A modular synthesis of 1,4,5-trisubstituted 1,2,3-triazoles with ferrocene moieties

Article abstract of DOI:10.1007/s00706-015-1490-z

Abstract Regioselective synthesis of 1,2,3-triazoles with ferrocenyl moieties in positions 1, 4, and 5 was carried out in a two-step reaction sequence: a copper-mediated azide-alkyne cycloaddition followed by a palladium-catalyzed cross-coupling. A new ro

Full text of DOI:10.1007/s00706-015-1490-z

Monatsh Chem
DOI 10.1007/s00706-015-1490-z
ORIGINAL PAPER
A modular synthesis of 1,4,5-trisubstituted 1,2,3-triazoles
with ferrocene moieties
1
Klaudia Feher Agnes Gomory Rita Skoda-Foldes
2
1
´
•
•
´
¨
¨
¨
Received: 16 March 2015 / Accepted: 3 May 2015
Ó Springer-Verlag Wien 2015
Abstract Regioselective synthesis of 1,2,3-triazoles with
ferrocenyl moieties in positions 1, 4, and 5 was carried out
in a two-step reaction sequence: a copper-mediated azide–
alkyne cycloaddition followed by a palladium-catalyzed
cross-coupling. A new route towards 5-iodo-1,2,3-triazoles
was developed using N-iodomorpholine hydrogen iodide,
instead of the corrosive and toxic ICl, as the I? source. The
novel methodology together with a consecutive Suzuki or
Sonogashira reaction was shown to be a useful procedure
for the synthesis of a wide range of ferrocenyl 1,2,3-tria-
zoles with di- and triferrocenyl derivatives among them.
Keywords Copper Á Cycloadditions Á
Homogeneous catalysis Á Iodotriazole Á Metallocenes Á
Palladium
Introduction
The 1,2,3-triazole moiety can be found in a great variety of
pharmacologically active compounds bearing antimicro-
bial, antimycobacterial, antimalarial, antiviral, or
anticancer effect [1, 2]. The efficiency and action of these
compounds may strongly depend on the nature and position
of the substituents of the triazole ring.
Graphical abstract
Grafting a ferrocene moiety into molecules with biolo-
gical interest may lead to an increase in the activity of the
parent compound [3–7]. 1,4- and 1,5-disubstituted-1,2,3-
triazole benzenesulfonamides obtained from ethynylfer-
rocene showed inhibition of carbonic anhydrase, so they
are possible candidates in an anticancer therapy [8].
1-Ferrocenyl-1,2,3-triazoles were used efficiently as anion
and cation sensors [9], taking advantage of the presence of
the ferrocenyl moiety that enables the electrochemical
detection of ferrocene derivatives or host–guest complexes
derived thereof [10]. Recently, electron transfer properties
of heterocycles with multiple ferrocenyl units were inves-
tigated in detail [11].
The most versatile method for the synthesis of 1,4-dis-
ubstituted triazoles is the copper-catalyzed azide–alkyne
cycloaddition (CuAAC) [12, 13] that can be carried out
efficiently even under flow conditions [14] with the use of
suitable ligands. The CuAAC reaction has been used ex-
tensively for the synthesis of 1-ferrocenyl- or 4-ferrocenyl-
1,2,3-triazoles [15]. 1,5-Disubstituted 1,2,3-triazoles can be
obtained selectively by carrying out the cycloaddition in
the presence of ruthenium catalysts [16]. At the same time,
¨
& Rita Skoda-Foldes
skodane@almos.vein.hu;
skodane@almos.uni-pannon.hu
1
Department of Organic Chemistry, Institute of Chemistry,
University of Pannonia, Egyetem u. 10, P.O.Box 158,
´
8200 Veszprem, Hungary
2
Research Centre for Natural Sciences, Hungarian Academy
¨
Hungary
´
´
of Sciences, Magyar Tudosok korutja 2, 1117 Budapest,
123

´
K. Feher et al.
development of reaction routes towards 1,4,5-trisubstituted
triazoles has gained attention only recently.
corrosive and toxic ICl, can efficiently be used as the
source of the I? electrophile to capture the cop-
per(I) triazolide intermediate of the azide–alkyne
cycloaddition. By this methodology and a further func-
tionalization of the iodotriazoles in coupling reactions, a
wide range of ferrocene-labeled 1,4,5-trisubstituted 1,2,3-
triazoles were obtained.
5-Alkynyl-1,2,3-triazoles can be prepared directly in the
reaction of terminal alkynes and organic azides in the
presence of a copper catalyst [17]. The same reaction can
be carried out with organic azides formed in situ from alkyl
halides and sodium azides [18]. However, in these reac-
tions, the substituents on C-4 and C-5 cannot be varied
independently, as both of them are derived from the same
alkyne component.
Results and discussion
Regiocontrolled synthesis of 1,4,5-trisubstituted tria-
zoles can be affected either by the direct arylation of 1,4-
disubstituted triazoles at elevated temperature (140 °C) in
the presence of a copper catalyst, a strong base, and a three-
fold excess of an aryl iodide [19] or by palladium-catalyzed
coupling reactions of 5-iodo-1,2,3-triazoles under mild
conditions (Suzuki, Heck, and Sonogashira reaction [20],
Sonogashira coupling [21–23], Suzuki coupling [24, 25],
Stille coupling [26], Intramolecular Heck reaction [27, 28],
Intramolecular homo coupling [29, 30]).
