2
4
4
a (Å)
b (Å)
c (Å)
12.2582(16)
9.3647(19)
19.761(3)
90
103.379(16)
90
2206.9(6)
1.383
0.763
10.1838(2)
10.8117(2)
13.1426(1)
68.530(1)
77.160(1)
76.880(1)
1295.94(4)
1.36
11.9488(8)
12.7269(8)
19.3795(12)
91.982(2)
105.845(2)
115.317(2)
2523.7(3)
1.39
20.219(4)
5.9126(6)
22.737(4)
90
109.59(2)
90
2680.8(7)
1.524
0.789
a
(°)
b (°)
c
(°)
Volume (Å3)
Dcalc (g/cm3)
Absorption coefficient (mmÀ1
Reflections collected
Observed reflections
)
0.66
13372
0.68
26771
14127
11836
972 (I > 2r(I))
3316 (I > 2r(I))
4892 (I > 2
r
(I))
8770 (I > 2r(I))
Independent reflections (Rint
Absorption correction
Maximum and minimum transmission
Refinement method
)
3715 (0.0696)
None
5881 (0.0539)
Semi-empirical from equivalents
0.89 and 0.83
12437 (0.0467)
4379 (0.1428)
None
0.95 and 0.88
Full-matrix least-squares on F2
3715/0/276
1.00
Data/restraints/parameters
5881/0/328
1.03
12437/0/655
1.10
4379/0/349
0.88
Goodness-of-fit on F2
Final R indices (I > 2
r(I))
R1 = 0.029, wR2 = 0.067
R1 = 0.037, wR2 = 0.099
R1 = 0.067, wR2 = 0.130
R1 = 0.044, wR2 = 0.059
Fig. 3. Cyclic voltammograms of isoxazole 4a (left) and 4f (right) (recorded in dichloromethane at 20 °C, 0.1 m nBu4NPF6, Pt as working electrode, Ag/AgCl as reference
electrode, and Pt as counter electrode).
4
3
2
1
0
-1
HOMO-3
HOMO-2
HOMO-1
HOMO
LUMO
Fig. 4. DFT-computed frontier orbitals of the monoferrocenyl substituted isoxazole 4a.

B. Willy et al. / Journal of Organometallic Chemistry 694 (2009) 942–949
947
4
3
2
1
0
-1
HOMO-5
HOMO-4
HOMO-3
HOMO-2
LUMO
HOMO-1
HOMO
Fig. 5. DFT-calculated frontier orbitals of bisferrocenyl substituted isoxazole 4f.
that is centered on the ferrocenoyl moiety. As computed for com-
pound 4a the LUMO of 4f is delocalized over the isoxazole core
and the ferrocenoyl substituent. Hence, the isoxazole carbonyl
bridge does not support electronic communication of the ferroce-
nyl units, however, as a consequence of the substitution pattern
and the electronic character of the isoxazole core the frontier orbi-
tal energies are relatively close.
of the Heinrich-Heine-Universität Düsseldorf. X-ray structures
were measured with an Bruker Smart APEX or an Bruker Smart
CCD.
4.2. General procedure for the one-pot three-component synthesis of
isoxazoles 4
In a 10 mL Schlenk tube PdCl2(PPh3)2 (15 mg, 0.02 mmol) and
CuI (8 mg, 0.04 mmol) were dissolved in degassed THF (5 mL). To
3. Conclusion
this orange solution acid chloride
1 (1.00 mmol), alkyne 2
(1.00 mmol) and triethylamine (1.05 mmol) were added. The reac-
tion mixture was stirred at room temp for 1 h. Finally, aryl hydrox-
iminoyl chloride 3 (1.00 mmol) and triethylamine (1.1 mmol) were
added to this suspension and the reaction mixture was stirred 4 h at
room temp. The solvents were removed under reduced pressure and
the residue was purified by silica gel flash column chromatography
(hexane/ethyl acetate 50/1) to afford the analytically pure product 4
as a red solid and in some cases the alkynone 5 as a by product.
In conclusion ferrocenyl substituted isoxazoles were prepared
by a straightforward one-pot three-component synthesis in the
sense of a consecutive coupling-cycloaddition sequence. The flexi-
ble synthetic strategy enables access to electronically diverse
substituted ferrocenyl isoxazoles. As a consequence of the peculiar
electronic nature of the central isoxazoloyl unit ferrocenyl substit-
uents as redox active organometallic probes can be fine tuned by
the substitution pattern on the isoxazoles. Furthermore, com-
pounds like 4d placing ether and ester masked phenol and acid
moieties in ring position 3 and 5 can be considered as sections of
polyesters with redox active sidechains. Further studies exploiting
the synthetic potential of the three-component synthesis for
addressing tailor-made molecular materials are currently
underway.
