Alkyne-azide cycloadditions with copper powder in a high-pressure continuous-flow reactor: High-temperature conditions versus the role of additives

Article abstract of DOI:10.1002/asia.201201125

A safe and efficient flow-chemistry-based procedure is presented for 1,3-dipolar cycloaddition reactions between organic azides and acetylenes. This simple and inexpensive technique eliminates the need for costly special apparatus and utilizes Cu powder a

Full text of DOI:10.1002/asia.201201125

FULL PAPER
DOI: 10.1002/asia.201201125
Alkyne–Azide Cycloadditions with Copper Powder in a High-Pressure
Continuous-Flow Reactor: High-Temperature Conditions versus the Role of
Additives
Sꢀndor B. ꢁtvçs, Istvꢀn M. Mꢀndity, Lꢂrꢀnd Kiss, and Ferenc Fꢃlçp*[a]
Abstract: A safe and efficient flow-
chemistry-based procedure is presented
for 1,3-dipolar cycloaddition reactions
between organic azides and acetylenes.
This simple and inexpensive technique
eliminates the need for costly special
apparatus and utilizes Cu powder as
a plausible CuI source. To maximize
the reaction rates, high-pressure/high-
temperature conditions are utilized; al-
ternatively, the harsh reaction condi-
tions can be moderated at room tem-
perature by the joint application of
basic and acidic additives. A compari-
son of the performance of these two
approaches in a series of model reac-
tions has resulted in the formation of
useful 1,4-disubstituted 1,2,3-triazoles
in excellent yields. The risks that are
associated with the handling of azides
are lowered, thanks to the benefits of
flow processing, and gram-scale pro-
duction has been safely implemented.
The synthetic capability of this continu-
ous-flow technique is demonstrated by
the efficient syntheses of some highly
functionalized derivatives of the anti-
fungal cispentacin.
Keywords: alkynes · azides · click
chemistry · continuous-flow reac-
tors · copper
Introduction
The Huisgen 1,3-dipolar cycloaddition reaction of organic
azides with acetylenes is a simple route to useful 1,2,3-tria-
zoles.[1] Following thermal induction, this reaction results in
an approximate 1:1 mixture of 1,4- and 1,5-disubstituted tri-
azole isomers.[2] Owing to the pioneering work of Sharpless
and co-workers[3] and Meldal and co-workers[4] on copper
catalysis, the Huisgen reaction has captured enormous inter-
est in the field of synthetic chemistry. In contrast with the
thermal route, the CuI-catalyzed azide–alkyne cycloaddition
(CuAAC) reaction is regioselective, thereby exclusively
giving the 1,4-regioisomer within a short reaction time
(Scheme 1). The selective formation of 1,5-disubstituted
1,2,3-triazoles through ruthenium catalysis has also been de-
scribed,[5] but the broad applicability, reliability, and efficien-
cy of CuAAC has led to it becoming the standard of the
“click chemistry” concept. Applications of CuAAC can in-
creasingly be found in many areas of modern chemistry,
such as polymer and materials sciences,[6] supramolecular
chemistry,[7] bioconjugation,[8] and combinatorial chemistry.[9]
The CuAAC reaction is also significant from the viewpoint
of drug discovery,[10] because 1,2,3-triazoles possess a wide
range of biological properties, such as antiviral (1),[11] anti-
Scheme 1. 1,3-Dipolar cycloaddition reactions between organic azides
and acetylenes, which result in disubstituted triazoles.
bacterial (2),[12] antifungal (3),[13] and anticancer activities (4;
Scheme 2).[14] The 1,2,3-triazole moiety is extensively used in
medicinal chemistry as a pharmacophore to modify known
bioactive molecules and to potentiate their biological activi-
ties. For example, the 1,2,3-triazole analogues of antiviral
agent zanamivir (5)[15] and the well-known bioactive carba-
nucleoside neplanocin A (6) exhibit notable antiviral activity
(Scheme 2).[16]
Flow-chemistry techniques are currently enjoying an up-
surge in interest because they offer great advantages over
traditional batch-based synthetic procedures.[17] The well-
regulated continuous-flow (CF) reactor concept allows the
efficient mixing of substrates and faster heat and mass trans-
fer,[18] so that reactions can be performed with an unprece-
dented level of control within short reaction times.[19] Be-
[a] S. B. ꢀtvçs, Dr. I. M. Mꢁndity, Dr. L. Kiss, Prof. Dr. F. Fꢂlçp
Institute of Pharmaceutical Chemistry
University of Szeged
H-6720 Szeged, Eçtvçs u. 6 (Hungary)
Fax : (+36)62-545-705
E-mail: fulop@pharm.u-szeged.hu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201201125.
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Ferenc Fꢂlçp et al.
tions. The risks that are associated with the handling of ex-
plosive azides were minimized as a consequence of the ben-
eficial features of CF technology. We also applied this
method to the synthesis of highly functionalized derivatives
of the antifungal cispentacin, (1R,2S)-2-aminocyclopentane-
carboxylic acid, which is an interesting precursor for new tri-
azole carbanucleosides. Scale-up experiments were also per-
formed, thus achieving gram-scale syntheses.
Results and Discussion
Method
The CF experiments were performed in a dedicated high-
pressure/high-temperature reactor (H-Cube, operated in “no
H2” mode) that consisted of a replaceable stainless steel car-
tridge (internal dimensions: 70 mmꢄ4 mm) as a catalyst
bed, a Peltier heating system to heat the cartridge up to
1008C, and a pressure-control unit to ensure constant pres-
sures of up to 100 bar (Figure 1).[26] The reaction mixture
was pumped through the cartridge by using a HPLC pump
(Knauer WellChrom HPLC-pump K-120). The experimental
setup allowed the safe application of high-pressure/high-
temperature conditions for unstable reactants, such as
azides, without the potential hazard of an explosion, because
only limited amounts of the reactants were exposed to the
zone of harsh reaction conditions and, even then, only for
a safely controllable, short amount of time. Fine-tuning of
the most important reaction parameters, such as pressure,
temperature, and flow rate, is simple and efficient, thus
making the whole screening process promisingly rapid.