Homogeneous catalytic reactions were proved to be ver-
satile tools for the functionalization of the ferrocene core
[40, 41]. In the course of our ongoing interest in the use of
this methodology in labeling of biologically active mole-
cules with ferrocene [42–44], we decided to explore the
possibility of the regioselective introduction of the fer-
rocene moiety to various positions of the 1,2,3-triazole
ring. The synthetic strategy involved the synthesis of
5-iodo-1,2,3-triazoles, followed by a palladium-catalyzed
coupling. The ferrocene moiety can be incorporated in any
of the three reactions partners, the azide or the alkyne of
the cycloaddition step, or the organometallic reagent of the
palladium-catalyzed cross-coupling (Scheme 1).
The starting material of the latter reaction, 5-iodo-1,2,3-
triazoles, can be produced using either a catalytic or a
stoichiometric amount of a copper salt. The most elegant
route involves the copper-catalyzed cycloaddition of or-
ganic azides and iodoalkynes ([25], Intramolecular Heck
reaction [27], Intramolecular homo coupling [29–32]) (a
similar reaction for the synthesis of 5-bromo-1,2,3-triazoles
from bromoalkynes was reported by Rutjes [33]). Although
the two-step reaction, the conversion of the terminal alkyne
into a 1-iodoalkyne in the presence of N-iodomorpholine
hydrogen iodide as the iodine source, and the cycloaddition
can be carried out in one pot [25], special ligands should be
used in most cases in order to achieve good results in
triazole formation. As a consequence, several methods
were published for the synthesis of the iodotriazoles di-
rectly from terminal alkynes.
To the best of our knowledge, there is only one example
for the synthesis of a ferrocene-substituted 5-iodo-1,2,3-
triazole, obtained from ethynylferrocene and benzyl azide
in the presence of the CuI/ICl system (Stille coupling,
[26]). So we undertook to investigate and compare the
efficiency of possible synthetic routes towards 5-iodo-
1,2,3-triazoles bearing the ferrocene moiety in different
positions.
In the model reaction, ferrocenylmethyl azide (1a) was
chosen as the ferrocene-substituted reaction partner. First,
the synthesis of 1-(ferrocenylmethyl)-5-iodo-4-phenyl-1,2,3-
triazole (3a) was attempted in a copper-catalyzed cycload-
dition with 1-iodo-2-phenylacetylene (2) (Scheme 2) in the
presence of amine ligands (Table 1).
The copper(I) triazolide intermediate of the copper-
catalyzed azide–alkyne cycloaddition can be trapped by
electrophilic reagents such as ICl [34]. CuI as copper
source can be used in a dual role: as a catalyst for the
azide–alkyne 1,3-dipolar cycloaddition and as the source of
iodine to be introduced into the triazole [35]. In these re-
actions, an oxidizing agent, such as NBS (Sonogashira
coupling [21, 35]), NCS [36], or NIS [37] is also added to
convert I- to I?. As a consequence, both CuI and the
oxidizing agent should be present in at least equimolar
amounts to the reactants. Another possibility is the appli-
cation of Cu(ClO4)2 [38, 39] or CuCl2 [37] together with
NaI or KI to produce a copper(I) catalyst and triiodide as
the electrophile [38].
The formation of the desired product could be observed
by TLC using the CuI/Et3N catalytic system, but an isol-
able amount of 3a was obtained only by increasing the ratio
of the copper catalyst from 5 to 25 mol% (Table 1, entry
2). The change of the amine ligand to TBTA (N,N,N-
tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine) clearly
enhanced the reaction rate, but the yield of the product
could not be increased (entry 4). Nevertheless, in the
presence of TBTA, the same result was obtained in a
shorter reaction time and with a lower amount of catalyst.
It should also be mentioned that yields could not be in-
creased further by the use of longer reaction times with
either of the two catalytic systems.
During the quest for optimal conditions for the synthesis
of ferrocene-substituted 5-iodo-1,2,3-triazoles, we found
that N-iodomorpholine hydrogen iodide, instead of the
Next, the application of a stoichiometric amount of
copper was taken into consideration. Both the CuI/ICl and
123

A modular synthesis of 1,4,5-trisubstituted 1,2,3-triazoles with ferrocene moieties
Scheme 1
Scheme 2
catalyzed conversion of terminal alkynes to iodoalkynes
[45], as well as in the in situ generation of iodoalkynes
during a hydroamination reaction [42–44], the possibility
of the use of this compound as the iodine source was in-
vestigated. Fokin’s group observed that the addition of N-
iodomorpholine to a mixture of the organic azide and the
terminal alkyne resulted in the formation of 1-iodoalkyne
but failed to give the cycloaddition product [25]. Never-
theless, to our satisfaction we found that using a
stoichiometric amount of copper and Et3N as ligand, 3a
was obtained in comparable yield in the presence of N-
iodomorpholine to that achieved with CuCl2Á2H2O/NaI,
although in longer reaction time (entry 5). It should be
mentioned, however, that under our conditions, the product
appeared to be less sensitive to decomposition (entry 6).