4.2.1. (3-(4-Methoxyphenyl)-5-(trimethylsilyl)-isoxazol-4-yl)-
ferrocenylmethanone (4a)
According to the general procedure the reaction of 249 mg of
acid chloride 1a, 99 mg of alkyne 2a, and 186 mg aryl hydroximi-
noyl chloride 3a furnish 363 mg (79%) of 4a as deep red crystals,
mp. 147 °C.
1H NMR (500 MHz, CDCl3): d 0.28 (s, 9H), 3.79 (s, 3H), 3.92 (s,
5H), 4.46 (t, 3J = 1.7 Hz, 2H), 4.60 (d, 3J = 1.7 Hz, 2H), 6.93 (d,
3J = 8.6 Hz, 2H), 7.71 (d, 3J = 8.6 Hz, 2H). 13C NMR (125 MHz, CDCl3):
d À1.6 (3CH3), 55.3 (CH3), 69.7 (5CH), 71.0 (2CH), 72.6 (2CH), 81.4
(Cquat), 114.0 (2CH), 121.3 (Cquat), 128.6 (Cquat), 130.6 (2CH), 159.5
(Cquat), 160.9 (Cquat), 178.5 (Cquat), 195.3 (Cquat). EI MS (70 eV, m/z
(%)): 459 ([M]+, 13), 298 (18), 282 (42), 239 (18), 238 (100), 224
(10), 223 (52), 195 (19), 180 (10), 152 (19), 151 (10), 150 (11),
149 (80), 135 (35), 134 (12), 133 (12), 119 (15), 106 (13), 57 (13),
~
4. Experimental
4.1. General information
All reactions involving water-sensitive compounds were carried
out in flame-dried Schlenk glassware under nitrogen atmosphere
unless stated otherwise. Reagents and catalysts were purchased re-
agent grade and used without further purification. Solvents were
dried and distilled according to standard procedures. Aldoximes
and corresponding hydroximinoyl chlorides 4 were synthesized
according to literature procedures [18]. Flash column chromatog-
raphy: silica gel 60, mesh 230–400, Merck. TLC: silica gel plates
(60 F254 Merck, Darmstadt). 1H-, 13C-, DEPT-, NOESY-, COSY-,
HMQC-, and HMBC spectra were recorded with Bruker ARX 250,
Bruker DRX 300 or Bruker DRX 500 spectrometers by using CDCl3
as solvent unless stated otherwise. The assignments of quaternary
C, CH, CH2 and CH3 were made on the basis of DEPT spectra. Mass
spectra were recorded with JEOL JMS-700 und Finnigan TSQ 700
spectrometers. The melting points (uncorrected) were measured
with Stuart Scientific Melting Point Apparatus SMP3. Elemental
analyses were carried out on a Perkin–Elmer CHN-Analyzer 2400
in the microanalytical laboratory of the Pharmazeutische Chemie
43 (14). IR (KBr):
m
= 2957 cmÀ1 (w), 1638 (m), 1452 (m), 1376 (s),
1277 (s), 1176 (w), 1125 (m), 1073 (w), 1025 (m), 845 (s), 765
(w). UV–Vis (CH2Cl2): kmax ) 240 (36500), 272 (22800), 358
(e
(2200), 487 nm (1500). Anal. Calc. for C24H25FeNO3Si (459.4): C,
62.75; H, 5.49; N, 3.08. Found: C, 63.03; H, 5.37; N, 3.21%.
4.2.2. (3-(4-Nitrophenyl)-5-(trimethylsilyl)-isoxazol-4-yl)-
ferrocenylmethanone (4b)
According to the general procedure the reaction of 249 mg of
acid chloride 1a, 99 mg of alkyne 2a, and 201 mg aryl hydroximi-
noyl chloride 3b furnish 138 mg (29%) of 4b as a deep red solid,
mp. 162 °C, and 103 mg (33%) of 5a.
