Continuous-flow azide-alkyne cycloadditions with an effective bimetallic catalyst and a simple scavenger system

Article abstract of DOI:10.1039/c4ra07954j

A flow chemistry-based technique is presented herein for Cu(i)-catalyzed azide-alkyne cycloadditions with a copper on iron bimetallic system as the catalyst and iron powder as a readily available copper scavenger. The method proved to be rapid and safe as

Full text of DOI:10.1039/c4ra07954j

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Continuous-flow azide–alkyne cycloadditions with
an effective bimetallic catalyst and a simple
scavenger system†
Cite this: RSC Adv., 2014, 4, 46666
Sandor B. O¨ tvos,a Gabor Hatoss,a A´dam Georgiades,a Szabolcs Kovacs,b
´
¨
´
´
´
¨ ¨
´
a
b
a
*
Istvan M. Mandity, Zoltan Novak and Ferenc Fulop
´
´
´
´
A flow chemistry-based technique is presented herein for Cu(I)-catalyzed azide–alkyne cycloadditions with
a copper on iron bimetallic system as the catalyst and iron powder as a readily available copper scavenger.
The method proved to be rapid and safe as compared with the conventional batch experiment; and by using
an in-line copper scavenger, the level of copper impurities in the triazole products could readily be reduced
to negligibly small amounts. The process was widely applicable, as not only terminal alkynes, but also
various disubstituted acetylenes were nicely tolerated as dipolarophiles leading to useful 1,4,5-
trisubstituted 1,2,3-triazoles.
Received 1st August 2014
Accepted 15th September 2014
DOI: 10.1039/c4ra07954j
www.rsc.org/advances
The synthesis of 1,2,3-triazoles via CuAAC comprises an
extraordinarily robust and straightforward transformation,
Introduction
which can be performed under a wide array of reaction condi-
tions.11 For such reactions, the safety aspects associated with
the handling of explosive azides,12 the inherent scalability of
continuous processing and the plausible opportunity for auto-
mation have made CF CuAAC approaches particularly
appealing.13 In CF reaction technology, mainly heterogeneous
approaches, such as copper-in-charcoal (Cu/C),14 immobilized
Cu(I) complexes,15 copper powder16 or heated copper tubing17
are employed as sources of catalytically active copper species.
Despite using a heterogeneous catalyst, metal impurities oen
reduce the organic purity of the triazole product due to signif-
icant leaching of copper from the catalytic source.14b Flow
chemistry enables various in-line techniques (such as the use of
metal scavenger resins or CF extraction processes) to reduce
copper contamination and to obtain sufficiently pure products
with less purication and work-up steps.15b,18
Herein, we report an effective CF technique for CuAAC
reactions employing the combination of a copper on iron (Cu/
Fe) bimetallic catalytic system and iron powder as a readily
available copper scavenging unit, which can practically act as an
in situ generated catalyst aer several hours of continuous
operation as a scavenger. The synthetic capabilities of the CF
process were validated with the synthesis of a series of 1,4-
disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles.
The 1,3-dipolar cycloaddition of organic azides with alkynes as
dipolarophiles is the most straightforward way to obtain useful
1,2,3-triazoles.1 The classical Huisgen reaction utilizes only
thermal induction and gives an approximately 1 : 1 mixture of
1,4- and 1,5-disubstituted 1,2,3-triazoles,2 but with Cu(I) catal-
ysis the 1,4-disubstituted isomer is formed regioselectively.3
Applications of the Cu(I)-catalyzed azide–alkyne cycloaddition
(CuAAC) have contributed to many areas of modern chemistry,
such as bioconjugation, peptidomimetic chemistry, polymer
and materials sciences and supramolecular chemistry.4 As a
consequence of the potential biological properties of 1,2,3-
triazole-containing compounds, the CuAAC reaction has
recently become a versatile tool for the drug discovery.5
As a novel sustainable alternative for conventional batch-
based synthetic techniques, continuous-ow (CF) processing
has recently emerged in academic and industrial research of
ne chemicals.6 CF-based approaches offer signicant advan-
tages over classical segmented unit operations,7 such as
enhanced heat and mass transfer and improved mixing prop-
erties,8 increased parameter space with an unprecedented level
of control over the most important reaction conditions,9 and
inherently safer and greener chemistry and higher reaction
rates.10
a
¨
¨
Institute of Pharmaceutical Chemistry, University of Szeged, Eotvos u. 6, 6720 Szeged,
Experimental
CF methodology
Hungary. E-mail: fulop@pharm.u-szeged.hu
b
¨
MTA-ELTE “Lendulet” Catalysis and Organic Synthesis Research Group, Institute of
¨
¨
´
´
´
´
Chemistry, Eotvos Lorand University, Pazmany Peter stny. 1/a, Budapest, 1117,
Experiments were conducted in a CF reactor system shown in
Fig. 1. A stainless steel cartridge (with internal dimensions of 70
ꢀ 4 mm) was employed as the catalyst bed, which was placed in
Hungary
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra07954j
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a heating unit or an ultrasonic bath (with a power of 150 W). The that elapsed between the rst contact of the dye with the catalyst
catalyst bed was combined with a coiled stainless steel line bed and the moment when the colored solution appeared at the
(with an internal diameter of 500 mm) for preheating of the column output was measured.