Cu powder was utilized as a simple and cheap source of
CuI. When exposed to air, Cu metal undergoes constant oxi-
dation, with the formation of non-self-protecting layers of
different Cu oxides, such as Cu2O.[27] Thus, Cu powder can
be regarded as a “supported” CuI catalyst. Accordingly, if
the oxide layers are removed from the Cu surface, the cata-
lytic activity decreases significantly.[22b] For the flow experi-
ments, Cu powder (900 mg) with an average particle size of
about 200 mm was incorporated into the catalyst cartridge.
Scheme 2. Some examples of bioactive 1,2,3-triazoles.
cause the need for the large-scale use of reagents and sol-
vents is eliminated, the screening of the reaction conditions
becomes simple, time- and cost-efficient, and safe.[20] These
benefits facilitate rapid library synthesis and afford an op-
portunity for automatization and excellent transferability
between laboratory-based investigations and subsequent
production scales.[21]
A number of CF strategies for CuAAC reactions have
been reported. The most popular sources of CuI for CF
methods are heterogeneous approaches that employ copper-
in-charcoal (Cu/C),[22] immobilized CuI species,[23] or copper
flow-reactor technology without extraneous CuI salts,[24] etc.
In contrast, Hessel and co-workers recently reported an effi-
cient homogeneous approach for CF CuAAC reactions, by
using [CuACHTUNGTRENNUNG(phen)ACHTUNGTRENNUNG
(PPh3)2]NO3 as a catalyst.[25]
To improve the practical applicability of CF CuAAC pro-
cedures, we set out to develop a simple and inexpensive
technique that could eliminate the need for costly apparatus
or special catalyst types, whilst at the same time being safe
and efficient. Thus, we used Cu powder as the cheapest
available source of CuI and exploited the merits of flow
processing by increasing the reaction rates with high-pres-
sure/high-temperature conditions; we were subsequently
able to moderate these harsh reaction conditions through
the use of both basic and acidic additives at room tempera-
ture. The results that were obtained by using these two
methods were compared for a series of model CuAAC reac-
Optimization of the Reaction Conditions
To achieve the maximum conversion within the shortest pos-
sible process time, the most important reaction conditions
(pressure, temperature, flow rate, and additives) were sys-
tematically fine-tuned. For the optimization studies, the 1,3-
dipolar cycloaddition reaction between benzyl azide and
phenylacetylene was chosen as a test reaction (Scheme 3).
Figure 1. Experimental setup for the CF CuAAC procedure.
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Scheme 3. 1,3-Dipolar cycloaddition reaction between benzyl azide and
phenylacetylene as a test reaction for optimization of the CF reaction
conditions.
On the basis of literature data, CH2Cl2 was used as the sol-
vent.[28] To achieve maximum productivity, we planned to
apply the highest possible azide concentration and 0.085m
was found to be the most appropriate: Higher concentra-
tions led to the precipitation of the triazole product in the
CF reactor. In small-scale test experiments, aliquots
(2.5 mL) of a reaction mixture that contained 1 equivalent
of benzyl azide and 1.5 equivalents of phenylacetylene were
pumped through the system in each run.
First, we set out to maximize the rate of the test reaction
under high-pressure/high-temperature conditions. Thus, the
pressure was increased from atmospheric pressure to
100 bar, whilst the temperature and flow rate were kept con-
stant at room temperature and 0.5 mLminÀ1, respectively.
At atmospheric pressure, a conversion of only 20% could
be achieved and the pressure had to be increased to
>80 bar to obtain higher conversion (Figure 2). At 100 bar,
a conversion of 34% was achieved, which was taken as the
optimal value. Elevation of the pressure not only increased
the rate of triazole production, in accordance with Le Cha-
Figure 3. Investigation of the temperature dependence of the test reac-
tion at 100 bar between benzyl azide and phenylacetylene in CF (flow
rate: 0.5 mLminÀ1) without any additives.
longer process times. Because quantitative conversion was
obtained under the previously optimized conditions
(100 bar, 1008C) at a flow rate of 0.5 mLminÀ1, it was un-
necessary to decrease the flow rate. However, when we at-
tempted to decrease the residence time on the catalyst bed
by increasing the flow rate, we found that the conversion de-
creased dramatically. For example, at
a flow rate of
1 mLminÀ1, the conversion was only 31% and, when the
flow rate was increased to as high as 3 mLminÀ1, the conver-
sion fell sharply to about 10% (Figure 4).
It is well-known that the application of amines as basic
additives can boost the reactivity of the CuAAC reaction
considerably.[29] The amine serves as a ligand to liberate the
Figure 4. Fine-tuning of the flow rate in the test reaction between benzyl
azide and phenylacetylene under high-pressure/high-temperature and
high-pressure/RT conditions with additives in CF: ~ 100 bar, 1008C, no
Figure 2. Investigation of the pressure dependence of the test reaction be-
tween benzyl azide and phenylacetylene under CF: ~ room temperature,
flow rate: 0.5 mLminÀ1, no additives; & room temperature, flow rate:
0.5 mLminÀ1, DIEA (0.04 equiv)+HOAc (0.04 equiv).
additives;
& 100 bar, room temperature, DIEA (0.04 equiv)+HOAc
(0.04 equiv).
catalytically active CuI species from its matrix by coordinat-
À
ing to it and accelerating the formation of a distinct Cu
telier’s principle, but also allowed the use of higher tempera-
tures without the solvent boiling over. In this way, the
system could be heated to well above the boiling point of
CH2Cl2, whilst the pressure and flow rate were maintained
at 100 bar and 0.5 mLminÀ1, respectively. Figure 3 shows
that the conversion started to increase sharply at about
408C; at 508C, the conversion exceeded 90% and, at 1008C,
practically quantitative conversion was obtained.