Other 5-iodo 1,2,3-triazoles (3c–3e) were also obtained
in good yield by the same methodology (entries 11–14),
which was proved to be more efficient in the synthesis of
the known compound 3e than using CuI/ICl and leading to
the product in 60 % yield (Stille coupling, [26]). Besides,
the corrosive and toxic ICl could be replaced by a milder
reagent. Thus, it was shown that ferrocene could be in-
troduced either into C-4 (3e) or N-1 (3a, 3b) or both (3c)
positions of 5-iodo-1,2,3-triazoles in a cycloaddition
the CuCl2Á2H2O/NaI reagents were found to give superior
results (Table 2, entries 1, 2) compared to the catalytic
reactions. Although CuCl2Á2H2O/NaI probably generates
CuI/I2, Brotherton et al. found that the in situ system was
more reactive than the pure forms of CuI and I2 [38]; as a
consequence, we decided to test the efficiency of the for-
mer reagent. Shorter reaction times than those indicated in
the table, gave considerably lower conversions. Longer
reaction times led to a decrease in the yield showing the
decomposition of the product (entries 3, 4).
As N-iodomorpholine hydrogen iodide was previously
found to be an efficient iodinating agent in the copper-
Table 1 Copper-catalyzed azide–alkyne cycloaddition of 1a and 2
Entry
Method
CuI/mol%
Ligand
Ligand/1a ratio
React. time/h
Yield of 3a/%a
1
2
3
4
A
A
B
B
5
25
5
Et3N
0.4
2
6
Traces
23
Et3N
6
TBTA
TBTA
0.05
0.05
0.75
3
Traces
22
5
Reaction conditions: 0.2 mmol 1a, 0.2 mmol 2, 1 cm3 THF, rt
TBTA, N,N,N-tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine
a
Isolated yield
123

´
K. Feher et al.
Table 2 Azide–alkyne cycloaddition of alkynes 4a–4c and azides 1a, 1b in the presence of stoichiometric amount of copper salts
Entry
Alkyne
Azide
Method
Copper salt
Reagent
Reaction time/h
Product
Yield/%a
1
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4c
4c
4a
4c
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
Cb
Dc
Dc
Dc
Ed
Ed
Dc
Dc
Ed
Ed
Ed
Ed
Ed
Ed
CuI
ICl
NaIc
NaIc
6
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3c
3c
3d
3e
32
39
38
32
40
40
47
39
39
60
49
74
60
70
2
CuCl2
CuCl2
CuCl2
CuI
1.5
4.5
7
3
4
NaIc
5
N-iodomorpholine.HI
N-iodomorpholine.HI
NaIc
5
6
CuI
16
1.5
4.5
5
7
CuCl2
CuCl2
CuI
8
NaIc
9
N-iodomorpholine.HI
N-iodomorpholine.HI
N-iodomorpholine.HI
N-iodomorpholine.HI
N-iodomorpholine.HI
N-iodomorpholine.HI
10
11
12
13
14
a
CuI
20
16
24
24
24
CuI
CuI
CuI
CuI
Isolated yield
b
c
d
1a/4a/CuI/ICl/Et3N = 1/1/1/1/1.2, in THF, rt
1/4/CuCl2/NaI/Et3N = 1/1/1/12/1, in acetonitrile, rt
1/4/CuI/N-iodomorpholine.HI/Et3N = 1/1/1/1/1.2, in THF, rt
Scheme 3
reaction starting from the corresponding terminal alkynes
under mild conditions. It should be mentioned that no
formation of regioisomeric 4-iodotriazoles could be de-
tected in any of the above reactions.
carried out in the presence of a supported palladium
catalyst (SILP-Pd, Fig. 1). In our group, an immobilized
palladium catalyst had been produced by supporting
palladium on an ionic liquid modified silica that had
shown high efficiency in Heck reactions [46]. The same
catalyst was found to give excellent results in the Suzuki
reaction of the 5-iodo-1,2,3-triazoles giving 6a and 6c in
95 and 96 % yields, respectively. Moreover, the catalyst
could be recycled with a small loss of activity leading to
6a in 93 and 88 % yield in the second and third runs,
respectively.
With the 5-iodo-1,2,3-triazoles 3a–3e in hand, 1,4,5-
trisubstituted derivatives were synthesized via Suzuki-
(Scheme 3) and Sonogashira coupling reactions
(Scheme 4).
Suzuki coupling of 5-iodo-1,2,3-triazoles 3a, 3b, 3e
with phenylboronic acid (5a) led to the products 6a–6c in a
facile reaction. Coupling of ferrocenylboronic acid (5b)
was more sluggish but resulted in the formation of 6d in
acceptable yield.
Another possibility for the functionalization of 5-iodo-
1,2,3-triazoles is the Sonogashira reaction (Scheme 4). The
coupling of 4-ferrocenyl derivatives 3c and 3e was less
facile than their 4-propyl- (3b) or 4-phenyl substituted (3d)
Besides the usual homogeneous catalytic conditions,
the reaction of 5-iodo-triazoles 3a, 3e with 5a was
123

A modular synthesis of 1,4,5-trisubstituted 1,2,3-triazoles with ferrocene moieties
Scheme 4
CH3
CH3
Experimental
N
N
Cl
1-Pentyne (4b), ethynylferrocene (4c), phenylboronic acid
(5a), ferrocenylboronic acid (5b), copper salts, and palla-
dium complexes were supplied by Sigma-Aldrich,
phenylacetylene (4a) was a Merck product. 1-Iodo-2-
phenylacetylene (2) and N-iodomorpholine hydrogen io-
dide [25], TBTA [47], and benzyl azide (1b) [48] were
synthesized by literature methods. Ferrocenylmethyl azide
(1a) was obtained [49] from ferrocenylmethanol [50].