liquid phase before entering the column. A backpressure
regulator ensured constant pressures up to a maximum of 100
bar, and the mixture of the reactants was pumped through the
system continuously by means of a conventional HPLC pump.
For reactions with in line copper scavenging, a second cartridge
(with the same dimensions) was lled with scavenger and tted
into the ow line.
Product analysis
The obtained 1,2,3-triazoles were characterized by NMR exper-
iments and elemental analyses. H and 13C NMR spectra were
1
recorded on a Bruker Avance DRX 400 spectrometer, in CDCl3 as
solvent, with TMS as internal standard, at 400.1 and 100.6 MHz,
respectively. Microanalyses were performed on a Perkin-Elmer
2400 elemental analyzer.
Materials
The copper concentration of the samples was determined by
inductively coupled plasma mass spectrometer (ICP-MS), using
an Agilent 7700x-type instrument equipped with a collision cell
aer digestion with concentrated HNO3. The determination was
carried out on the isotope 63Cu, with He as collision gas.
The morphology of the catalyst and the scavenger was
examined with scanning electron microscopy (SEM – Hitachi S-
4700 microscope with varying acceleration voltage). The
samples were xed on a double-sided adhesive carbon tape and
were coated with gold using a sputter coater (Quorum Tech-
nologies SC7620). The approximate composition and the
Copper powder (average particle size: 200 mm) and 5 wt% Cu/C
(average particle size: 20 mm) were purchased from Aldrich, and
used as received. 5 wt% Cu/Fe (average particle size: 200 mm)
was prepared from CuSO4 and iron powder as reducing agent,
according to the previously described procedure.19 Iron powder
(used as scavenger) was purchased from Alfa Aesar with an
average particle size of 200 mm. Azides, as starting materials
were prepared with literature procedures in purities of >99%,
and were therefore used without further purication.16a,19b,20
¨
elemental map of the substances were investigated by a Rontec
General procedure
QX2 energy dispersive X-ray uorescence spectrometer (EDX)
In the case of copper powder and Cu/Fe, 1 g of the heteroge-
neous catalyst was lled into a catalyst bed, respectively. Due to
the large porosity of activated charcoal, it was possible to load
only 0.5 g of Cu/C into the cartridge at a maximum. The scav-
enger column was loaded with 1 g of iron powder.
coupled to the microscope.
Results and discussion
Cu/Fe is a versatile bimetallic catalyst system which consists of
nano-sized copper particles deposited onto an iron surface
(Fig. 2).19,21 It can easily be prepared from Cu(II) salts and iron
powder which serves as a non-toxic reducing agent and a
For the small-scale CF reactions, 0.84 mmol (1 equiv.) of the
azide and 1.26 mmol (1.5 equiv.) of the alkyne were dissolved in
10 mL CH2Cl2. If necessary, 0.0336 mmol (0.04 equiv.) of N,N-
diisopropylethylamine (DIEA) and 0.0336 mmol (0.04 equiv.) of
glacial acetic acid (AcOH) were added as additives. Aer
homogenization, the solution was pumped through the CF
reactor under the appropriate conditions. Between two CF
reactions the catalyst bed and the scavenger were washed at
room temperature (RT) for 10 min with CH2Cl2 at a ow rate of 1
mL minꢁ1. The concentration of the reactants was not varied
upon scaling-up, and a larger amount of starting medium was
simply pumped through the instrument. The crude products
were checked by thin-layer chromatography with a mixture of n-
hexane–EtOAc as eluent, and the solvent was next evaporated off
under vacuum. If necessary, column chromatographic puri-
cation was carried out on silica gel with a mixture of n-hexane–
EtOAc as eluent.
To determine the residence time on the lled catalyst bed, a
solution of a dye was pumped through the cartridge. The time Fig. 2 SEM image of the Cu/Fe catalyst.
Fig. 1 Experimental setup for the CF reactions.