alkyne complex (Scheme 4).[3,28,30] It was recently demon-
strated that catalytic amounts of certain acids could further
improve the rate of the reaction through acceleration of the
À
conversion of intermediates that contained C Cu bonds by
protonation (Scheme 4).[28,31] With the aim of moderating
the harsh reaction conditions, we set out to check the effects
of both basic and acidic additives on the rate of the test
CuAAC reaction at room temperature. On the basis of liter-
ature data, N,N-diisopropylethylamine (DIEA) and HOAc
were chosen as the basic and acidic additives, respective-
ly.[28,31] With no additives, at 100 bar, room temperature, and
The fine-tuning of the flow rate is related to the optimiza-
tion of the residence time on the catalyst bed. Longer resi-
dence times lead to higher conversions, but also involve
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As a result of this screening process, we selected two dis-
tinct parameter sets as our optimal conditions: 1) 100 bar,
1008C, flow rate: 0.5 mLminÀ1, without any additives (con-
ditions CF A) and 2) 100 bar, room temperature, flow rate:
0.5 mLminÀ1, with DIEA (0.04 equiv)+HOAc (0.04 equiv)
(conditions CF B). Both sets of conditions afforded quanti-
tative conversion in the test CuAAC reaction between
benzyl azide and phenylacetylene and selectively gave the
1,4-disubstituted 1,2,3-triazole isomer (7) as the product.
These small-scale test experiments afforded about 50 mg of
triazole 7 in each run, without the need for further purifica-
tion after evaporation. At the optimal flow rate of
0.5 mLminÀ1, the residence time on the catalyst bed was as
low as 1.5 min and a process time of only 5 min was needed
to pump through the 2.5 mL aliquot of the reaction mixture.
Scheme 4. Catalytic cycle of the CuAAC reaction, jointly promoted by
an acid and a base.[3,28,30,31]
a flow rate of 0.5 mLminÀ1, a conversion of 34% could be
achieved (Table 1, entry 1). Upon the addition of 0.1 equiva-
lents of HOAc, with maintenance of the same pressure, tem-
perature, and flow rate, the conversion improved to 56%
(Table 1, entry 2) and, when 0.1 equivalents of DIEA were
Scale-Up Experiments
One of the most appealing advantages of flow processing is
its inherent scalability, which means that, in CF production,
the volume is given as a function of time and flow rate,
whereas, in standard flask-based (batch) processes, the
output depends on the batch size.[21b,d,e] The batch scale-up
of processes that involve unstable reactants, such as azides,
can be dangerous, because the accumulation of high concen-
trations of these materials can give rise to an explosive
hazard, whereas, in CF processes, this risk is minimized be-
cause the residence time in the active zone of the reactor is
nicely controllable and the procedure remains simple and
safe, even upon scale-up.
Table 1. Effect of the DIEA/HOAc ratio on the reaction between benzyl
azide and phenylacetylene in a CF reactor.[a]
Entry
DIEA [equiv]
HOAc [equiv]
Conversion[b] [%]
1
2
3
4
5
6
7
8
0
0
0
0.1
0
0.1
0.08
0.04
0.02
0.01
34
56
96
0.1
0.1
0.08
0.04
0.02
0.01
quantitative
quantitative
quantitative
63
To probe the preparative abilities of our above-described
CF methods, the CuAAC reaction between benzyl azide
and phenylacetylene was scaled-up under both conditions
CF A and CF B. A reaction mixture of the azide (1 equiv,
40
[a] 100 bar, room temperature, flow rate: 0.5 mLminÀ1. [b] Determined
1
by H NMR spectroscopy of the crude material.
c
azide =0.085m), the alkyne (1.5 equiv), and DIEA (0.04 equi-
used, the conversion rose further to 96% (Table 1, entry 3).
The best result was obtained with both additives together:
With DIEA (0.1 equiv)+HOAc (0.1 equiv), the reaction
proceeded quantitatively (Table 1, entry 4). Next, we exam-
ined the effect of the amount of DIEA+HOAc on the reac-
tion rate. The addition of 0.04 equivalents of each additive
was sufficient to obtain quantitative conversion (Table 1, en-
tries 5 and 6); however, lower amounts gave lower conver-
sions (Table 1, entries 7 and 8). The pressure dependence of
the reaction with the use of additives was also investigated.
We found that lowering the pressure from 100 bar to atmos-
pheric pressure led to a moderate decrease in conversion
(Figure 2). Consequently, elevated pressure is needed to
obtain good conversions. When the flow rate was increased,
to decrease the residence time on the catalyst bed, at
100 bar and room temperature, with DIEA (0.04 equi-
v)+HOAc (0.04 equiv), we found that the drop in the con-
version was not as steep as under the high-pressure/high-
temperature conditions (Figure 4). This result means that
the joint use of basic and acidic additives can successfully
relive the harsh reaction conditions and appreciably enhance
the efficiency of the flow process.
v)+HOAc (0.04 equiv, only under conditions CF B) in
CH2Cl2 was continuously pumped through the system. In
both experiments, 75 mL of the reaction mixture was
pumped through in 150 min, thus leading to the formation
of about 1.5 g of triazole 7, which was equivalent to a yield
of 99%. This result meant that, altogether, almost 3 g of the
triazole product could be isolated (after evaporation) within
5 h, without the need for any further work-up or purification
steps, in a simple and safe manner.
Investigation of the Scope and Applicability of these CF
Methods
To determine the scope of these CF procedures, a series of
model reactions were performed, some of which afforded
possible precursors of biologically useful compounds. These
reactions were performed under both sets of optimal condi-
tions (CF A and CF B) and the efficacies of these methods
were then compared. In all cases, when terminal alkynes
were used, their corresponding 1,4-disubstituted 1,2,3-tria-
zole isomers were formed selectively.
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Table 2. Model reactions between phenylacetylene and various azides
under optimized conditions in a CF reactor.