1H NMR (500 MHz, CDCl3): d 0.26 (s, 9H), 3.90 (s, 5H), 4.48
(t, 3J = 1.6 Hz, 2H), 4.60 (d, 3J = 1.6 Hz, 2H), 8.05 (d, 3J = 9.0 Hz,

948
B. Willy et al. / Journal of Organometallic Chemistry 694 (2009) 942–949
2H), 8.32 (d, 3J = 9.0 Hz, 2H). 13C NMR (125 MHz, CDCl3): d À0.8
(3CH3), 68.5 (5CH), 70.2 (2CH), 72.3 (2CH), 82.4 (Cquat), 113.7
(Cquat), 124.4 (2CH), 126.2 (2CH), 135.1 (Cquat), 147.9 (Cquat),
159.2 (Cquat), 178.5 (Cquat), 193.9 (Cquat). EI MS (70 eV, m/z (%)):
474 ([M]+, 22), 311 ([M+H]+, 24), 310 ([M]+, 100), 267 (21), 238
(53), 210 (10), 203 (16), 152 (12), 148 (25), 146 (13), 145 (11),
inoyl chloride 3a furnish 306 mg (51%) of 4e as deep red crystals,
mp. 121 °C, and 108 mg (24%) of 5c.
1H NMR (500 MHz, acetone-d6): d 3.42 (s, 3H), 3.77 (s, 3H), 4.29
(s, 5H), 4.66 (t, 3J = 1.7 Hz, 2H), 4.99 (d, 3J = 1.7 Hz, 2H), 6.82 (d,
3J = 8.6 Hz, 2H), 6.95–7.02 (m, 3H), 7.15 (dd, 3J = 7.6 Hz,
3J = 1.2 Hz, 1H), 7.23 (t, 3J = 7.7 Hz, 1H), 7.44 (d, 3J = 8.6 Hz, 2H),
7.46 (d, 3J = 1.7 Hz, 1H), 7.56 (dd, 3J = 8.4 Hz, 3J = 1.7 Hz, 1H). 13C
NMR (125 MHz, acetone-d6): d 37.0 (CH3), 55.8 (CH3), 72.1 (2CH),
72.2 (5CH), 74.9 (2CH), 83.0 (Cquat), 114.1 (2CH), 115.7 (Cquat),
116.3 (Cquat), 116.4 (CH), 116.8 (CH), 119.9 (Cquat), 123.9 (Cquat),
125.1 (CH), 125.4 (Cquat), 128.8 (CH), 129.8 (CH), 129.9 (2 CH),
132.5 (CH), 134.8 (CH), 146.6 (Cquat), 149.8 (Cquat), 160.0 (Cquat),
160.6 (Cquat), 168.1 (Cquat), 181.5 (Cquat). EI MS (70 eV, m/z (%)):
599 ([M+H]+, 17), 598 ([M]+, 42), 450 (30), 449 (100), 358 (14),
357 (58), 343 (13), 342 (53), 286 (22), 285 (10), 241 (30), 226
(19), 225 (21), 217 (15), 213 (10), 149 (12), 134 (18). IR (KBr):
À1
~
m
121 (13), 56 (10). IR (KBr):
= 2959 cm
(m), 1639 (s), 1603
(w), 1570 (w), 1535 (s), 1458 (m), 1413 (w), 1347 (s), 1290 (s),
1126 (m), 1729 (s), 1073 (m), 1037 (w), 1014 (w), 918 (w), 854
(s), 832 (m), 743 (m), 729 (s), 708 (m), 683 (m), 539 (w). UV–Vis
(CH2Cl2): kmax (e) 276 (22000), 355 (1200), 477 nm (400). Anal.
Calc. for C24H25FeNO3Si (474.4): C, 58.24; H, 4.67; N, 5.91. Found:
C, 58.32; H, 4.79; N, 5.83%.
4.2.3. (3-(9-Anthranyl)-5-(trimethylsilyl)-isoxazol-4-yl)-
ferrocenylmethanone (4c)
According to the general procedure the reaction of 249 mg of
acid chloride 1a, 99 mg of alkyne 2a, and 256 mg aryl hydroximi-
noyl chloride 3c furnish 329 mg (62%) of 4c as a deep red solid,
mp. 138 °C.