Preparation and characterization of the SILP-Pd catalyst
has been reported recently [46].
Cl
N
N
Pd
Pd
Si
O O
Si
O O OEt
OEt
1H and 13C NMR spectra were recorded in CDCl3 on a
Varian Inova 400 spectrometer at 400.13 MHz and
100.62 MHz, respectively. Chemical shifts are reported in
SILP-Pd
1
ppm relative to CHCl3 (7.26 and 77.00 ppm for H and
13C, respectively). GC–MS analysis was carried out on a
Shimadzu GC–MS-QP2010SE instrument. Mass spectra of
3c, 6d, 7c, and 7e were obtained by using triple quadruple
(QqQ) Micromass Quattro Micro mass spectrometer
(Waters, Milford, MA, USA), which was operated in
positive electrospray ionization mode. The capillary volt-
age was 3.0 kV, cone voltage 25 V, source temperature
140 °C. Data acquisition and processing were performed
using MassLynx 4.1 software (Waters, Milford, MA,
USA). IR spectra were made using a Thermo Nicolet
Avatar 330 FT-IR instrument. Samples were prepared as
KBr pellets.
Fig. 1 The supported palladium catalyst (SILP-Pd) used in the
Suzuki coupling of 3a, 3e, and 5a
counterparts, but even the triferrocenyl triazole 7c could be
produced in 26 % yield.
Conclusions
It was shown that N-iodomorpholine hydrogen iodide could
be used as an efficient I? source in the synthesis of 5-iodo-
1,2,3-triazoles starting from terminal alkynes and organic
azides. In case of ferrocene substituted substrates, the novel
method was proved to be clearly superior to those reported
previously. Supplemented by a palladium-catalyzed cross-
coupling, such as Suzuki or Sonogashira reaction, 1,4,5-
trisubstituted triazoles with ferrocenyl groups in the desired
substitution pattern can be obtained. It was demonstrated
with two examples that the efficiency of this methodology
can be further enhanced by the application of a heteroge-
neous catalyst in the Suzuki reaction.
Synthesis of 1-(ferrocenylmethyl)-5-iodo-4-phenyl-
1,2,3-triazole (3a) with a catalytic amount of copper
Method A 45.6 mg 1-iodo-2-phenylacetylene (2, 0.2 m-
mol) and 48.2 mg ferrocenylmethyl azide (1a, 0.2 mmol)
were dissolved in 1 cm3 THF. CuI (0.05 mmol, 9.5 mg)
and 55 mm3 triethylamine (0.4 mmol) were added to the
mixture and stirred under argon at room temperature for
6 h. The reaction mixture was purified by column
123

´
K. Feher et al.
81.5, 75.8, 69.5, 69.0, 68.8, 50.8 ppm; IR (KBr): mꢀ = 3084,
2925, 2848, 1442, 1328, 1225, 1107, 1041, 976, 813, 776,
698, 482 cm-1; MS (70 eV): m/z (%) = 469 (M?, 100),
343 (13), 248 (8), 207 (16), 199 (34), 167 (14), 153 (7), 152
(6), 121 (40), 89 (26), 56 (18); Rf = 0.4 (toluene/ethyl
acetate 15/1).
chromatography (silica, eluent: toluene/ethyl acetate 8/1).
3a was obtained in 23 % yield (21.6 mg, 0.05 mmol).
Method B 1.9 mg CuI (0.01 mmol) and 5.3 mg TBTA
(0.01 mmol) were dissolved in 2 cm3 THF and stirred for
20 min until a homogeneous solution was formed. 1-Iodo-
2-phenylacetylene (2, 0.2 mmol, 45.6 mg) and 48.2 mg
ferrocenylmethyl azide (1a, 0.2 mmol) were solved in
1 cm3 THF and added to the homogeneous solution. The
mixture was stirred for 3 h. The reaction mixture was pu-
rified by column chromatography (silica, eluent: toluene/
ethyl acetate 8/1). 3a was obtained in 22 % yield (20.6 mg,
0.04 mmol).
1-(Ferrocenylmethyl)-5-iodo-4-propyl-1,2,3-triazole
(3b, C16H18FeIN3)
Yellow solid; 60 % yield; m.p.: 91–93 °C; 1H NMR
(400 MHz, CDCl3): d = 5.26 (s, 2H), 4.35 (t, J = 1.8 Hz,
2H), 4.15 (s, 5H), 4.12 (t, J = 1.8 Hz, 2H), 2.57 (t,
J = 7.3 Hz, 2H), 1.67 (sext, J = 7.3 Hz, 2H), 0.92 (t,
J = 7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d = 151.9, 81.7, 77.6, 69.4, 69.0, 68.7, 50.4, 28.2, 22.5,
Synthesis of 5-iodo-1,2,3-triazoles 3a–3e
with stoichiometric amount of copper
ꢀ
13.9 ppm; IR (KBr): m = 3101, 2962, 2921, 2848, 1426,
1197, 1102, 1029, 800, 478 cm-1; MS (70 eV): m/
z (%) = 435 (M?, 100), 370 (11), 264 (19), 199 (40),
183 (7), 134 (10), 121 (52), 56 (13); Rf = 0.25 (toluene/
ethyl acetate 15/1).