Outstanding results were obtained in the reactions be-
tween phenylacetylene and various azides. As shown in
Table 2, both aromatic and aliphatic azides were found to be
excellent substrates for the CF CuAAC reaction. In the case
of aromatic azides, we found that both electron-withdrawing
(Table 2, entries 2–7) and electron-donating groups (Table 2,
entries 8–10) on the phenyl rings were nicely tolerated and
the yields were not significantly affected by the position of
the substituent(s). a-Azido ketones are known to be less re-
active than simple azides in CuAAC reactions, but their cy-
cloaddition reactions with different alkynes can lead to a di-
verse range of compounds of pharmaceutical importance.[32]
Thus, the reaction of 2-azidoacetophenone with phenylace-
tylene was also studied (Table 2, entry 13) and we found
that both CF methods afforded triazole 19 in excellent
yields. Interestingly, the use of additives (conditions CF B)
gave slightly better results in terms of the azide scope and,
in certain cases, somewhat higher yields were afforded than
with method CF A (Table 2, entries 2, 5, 7–9, and 11–13).
As shown in Table 3, a series of alkynes were also tested
as reaction partners of benzyl azide. We found that, besides
phenylacetylene, non-aromatic alkynes, such as pent-1-yne
and ethyl propiolate, performed well in the CF CuAAC re-
action (Table 3, entries 1 and 2). A non-terminal alkyne, di-
ethyl acetylenedicarboxylate, was also successfully utilized
as a dipolarophile, thus giving a high yield of 1,4,5-trisubsti-
tuted triazole 24 (Table 3, entry 3), which is known to be
a potent antitubercular agent.[33] Ferrocene-substituted bio-
molecules are of increasing interest in medicinal chemis-
try:[34] The labeling of biomolecules with ferrocene has been
extensively used for electrochemical detection or for immu-
noassays[35] and the incorporation of ferrocene into amino
acids or peptides has received considerable attention in the
investigation of the secondary structures of different pep-
tides.[36] Thus, the scope of this method was further broad-
ened by the reaction between benzyl azide and ethynyl fer-
rocene. The corresponding ferrocenyl triazole model com-
pound (25) was obtained in excellent yield (99%) with both
CF methods (Table 3, entry 4). In general, conditions CF A
and CF B performed equally well in tests of the alkyne
scope.
Entry
1
Azide
Product
Yield [%][a]
CF A[b] CF B[c]
99
98
99
99
2
3
99
99
4
5
6
99
93
99
99
99
99
7
94
99
8
83
72
99
99
94
99
9
Notably, when the conversion was quantitative and any
excess alkyne could be volatilized on evaporation (phenyla-
cetylene, pent-1-yne, and ethyl propiolate), no further work-
up or purification step was needed.
10
Batch and CF Syntheses of Highly Functionalized
Cispentacin Derivatives
11
12
94
77
99
98
Cispentacin is a naturally occurring carbocyclic b-amino
acid that possesses strong antifungal properties.[37] Several
other related alicyclic b-amino acid derivatives (e.g., icofun-
gipen, oryzoxymycin, etc.) have also been reported to be an-
tibacterial agents.[38] Carbocyclic and heterocyclic b-amino
acids are key elements of a series of bioactive products with
antitumoral, antibacterial, or antiviral activities.[39]
13
96
99
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with ethyl propiolate or diethyl acetylenedicarboxylate,[41]
the batch reactions of phenylacetylene with azido esters 26
or 27 under thermal conditions did not result in the desired
triazole derivatives (28 and 29, respectively). Thus, the use
of a CuI catalyst was necessary. In the presence of CuI in
MeCN at reflux for 12 h, the reactions afforded triazole-sub-
stituted cispentacin derivatives 28 and 29 in only moderate
yields (69% and 73%, respectively; Table 4, entries 1 and
2). For both triazoles, method CF A resulted in yields that
were comparable with those of the batch processes, but,
under conditions CF B, the yields were significantly higher
(99% in both cases) and both triazoles 28 and 29 could be
obtained in their pure form without the need for any further
work-up steps after evaporation (Table 4, entries 1 and 2).
We measured and compared the copper content in unpuri-
fied triazoles 28 and 29 that were synthetized by using both
methods (CF A and CF B). The analytical data in Table 5,
entries 1–4, showed that the level of copper contamination
in the samples that were obtained without any additives
(method CF A) were lower than those when DIEA+HOAc
were jointly applied (method CF B).
Table 2. (Continued)
Entry
Azide
Product
Yield [%][a]
CF A[b] CF B[c]
14
99
99
99
99
15
[a] Yield of isolated product. [b] Conditions CF A: 100 bar, 1008C, flow
rate: 0.5 mLminÀ1, without any additives. [c] Conditions CF B: 100 bar,
room temperature, flow rate: 0.5 mLminÀ1
, with DIEA (0.04 equi-
v)+HOAc (0.04 equiv).
Table 3. Model reactions between benzyl azide and various alkynes
under optimized conditions in a CF reactor.
Next, azido-substituted cispentacin derivatives 26 and 27
were subjected to dipolar cycloaddition with ethynyl ferro-
cene in batch processes in the presence of CuI at reflux in
MeCN. Surprisingly, no transformations were detected
under these conditions. On changing the catalyst from CuI
to CuSO4/ascorbic acid, the reaction furnished ferrocenyl tri-
azole derivatives 30 and 31 in moderate yields (51% and
69%, respectively) within 14 h (Table 4, entries 3 and 4). In
contrast, under conditions CF A or CF B, triazoles 30 and 31
were obtained in excellent yields (99%) in both cases
(Table 4, entries 3 and 4). Because the excess ethynyl ferro-
cene was not volatilized on evaporation, purification of the
crude product by column chromatography on silica gel was
required after both CF reactions. In the cases of triazoles 30
and 31, their copper content was determined after purifica-
tion. As shown in Table 5, entries 5–8, the levels of copper
impurities in both methods decreased considerably after
flash column chromatography.