À1
~
m
= 2963 cm
(m), 2183 (m), 1775 (w), 1686 (m), 1655 (m),
1618 (s), 1572 (m), 1544 (m), 1499 (m), 1451 (s), 1375 (w), 1334
(m), 1261 (s), 1104 (s), 1072 (s), 1024 (s), 871 (m), 803 (s), 748
(m), 699 (m), 673 (m), 606 (m), 578 (m). UV–Vis (CH2Cl2): kmax
(e) 274 (31600), 322 (10900), 483 nm (900). Anal. Calc. for
C31H25Fe2NO2 (598.6): C, 68.23; H, 4.38; N, 4.68. Found: C, 68.15;
1H NMR (500 MHz, CDCl3): d À0.31 (s, 9H), 4.36 (s, 5H), 4.79 (m,
2H), 5.40 (m, 2H), 7.57–7.62 (m, 4H), 7.70–7.74 (m, 2H), 8.42–8.44
(m, 2H), 8.68 (s, 1H). 13C NMR (125 MHz, CDCl3): d À1.5 (3CH3),
70.5 (5CH), 71.4 (2CH), 73.9 (2CH), 81.2 (Cquat), 105.5 (Cquat),
125.3 (2CH), 126.4 (2CH), 129.0 (4CH), 130.6 (CH), 132.8 (2 Cquat),
133.3 (Cquat), 134.1 (2Cquat), 157.1 (Cquat), 165.2 (Cquat), 194.2
(Cquat). EI MS (70 eV, m/z (%)): 531 ([13C2ÀM]+, 11), 530
([13CÀM]+, 38), 529 ([M]+, 100), 502 (12), 501 (36), 326 (33), 298
(13), 291 (11), 290 (15), 204 (18), 203 (94), 202 (14), 201 (12),
195 (43), 185 (14), 177 (13), 176 (À211), 145 (11), 129 (18), 121
~
H, 4.56; N, 4.61%.
4.2.6. (3-(4-Methoxyphenyl)-5-(ferrocenyl)-isoxazol-4-yl)-
ferrocenylmethanone (4f)
According to the general procedure the reaction of 249 mg of
acid chloride 1a, 211 mg of alkyne 2d, and 186 mg aryl hydroxim-
inoyl chloride 3a furnish 292 mg (47%) of 4f as a deep red solid,
mp. 188 °C, and 106 mg (25%) of 5d.
1H NMR (500 MHz, CDCl3): d 3.79 (s, 3H), 3.88 (s, 5H), 4.22 (s,
5H), 4.39 (m, 4H), 4.54 (m, 2H), 4.83 (m, 2H), 6.90 (d, 3J = 8.6 Hz,
2H), 7.71 (d, 3J = 8.6 Hz, 2H). 13C NMR (125 MHz, CDCl3): d 55.2
(CH3), 68.4 (2CH), 69.7 (5CH), 70.0 (5CH), 70.1 (Cquat), 70.4 (2CH),
70.8 (2CH), 72.7 (2CH), 80.0 (Cquat), 114.0 (2CH), 121.2 (2Cquat),
130.1 (2CH), 160.84 (Cquat), 160.87 (Cquat), 170.6 (Cquat), 194.2
(Cquat). EI MS (70 eV, m/z (%)): 572 ([M+H]+, 34), 571 ([M]+, 100),
569 (14), 506 (23), 505 (15), 386 (22), 317 (12), 286 (14), 238
(19), 223 (10), 186 (15), 185 (10), 129 (12), 121 (26), 43 (10). IR
(18), 73 (25). IR (KBr):
m = 3049 cm (m), 2960 (m), 1677 (m),
1636 (s), 1542 (m), 1443 (s), 1410 (w), 1375 (m), 1331 (w), 1257
(s), 1106 (m), 1036 (m), 897 (m), 845 (s), 781 (m), 759 (m), 732
(s), 693 (m), 638 (m), 611 (m), 582 (w), 550 (w). UV–Vis (CH2Cl2):
kmax (e) 250 (26700), 257 (43600), 334 (11400), 349 (18600), 366
(29000), 386 (28000), 404 nm (14300). Anal. Calc. for C31H27Fe-
NO2Si (529.5): C, 70.32; H, 5.14; N, 2.65. Found: C, 70.31; H,
5.20; N, 2.88%.
À1
~
m
(KBr):
= 2974 cm (m), 1590 (w), 1520 (w), 1446 (w), 1262 (s),
4.2.4. Methyl 4-(4-ferrocenoyl-3-(4-methoxyphenyl)isoxazol-5-yl)-
benzoate (4d)
According to the general procedure the reaction of 249 mg of
acid chloride 1a, 161 mg of alkyne 2b, and 186 mg aryl hydroxim-
inoyl chloride 3a furnish 267 mg (51%) of 4d as a deep red solid,
mp. 164 °C, and 138 mg (37%) of 5b.