Method C 48.2 mg ferrocenylmethyl azide (1a, 0.2 mmol),
38 mg CuI (0.2 mmol), 22 mm3 phenylacetylene (4a,
0.2 mmol) and 32.5 mg ICl (0.2 mmol) were stirred under
argon in the presence of 33 mm3 triethylamine (0.24 m-
mol) and 2 cm3 THF under argon at room temperature. The
reaction mixture was concentrated and purified by column
chromatography (silica, eluent: toluene/ethyl acetate 8/1).
3a was obtained in 32 % yield (30.0 mg, 0.06 mmol).
Method D 34 mg CuCl2Á2H2O (0.2 mmol) was dis-
solved under argon in 2 cm3 acetonitrile. Alkyne 4a or 4b
(0.2 mmol) and 28 mm3 triethylamine (0.2 mmol) was
added to the solution. NaI (12 eq., 2.4 mmol, 360 mg) was
dissolved in 0.2 cm3 distilled water and the aqueous solu-
tion was added to the organic phase. Ferrocenylmethyl
azide (1a, 0.2 mmol, 48.2 mg) was added to the mixture
and stirred at room temperature. The yellow reaction
mixture was concentrated and purified by column chro-
matography (silica, eluent: toluene/ethyl acetate 8/1). The
products were obtained in 39 % (3a, 36.6 mg, 0.08 mmol)
and 47 % (3b, 40.9 mg, 0.09 mmol) yield.
4-Ferrocenyl-1-(ferrocenylmethyl)-5-iodo-1,2,3-triazole
(3c, C23H20Fe2IN3)
Orange solid; 74 % yield; m.p.: 212–215 °C; 1H NMR
(400 MHz, CDCl3): d = 5.32 (s, 2H), 4.98 (t, J = 1.9 Hz,
2H), 4.37 (t, J = 1.9 Hz, 2H), 4.29 (t, J = 1.9 Hz, 2H),
4.17 (s, 5H), 4.15 (t, J = 1.9 Hz, 2H), 4.09 (s, 5H) ppm;
13C NMR (100 MHz, CDCl3): d = 149.3, 81.6, 74.8, 73.9,
69.4, 69.0, 68.9, 68.7, 68.5, 66.9, 50.2 ppm; IR (KBr):
ꢀ
m = 3089, 2917, 2851, 1409, 1234, 1099, 1021, 997, 805,
478 cm-1 MS (ESI): m/z = 577 (M?); Rf = 0.34
;
(toluene/ethyl acetate 15/1).
5-Iodo-4-phenyl-1-(phenylmethyl)-1,2,3-triazole (3d)
White solid; 60 % yield; m.p.: 135–138 °C; its spectro-
scopic data were identical with those reported before [19,
33]; Rf = 0.43 (toluene/ethyl acetate 15/1).
Method E (general procedure for the synthesis of 5-iodo-
1,2,3-triazoles 3a–3e): The alkyne 4a–4c (0.4 mmol), azide
1a, 1b (0.4 mmol), 76 mg CuI (0.4 mmol), and 136.4 mg
N-iodomorpholine hydrogen iodide (0.4 mmol) were stir-
red under argon in the presence of 66 mm3 triethylamine
(0.48 mmol) in 2 cm3 THF at room temperature. The re-
action mixture was concentrated and purified by column
chromatography (silica, eluent: toluene/ethyl acetate 8/1,
toluene/ethyl acetate 15/1).
4-Ferrocenyl-5-iodo-1-(phenylmethyl)-1,2,3-triazole
(3e)
Yellow solid; 70 % yield; m.p.: 167–170 °C; its spectro-
scopic data were identical with those reported before [19];
Rf = 0.38 (toluene/ethyl acetate 15/1).
General procedure for the Suzuki coupling
of 5-iodo-1,2,3-triazoles 3a–3e
A mixture of the 5-iodo-1,2,3-triazole 3a–3e (0.1 mmol),
the boronic acid 5a, 5b (0.2 mmol), 5.8 mg Pd(PPh3)4
(0.005 mmol) (or the supported catalyst SILP-Pd with the
same palladium-content) and 69 mg K2CO3 (0.5 mmol) in
1/1 cm3 THF/distilled water was stirred under argon at
60 °C for 10 h. The product was extracted with CH2Cl2
(3 9 2 cm3). The combined organic phases were dried
1-(Ferrocenylmethyl)-5-iodo-4-phenyl-1,2,3-triazole
(3a, C19H16FeIN3)
Yellow solid; 40 % yield; m.p.: 184–186 °C; 1H NMR
(400 MHz, CDCl3): d = 7.87 (d, J = 7.2 Hz, 2H), 7.46 (t,
J = 7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 5.34 (s, 2H),
4.50 (s, 2H), 4.28 (s, 5H), 4.24 (s, 2H) ppm; 13C NMR
(100 MHz, CDCl3): d = 149.9, 130.5, 128.7, 128.7, 127.6,
123

A modular synthesis of 1,4,5-trisubstituted 1,2,3-triazoles with ferrocene moieties
(100 MHz, CDCl3): d = 145.2, 131.9, 129.1, 128.7, 128.1,
127.9, 83.5, 71.9, 69.5, 69.3, 69.0, 69.0, 68.1, 68.1,
over Na2SO4 and concentrated. The product was purified
by column chromatography (silica, eluent: toluene/ethyl
acetate 15/1). In the recycling experiment, the catalyst was
removed by simple filtration and was reused without
purification.