Entry
1
Acetylene
Product
Yield [%][a]
CF A[b] CF B[c]
94
99
91
99
2
3
84
99
82
99
4
Thus, method CF B was found to be more efficient for the
synthesis of triazole-modified cispentacin derivatives. How-
ever, a direct comparison with the batch results is difficult,
because the local copper concentration in the flow tech-
nique is much higher than that in a simple flask reaction
and the batch reactions were performed in larger volumes
than the CF experiments. Nonetheless, the short process
times, the excellent yields and efficacy, the ease of product
isolation, and the opportunity for the simple and safe scale-
up of the reaction demonstrate the outstanding synthetic ca-
pabilities of this CF method. This CF method may also be
useful for the synthesis of products that are derived from
large biomolecules (such as peptides, dendrimers, and
sugars),[42] although its applicability to hydrophilic structures
is limited, owing to the non-polar reaction medium that is
used. The presence of trace amounts of copper in the isolat-
ed reaction products must be acknowledged as another po-
tential drawback. However, it should be emphasized that
[a] Yield of isolated product. [b] Conditions CF A: 100 bar, 1008C, flow
rate: 0.5 mLminÀ1, without any additives. [c] Conditions CF B: 100 bar,
room temperature, flow rate: 0.5 mLminÀ1
, with DIEA (0.04 equi-
v)+HOAc (0.04 equiv).
We investigated the application of our CF CuAAC proce-
dures (CF A and CF B) for the synthesis of potentially bio-
active 1,2,3-triazole-modified cispentacin derivatives, in
comparison with the results that were obtained by using
standard batch techniques. In all cases, the 1,4-disubstituted
triazole isomers were formed selectively. To prepare tria-
zole-modified cispentacins, either under batch conditions or
by using CF methods, the previously synthetized azido-sub-
stituted cispentacins (26 and 27) were used as reaction part-
ners of phenylacetylene or ethynyl ferrocene.[40] Compounds
26 and 27 were racemates; the structures in Table 4 show
their relative stereochemistry. In contrast to the reactions
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Table 4. Synthesis of highly functionalized cispentacin derivatives in a CF reactor and under standard batch condi-
tions.
Conclusions
A simple and inexpensive CF
method was implemented for
the 1,3-dipolar cycloaddition of
organic azides and acetylenes,
which utilized Cu powder as
the cheapest available CuI
source. The need for costly ap-
paratus and special catalyst spe-
cies is eliminated and the high-
pressure/high-temperature con-
ditions were successfully mod-
erated through the joint use of
basic and acidic additives to
maximize the reaction rates.
The benefits of flow processing
meant that the risks that were
associated with the handling of
dangerous azides were signifi-
cantly reduced and gram-scale
syntheses were successfully ach-
Entry
1
Azide
Acetylene
Product
Yield [%][a]
CF A[b]
CF B[c]
Batch
69[d]
62
99
99
2
3
42
99
73[d]
99
99
51[e]
ieved in
a safe and simple
4
99
69[e] manner. This CF technique has
a wide scope for azides and al-
kynes and selectively results in
[a] Yield of isolated product. [b] Conditions CF A: 100 bar, 1008C, flow rate: 0.5 mLminÀ1, without any additives.
synthetically useful 1,4-disubsti-
tuted 1,2,3-triazole compounds
in excellent yields within short
process times, some of which
have notable biological activity.
The utilization of additives in
flow processes not only im-
proved the safety but also effi-
[c] Conditions CF B: 100 bar, room temperature, flow rate: 0.5 mLminÀ1
, with DIEA (0.04 equiv)+HOAc
(0.04 equiv). [d] To a solution of azido ester 26 or 27 (1 equiv) in MeCN were added CuI (1 equiv) and alkyne
(1.1 equiv) and the mixture was stirred under reflux for 12 h. [e] To a solution of azido ester 26 or 27 (1 equiv) in
EtOH/water (12:1) were added CuSO4 (1 equiv), ascorbic acid (1 equiv), and alkyne (1.1 equiv) and the mixture
was stirred at room temperature for 14 h.
cacy of these reactions and typically afforded higher yields
than under the high-temperature conditions. Some highly
functionalized derivatives of the antifungal cispentacin were
also effectively synthetized with this CF methodology and
also with conventional batch procedures, thus demonstrating
the outstanding synthetic capabilities of flow processing.
The cispentacin derivatives are interesting precursors for
new triazole carbanucleosides with possible biological activi-
ties.
Table 5. Copper content in the triazole-modified cispentacins that were
obtained by using various CF methods.
[a]
Entry
Triazole product
Method
Copper content [mggÀ1
]
1
2
3
4
5
6
7
8
28
28
29
29
30
30
31
31
CF A
CF B
CF A
CF B
CF A
CF B
CF A
CF B
14.8
70.1
(Æ1.4)[b]
12.1
(Æ0.7)[b]
66.2
(Æ1.5)[b]
4.4
(Æ0.3)[c]
7.1
(Æ0.6)[c]
5.2
(Æ0.5)[c]
7.3
(Æ0.7)[c]
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[a] Determined by ICP-MS. [b] Without chromatographic purification.
[c] After purification by column chromatography on silica gel.
Experimental Section
General Information
The reagents and materials were of the highest commercially available
purity and were used without any further purification steps. Flash column
chromatography was performed on Merck silica gel 60 (particle size: 63–
200 mm) and analytical thin-layer chromatography (TLC) was performed
on Merck silica gel 60 F254 plates. Compounds were visualized by UV ir-
radiation or by staining with KMnO4. 1H NMR, 13C HSQC, and
13C HMBC NMR spectra were recorded on a Bruker Avance DRX 400
spectrometer in CDCl3 with TMS as an internal standard (1H: 400.1, 13C:
100.6 MHz). Microanalysis was performed on a Perkin–Elmer 2400 ele-
mental analyzer. A H-Cube system was used as a CF reactor.
copper is a biogenic substance, unlike many other heavy
metals, and simple chromatographic purification can de-
crease its content substantially, as shown in Table 5. The
copper content in our triazole products compare well with
other literature results of CF[22b] or batch processes.[43]
Chem. Asian J. 2013, 8, 800 – 808
806
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org
Ferenc Fꢂlçp et al.