1179 (w), 1084 (m), 1049 (s), 880 (m), 832 (m), 592 (w), 552
(w). UV–Vis (CH2Cl2): kmax ) 251 (31600), 283 (19300), 364
(e
(2100), 475 nm (1200). Anal. Calc. for C31H25Fe2NO2 (571.2): C,
65.18; H, 4.41; N, 2.45. Found: C, 65.41; H, 4.29; N, 2.39%.
4.2.7. (3-(4-Methoxyphenyl)-5-ferrocenyl-isoxazol-4-yl)(thiophen-
2-yl)methanone (4g)
According to the general procedure the reaction of 147 mg of
acid chloride 1b, 211 mg of alkyne 2d, and 186 mg aryl hydroxim-
inoyl chloride 3a furnish 287 mg (53%) of 4g as a deep red solid,
mp. 153 °C, and 142 mg (41%) of 5d.
1H NMR (500 MHz, CDCl3): d 3.79 (m, 8H), 3.90 (s, 3H), 4.38 (s,
2H), 4.49 (s, 2H), 6.92 (d, 3J = 8.4 Hz, 2H), 7.75 (d, 3J = 8.3 Hz, 2H),
7.94 (d, 3J = 8.0 Hz, 2H), 8.09 (d, 3J = 8.1 Hz, 2H). 13C NMR
(125 MHz, CDCl3): d 52.3 (CH3), 55.2 (CH3), 69.6 (5CH), 70.7
(2CH), 73.2 (2CH), 79.6 (Cquat), 114.2 (2CH), 116.8 (Cquat), 120.7
(Cquat), 127.8 (2CH), 130.0 (2CH), 130.1 (2CH), 131.0 (Cquat), 131.9
(Cquat), 161.1 (Cquat), 161.5 (Cquat), 166.1 (Cquat), 166.6 (Cquat),
194.3 (Cquat). EI MS (70 eV, m/z (%)): 522 ([M+H]+, 33), 521 ([M]+,
100), 520 (20), 457 (10), 456 (36), 163 (19), 141 (10), 135 (18),
1H NMR (300 MHz, CDCl3): d 3.76 (s, 3H), 4.11 (s, 5H), 4.38 (t,
3J = 1.9 Hz, 2H), 4.76 (t, 3J = 1.9 Hz, 2H), 6.84 (d, 3J = 8.9 Hz, 2H),
6.91–6.95 (m, 2H), 7.38 (dd, 3J = 3.8 Hz, 3J = 1.1 Hz, 1H), 7.43–7.48
(m, 1H), 7.55 (d, 3J = 8.9 Hz, 2H), 7.63 (dd, 3J = 4.9 Hz, 3J = 1.1 Hz,
1H). 13C NMR (75 MHz, CDCl3): d 55.1 (CH3), 55.3 (CH3), 68.1
(CH), 69.3 (Cquat), 69.9 (CH, 5C), 70.5 (CH), 112.0 (Cquat), 114.1
(CH), 114.3 (CH), 114.8 (Cquat), 118.9 (Cquat), 120.5 (Cquat), 128.3
(CH), 129.4 (CH), 129.6 (CH), 130.1 (CH), 135.3 (CH), 135.5 (CH),
144.4 (Cquat), 155.8 (Cquat), 160.7 (Cquat), 160.8 (Cquat), 160.9 (Cquat),
161.5 (Cquat), 171.6 (Cquat), 182.6 (Cquat). EI MS (70 eV, m/z (%)): 469
([M]+, 100), 467 (15), 404 (61), 385 (13), 320 (7), 316 (11), 312 (38),
~
À1
~
m
133 (11), 121 (18). IR (KBr):
= 2959 cm (m), 1729 (s), 1634
(m), 1527 (w), 1455 (m), 1278 (s), 1180 (w), 1123 (m), 1073 (m),
1026 (w), 840 (m), 774 (m), 743 (m), 696 (w), 604 (w), 583 (w),
524 (w). UV–Vis (CH2Cl2): kmax (e) 276 (34600), 353 (1200), 491
nm (900). Anal. Calc. for C29H23FeNO5 (521.3): C, 66.81; H, 4.45;
N, 2.69. Found: C, 66.59; H, 4.17; N, 2.76%.