ꢀ
47.8 ppm; IR (KBr): m = 3085, 2921, 2852, 1417, 1335,
1290, 1103, 1005, 821, 780, 735, 702, 486 cm-1; MS
(ESI): m/z = 528 ([M?H]?); Rf = 0.28 (toluene/ethyl
acetate 15/1).
1-(Ferrocenylmethyl)-4,5-diphenyl-1,2,3-triazole
(6a, C25H21FeN3)
Yellow solid; 72 % yield; m.p.: 162–164 °C; 1H NMR
(400 MHz, CDCl3): d = 7.54–7.46 (m, 5H), 7.30–7.17 (m,
5H), 5.10 (s, 2H), 4.18 (s, 5H), 4.11 (s, 2H), 4.04 (s, 2H)
ppm; 13C NMR (100 MHz, CDCl3): d = 144.3, 133.2,
131.2, 130.4, 129.8, 129.4, 128.5, 128.3, 127.7, 126.9,
General procedure for the Sonogashira coupling
of 5-iodo-1,2,3-triazoles 3a–3e
A mixture of the 5-iodo-1,2,3-triazole 3a–3e (0.1 mmol),
the alkyne 4a–4c (0.2 mmol), 3.5 mg Pd(PPh3)2Cl2
(0.005 mmol), and 1.0 mg CuI (0.005 mmol) was stirred in
2 cm3 DMF under argon in the presence of 28 mm3 tri-
ethylamine (0.2 mmol) at 60 °C for 6 h. The solvent was
removed in vacuo and the product was purified by column
chromatography (silica, eluent: toluene/ethyl acetate 15/1).
ꢀ
81.8, 69.2, 68.9, 68.6, 48.4 ppm; IR (KBr): m = 3052,
2917, 2845, 1442, 1327, 1245, 1107, 1025, 980, 809, 764,
698, 478 cm-1; MS (70 eV): m/z (%) = 419 (M?, 100),
354 (8), 326 (14), 299 (7), 223 (14), 210 (8), 199 (17), 165
(16), 145 (8), 121 (23), 89 (8), 56 (16); Rf = 0.49 (toluene/
ethyl acetate 8/1).
1-(Ferrocenylmethyl)-5-(phenylethynyl)-4-propyl-1,2,3-
triazole (7a, C24H23FeN3)
1-(Ferrocenylmethyl)-5-phenyl-4-propyl-1,2,3-triazole
(6b, C22H23FeN3)
Orange solid; 68 % yield; m.p.: 78–80 °C; 1H NMR
(400 MHz, CDCl3): d = 7.55–7.52 (m, 2H), 7.42–7.38 (m,
3H), 5.30 (s, 2H), 4.36 (s, 2H), 4.13 (s, 7H), 2.72 (t,
J = 7.4 Hz, 2H), 1.75 (sext, J = 7.4 Hz, 2H), 0.96 (t,
J = 7.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d = 150.7, 131.4, 129.4, 128.6, 121.7, 118.1, 100.8, 81.9,
74.8, 69.1, 68.7, 68.5, 48.7, 27.6, 22.2, 13.8 ppm; IR
(KBr): mꢀ = 3088, 2958, 2868, 1446, 1324, 1238, 1193,
1107, 1029, 825, 760, 690, 478 cm-1; MS (70 eV): m/
z (%) = 409 (M?, 100), 344 (9), 247 (11), 234 (12), 199
(28), 191 (17), 169 (8), 121 (31), 56 (15); Rf = 0.33
(toluene/ethyl acetate 15/1).
Yellow solid; 60 % yield; m.p.: 90–93 °C; 1H NMR
(400 MHz, CDCl3): d = 7.48–7.44 (m, 3H), 7.22–7.18 (m,
2H), 5.13 (s, 2H), 4.05 (s, 5H), 4.00 (t, J = 1.8 Hz, 2H),
3.92 (t, J = 1.8 Hz, 2H), 2.52 (t, J = 7.3 Hz, 2H), 1.58
(sext, J = 7.3 Hz, 2H), 0.82 (t, J = 7.3 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3): d = 145.7, 133.8, 130.0, 129.3,
129.0, 128.1, 82.2, 69.1, 68.9, 68.5, 48.2, 27.2, 23.0,
ꢀ
14.0 ppm; IR (KBr): m = 3093, 2962, 2929, 2848, 1450,
1266, 1103, 1041, 1009, 805, 756, 702, 478 cm-1; MS
(70 eV): m/z (%) = 385 (M?, 100), 320 (14), 292 (9), 223
(11), 199 (19), 135 (9), 121 (31), 56 (14); Rf = 0.28
(toluene/ethyl acetate 8/1).