Determination of the Copper Content of the Triazole Products
Measurement of the Residence Time on the Catalyst Bed
Copper concentrations were determined by inductively coupled plasma
mass spectrometry on an Agilent 7700x-type instrument that was
equipped with a collision cell. Determination of the copper content was
performed on the 63Cu isotope by using He as a collision gas. The stan-
dard solutions for external calibration were prepared from a stock solu-
tion (Certipur, Merck), by dilution with doubly deionized water (Milli-
pore MillQ, Merck). All glassware and plastic utensils that were used
during the determination were pre-cleaned by alternately soaking in solu-
tions of trace-quality nitric acid and hydrochloric acid (Suprapur,
Merck), followed by rinsing with copious amounts of doubly deionized
water.
A solution of a blue ink in CH2Cl2 was pumped through the system and
the time that elapsed between the first contact of the ink with the cata-
lyst bed and the moment when the blue color appeared at the column
output was measured to determine the residence time.
Acknowledgements
We are grateful to the Hungarian Research Foundation (OTKA;
NK81371, PD103994, and K100530). I.M.M. acknowledges the award of
a Jꢁnos Bolyai Scholarship from the Hungarian Academy of Sciences.
Preparation of Benzylic and Aliphatic Azides
NaN3 (25 mmol, 1.5 equiv) was added to a stirring solution of the corre-
sponding bromide (17 mmol, 1 equiv) in DMSO (25 mL) and the result-
ing mixture was stirred at 608C for 4 h. Then, brine and Et2O were
added to the solution and the organic layer was washed thoroughly with
brine. Next, the combined organic layers were dried over Na2SO4 and the
solvent was removed under reduced pressure. The corresponding azides
were obtained in a purity of >99% and were used in subsequent reac-
tions without further work-up.[44]
[1] R. Huisgen in 1,3-Dipolar Cycloadditional Chemistry (Ed.: A.
Padwa), Wiley, New York, 1984, pp. 1–176.
[2] a) R. Huisgen, G. Szeimis, L. Moebius, Chem. Ber. 1967, 100, 2494;
b) R. Huisgen, Pure Appl. Chem. 1989, 61, 613.
[3] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew.
Chem. 2002, 114, 2708; Angew. Chem. Int. Ed. 2002, 41, 2596.
[4] C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67,
3057.
Preparation of Phenyl Azide
[5] L. Zhang, X. Chen, P. Xue, H. H. Y. Sun, I. D. Williams, K. B. Sharp-
less, V. V. Fokin, G. Jia, J. Am. Chem. Soc. 2005, 127, 15998.
[6] For reviews, see: a) R. K. Iha, K. L. Wooley, A. M. Nystrom, D. J.
Burke, M. J. Kade, C. J. Hawker, Chem. Rev. 2009, 109, 5620;
b) A. J. Qin, J. W. Y. Lam, B. Z. Tang, Chem. Soc. Rev. 2010, 39,
2522; c) K. Kempe, A. Krieg, C. R. Becer, U. S. Schubert, Chem.
Soc. Rev. 2012, 41, 176.
[7] For reviews, see: a) Y. Hua, A. H. Flood, Chem. Soc. Rev. 2010, 39,
1262; b) A. C. Fahrenbach, J. F. Stoddart, Chem. Asian J. 2011, 6,
2660; c) P.-A. Faugeras, B. Boens, P.-H. Elchinger, F. Brouillette, D.
Montplaisir, R. Zerrouki, R. Lucas, Eur. J. Org. Chem. 2012, 4087.
[8] For reviews, see: a) A. H. El-Sagheer, T. Brown, Chem. Soc. Rev.
2010, 39, 1388; b) X. Li, Chem. Asian J. 2011, 6, 2606; c) D. S. Peder-
sen, A. Abell, Eur. J. Org. Chem. 2011, 2399.
[9] For reviews, see: a) K. B. Sharpless, R. Manetsch, Expert Opin.
Drug Discovery 2006, 1, 525; b) K. A. Kalesh, P.-Y. Yang, R. Sriniva-
san, S. Q. Yao, QSAR Comb. Sci. 2007, 26, 1135; c) C. M. Salisbury,
B. F. Cravatt, QSAR Comb. Sci. 2007, 26, 1229.
[10] For reviews, see: a) C. Hein, X.-M. Liu, D. Wang, Pharm. Res. 2008,
25, 2216; b) A. D. Moorhouse, J. E. Moses, ChemMedChem 2008, 3,
715; c) S. G. Agalave, S. R. Maujan, V. S. Pore, Chem. Asian J. 2011,
6, 2696; d) J. L. Hou, X. F. Liu, J. Shen, G. L. Zhao, P. G. Wang,
Expert Opin. Drug Discovery 2012, 7, 489.
Aniline (10 mmol, 1 equiv) was suspended in 17% hydrochloric acid
(60 mL) at RT and EtOH (5 mL) was added. The mixture was cooled to
08C and NaNO2 (15 mmol, 1.5 equiv) was added in small portions. After
stirring at 08C for 30 min, NaN3 (15 mmol, 1.5 equiv) was slowly added
and the mixture was stirred for an additional 2 h at RT. The reaction mix-
ture was extracted with Et2O and the combined organic layers were
washed with a saturated solution of NaHCO3 and with brine.[44] After
drying over Na2SO4, the solvent was evaporated and phenyl azide was
obtained in a purity of 98%. The product was used in subsequent reac-
tions without further work-up.[44]
General Procedure for the CF Reactions
For the CF reactions, the azide (0.21 mmol, 1 equiv) and the alkyne
(0.32 mmol, 1.5 equiv), as well as DIEA (0.0084 mmol, 0.04 equiv) and
HOAc (0.0084 mmol, 0.04 equiv) in method CF B, were dissolved in
CH2Cl2 (2.5 mL). The solution was homogenized by sonication for 1 min
and then pumped through the CF reactor under the appropriate condi-
tions. The crude product was checked by TLC (n-hexane/EtOAc) and the
solvent was removed under reduced pressure. If necessary, the products
were purified by column chromatography on silica gel (n-hexane/
EtOAc). The triazole products were characterized by elemental analysis
and NMR spectroscopy. For detailed analytical data, see the Supporting
Information. Between two reactions in the CF reactor, the catalyst bed
[11] Y. Xia, Z. Fan, J. Yao, Q. Liao, W. Li, F. Qu, L. Peng, Bioorg. Med.