235 (16), 216 (10), 139 (14), 111 (10). IR (KBr):
m
= 3110 cmÀ1 (w),
4.2.5. (3-(4-Methoxyphenyl)-5-(10-methyl-10H-phenothiazinyl)-
isoxazol-4-yl)ferrocenylmethan-one (4e)
According to the general procedure the reaction of 249 mg of
acid chloride 1a, 238 mg of alkyne 2c, and 186 mg aryl hydroxim-
1598 (s), 1513 (m), 1456 (w), 1404 (s), 1353 (m), 1300 (s), 1228 (s),
1105 (w), 1079 (w), 1059 (w), 1040 (m), 1002 (m), 970 (s), 896 (w),
855 (s), 821 (s), 743 (s), 723 (s), 649 (w), 630 (w), 548 (w), 519 (m),

B. Willy et al. / Journal of Organometallic Chemistry 694 (2009) 942–949
949
[10] (a) M. de Champdoré, G. Di Fabio, A. Messere, D. Montesarchio, G. Piccialli, R.
Loddo, M. La Colla, P. La Colla, Tetrahedron 60 (2004) 6555;
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[11] K.E. Dombrowski, W. Baldwin, J.E. Sheats, J. Organomet. Chem. 302 (1986)
281.
501 (s). UV–Vis (CH2Cl2): kmax (e) 269 (35600), 322 nm (51700),
388 nm (6700), 486 nm (6100). HRMS: calcd. for C26H21NO2S:
469.0435. Found: 469.0428. Anal. Calc. for C25H19FeNO3S (469.4):
C, 63.98; H, 4.08; N, 2.98. Found: C, 63.73; H, 4.00; N, 2.99%.
[12] For a recent review on bioorganic chemistry of ferrocene, see e.g.: D.R. van
Staveren, N. Metzler-Nolte, Chem. Rev. 104 (2004) 5931.
[13] (a) For a recent reviews on multi-component synthesis of heterocycles by
transition-metal catalysis, see e.g.: D.M. D’Souza, T.J.J. Müller, Chem. Soc. Rev.
36 (2007) 1095;
Acknowledgement
The Fonds der Chemischen Industrie and BASF SE are gratefully
acknowledged.
(b) T.J.J. Müller, Chim. Oggi/Chem. Today 25 (2007) 70;
(c) T.J.J. Müller, Targets Heterocycl. Syst. 10 (2006) 54;
(d) B. Willy, T.J.J. Müller, ARKIVOC Part I (2008) 195.
[14] (a) B. Willy, F. Rominger, T.J.J. Müller, Synthesis (2008) 293;
(b) A.V. Rotaru, I.D. Druta, T. Oeser, T.J.J. Müller, Helv. Chim. Acta 88 (2005)
1798.
Appendix A. Supplementary material
[15] (a) For lead reviews on Sonogashira couplings, see e.g.: S. Takahashi, Y.
Kuroyama, K. Sonogashira, N. Hagihara, Synthesis (1980) 627;
(b) K. Sonogashira, in: F. Diederich, P.J. Stang (Eds.), Metal Catalyzed Cross-
coupling Reactions, Wiley-VCH, Weinheim, 1998, p. 203;
CCDC 698830, 699931, 699932, and 698831 contain the supple-
mentary crystallographic data for (4a), (4c Modifikation 1), (4c
Modifikation 2), and (4d). These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. Supplementary data associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.jorganchem.2008.10.050.
(c) K. Sonogashira, J. Organomet. Chem. 653 (2002) 46;
(d) E.-I. Negishi, L. Anastasia, Chem. Rev. 103 (2003) 1979;
(e) J.A. Marsden, M.M. Haley, in: A. de Meijere, F. Diederich (Eds.), Metal
Catalyzed Cross-coupling Reactions, Wiley-VCH, Weinheim, 2004, p. 319;
(f) H. Doucet, J.-C. Hierso, Angew. Chem., Int. Ed. 46 (2007) 834;
(g) L. Yin, J. Liebscher, Chem. Rev. 107 (2007) 133.
[16] Y. Toda, K. Sonogashira, N. Hagihara, Synthesis (1977) 777.
[17] (a) A.S. Karpov, T.J.J. Müller, Org. Lett. 5 (2003) 3451;
(b) A.S. Karpov, T.J.J. Müller, Synthesis (2003) 2815;
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