4-Ferrocenyl-5-(phenylethynyl)-1-(phenylmethyl)-1,2,3-
triazole (7b, C27H21FeN3)
4-Ferrocenyl-5-phenyl-1-(phenylmethyl)-1,2,3-triazole
(6c, C25H21FeN3)
Yellow solid; 45 % yield; m.p.: 72–75 °C; 1H NMR
(400 MHz, CDCl3): d = 7.49–7.52 (m, 2H), 7.44–7.39 (m,
3H), 7.36–7.29 (m, 5H), 5.61 (s, 2H), 5.02 (s, 2H), 4.32 (s,
2H), 4.07 (s, 5H) ppm; 13C NMR (100 MHz, CDCl3):
d = 149.4, 135.1, 131.5, 129.7, 129.0, 128.9, 128.6, 128.1,
121.9, 116.4, 102.1, 75.8, 74.8, 69.8, 69.3, 67.1, 53.0 ppm;
Yellow solid; 86 % yield; m.p.: 153–156 °C; 1H NMR
(400 MHz, CDCl3): d = 7.52–7.42 (m, 3H), 7.27–7.21 (m,
3H), 7.17–7.13 (m, 2H), 7.00–6.95 (m, 2H), 5.35 (s, 2H),
4.45 (s, 2H), 4.15 (s, 2H), 3.98 (s, 5H) ppm; 13C NMR
(100 MHz, CDCl3): d = 143.9, 135.5, 132.4, 130.2, 129.6,
128.8, 128.6, 127.9, 127.9, 127.3, 75.7, 69.3, 68.3, 66.6,
ꢀ
IR (KBr): m = 3082, 3031, 2925, 2843, 1437, 1266, 1074,
1017, 919, 751, 678, 527 cm-1
;
MS (70 eV): m/
ꢀ
51.9 ppm; IR (KBr): m = 3109, 3036, 2933, 1458, 1221,
z (%) = 443 (M?, 100), 415 (8), 349 (12), 324 (24), 211
(10), 176 (9), 141 (10), 121 (43), 91 (27), 56 (14);
Rf = 0.77 (toluene/ethyl acetate 15/1).
1168, 1099, 1066, 997, 808, 768, 739, 706, 498 cm-1; MS
(70 eV): m/z (%) = 419 (M?, 100), 325 (14), 300 (69), 197
(23), 165 (11), 153 (14), 152 (12), 141 (21), 121 (46), 91
(23), 56 (13); Rf = 0.23 (toluene/ethyl acetate 15/1).
4-Ferrocenyl-5-(phenylethynyl)-1-(ferrocenylmethyl)-
1,2,3-triazole (7c, C35H29Fe3N3)
5-Ferrocenyl-1-(ferrocenylmethyl)-4-phenyl-1,2,3-triazole
(6d, C29H25Fe2N3)
Orange solid; 42 % yield; m.p.: 145–148 °C; 1H NMR
(400 MHz, CDCl3): d = 7.61–7.59 (m, 2H), 7.42–7.35 (m,
3H), 5.65 (s, 2H), 4.39 (s, 2H), 4.36 (s, 2H), 4.24 (s, 2H),
4.19 (s, 5H), 4.17 (s, 2H), 4.02 (s, 5H) ppm; 13C NMR
Orange solid; 29 % yield; m.p.: 169–171 °C; 1H NMR
(400 MHz, CDCl3): d = 5.33 (s, 2H), 5.05 (t, J = 1.8 Hz,
2H), 4.65 (t, J = 1.8 Hz, 2H), 4.43 (t, J = 1.8 Hz, 2H),
4.40 (t, J = 1.8 Hz, 2H), 4.35 (t, J = 1.8 Hz, 2H), 4.34 (s,
5H), 4.21–4.19 (m, 7H), 4.13 (s, 5H) ppm; 13C NMR
123

´
K. Feher et al.
11. Hildebrandt A, Lang H (2013) Organometallics 32:5640
12. Rostovtsev VV, Green LK, Fokin VV, Sharpless KB (2002)
Angew Chem Int Ed 41:2596
13. Tornøe CW, Christensen C, Meldal M (2002) J Org Chem
67:3057
(100 MHz, CDCl3): d = 148.1, 116.4, 101.8, 82.3, 74.9,
72.2, 71.5, 70.0, 69.6, 69.5, 68.9, 68.8, 68.8, 68.4, 66.7,
ꢀ
63.3, 48.5 ppm; IR (KBr): m = 3077, 2925, 2848, 2210,
1413, 1319, 1209, 1099, 1029, 1005, 813, 486 cm-1; MS
(ESI): m/z = 660 ([M?H]?); Rf = 0.32 (toluene/ethyl
acetate 15/1).