Chem. Lett. 2006, 16, 2693.
was washed for 5 min with CH2Cl2 at a rate of 1 mLminÀ1
.
[12] F. Reck, F. Zhou, M. Girardot, G. Kern, C. J. Eyermann, N. J. Hales,
R. R. Ramsay, M. B. Gravestock, J. Med. Chem. 2005, 48, 499.
[13] P. M. Chaudhary, S. R. Chavan, F. Shirazi, M. Razdan, P. Nimkar,
S. P. Maybhate, A. P. Likhite, R. Gonnade, B. G. Hazara, M. V.
Deshpande, S. R. Deshpande, Bioorg. Med. Chem. 2009, 17, 2433.
[14] M. J. Soltis, H. J. Yeh, K. A. Cole, N. Whittaker, R. P. Wersto, E. C.
Kohn, Drug Metab. Dispos. 1996, 24, 799.
General Procedure for the CuI-Catalyzed Batch Reaction
CuI (1.95 mmol, 1 equiv) and alkyne (2.15 mmol, 1.1 equiv) were added
to a solution of azido ester 26 or 27 (1.95 mmol, 1 equiv) in MeCN and
the mixture was stirred under reflux for 12 h. The solvent was then re-
moved under vacuum and the residue was purified by column chromatog-
raphy on silica gel (n-hexane/EtOAc, 2:1).
[15] J. Li, M. Zheng, W. Tang, P.-L. He, W. Zhu, T. Li, J.-P. Zuo, H. Liu,
H. Jiang, Bioorg. Med. Chem. Lett. 2006, 16, 5009.
[16] J. H. Cho, D. L. Bernard, R. W. Sidwell, E. R. Kern, C. K. Chu, J.
Med. Chem. 2006, 49, 1140.
[17] a) Microreactors in Organic Synthesis and Catalysis (Ed.: T. Wirth),
Wiley-VCH, Weinheim, 2008; for reviews, see: b) T. Razzaq, C. O.
Kappe, Chem. Asian J. 2010, 5, 1274; c) C. Wiles, P. Watts, Chem.
Commun. 2011, 47, 6512; d) J. Yoshida, H. Kim, A. Nagaki, Chem-
SusChem 2011, 4, 331; e) C. Wiles, P. Watts, Green Chem. 2012, 14,
38; f) J. Wegner, S. Ceylan, A. Kirschning, Adv. Synth. Catal. 2012,
354, 17.
General Procedure for the CuSO4/Ascorbic-Acid-Catalyzed Batch
Reaction
CuSO4 (1.95 mmol, 1 equiv), ascorbic acid (1.95 mmol, 1 equiv), and
alkyne (2.15 mmol, 1.1 equiv) were added to a solution of azido ester 26
or 27 (1.95 mmol, 1 equiv) in EtOH (6 mL) and water (0.5 mL) and the
mixture was stirred at RT for 14 h. The solvent was removed under
vacuum and the residue was purified by column chromatography on
silica gel (n-hexane/EtOAc, 1:1).
[18] a) V. Hessel, Chem. Eng. Technol. 2009, 32, 1655; b) R. L. Hartman,
J. P. McMullen, K. F. Jensen, Angew. Chem. 2011, 123, 7642; Angew.
Chem. Asian J. 2013, 8, 800 – 808
807
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org
Ferenc Fꢂlçp et al.
Chem. Int. Ed. 2011, 50, 7502; c) K. D. Nagy, B. Shen, T. F. Jamison,
K. F. Jensen, Org. Process Res. Dev. 2012, 16, 976.
[29] For a review, see: a) M. Meldal, C. W. Tornoe, Chem. Rev. 2008, 108,
2952; and references therein.
[19] a) A. J. deMello, Nature 2006, 442, 394; b) N. W. Wang, T. Matsumo-
to, M. Ueno, H. Miyamura, S. Kobayashi, Angew. Chem. 2009, 121,
4838; Angew. Chem. Int. Ed. 2009, 48, 4744; c) J. Yoshida, Chem.
Rec. 2010, 10, 332; d) S. B. ꢀtvçs, I. M. Mꢁndity, F. Fꢂlçp, ChemSu-
sChem 2012, 5, 266; e) S. B. ꢀtvçs, I. M. Mꢁndity, F. Fꢂlçp, J. Catal.
2012, 295, 179.
[20] a) M. Ueno, T. Suzuki, T. Naito, H. Oyamada, S. Kobayashi, Chem.
Commun. 2008, 1647; b) J. Yoshida, A. Nagaki, T. Yamada, Chem.
Eur. J. 2008, 14, 7450; c) D. Popa, R. Marcos, S. Sayalero, A. Vidal-
Ferran, M. A. Pericas, Adv. Synth. Catal. 2009, 351, 1539; d) S. B.
ꢀtvçs, I. M. Mꢁndity, F. Fꢂlçp, Mol. Diversity 2011, 15, 605; e) M.
Rasheed, T. Wirth, Angew. Chem. 2011, 123, 374; Angew. Chem. Int.
Ed. 2011, 50, 357; f) A. J. Parrott, R. A. Bourne, G. R. Akien, D. J.
Irvine, M. Poliakoff, Angew. Chem. 2011, 123, 3872; Angew. Chem.
Int. Ed. 2011, 50, 3788.
[30] V. O. Rodionov, V. V. Fokin, M. G. Finn, Angew. Chem. 2005, 117,
2250; Angew. Chem. Int. Ed. 2005, 44, 2210.
[31] a) C. Nolte, P. Mayer, B. F. Straub, Angew. Chem. 2007, 119, 2147;
Angew. Chem. Int. Ed. 2007, 46, 2101; b) C. Shao, G. Cheng, D. Su,
J. Xu, X. Wang, Y. Hu, Adv. Synth. Catal. 2010, 352, 1587; c) C.
Shao, X. Wang, J. Xu, J. Zhao, Q. Zhang, Y. Hu, J. Org. Chem. 2010,
75, 7002.
[32] For a review, see: T. Patonay, K. Konya, E. Juhasz-Toth, Chem. Soc.