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support for copper particles at the same time. As the beginning was necessary to obtain quantitative conversionꢂ with copper
of our study, we explored the merits of the Cu/Fe system for powder as catalytic source.16a At 100 bar and 100 C Cu/Fe and
CuAAC reactions in a high-pressure CF device in comparison copper powder performed equally well, as quantitative conver-
with Cu/C and copper powder as commercially available Cu(I) sion was achieved in both test reactions (entries 3 and 13). In
sources and also with literature batch data employing the same contrast, with Cu/C a conversion of only 38% was found
catalyst (Table 1). The 1,3-dipolar cycloaddition between benzyl (entry 8). However due to the risks associated with the handling
azide and phenylacetylene was chosen as a test reaction with of explosive azides it is highly benecial to improve the rates of
CH2Cl2 as solvent. A reaction mixture containing 1 equiv. of the the CuAAC reactions without high temperatures. Amines, as
azide and 1.5 equiv. of the alkyne was pumped through the basic additives, are known to boost the reactivity of the CuAAC
reactor in each run. The azide was applied in a concentration of considerably,3a,11,22 and it was recently shown that the addition
0.085 M, which was the highest possible concentration pre- of catalytic amounts of certain acids can further accelerate the
venting the precipitation of the resulting product and a triazole formation and also prevent the accumulation of
blockage in the channels of the reactor. All CF reactions were unwanted byproducts.23 To realize the CF CuAAC at ambient
carried out at a ow rate of 0.5 mL minꢁ1 which involved a temperature, we utilized 0.04 equiv. of DIEA and 0.04 equiv. of
residence time on the catalyst bed as low as 1.5 min, and thus a AcOH jointly as additives.16a We were pleased to nd that the
prominently short process time.
performance of the Cu/Fe catalyst was comparable with copper
At ambient temperature and pressure, low conversion was powder, and quantitative conversion was achieved with addi-
obtained with each catalyst (entries 1, 6 and 11), and thus tives in both cases (entries 4 and 14). In case of Cu/C the use of
various approaches were evaluated to improve the reactivity. additives nicely improved the reactivity as compared with the
High pressures can enhance the rate of the triazole formation in high-temperature/high-pressure conditions, and gave an
accordance with Le Chatelier's principle, and accordingly we acceptable conversion of 81% (entry 9). We also checked the
found higher conversions at 100 bar (entries 2, 7 and 12).16a effects of ultrasound promotion to relieve harsh reaction
Elevation of the pressure allowed the use of temperatures well conditions.24 For this, the lled catalyst column was simply
above the boiling point of CH2Cl2, thus, as a next step, high- placed into an ultrasonic bath. It was found that sonication
temperature conditions were examined. We had previously improved the rates of the CF reaction at ambient temperature in
concluded that the rate of the triazole formation is highly case of the bimetallic Cu/Fe system and copper powder, but the
ꢂ
dependent on the temperature, and heating to at least 100 C efficacy of this approach fell behind the use of additives, as a
Table 1 Effects of different catalysts and reaction conditions on the CF CuAAC
Additives
Entry
Catalyst
p (bar)
T (ꢂC)
DIEA (equiv.)
AcOH (equiv.)
Conversion of 1a (%)
1
2
3
4
5
6
Copper powder
Copper powder
Copper powder
Copper powder
Copper powder
Cu/C
1
100
100
100
100
1
RT
RT
0
0
0
0.04
0
0
0
0
0
0.04
0
0
19
31
Quant.
Quant.
54
6
100
RT
RT/USc
RT
7
8
9
10
11
12
13
14
15
16b
Cu/C
Cu/C
Cu/C
Cu/C
Cu/Fe
Cu/Fe
Cu/Fe
Cu/Fe
100
100
100
100
1
100
100
100
100
1
RT
0
0
0.04
0
0
0
0
0.04
0
0
0
0.04
0
0
0
0
0.04
0
11
38
81
15
21
28
100
RT
RT/USc
RT
RT
100
RT
Quant. (98)d
Quant. (99)d
49
Cu/Fe
Cu/Fe
RT/USc
30
0
0
Quant. (98)d
a
Determined by 1H NMR spectroscopic analysis of the crude material. b Batch reference data.19b Reaction conditions: azide (0.5 mmol, 1 equiv.),
acetylene (0.5 mmol, 1 equiv.), Cu/Fe (5 mol%, 5 wt%) (32 mg, 0.025 mmol copper), CH2Cl2, (300 mL), stirring at 30 ꢂC for 8 h. c US stands for ultra
sound. d Isolated yield.
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conversion of only ꢃ50% was obtained with both catalysts
The development of the Cu/Fe bimetallic catalyst system
(entries 5 and 15). In case of Cu/C, not more than a negligible inspired us to employ iron powder in our CF system as a readily
conversion increase was found upon sonication (entry 10). The available copper scavenger. Thus, iron powder was lled in a
overall lower reactivity of Cu/C may be explained with the poorer second cartridge which was placed into the ow line according
accessibility of the catalytically active Cu(I) species in the acti- to Fig. 1. We were pleased to nd that the utilization of iron
vated charcoal matrix and with the lower catalyst loading in the powder as scavenger dramatically reduced the copper content of
cartridge than is the case of Cu/Fe and copper powder.
the triazole product (Table 2, entries 2 vs. 4), it proved nearly as
The CF results with the Cu/Fe catalyst system (obtained effective as a conventional off line purication with column
either under high-temperature/high-pressure conditions or chromatography (entries 3 vs. 4). With in-line copper scav-
under ambient temperature with additives) compare well with enging, the corresponding 1,4-disubstituted 1,2,3-triazole
the corresponding literature batch data utilizing the same product was achieved without work-up and purication steps as
ꢂ
catalyst and conventional mechanical stirring at 30 C (entries conversion was quantitative and any excess alkyne could
13, 14 vs. 16).19b It should be pointed out that the batch reaction evaporated.
required 8 h of reaction time for completion, whereas the
We next investigated the large-scale synthetic capabilities of
continuous process offered quantitative conversion in a short the Cu/Fe + Fe catalyst and scavenger system with the test
residence time on the catalyst bed, and thus it proved to be reaction between benzyl azide and phenylacetylene at a ow rate
much more rapid. Another point is that the CF method tends to of 0.5 mL minꢁ1, a pressure of 100 bar, and at ambient
be safer due to the contained environment, the lack of head- temperature with the joint use of DIEA and AcOH as additives.
space and the well-dened short residence time.
The concentration and ratio of the starting materials were not
In reactions involving heterogeneous catalysts, leaching of changed upon scaling-up. Fractions of the reaction product
copper from the catalyst bed can reduce the purity of the tri- were collected every 15 minutes, and conversion was deter-
azole products and necessitate further work-up and purication mined for each portion. We were pleased to nd that the activity
steps. In our CF reactions, trace amounts of copper were of the catalyst remained constant aer 150 min of continuous
determined by means of ICP-MS measurements in the quanti- use, and 1.38 g of triazole 1 was obtained without the need for
tatively obtained triazole products (Table 2) without any work- further work-up or purication steps (Table 3). In this experi-
up and purication steps other than a simple evaporation ment, an overall yield of 94% and a productivity of 3 (in mmol
(except for entry 3). The analytical data show that the copper product ꢀ mmol per catalyst per h) was achieved. We presumed
content of the crude products obtained under high-pressure/ that the iron powder used as scavenger in the large-scale
high-temperature conditions without any additives were lower experiment may have catalytic activity in CuAAC reactions due
than those when DIEA and AcOH were jointly applied (entries 1 to various copper species adsorbed on its surface. Thus the
vs. 2). This is because amines, as basic additives, can coordinate cartridge containing iron powder aer 150 min of continuous
to the catalytically active Cu(I) species and promote their liber- copper scavenging was recycled as an in line-generated catalyst
ation from the copper matrix, thereby increasing the copper column (marked as ‘Cu’/Fe from here on) in a large-scale run
content of the crude product. In spite of this fact, the utilization utilizing the same reactants and conditions as in the previous
of additives for rate enhancement in the CF CuAAC is much experiment (Table 4). It was found that ‘Cu’/Fe effectively cata-
wiser than the use of harsh reaction conditions due to safety lyzed the CF CuAAC reaction with constant activity in the rst
considerations. Thus, to reduce metal contamination of the 100 min. Aer that, the activity started to decrease, and in the
triazole product an in-line copper scavenging methodology is nal fraction a conversion of 31% was obtained. The experi-
highly benecial.
ment allowed for the isolation of 1.10 g of pure triazole 1 with a
Table 2 Copper contents in the triazole product obtained with different approaches
Entry
Description of the reaction conditionsa
Copper contentb,c (mg gꢁ1
)
1
2
3
4
Cu/Fe, 100 bar, 100 ꢂC, without additives
41.0 ꢄ 0.8
318.3 ꢄ 2.9
7.8 ꢄ 0.3
Cu/Fe, 100 bar, RT, with additivesd
Cu/Fe, 100 bar, RT, with additives,d purication on a ash column
Cu/Fe, 100 bar, RT, with additives,d in line purication with scavenger
19.4 ꢄ 0.6
a
Unused portions of the catalyst and the scavenger were used for each reactions. b Determined by ICP-MS. c 10 mL aliquots of the reaction mixture
was pumped through the system for each ICP-MS samples. d Additives: 0.04 equiv. DIEA + 0.04 equiv. AcOH.
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Table 3 Investigation of the large-scale synthetic capabilities of the Cu/Fe + Fe catalytic system in CF
Fractiona
Time (min)
Conversion of 1b (%)
Fractiona
Time (min)
Conversion of 1b (%)
1
2
3
4
5
0–15
Quant.
Quant.
Quant.
Quant.
Quant.
6
7
8
9
75–90
Quant.
Quant.
Quant.
Quant.
Quant.
15–30
30–45
45–60
60–75
90–105
105–120
120–135
135–150
10
a
1.38 g of 1 was collected in the whole experiment. An overall yield of 94% and a productivity of 3 (in mmol product ꢀ mmol per catalyst per h) was
obtained. b Determined by 1H NMR spectroscopic analysis of the crude material.
Table 4 Investigation of the catalytic capabilities of the same portion of iron powder previously used as copper scavenging unit in the
experiment shown in Table 3
Fractiona
Time (min)
Conversion of 1b (%)
Fractiona
Time (min)
Conversion of 1b (%)
1
2
3
4
5
0–15
Quant.
Quant.
Quant.
Quant.
Quant.
6
7
8
9
75–90
Quant.
99
56
37
31
15–30
30–45
45–60
60–75
90–105
105–120
120–135
135–150
10
a
1.10 g of 1 was collected in the whole experiment. An overall yield of 75% was obtained. b Determined by 1H NMR spectroscopic analysis of the
crude material.
good overall yield of 75%. The SEM images of the iron powder veried our suspicion that the small dots on the surface of ‘Cu’/
nicely supported the above ndings. As shown in Fig. 3a, the Fe are copper nanoparticles, which allowed for catalytic activity
surface of the unused iron powder is smooth, but aer 150 min in the CuAAC reaction. Thus, the above sustainable procedure
of continuous use as a scavenger, small particles appeared on it allows not only for CF triazole formation with in line copper
(Fig. 3b), and the morphology of the surface became similar to scavenging but, at the same time, its efficacy for continuous
that of the Cu/Fe catalyst (Fig. 3b vs. 2). The EDX measurements catalyst generation is also noted. The fact that the iron powder
used as scavenger in continuo for 150 min works nicely as an in
situ generated ‘Cu’/Fe catalyst and the SEM experiments lead us
to suggest that, under the present conditions, the scavenger
cartridge should be replaced every 2.5 h to maintain the
maximum copper scavenging efficiency. However, the use of a
larger amount of iron powder (e.g. in a longer column) would
possibly allow a longer period with constant efficacy.
To investigate the applicability of the CF method, a wide
array of CuAAC reactions were carried out utilizing the Cu/Fe
catalytic system at a ow rate of 0.5 mL minꢁ1, a pressure of
100 bar, with the joint use of DIEA and AcOH as additives at
ambient temperature. At rst, the azide scope was examined,
Fig. 3 SEM images of the iron powder: (a) unused iron powder; (b)
used iron powder, sample taken after 150 min of CF operation as
scavenger (see Table 3).
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Table 5 Investigation of the scope of the CF CuAAC methodology with the Cu/Fe catalyst systema
Entry
Azide (1 equiv.)
Alkyne (1.5 equiv.)
Product
Conv.b (%)
Quant.
Yieldc (%)
98
1
2
3
99
97
98
Quant.
4
Quant.
96
5
6
Quant.
98
94
99
7
8
97
93
98
Quant.
9
Quant.
98
10
11
Quant.
Quant.
93
98
12
Quant.
97
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Table 5 (Contd.)
Entry
13
Azide (1 equiv.)
Alkyne (1.5 equiv.)
Product
Conv.b (%)
90
Yieldc (%)
83
14
Quant.
98
15
16
17
94
86
75
92
83
Quant.
18
Quant.
90
19
20
Quant.
90
21
43
27
21
55
a
b
Conditions: cazide ¼ 0.085 M, 100 bar, RT, 0.5 mL minꢁ1 ow rate, with 0.04 equiv. DIEA + 0.04 equiv. AcOH. Determined by 1H NMR
spectroscopic analysis of the crude material. c Yield of isolated product.
employing phenylacetylene as dipolarophile. As can be seen in yne, ethyl propiolate and propargyl acetate, are nicely tolerated
Table 5, excellent results were achieved with either aliphatic or (entries 13–16). Ferrocene–triazole conjugates are widely
aromatic azides. In the case of aromatic azides, it was found applied in medicinal chemistry for the labeling and detection of
that either electron-withdrawing (entries 2–4) or electron- various systems.25 Thus, CuAAC of benzyl azide with ethynyl
donating substituents (entries 5 and 6) are nicely tolerated on ferrocene was also attempted, and ferrocene-substituted tri-
the aromatic ring. High conversions and yields were achieved azole 18 was obtained in an excellent yield of 90% (entry 18). In
with cyclic, linear, branched and unsaturated non-aromatic the above experiments the corresponding 1,4-disubstituted
azides as well (entries 7–12). Reactions of a series of alkynes 1,2,3-triazole isomers were formed regioselectively, and forma-
with benzyl azide were also carried out. It was found that, tion of the 1,5-disubsituted products was not observed. No
besides phenylacetylene, non-aromatic alkynes, such as pent-1- work-up or purication steps were necessary when the triazole
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formation was quantitative and any excess alkyne could be use as scavenger, the iron powder can be reused as an in situ
volatilized on evaporation (entries 1–6 and 8–12). formed catalyst for CuAAC reactions thereby extending the
Cycloaddition of disubstituted acetylenes with azides leads synthetic capabilities of the methodology. The scope and
to synthetically useful 1,4,5-trisubstituted 1,2,3-triazoles, applicability of the CF process was found extremely wide for
however the scope of this transformation is mostly limited to 1- different azides and alkynes. Not only terminal alkynes, but
haloalkynes.26 Other internal acetylenes have only rarely been electron decient disubstituted acetylenes were also tolerated
used as dipolarophiles in CuAAC reactions,27 mainly due to the as dipolarophiles, leading to synthetically useful 1,4,5-trisub-
fact that the activation toward cycloaddition via coordination of stituted 1,2,3-triazoles.
Cu(I) to the alkyne without the possibility of deprotonation
involves a signicantly higher energetic barrier than is the case
with terminal alkynes.28 However, the high activity of the Cu/Fe
Acknowledgements
catalyst system in CuAAC prompted us to test its reactivity with We are grateful to the Hungarian Research Foundation (OTKA
´
internal alkynes as well. Reactions of benzyl azide with various NK81371 and PD103994) and TAMOP-4.2.2/A-11/1/KONV-2012-
¨
´
¨
disubstituted acetylenes were thus explored. We found that in 0035 for nancial support. S. B. Otvos acknowledges TAMOP
case of electron-decient alkynes the use of the CF system with 4.2.4.A/2-11-1-2012-0001 ‘National Excellence Program’, the
the Cu/Fe catalyst (further conditions are as follows: a ow rate project was supported by the European Union and the State of
of 0.5 mL minꢁ1, a pressure of 100 bar, with 0.04 equiv. DIEA + Hungary, co-nanced by the European Social Fund. I.M.M.
´
0.04 equiv. AcOH at ambient temperature) allowed for the acknowledges the award of a Janos Bolyai scholarship from the
desired trisubstituted triazoles. For example, triazole 19, which Hungarian Academy of Sciences. Z.N. acknowledges for the
is itself a potent antitubercular agent,29 could be obtained from generous support of “Lendulet” Research Scholarship Fund of
¨
diethyl acetylenedicarboxylate and benzyl azide in quantitative the Hungarian Academy of Sciences (LP2012-48/2012), and
conversion and with a yield of 90% (entry 19). Conversion OTKA-NKTH (CK80763). The authors also thank Prof. Tim
decreased signicantly when more electron rich alkynes, such Peelen (Lebanon Valley College) for the proofreading of this
as 1,4-dichlorobut-2-yne and 1-iodo-2-(trimethylsilyl)acetylene, manuscript.
were reacted (entries 20 and 21). Formation of trisubstituted
triazoles was not observed from internal alkynes decorated with
two electron donating substituents, such as oct-4-yne and
References
diphenylacetylene. This suggests that the electron density of the
triple bond is a crucial factor in the reactions of disubstituted
acetylenes.
We would like to emphasize that the investigation of the
scope and applicability (Table 5) was fullled with a single
portion of catalyst without the need for reloading. Aer this
series of experiments no decrease in activity was found. Besides
the successful gram-scale synthetic experiment shown in Table
3, this clearly indicates that we managed to create a highly
robust system for triazole synthesis.
1 C.-K. Sha and A. K. Mohanakrishnan, in Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry Toward
Heterocycles and Natural Products, John Wiley & Sons, 2003,
pp. 623–679.
2 R. Huisgen, Angew. Chem., Int. Ed., 1963, 2, 565.
3 (a) V. V. Rostovtsev, L. G. Green, V. V. Fokin and
K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2596; (b)
C. W. Tornøe, C. Christensen and M. Meldal, J. Org. Chem.,
2002, 67, 3057.
4 (a) K. Kempe, A. Krieg, C. R. Becer and U. S. Schubert, Chem.
Soc. Rev., 2012, 41, 176; (b) X. Li, Chem.–Asian J., 2011, 6,
2606; (c) D. S. Pedersen and A. Abell, Eur. J. Org. Chem.,
2011, 2399; (d) Y. Hua and A. H. Flood, Chem. Soc. Rev.,
2010, 39, 1262.
5 (a) S. G. Agalave, S. R. Maujan and V. S. Pore, Chem.–Asian J.,
2011, 6, 2696; (b) A. D. Moorhouse and J. E. Moses,
ChemMedChem, 2008, 3, 715.
Conclusions
The efficacy of Cu/Fe bimetallic catalyst system for CuAAC
reactions was evaluated in a continuously operating system. It
was found that Cu/Fe acts as an outstandingly active and robust
catalyst. Due to the high ow rate and short process time
utilized for the cycloaddition, the CF technique proved much
more rapid than the corresponding batch method. As an addi-
tional advantage, the continuous operation provided a con-
tained environment free from harsh reaction conditions to
minimize the hazards associated with the handling of explosive
azides. It was shown that a column lled with simple iron
powder can act as a readily available copper scavenging unit and
decrease the copper contaminations of the triazole products
signicantly. With the opportunity of in-line copper scavenging,
the level of copper concentrations can readily be reduced to
negligibly small amounts and synthetically useful 1,2,3-triazoles
can be obtained in a simple and easy manner without any
purication or work-up steps. Aer several hours of continuous
6 T. Wirth, Microreactors in Organic Chemistry and Catalysis,
John Wiley & Sons, 2013.
7 (a) C. Wiles and P. Watts, Green Chem., 2014, 16, 55; (b)
D. T. McQuade and P. H. Seeberger, J. Org. Chem., 2013,
78, 6384; (c) C. Wiles and P. Watts, Green Chem., 2012, 14,
38; (d) J. Wegner, S. Ceylan and A. Kirschning, Adv. Synth.
Catal., 2012, 354, 17; (e) J. Wegner, S. Ceylan and
A. Kirschning, Chem. Commun., 2011, 47, 4583.
8 R. L. Hartman, J. P. McMullen and K. F. Jensen, Angew.
Chem., Int. Ed., 2011, 50, 7502.
¨
9 (a) V. Hessel, D. Kralisch, N. Kockmann, T. Noel and
Q. Wang, ChemSusChem, 2013, 6, 746; (b) J.-i. Yoshida,
Y. Takahashi and A. Nagaki, Chem. Commun., 2013, 49, 9896.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 46666–46674 | 46673

View Article Online
RSC Advances
Paper
10 (a) S. G. Newman and K. F. Jensen, Green Chem., 2013, 15, 19 (a) S. Kovacs and Z. Novak, Org. Biomol. Chem., 2011, 9, 711;
´
´
´
´ ´
´
´
1456; (b) S. V. Ley, Chem. Rec., 2012, 12, 378–390; (c)
J.-i. Yoshida, H. Kim and A. Nagaki, ChemSusChem, 2011,
4, 331.
(b) S. Kovacs, K. Zih-Perenyi, A. Revesz and Z. Novak,
´
´
Synthesis, 2012, 44, 3722; (c) A. Szekely, A. Sinai, E. Toth
and Z. Novak, Synthesis, 2014, 46, 1871.
´
11 M. Meldal and C. W. Tornøe, Chem. Rev., 2008, 108, 2952.
20 Z. Gonda and Z. Novak, Dalton Trans., 2010, 39, 726.
¨
12 S. Brase, C. Gil, K. Knepper and V. Zimmermann, Angew. 21 R. Hudson, C.-J. Li and A. Moores, Green Chem., 2012, 14,
Chem., Int. Ed., 2005, 44, 5188. 622.
13 (a) N. Kockmann, M. Gottsponer and D. M. Roberge, Chem. 22 (a) V. O. Rodionov, V. V. Fokin and M. G. Finn, Angew. Chem.,
Eng. J., 2011, 167, 718; (b) C. J. Smith, N. Nikbin, S. V. Ley,
H. Lange and I. R. Baxendale, Org. Biomol. Chem., 2011, 9,
Int. Ed., 2005, 44, 2210; (b) C. Shao, X. Wang, Q. Zhang,
S. Luo, J. Zhao and Y. Hu, J. Org. Chem., 2011, 76, 6832.
1938; (c) P. J. Nieuwland, R. Segers, K. Koch, J. C. M. van 23 (a) C. Nolte, P. Mayer and B. F. Straub, Angew. Chem., Int. Ed.,
Hest and F. P. J. T. Rutjes, Org. Process Res. Dev., 2011, 15,
783.
14 (a) B. H. Lipshutz and B. R. Ta, Angew. Chem., Int. Ed., 2006,
45, 8235; (b) M. Fuchs, W. Goessler, C. Pilger and
C. O. Kappe, Adv. Synth. Catal., 2010, 352, 323.
2007, 46, 2101; (b) C. Shao, G. Cheng, D. Su, J. Xu, X. Wang
and Y. Hu, Adv. Synth. Catal., 2010, 352, 1587; (c) C. Shao,
X. Wang, J. Xu, J. Zhao, Q. Zhang and Y. Hu, J. Org. Chem.,
2010, 75, 7002.
24 N. Tu, J. Hochlowski and S. Djuric, Mol. Diversity, 2012, 16,
53.
¨
`
15 (a) C. Girard, E. Onen, M. Aufort, S. Beauviere, E. Samson
and J. Herscovici, Org. Lett., 2006, 8, 1689; (b) C. D. Smith, 25 V. Ganesh, V. S. Sudhir, T. Kundu and S. Chandrasekaran,
I. R. Baxendale, S. Lanners, J. J. Hayward, S. C. Smith and Chem.–Asian J., 2011, 6, 2670.
S. V. Ley, Org. Biomol. Chem., 2007, 5, 1559; (c) E. Ozkal, 26 (a) B. H. M. Kuijpers, G. C. T. Dijkmans, S. Groothuys,
S. Ozcubukcu, C. Jimeno and M. A. Pericas, Catal. Sci.
Technol., 2012, 2, 195; (d) E. Ozkal, P. Llanes, F. Bravo,
A. Ferrali and M. A. Pericas, Adv. Synth. Catal., 2014, 356,
857.
P. J. L. M. Quaedieg, R. H. Blaauw, F. L. van Del and
F. P. J. T. Rutjes, Synlett, 2005, 3059; (b) J. E. Hein,
J. C. Tripp, L. B. Krasnova, K. B. Sharpless and V. V. Fokin,
Angew. Chem., Int. Ed., 2009, 48, 8018; (c) J. Garcia-Alvarez,
J. Diez and J. Gimeno, Green Chem., 2010, 12, 2127; (d)
¨
¨
´
¨
¨
16 (a) S. B. Otvos, I. M. Mandity, L. Kiss and F. Fulop, Chem.–
¨
´
¨
´
´ˇ
Asian J., 2013, 8, 800; (b) S. B. Otvos, A. Georgiades,
M. Jurıcek, K. Stout, P. H. J. Kouwer and A. E. Rowan, Org.
´
¨
¨
I. M. Mandity, L. Kiss and F. Fulop, Beilstein J. Org. Chem.,
Lett., 2011, 13, 3494.
´
´
2013, 9, 1508.
27 (a) S. Dıez-Gonzalez, A. Correa, L. Cavallo and S. P. Nolan,
Chem.–Eur. J., 2006, 12, 7558; (b) F. Cuevas, A. I. Oliva and
M. A. Pericas, Synlett, 2010, 1873; (c) R. K. Arigela,
A. K. Mandadapu, S. K. Sharma, B. Kumar and B. Kundu,
Org. Lett., 2012, 14, 1804.
17 (a) A. R. Bogdan and N. W. Sach, Adv. Synth. Catal., 2009,
351, 849; (b) A. R. Bogdan and K. James, Chem.–Eur. J.,
2010, 16, 14506; (c) S. Ceylan, T. Klande, C. Vogt, C. Friese
and A. Kirschning, Synlett, 2010, 2009; (d) A. R. Bogdan
and K. James, Org. Lett., 2011, 13, 4060.
28 R. Berg and B. F. Straub, Beilstein J. Org. Chem., 2013, 9, 2715.
¨
18 A. C. Varas, T. Noel, Q. Wang and V. Hessel, ChemSusChem, 29 P. Shanmugavelan, S. Nagarajan, M. Sathishkumar,
2012, 5, 1703.
A. Ponnuswamy, P. Yogeeswari and D. Sriram, Bioorg. Med.
Chem. Lett., 2011, 21, 7273.
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