14. Orthaber A, Fuchs M, Belaj F, Rechberger GN, Kappe CO, Pi-
etschnig R (2011) Eur J Inorg Chem 2588
¨
15. Balogh J, Skoda-Foldes R (2011) Transition-metal catalyzed re-
actions in the synthesis of ferrocene. In: Phillips ES (ed)
Ferrocenes: compounds, properties and applications. Nova Pub-
lishers, USA, pp 107–147
5-(Ferrocenylethynyl)-4-phenyl-1-(phenylmethyl)-1,2,3-
triazole (7d, C27H21FeN3)
Yellow solid; 59 % yield; m.p.: 98–103 °C; 1H NMR
(400 MHz, CDCl3): d = 8.20–8.18 (m, 2H), 7.46–7.42 (m,
2H), 7.38–7.29 (m, 6H), 5.62 (s, 2H), 4.50 (s, 2H), 4.31 (s,
2H), 4.19 (s, 5H) ppm; 13C NMR (100 MHz, CDCl3):
d = 147.3, 134.9, 130.5, 128.8, 128.5, 128.4, 128.3, 127.9,
125.9, 117.9, 102.6, 71.7, 71.6, 70.0, 69.6, 62.7, 52.7 ppm;
16. Zhang L, Chen X, Xue P, Sun HHY, Williams ID, Sharpless KB,
Fokin VV, Jia G (2005) J Am Chem Soc 127:15998
17. Li LJ, Zhang YQ, Zhang Y, Zhu AL, Zhang GS (2014) Chin
Chem Lett 25:1161
18. Alonso F, Moglie Y, Radivoy G, Yus M (2012) Synlett 23:2179
19. Ackermann L, Potukuchi HK, Landsberg D, Vicente R (2008)
Org Lett 10:3081
20. Deng J, Wu YM, Chen QY (2005) Synthesis 2730
21. Morris JC, Chiche J, Grellier C, Lopez M, Bornaghi LF, Maresca
ꢀ
IR (KBr): m = 3105, 2921, 2848, 2214, 1458, 1352, 1319,
1221, 1102, 1005, 813, 768, 739, 694, 494 cm-1; MS
(70 eV): m/z (%) = 443 (M?, 100), 324 (38), 312 (8), 176
(14), 165 (20), 121 (23), 91 (18), 56 (10); Rf = 0.48
(toluene/ethyl acetate 15/1).
´
A, Supuran CT, Pouyssegur J, Poulsen SA (2011) J Med Chem
54:6905
22. Joubert N, Schinazi RF, Agrofoglio LA (2005) Tetrahedron
61:11744
23. Ostrowski T, Januszczyk P, Cieslak M, Kazmierczak-Baranska J,
Nawrot B, Bartoszak-Adamska E, Zeidler J (2011) Bioorg Med
Chem 19:4386
4-Ferrocenyl-5-(ferrocenylethynyl)-1-(phenylmethyl)-
1,2,3-triazole (7e, C31H25Fe2N3)
´
´
´
´
24. Garcıa-Alvarez J, Dıez J, Gimeno J, Suarez FJ, Vincent C (2012)
Orange solid; 43 % yield; m.p.: 98–101 °C; 1H NMR
(400 MHz, CDCl3): d = 7.41–7.32 (m, 5H), 5.61 (s, 2H),
5.05 (t, J = 1.8 Hz, 2H), 4.55 (t, J = 1.8 Hz, 2H), 4.36–
4.33 (m, 4H), 4.23 (s, 5H), 4.12 (s, 5H) ppm; 13C NMR
(100 MHz, CDCl3): d = 148.4, 135.1, 128.8, 128.3, 127.7,
116.9, 102.1, 74.7, 71.8, 71.4, 69.9, 69.6, 69.5, 68.8, 66.7,
Eur J Inorg Chem 5854
25. Hein JE, Tripp JC, Krasnova LB, Sharpless KB, Fokin VV (2009)
Angew Chem Int Ed 48:8018
ˆ
26. Carcenac Y, David-Quillot F, Abarbri M, Duchene A, Thibonnet
J (2013) Synthesis 45:633
27. Panteleev J, Geyer K, Aguilar-Aguilar A, Wang L, Lautens M
(2010) Org Lett 12:5092
28. Schulman JM, Friedman AA, Panteleev J, Lautens M (2012)
Chem Commun 48:55
ꢀ
63.1, 52.6 ppm; IR (KBr): m = 3089, 2917, 2850, 2214,
1406, 1331, 1217, 1107, 1045, 1029, 997, 817, 735,
490 cm-1; MS (ESI): m/z = 552 ([M?H]?); Rf = 0.32
(toluene/ethyl acetate 15/1).
´ˇ
29. Jurıcek M, Stout K, Kouwer PHJ, Rowan AE (2011) Org Lett
13:3494
30. Bogdan AR, James K (2011) Org Lett 13:4060
´
31. Garcıa-Alvarez J, Dıez J, Gimeno J, Suarez FJ, Vincent C (2012)
´
Eur J Inorg Chem 5854
32. Cheng W, Jilin Y, Wei Z, Lan Z, Zheng Z (2013) J South Med
Univ 33:779
´
´
Acknowledgments The authors thank for the support of the Hun-
garian National Science Foundation (OTKA K105632) as well as the
´
project TAMOP-4.2.2.A-11/1/KONV-2012-0071, realized with the
33. Kuijpers BHM, Dijkmans GCT, Groothuys S, Quaedflieg PJLM,
Blaauw RH, van Delft FL, Rutjes FPJT (2005) Synlett 3059
34. Wu YM, Deng J, Li Y, Chen QY (2005) Synthesis 1314
35. Li L, Zhang G, Zhu A, Zhang L (2008) J Org Chem 73:3630
36. Li L, Li Y, Li R, Zhu A, Zhang G (2011) Aust J Chem 64:1383
37. Yan R, El-Emir E, Rajkumar V, Robson M, Jathoul AP, Pedley
support of the Hungarian Government and the European Union, with
the co-funding of the European Social Fund.
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