Rev. 2011, 40, 2797.
[33] P. Shanmugavelan, S. Nagarajan, M. Sathishkumar, A. Ponnuswamy,
P. Yogeeswari, D. Sriram, Bioorg. Med. Chem. Lett. 2011, 21, 7273.
[34] For reviews, see: a) M. F. R. Fouda, M. M. Abd-Elzaher, R. A. Ab-
delsamaia, A. A. Labib, Appl. Organomet. Chem. 2007, 21, 613;
b) V. Ganesh, V. S. Sudhir, T. Kundu, S. Chandrasekaran, Chem.
Asian J. 2011, 6, 2670.
[21] a) M. Baumann, I. R. Baxendale, S. V. Ley, C. D. Smith, G. K.
Tranmer, Org. Lett. 2006, 8, 5231; b) P. J. Nieuwland, R. Segers, K.
Koch, J. C. M. van Hest, F. P. J. T. Rutjes, Org. Process Res. Dev.
2011, 15, 783; c) C. J. Smith, N. Nikbin, S. V. Ley, H. Lange, I. R.
Baxendale, Org. Biomol. Chem. 2011, 9, 1938; d) N. Kockmann, M.
Gottsponer, D. M. Roberge, Chem. Eng. J. 2011, 167, 718; e) L. L.
Wong, R. L. Wong, G. Loh, P. E. W. Tan, S. K. Teoh, S. M. Shaik,
P. N. Sharratt, W. Chew, S. T. Tan, D. Wang, Org. Process Res. Dev.
2012, 16, 1003.
[22] a) B. H. Lipshutz, B. R. Taft, Angew. Chem. 2006, 118, 8415; Angew.
Chem. Int. Ed. 2006, 45, 8235; b) M. Fuchs, W. Goessler, C. Pilger,
C. O. Kappe, Adv. Synth. Catal. 2010, 352, 323.
[23] a) C. Girard, E. Onen, M. Aufort, S. Beauviꢅre, E. Samson, J. Her-
scovici, Org. Lett. 2006, 8, 1689; b) C. D. Smith, I. R. Baxendale, S.
Lanners, J. J. Hayward, S. C. Smith, S. V. Ley, Org. Biomol. Chem.
2007, 5, 1559; c) S. ꢀzÅubukÅu, E. Ozkal, C. Jimeno, M. A. Pericꢁs,
Org. Lett. 2009, 11, 4680; d) E. Ozkal, S. ꢀzÅubukÅu, C. Jimeno,
M. A. Pericꢁs, Catal. Sci. Technol. 2012, 2, 195.
[35] a) H. Song, K. Kerman, H.-B. Kraatz, Chem. Commun. 2008, 502;
b) D. Ge, R. Levicky, Chem. Commun. 2010, 46, 7190.
[36] For reviews, see: D. R. van Staveren, N. Metzler-Nolte, Chem. Rev.
2004, 104, 5931.
[37] M. Konishi, M. Nishio, K. Saitoh, T. Miyaki, T. Oki, H. Kawaguchi,
J. Antibiot. 1989, 42, 1749.
[38] a) T. Goto, Y. Toya, T. Kondo, Nucleic Acids Symp. Ser. 1980, 8, 73;
b) M. E. Bunnage, T. Ganesh, I. B. Masesane, D. Orton, P. G. Steel,
Org. Lett. 2003, 5, 239; c) A. Hasenoehrl, T. Galic, G. Ergovic, N.
Marsic, M. Skerlev, J. Mittendorf, U. Geschke, A. Schmidt, W.
Schoenfeld, Antimicrob. Agents Chemother. 2006, 50, 3011.
[39] For a review, see: a) F. Fꢂlçp, Chem. Rev. 2001, 101, 2181; b) L.
Kiss, E. Forro, F. Fꢂlçp in Amino Acids, Peptides and Proteins in Or-
ganic Chemistry (Ed.: A. B. Hughes), Wiley-VCH, Weinheim, 2009,
pp. 367–409.
[40] a) L. Kiss, E. Forro, R. Sillanpaa, F. Fꢂlçp, J. Org. Chem. 2007, 72,
8786; b) L. Kiss, E. Forro, F. Fꢂlçp, Synthesis 2010, 153.
[41] a) L. Kiss, E. Forro, R. Sillanpaa, F. Fꢂlçp, Tetrahedron 2010, 66,
3599; b) L. Kiss, E. Forro, R. Sillanpaa, F. Fꢂlçp, Tetrahedron:
Asymmetry 2008, 19, 2856.
[24] a) A. R. Bogdan, N. W. Sach, Adv. Synth. Catal. 2009, 351, 849;
b) A. R. Bogdan, K. James, Chem. Eur. J. 2010, 16, 14506; c) S.
Ceylan, T. Klande, C. Vogt, C. Friese, A. Kirschning, Synlett 2010,
2009; d) A. R. Bogdan, K. James, Org. Lett. 2011, 13, 4060.
[25] A. C. Varas, T. Noel, Q. Wang, V. Hessel, ChemSusChem 2012, 5,
1703.
[42] M. L. Conte, M. J. Robb, Y. Hed, A. Marra, M. Malkoch, C. J.
Hawker, A. Dondoni, J. Polym. Sci. Part A 2011, 49, 4468.
[43] S. Kovacs, K. Zih-Perenyi, A. Revesz, Z. Novak, Synthesis 2012, 44,
3722.
[26] R. V. Jones, L. Godorhazy, N. Varga, D. Szalay, L. Urge, F. Darvas,
J. Comb. Chem. 2006, 8, 110.
[44] I. Wilkening, G. d. Signore, C. P. R. Hackenberger, Chem. Commun.
2011, 47, 349.
[27] J. E. Boggio, J. Chem. Phys. 1979, 70, 5054.
Received: November 26, 2012
[28] C. Shao, X. Wang, Q. Zhang, S. Luo, J. Zhao, Y. Hu, J. Org. Chem.
2011, 76, 6832.
Revised: December 20, 2012
Published online: February 12, 2013
Chem. Asian J. 2013, 8, 800 – 808
808
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim