"Click" Chemistry: Application of Copper Metal in Cu-Catalyzed Azomethine Imine-Alkyne Cycloadditions

Article abstract of DOI:10.1021/acs.joc.6b00945

A series of 16 copper-catalyzed azomethine imine-alkyne cycloaddition (CuAIAC) reactions between four pyrazolidinone-1-azomethine imines and four terminal ynones gave the corresponding fluorescent cycloadducts as bimane analogues in very high yields. The applicability of CuAIAC was demonstrated by the fluorescent labeling of functionalized polystyrene and by using Cu-C and Cu-Fe as catalysts. Experimental evidence, kinetic measurements, and correlation between a clean catalyst surface and the reaction rate are in agreement with a homotopic catalytic system with catalytic Cu^I-acetylide formed from Cu⁰ by "in situ" oxidation. The availability of azomethine imines, mild reaction conditions, simple workup, and scalability make CuAIAC a viable supplement to the Cu-catalyzed azide-alkyne cycloaddition reaction in "click" chemistry.

Full text of DOI:10.1021/acs.joc.6b00945

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Article
'Click' chemistry: Application of copper metal in Cu-
catalyzed azomethine imine–alkyne cycloadditions (CuAIAC).
Eva Pušavec Kirar, Uroš Grošelj, Giorgio Mirri, Franc Pozgan,
Gregor Strle, Bogdan Stefane, Vasko Jovanovski, and Jurij Svete
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00945 • Publication Date (Web): 15 Jun 2016
Downloaded from http://pubs.acs.org on June 15, 2016
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'Click' chemistry: Application of copper metal in Cu-catalyzed azomethine
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imine–alkyne cycloadditions (CuAIAC).
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Eva Pušavec Kirar,† Uroš Grošelj,† Giorgio Mirri,†,1 Franc Požgan,† Gregor Strle,†,2 Bogdan
Štefane,† Vasko Jovanovski,‡ and Jurij Svete†,*,3
†
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-
1000 Ljubljana, Slovenia
‡ National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
E-mail: jurij.svete@fkkt.uni-lj.si
Abstract — A series of 16 copper metal-catalyzed CuAIAC reactions between four
pyrazolidinone-1-azomethine imines and four terminal ynones gave the corresponding
fluorescent cycloadducts as bimane analogues in very high yields. Applicability of CuAIAC was
demonstrated by fluorescent labelling of functionalized polystyrene and by using Cu–C and Cu–
Fe as catalysts. Experimental evidence, kinetic measurements and correlation between a clean
catalyst surface and the reaction rate are in agreement with homotopic catalytic system with
catalytic CuI-acetylide formed from Cu0 by 'in situ' oxidation. Availability of azomethine imines,
1
Current address: AquafilSLO D.o.o., Letališka cesta 15, SI-1001 Ljubljana, Slovenia
2
Current address: Krka, d.d., Šmarješka cesta 6, SI-8501 Novo mesto, Slovenia
3
Corresponding author. Tel.: +386 1 4798 562; Fax: +386 1 2419 144; e-mail:
jurij.svete@fkkt.uni-lj.si
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mild reaction conditions, simple workup, and scalability make CuAIAC a viable supplement to
CuAAC reaction in 'click' chemistry.
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Keywords: 'Click' Chemistry; Azomethine Imines; Terminal Ynones; Cu-Catalysis; Fluorescent
Labelling.
1. Introduction
Since its definition by Kolb, Finn, and Sharpless in 2001, 'click' chemistry became an
important methodology of modern synthetic organic chemistry comprising various highly
efficient reactions, such as nucleophilic opening of spring-loaded rings, non-aldol type carbonyl
chemistry, additions to C–C multiple bonds, and cycloadditions.1 Within a variety of 'click'
reactions, the Cu-catalyzed azide-alkyne cycloaddition (CuAAC), discovered independently by
the groups of Meldal2 and Fokin and Sharpless,3 has been the first and the most prominent
example of 'click' reaction.1–4 No wonder that CuAAC found a widespread use in connecting
different types of small as well as macromolecular units. Nowadays, CuAAC is a standard
ligation tool in combinatorial synthesis,4,5 bioconjugation,6 and in material science.7 A limitation
of CuAAC is due to explosive properties of organic azides – for the safety reasons CuAAC
reactions are usually performed on a small scale.
In their first publication,1 Sharpless and co-workers already recognized the potential of
selective 3+2 cycloadditions of azomethine imines for applications in 'click' chemistry.8 In the
shade of successful story of CuAAC that started next year, cycloadditions of azomethine imines
did not make their breakthrough in 'click' chemistry. Nevertheless, few yet relevant papers
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published in the meantime clearly revealed the potential of Cu-catalyzed azomethine imine-
alkyne cycloaddition (CuAIAC). In 2003 and 2005, Fu and co-workers reported CuAIAC as a
tool for regio- and enantioselective synthesis of bicyclic pyrazolidinones in excellent yields and
selectivity using CuI-based chiral catalysts.9a,b Since then, around dozen examples of highly
selective and efficient CuAIAC reactions have been reported.9c–f,10,11 These results clearly
showed suitability of CuAIAC for connecting azomethine imine- and acetylene-functionalized
molecules under conditions compliant with 'click' chemistry requirements. In the conventional
CuAAC 'click' chemistry, the azide- and alkyne-functionalized building blocks (BBs) are reacted
in the presence of Cu-catalyst to afford, regioselectively, the 1,2,3-triazole-linked conjugate. In
the CuAIAC version, the azide BB is replaced by its azomethine imine equivalent, easily
available from a pyrazolidinone and an aldehyde, to give 1-oxo-2,3-dihydro-1H,5H-pyrazolo[1,2-
a]pyrazole-linked conjugate. When CuAIAC is carried out with ynones (R2 = acyl), a yellow
fluorescent pyrazolo[1,2-a]pyrazole linker (a bimane12 analogue) is obtained. This implies
applicability of CuAIAC, not only as a ligation tool, but also in concomitant fluorescent labelling
(Figure 1).
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Figure 1. CuAAC and CuAIAC reaction.
Homogeneous chiral CuI-catalysts have been used in asymmetric CuAIAC reactions,9,11
while achiral, mostly heterogeneous CuI-catalysts have been employed for the preparation of
racemic cycloadducts.10,11 When 'click'-connection of two BBs is the primary objective, mild and
simple reaction conditions, broad scope, modularity, and ease of preparation become more
important than asymmetric induction. Although copper metal (Cu0) should be suitable catalyst for
this purpose, to the best of our knowledge, its use as a catalyst in CuAIAC reaction has not been
reported.
In continuation of our work on 3-pyrazolidinone-1-azomethine imines,10a,h,13 we recently
observed, that cycloadditions to ynones were catalyzed by copper metal. This triggered our
decision to study copper metal-catalyzed CuAIAC reaction and its applicability in 'click'
chemistry (cf. Figure 1). Herein, we report the results of this study showing copper metal as
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suitable catalyst and CuAIAC as a viable supplement to CuAAC reaction.
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2. Results and Discussion
2.1. Determination of optimum reaction conditions. Copper metal-catalyzed reaction of 2-
benzylidene-3,3-dimethyl-5-oxopyrazolidin-2-ium-1-ide 1{1}9a,10b,14a,b with 1.2 eq. methyl
propiolate 2{1} at r.t. was used for the optimization of reaction conditions with respect to the
solvent, reaction time and catalyst loading. The results are presented in Table 1. First, reactions
were performed in various standard solvents in the presence of 20 ww% of Cu-powder for 24 h
(Table 1, entries 1–8). The conversion was low in DMF, ethanol, and THF (10–25%). In
acetonitrile, 93% conversion was achieved. In the above solvents, formation of small amounts of
bright yellow insoluble CuC≡C–CO2Me (Cu-2{1})10g,15 was observed. Complete conversion was
obtained in EtOAc, toluene, CHCl3, and CH2Cl2. However, CHCl3 and CH2Cl2 were the most
suitable solvents due to fast and clean conversion and devoid of by-products formed in EtOAc
and toluene. Consequently, reaction in CH2Cl2 was further evaluated (Table 1, entries 9–11). The
conversion was slowed down by lower catalyst loading and almost stopped upon addition of
Hünig's base (DIPEA). This was surprising, since DIPEA worked well in combination with CuI-
catalyst.10h In the control experiment (Table 1, entry 12), only 5% conversion was achieved upon
19 h.
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Table 1. Optimization of reaction conditions.a,b
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Entry Solvent
Cu (mg) Time (h) Conversion (%)b
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DMF
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EtOAc
PhMe
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CHCl3
CH2Cl2
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CH2Cl2
CH2Cl2
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a) All reactions were performed at r.t. with 0.25 mmol of 1{1} and 0.30 mmol 2{1} in 1.5 mL of
b
1
solvent, followed by filtration and evaporation. ) The conversions were determined from the H
NMR spectra of the crude products. c) Small amount of Cu-acetylide precipitated. d) By-products
were formed. e) 100% conversion was achieved already after 16 h. f) In the presence of 0.5 equiv.
of DIPEA.
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2.2. Synthesis of representative cycloadducts. Four model azomethine imines 1{1–4}14 were
prepared by treatment of 5,5-dimethyl-3-pyrazolidinone (4)16 with benzaldehydes 5{1–4}
following general literature procedure.11,14c Next, a library of 16 cycloadducts 3{1–4; 1–4} was
synthesized by reacting the representative dipoles 1{1–4} with model terminal alkynes 2{1–4}
bearing different acyl groups. Reactions were performed under previously determined optimum
reaction conditions (cf. Table 1, entry 8). The workup comprised removal of the catalyst by
filtration, followed by evaporation. Purification by flash chromatography (FC) was sometimes
applied to remove excess of dipolarophile and to increase the purity (Scheme 1, Table 2). The
conversion of starting dipoles 1 was nearly quantitative after one day to give cycloadducts 3{1–4;
1–4} in 66–99% isolated yields. The experimental data revealed negligible effect of substituents
R1 and R2 on the reactivity of dipoles 1 and dipolarophiles 2. The only exception was a very slow
reaction of the bulkiest reactants 1{2} and 2{4} (Table 2, entry 8), which was explainable by the
steric hindrance between the 3,4,5-trimethoxybenzylidene residue of 1{2} and the benzoyl group
of 2{4}. In summary, neither the structure of dipole 1, nor the structure of ynone 2 did affect the
reaction time significantly. To test scalability, cycloaddition of 1{4} to 2{1} was also performed
on a 20 times larger scale without any effect on conversion and yield of 3{4; 1} (Table 2).
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Scheme 1. Synthesis of the representative cycloadducts 3{1–4; 1–4}.
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Reaction conditions: (i) aldehyde 5{1–4}, EtOH, TFA (cat.) r.t.; (ii) ynone 2{1–4}, CH2Cl2, Cu
powder (40 mg/mmol), r.t., 18–120 h.
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Table 2. Experimental data for a library of cycloadducts 3{1–4; 1–4}.a
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Entry Transformation
Time (h) Conversion (%)b
Yield (%)c
92
1
1{1}+2{1}→3{1; 1}
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95
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2
1{1}+2{2}→3{1; 2}
1{1}+2{3}→3{1; 3}
1{1}+2{4}→3{1; 4}
1{2}+2{1}→3{2; 1}
1{2}+2{2}→3{2; 2}
1{2}+2{3}→3{2; 3}
1{2}+2{4}→3{2; 4}
1{3}+2{1}→3{3; 1}
1{3}+2{2}→3{3; 2}
1{3}+2{3}→3{3; 3}
1{3}+2{4}→3{3; 4}
1{4}+2{1}→3{4; 1}
1{4}+2{2}→3{4; 2}
1{4}+2{3}→3{4; 3}
1{4}+2{4}→3{4; 4}
92
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a) All reactions were performed at r.t. with 0.5 mmol of 1 and 0.6 mmol of 2 in 3 mL of CH2Cl2
b
in the presence of 20 mg of Cu powder, followed by filtration and evaporation. ) Determined
from the 1H NMR spectra of the crude reaction mixtures. ) Isolated yield. d) Identical result was
c
obtained on a 10 mmol scale.
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2.3. Applicability. To test its applicability as a ligation tool, CuAIAC reaction was employed
for fluorescent labelling of functionalized polymeric materials. Attachment through the ynone
component was investigated first. Treatment of chloromethylated polystyrene (Merrifield resin
(6)) with propiolic acid in the presence of NaI and DIPEA provided the polymer-bound
propiolate 2{5},17 which was reacted with azomethine imine 1{1} in CH2Cl2 in the presence of
Cu-wire for 5 days to give the yellow fluorescent polymer-bound cycloadduct 3{1; 5} (Scheme
2, Method A, Figure 2). Next, labelling through polymer-bound benzaldehyde was explored. The
commercially available benzaldehyde on polystyrene 5{5} was treated with slight excess of 5,5-
dimethyl-3-pyrazolidinone (4) in methanol in the presence of catalytic amounts of trifluoroacetic
acid to provide the polymer bound dipole 1{5} which, upon treatment with methyl propiolate
2{1} in the presence of Cu-wire, afforded the polymer bound cycloadduct 3{5; 1} (Scheme 2,
Method B). To test some other forms of heterogeneous copper metal-catalyst, reactions with 10%
Cu-graphite (Cu–C) and with copper-coated iron powder (Cu–Fe) were also performed. Cu–C
was prepared following slightly modified literature procedure.18 Cycloaddition of 1{1} to methyl
propiolate 2{1} was performed on a 0.125 mmol scale in the presence of 25 mg of Cu–C for 24
h. The reaction proceeded similarly as with Cu-powder to give 3{1; 1} in quantitative yield upon
simple filtration workup. The same catalyst was used three more times in the same reaction
without the decrease of conversion. Due to higher purity of the product and lower catalyst
loading, Cu–C (graphite or charcoal) could be an interesting alternative or even replacement for
Cu-powder. Another interesting variation of the catalyst was Cu–Fe, which has already found use
in CuAAC reaction.19 It was prepared easily by stirring iron powder with aq. CuSO4 followed by
filtration, washing, and drying. Cycloaddition of 1{2} to 2{1} was performed on a 0.3 mmol
scale in the presence of 80 mg (~100%) of Cu–Fe for 24 h to give 3{2; 1} in quantitative yield.
The conversion remained 100% even upon using the same catalyst for three more runs. Easy
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separation of the catalyst from the reaction mixture by application of magnetic field is the major
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advantage of Cu–Fe-catalyzed reaction (Scheme 2).
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Scheme 2. Synthesis of fluorescent polymer-bound cycloadducts 3{1; 5} and 3{5; 1} and
synthesis of 3{1,2; 1} with Cu–C and Cu–Fe catalysts (4 runs).
Reaction conditions: (i) propiolic acid, NaI, DIPEA, DMF, r.t., 5 days; (ii) dipole 1{1}, CH2Cl2,
Cu-wire, r.t., 72 h; (iii) 5,5-dimethyl-3-pyrazolidinone (4), MeOH, TFA (cat.), r.t., 72 h; (iv)
methyl propiolate 2{1}, CH2Cl2, Cu-wire, r.t., 72 h; (v) methyl propiolate 2{1}, CH2Cl2, 50
ww% Cu–C, r.t., 24 h; (vi) methyl propiolate 2{1}, CH2Cl2, 100 ww% Cu–Fe, r.t., 24 h.
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Figure 2. Fluorescent polystyrene resin 3{1; 5} obtained from Merrifield resin via ynone
functionalization followed by CuAIAC reaction. The picture was taken under UV lamp (375 nm).
2.4. Mechanistic insight. Like in closely analogous CuAAC reaction,4,19 the generally
accepted plausible mechanism is based on the catalytic CuI-acetylide as the reactive species,
which undergoes cycloaddition, followed by protonation of the cuprated cycloadduct.10,11 This is
supported by experiments performed with copper(I) acetylides, deuterated acetylenes, and/or
proton sources, such as D2O and AcOD.10c,d,f,g CuI was, either used directly, or formed in situ by
reduction of CuII.10c,d,f In contrast to CuAAC, where CuI is essential for catalytic activity,4,20
recently reported CuII-catalyzed CuAIAC reactions indicate, that the mechanism may also
involve activation by Cu-Lewis acid.21 However, dipole 1{1} did not react with a non-terminal
ynone 2{6} (Table 3, entries 1 and 2), which was in agreement with the acetylide intermediate.
Activation by Lewis acid was ruled out, since the acetylide can only be formed from a terminal
ynone. To get insight into the catalytic cycle of copper metal-catalyzed CuAIAC, further
experiments were performed using the representative reaction, 1{1} + 2{1} → 3{1; 1}. With Cu-
powder as catalyst under usual conditions and under oxygen or argon similar conversions were
observed (Table 3, entries 3–5). Nevertheless, slightly faster conversion under oxygen suggested
that reaction was most probably catalyzed by CuI-species (Table 3, entry 4). On the other hand,
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Cu2O was a poor catalyst, whereas CuO was inactive in this respect (Table 3, entries 6 and 7).
Somewhat expectedly,10g,15 replacement of the dipolarophile 2{1} or Cu-catalyst with the
acetylide Cu-2{1}10g did not improve the conversion (Table 3, entries 8 and 9). To check the
importance of clean Cu-surface devoid of patina, two experiments were carried out with Cu
activated with 1 M H2SO4 or 50% N2H4·H2O.22 Indeed, the conversion increased with both
activated catalysts (Table 3, entries 10 and 11). Thus, clean catalyst's surface significantly
increased the conversion.
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Table 3. Cu-catalyzed cycloadditions of dipole 1{1} to methyl propiolate 2{1} and methyl 2-
butynoate 2{6}.a
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Entry Catalyst
R
Loading (mg) Time (h) Conversion (%)b
1
Cu
Me
Me
H
5
0c
5
5
5
8
7
5
8
5
5
72
72
5
0
c
2
0
3
Cu
14
17
12
3
4
Cud
H
5
5
Cue
H
5
6
Cu2O
CuO
Cu
H
5
7
H
5
<1
30
36g
67
76
8
Cuf
H
17
22
5
9
Cu-2{1}
Cuh
10
11
H
Cui
H
5
a) Reactions were performed at r.t. with 0.125 mmol of 1{1} and 0.15 mmol 2{1} in 0.75 mL of
b
1
CH2Cl2, followed by filtration and evaporation. ) The conversion was determined from the H
NMR spectra of the crude products. c) Without Cu-catalyst. d) Under O2 (balloon). e) Under argon
f
g
(balloon). ) Cu-2{1} was used as dipolarophile. ) 36% Conversion coincides with 36 mol% of
Cu-2{1} used as catalyst. h) Pre-washed with 1 M H2SO4. i) Pre-washed with 50% N2H4·H2O.
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Cycloaddition of 1{1} to deuterium-labelled methyl propiolate (2{1}-d)23 (D:H = 65:35)
afforded cycloadduct 3{1; 1} with only 8% deuterium incorporation (D:H = 8:92) compliant with
analogous results of other groups.4,10c,d,f,g
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Next, the kinetic profiles of the representative reaction in the presence of various Cu-catalysts
were determined by 1H NMR. Reactions were performed at 298 K with 0.125 mmol of 1{1} and
0.15 mmol 2{1} in 0.75 mL of CDCl3 with 5 mg of a catalyst. Kinetic profiles in the presence of
Cu, Cu2O, and CuO are shown in Figure 3. A common feature of reactions was a 45–60 min.
induction period, similar to that, observed in analogous copper metal-catalyzed CuAAC
reactions.24a Complete conversion within 12 h was obtained only with Cu (●,♦,■), the conversion
was lower (92%) in the presence of Cu2O (■), whereas CuO (●) showed no appreciable catalytic
activity. The shortest induction period and the fastest reaction progress was obtained with
activated (washed) Cu (●).
5 mg Cu
5 mg Cu2O
5 mg CuO
5 mg activated Cu
25 mg Cu
100
80
60
40
20
0
0
100
200
300
400
500
600
Time (min)
Figure 3. Kinetic profiles of the representative reaction in CDCl3 with activated Cu (●), Cu (♦,■),
Cu2O (■), and CuO (●) as catalysts.
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The kinetic profiles measured with Cu-granules (■) and with Cu-powder (●,♦) showed
dependence of the reaction rate on the specific surface area of Cu-metal (■ vs. ●,♦). On the other
hand, five times higher loading of Cu-powder had only limited effect on the reaction rate (♦ vs.
●), whereas duration of the induction period was very similar with all three catalysts (Figure 4).
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Figure 4. Kinetic profiles of the model reaction in CDCl3 in the presence of Cu-granules (■) and
Cu-powder (●, ♦).
Catalytic activity of Cu-powder was in line with activity of previously employed CuI-
catalysts.10 Like in related CuAAc reactions,4 also the CuAIAC reactions took longer for
completion with Cu-powder than with conventional CuI-catalysts, such as CuI10a,h and CuOAc.10g
The results of the above experiments with heterogeneous copper catalyst strongly suggested,
that Cu0 itself was not the heterotopic catalytic species but rather a source of a homogenous
catalytically active CuI-species. Thus, the catalytic system was most probably homotopic. To
check this hypothesis, mercury poisoning experiment,25 Cu-removal and re-addition experiment,
and the control experiment were performed in parallel for the model reaction, 1{1} + 2{1} →
3{1; 1}. Since Hg0 in mercury poisoning experiment failed to poison the system, it was safe to
conclude that catalytic system was homotopic.25,26 Surprisingly, the reaction was accelerated
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upon addition of Hg0 and became faster than the control reaction (Figure 5, ● vs. ■). On the other
hand, using only Hg0 as catalyst gave the same conversion as the non-catalyzed reaction.
Therefore, Hg0-induced increase of the reaction rate is explainable at best by (partial)
amalgamation that activates the catalyst's surface similarly as activation of Cu0 by acid or
hydrazine hydrate (cf. Figure 3).
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Control
+Hg
-Cu
60
50
40
30
20
10
0
Addition of Hg
Removal of Cu
0
50
100
150
200
250
300
350
Time (min.)
Figure 5. Partial reaction profiles (0–350 min.) for the mercury poisoning- (●), Cu-removal (▲),
and the control experiment (■).
Cu-removal-addition experiment also confirmed homotopicity of catalytic system. The
conversion gradually declined after removal of copper and was re-boosted upon re-addition. The
reaction curve was in agreement with the above hypothesis, yet it indicated reaction taking place
also at the surface of the catalyst. Heterogenous catalyst providing sufficient amount of fresh
unexploited homogenous catalytic species throughout the reaction course, e.g. by slow oxidation
of Cu0, seems a reasonable explanation (Figure 6).
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Figure 6. Reaction profile for the Cu-removal-addition experiment.
Formation of CuI-acetylide on the surface of Cu-nanoparticles has been reported,
unfortunately without any mechanistic explanation.24 In this study, small amounts of insoluble
Cu-2{1}10g were obtained when the model reaction was performed in polar solvents (cf. Table 1,
entries 1–4). To get more information, Cu0-catalyst was treated with excess propiolate 2{1} in
MeCN and CH2Cl2 for seven days. In MeCN, the conversion into Cu-2{1} was complete under
normal (i.e. 'aerobic') conditions and only partial under argon. In CH2Cl2 no precipitate was
formed and the reaction mixture became slightly yellowish.27 Thus, formation of polynuclear Cu-
2{1} was favored under 'aerobic' conditions in MeCN and suppressed in CH2Cl2. Thus, slow
oxidation of Cu0 in CH2Cl2 provides trace consumable amounts of oligonuclear low molecular
weight Cu-2{1}cat as catalytically active CuI-species. In contrast, oxidation of Cu0 in MeCN is
faster than consumption of the so formed catalytic low molecular weight Cu-acetylide, which
aggregates into inactive Cu-2{1} as insoluble precipitate.
The proposed catalytic cycle, compliant with related literature examples,4,9,10,24a is presented
on Scheme 3. Oxidation of Cu0 facilitated by traces of oxygen and moisture28 gives ligand-
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stabilized LnCuIOH24a with azomethine imine 1 as plausible ligand. Analogous stable carbene-
CuIOH complex has recently been reported,29 while oxidation of Cu0 with O2 is known to
produce various Cu/O2 adducts including oxygenated CuI species.30 This is also in agreement
with slight acceleration of the reaction carried out under oxygen (cf. Table 3, Entry 4).
Subsequent reaction of LnCuIOH with terminal ynone 2 gives the catalytic acetylide Cu-2cat,
which then coordinates the dipole 1 (if not coordinated before) and undergoes 3+2 cycloaddition
to afford the cuprated cycloadduct Cu-3cat. Protonation (SE) with water and ligand exchange
gives the cycloadduct 3 and LnCuIOH species (Scheme 3).
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Scheme 3. Proposed catalytic cycle of copper metal-catalyzed CuAIAC reaction.
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3. Conclusion
In summary, we have demonstrated, to the best of our knowledge, the first examples of
CuAIAC reaction using copper metal as the source of CuI-catalyst. In spite of longer reaction
times, the major advantages of copper metal over CuI-based catalysts are versatility of
(commercially) available forms of copper (e.g. powder, wire, turnings, granules, nanoparticles,
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etc.) and simple workup. This makes it easily applicable in most techniques of organic synthesis
including high-throughput synthesis and flow chemistry. Due to ease of access to substrates and
substrate tolerance the reaction is compliant with requirements of 'click' chemistry. Its
applicability in fluorescent labelling was also shown – upon modification, the reaction might also
be useful in bioconjugation and material functionalization. In this context, CuAIAC has two
advantages over classical CuAAC reaction: a) non-explosive nature of azomethine imines allows
large scale reactions and b) fluorescent products as bimane analogues enable direct application in
fluorescent labelling. Experimental evidence on the reaction mechanism shows that it is sensitive
to catalyst's particle size and oxidation state of the catalyst's surface. Correlation between clean
catalyst's surface and reaction rate strongly suggests, that the reactive CuI-species is formed from
Cu0 by 'in situ' oxidation rather than from patina on the catalyst's surface. This is in agreement
with homotopic low molecular weight catalytic CuI-acetylide9,10 formed from heterogeneous Cu0-
catalyst. The proposed catalytic cycle is compliant with the results of other groups for
CuAAC4,24a and CuAIAC reaction.9,10 Further studies on the scope and applications of this
reaction are currently in progress.
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4. Experimental
1
4.1. General methods. Reaction progress was monitored by TLC and by H NMR analysis
of the crude reaction mixture. Melting points were determined on a Kofler micro hot stage and on
an automated melting point system. The NMR spectra were recorded in CDCl3 and DMSO-d6
using TMS as the internal standard on a 300 MHz or 500 MHz instrument at 300 and 500 MHz
for 1H and at 75.5 and 126 MHz for 13C nucleus, respectively. High resolution mass spectra were
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recorded on a time-of-flight (TOF) mass spectrometer equipped with a double orthogonal
electrospray source at atmospheric pressure ionization (ESI) coupled to an HPLC instrument. IR
spectra were recorded on a FTIR ATR spectrophotometer. Microanalyses were performed by
combustion analysis on a CHN analyzer. Flash column chromatography (FC) was performed on
silica gel (particle size 35–70 μm). Benzaldehyde on polystyrene 5{5} (loading capacity 0.8–1.5
mmol/g resin), benzaldehydes 5{1–4}, Cu-powder (particle size < 10 μm), Cu-granules (particle
size 100–500 μm), Fe-powder (reduced), formylpolystyrene (loading capacity 2.0–3.0 mmol/g
resin, 100–200 mesh, cross-linked with 2% DVB), chloromethylated polystyrene (loading
capacity 1.1 mmol/g resin, 200–400 mesh, cross-linked with 1% DVB), methyl propiolate 2{1},
but-3-yn-2-one 2{3}, and 1-phenylprop-2-yn-1-one 2{4} are commercially available. 5,5-
Dimethyl-3-pyrazolidinone (4),16 azomethine imines 1{1,4}10b,c and 1{2,3},14c tert-butyl (2-
oxobut-3-yn-1-yl)carbamate 2{2},31 and 10% Cu-graphite catalyst18 were prepared according to
the literature procedures.
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4.2. Optimization of the reaction conditions. General procedure for the Cu0-catalyzed
CuAIAC of 1{1} to 2{1}. A mixture of 2-benzylidene-3,3-dimethyl-5-oxopyrazolidin-2-ium-1-
ide 1{1} (50 mg, 0.25 mmol), methyl propiolate 2{1} (25 μL, 0.3 mmol), Cu powder (10 mg)
and solvent (1.5 mL, cf. Table 1 in the Main Manuscript) was stirred at r.t. for 5–44 h. The
reaction progress was monitored by TLC (EtOAc/hexanes). The catalyst and small amounts of
insoluble by-products were removed by filtration, washed with solvent (2×1 mL), and the
1
combined filtrate was evaporated in vacuo. The conversion was determined from the H NMR
spectrum of the crude reaction mixture.
4.3. General procedure for the synthesis of cycloadducts 3{1–4; 1–4}. A mixture of
azomethine imine 1 (0.5 mmol), ynone 2 (0.6 mmol), Cu powder (20 mg) and CH2Cl2 (3 mL)
was stirred at r.t. for 12–120 h. The catalyst was removed by filtration, washed with CH2Cl2 (2×1
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mL), and the filtrate was evaporated in vacuo to give 3. The conversion was determined from the
1H NMR spectrum of the crude reaction mixture. Optionally, the crude product 3 was purified by
flash chromatography (FC) over silica gel (EtOAc/hexanes). Fractions containing the product were
combined and evaporated in vacuo to give the purified product 3.
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4.3.1.
Methyl 7,7-dimethyl-5-oxo-1-phenyl-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-
carboxylate 3{1; 1}. Prepared from 1{1} (101 mg, 0.5 mmol) and methyl propiolate 2{1} (50 μL,
1
0.6 mmol), 18 h. Yield: 131 mg (92%) of yellow solid; mp 154–157 °C. H NMR (300 MHz,
CDCl3): δ 1.15 (s, 3H); 1.23 (s, 3H); 2.39 (d, J = 15.5 Hz, 1H); 2.86 (d, J = 15.5 Hz, 1H); 3.61 (s,
3H); 5.46 (d, J = 1.5 Hz, 1H); 7.25–7.38 (m, 3H); 7.45 (m, 2H); 7.51 (d, J = 1.5 Hz, 1H). NMR
data are in agreement with the literature data.9d νmax (ATR) 3074, 1734 (C=O), 1687 (C=O),
1598, 1320, 1187, 715 cm–1.
4.3.2.
tert-Butyl (2-(7,7-dimethyl-5-oxo-1-phenyl-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyra-
zol-2-yl)-2-oxoethyl)carbamate 3{1; 2}. Prepared from 1{1} (101 mg, 0.5 mmol) and tert-butyl
(2-oxobut-3-yn-1-yl)carbamate 2{2} (112 mg, 0.6 mmol), 24 h, FC (EtOAc/hexanes = 1:1).
1
Yield: 179 mg (92%) of yellow solid; mp 147–151 °C. H NMR (500 MHz, CDCl3): δ 1.16 (s,
3H); 1.22 (s, 3H); 1.40 (s, 9H); 2.43 (d, J = 16.0 Hz, 1H); 2.88 (d, J = 16.0 Hz, 1H); 4.01 (dd, J =
19.0, 4.6 Hz, 1H); 4.19 (dd, J = 19.0, 5.2 Hz, 1H); 5.18–5.20 (m, 1H); 5.55 (s, 1H); 7.25–7.29
13
(m, 1H); 7.31–7.36 (m, 2H); 7.41–7.45 (m, 2H); 7.60 (s, 1H). C NMR (126 MHz, CDCl3): δ
19.0, 25.1, 28.4, 47.3, 49.4, 64.57, 64.61, 79.9, 123.0, 127.9, 128.1, 128.6, 129.3, 141.8, 155.7,
167.3, 190.1. m/z (HRMS) Found: 386.2075 (MH+). C21H27N3O4 requires: m/z = 386.2074.
(Found: C, 65.15; H, 7.09; N, 10.79. C21H27N3O4 requires: C, 65.44; H, 7.06; N, 10.90.); νmax
(ATR) 3445, 2977, 1730 (C=O), 1635, 1570, 1158, 1013 cm–1.
4.3.3.
6-Acetyl-3,3-dimethyl-5-phenyl-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one
3{1; 3}. Prepared from 1{1} (101 mg, 0.5 mmol) and but-3-yn-2-one 2{3} (47 μL, 0.6 mmol), 26
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h, FC (EtOAc/hexanes = 3:5). Yield: 102 mg (75%) of yellow solid; mp 139–142 °C. H NMR
(500 MHz, CDCl3): δ 1.16 (s, 3H); 1.21 (s, 3H); 2.19 (s, 3H); 2.41 (d, J = 16.0 Hz, 1H); 2.88 (d, J
= 16.0 Hz, 1H); 5.51 (br s, 1H); 7.23–7.28 (m, 1H); 7.29–7.39 (m, 2H); 7.41–7.45 (m, 2H); 7.52
(d, J = 1.5 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 18.8, 24.8, 26.8, 49.2, 64.3, 64.6, 126.4,
127.6, 127.7, 128.3, 129.4, 142.0, 167.5, 192.8. m/z (HRMS) Found: 271.1437 (MH+).
C16H19N2O2 requires: m/z = 271.1441. (Found: C, 70.79; H, 6.64; N, 10.27. C16H18N2O2 requires:
C, 71.09; H, 6.71; N, 10.36.); νmax (ATR) 1723 (C=O), 1650 (C=O), 1639, 1577, 1359, 1311,
1254, 1007, 699 cm–1.
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4.3.4.
6-Benzoyl-3,3-dimethyl-5-phenyl-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one
3{1; 4}. Prepared from 1{1} (101 mg, 0.5 mmol) and 1-phenylprop-2-yn-1-one 2{4} (79 mg, 0.6
mmol), 24 h, FC (EtOAc/hexanes = 2:1). Yield: 110 mg (66%) of yellow solid; mp 158–161 °C.
1H NMR (500 MHz, CDCl3): δ 1.20 (s, 3H); 1.25 (s, 3H); 2.44 (d, J = 15.5 Hz, 1H); 2.92 (d, J =
15.5 Hz, 1H); 5.79 (br s, 1H); 7.22–7.29 (m, 1H); 7.32–7.37 (m, 3H); 7.39–7.43 (m, 2H); 7.48–
7.54 (m, 1H); 7.54–7.60 (m, 2H); 7.64–7.70 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 19.0, 25.0,
49.4, 64.5, 65.5, 125.6, 127.7, 127.8, 128.3, 128.4, 128.5, 130.3, 132.3, 138.3, 141.7, 167.0,
190.2. m/z (HRMS) Found: 333.1596 (MH+). C21H21N2O2 requires: m/z = 333.1598. (Found: C,
75.69; H, 6.05; N, 8.27. C21H20N2O2 requires: C, 75.88; H, 6.06; N, 8.43.); νmax (ATR) 1714
(C=O), 1628, 1582, 1574, 1414, 1326, 1219, 1107, 1008, 716 cm–1.
4.3.5.
Methyl 7,7-dimethyl-5-oxo-1-(3,4,5-trimethoxyphenyl)-1,5,6,7-tetrahydropyrazolo-
[1,2-a]pyrazole-2-carboxylate 3{2; 1}. Prepared from 1{2} (146 mg, 0.5 mmol) and methyl
propiolate 2{1} (54 μL, 0.6 mmol), 26 h, FC (first EtOAc/hexanes = 1:1 to elute excess alkyne,
1
then EtOAc to elute the product). Yield: 177 mg (94%) of yellow solid; mp 106–109 °C. H
NMR (500 MHz, DMSO-d6): δ 1.145 (s, 3H); 1.153 (s, 3H); 2.40 (d, J = 15.8 Hz, 1H); 2.86 (d, J
= 15.8 Hz, 1H); 3.57 (s, 3H); 3.64 (s, 3H); 3.75 (s, 6H); 5.47 (d, J = 1.4 Hz, 1H); 6.70 (s, 2H);
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7.75 (d, J = 1.3 Hz, 1H). C NMR (126 MHz, DMSO-d6): δ 17.9, 24.1, 48.1, 51.3, 55.9, 59.9,
63.8, 64.7, 104.8, 114.9, 131.1, 131.2, 136.6, 138.5, 152.7, 163.7, 167.4. m/z (HRMS) Found:
404.2179 (MH+). C21H30N3O5 requires m/z = 404.2180. νmax (ATR) 2959, 1732 (C=O), 1692
(C=O), 1593, 1319, 1119, 766 cm–1. Physical and spectral are in agreement with the literature
data.14c
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4.3.6.
tert-Butyl
(2-(7,7-dimethyl-5-oxo-1-(3,4,5-trimethoxyphenyl)6,7-dihydro-1H,5H-
pyrazolo[1,2-a]pyrazol-2-yl)-2-oxoethyl)carbamate 3{2; 2}. Prepared from 1{2} (150 mg, 0.5
mmol) and tert-butyl (2-oxobut-3-yn-1-yl)carbamate 2{2} (112 mg, 0.6 mmol), 23 h, FC
1
(EtOAc/hexanes = 2:1). Yield: 233 mg (96%) of yellow solid; mp 154–158 °C. H NMR (500
MHz, CDCl3): δ 1.21 (s, 3H); 1.22 (s, 3H); 1.42 (s, 9H); 2.45 (d, J = 16.0 Hz, 1H); 2.91 (d, J =
16.0 Hz, 1H); 3.83 (s, 3H); 3.87 (s, 6H); 4.05 (dd, J = 18.0, 4.8 Hz, 1H); 4.21 (dd, J = 19.0, 5.2
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Hz, 1H); 5.24 (t, J = 4.9 Hz, 1H); 5.51 (s, 1H); 6.67 (s, 2H); 7.62 (s, 1H). C NMR (126 MHz,
CDCl3): δ 15.4, 18.9, 25.1, 28.4, 47.3, 49.3, 56.2, 60.9, 64.6, 64.7, 65.9, 79.9, 104.7, 122.8,
129.4, 137.3, 137.5, 153.2, 155.7, 167.4, 190.3. m/z (HRMS) Found: 476.2388 (MH+).
C24H34N3O7 m/z = 476.2391. (Found: C, 60.66; H, 7.01; N, 8.68. C24H33N3O7 requires: C, 60.62;
H, 6.99; N, 8.84.); νmax (ATR) 3069, 2973, 2932, 1719 (C=O), 1708 (C=O), 1664 (C=O), 1118
cm–1.
4.3.7.
6-Acetyl-3,3-dimethyl-5-(3,4,5-trimethoxyphenyl)-2,3-dihydropyrazolo[1,2-a]-
pyrazol-1(5H)-one 3{2; 3}. Prepared from 1{2} (146 mg, 0.5 mmol) and but-3-yn-2-one 2{3} (48
μL, 0.6 mmol), 18 h, FC (first EtOAc/hexanes = 2:1 to remove excess alkyne, then EtOAc to
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elute the product). Yield: 171 mg (87%) of yellow solid; mp 45–47 °C. H NMR (500 MHz,
DMSO-d6): δ 1.12 (s, 3H); 1.16 (s, 3H); 2.22 (s, 3H); 2.41 (d, J = 15.8 Hz, 1H); 2.87 (d, J = 15.9
Hz, 1H); 3.64 (s, 3H); 3.75 (s, 6H); 5.46 (d, J = 0.6 Hz, 1H); 6.67 (s, 2H); 8.18 (d, J = 1.2 Hz,
1H). 13C NMR (126 MHz, DMSO-d6) δ 17.7, 24.1, 26.8, 48.2, 55.8, 59.8, 63.6, 64.5, 104.9,
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124.8, 132.4, 136.5, 138.7, 152.5, 167.9, 192.9. m/z (HRMS) Found: 361.1755 (MH+).
C19H25N2O5 requires: m/z = 361.1758. (Found: C, 63.31; H, 6.91; N, 7.56. C19H24N2O5 requires:
C, 63.32; H, 6.71; N, 7.77.); νmax (ATR) 2965, 1719 (C=O), 1650 (C=O), 1580, 1228, 1121, 715
cm–1.
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4.3.8.
6-Benzoyl-3,3-dimethyl-5-(3,4,5-trimethoxyphenyl)-2,3-dihydropyrazolo[1,2-
a]pyrazol-1(5H)-one 3{2; 4}. Prepared from 1{2} (146 mg, 0.5 mmol) and 1-phenylprop-2-yn-1-
one 2{4} (79 mg, 0.6 mmol), 120 h, FC (EtOAc/hexanes = 1:2). Yield: 171 mg (81%) of yellow
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solid; mp 190–192 °C. H NMR (500 MHz, CDCl3): δ 1.25 (s, 3H); 1.26 (s, 3H); 2.46 (d, J =
15.8 Hz, 1H); 2.95 (d, J = 15.8 Hz, 1H); 3.82 (s, 3H); 3.89 (s, 6H); 5.75 (s, 1H); 6.83 (s, 2H);
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7.33 (d, J = 1.3 Hz); 7.39–7.46 (m, 2H); 7.50–7.55 (m, 1H); 7.66–7.71 (m, 2H). C NMR (126
MHz, CDCl3): δ 19.0, 25.2, 49.4, 56.2, 56.2, 60.8, 64.7, 65.6, 104.8, 125.5, 128.3, 128.6, 130.6,
132.5, 137.4, 138.4, 153.2, 167.3, 190.5. m/z (HRMS) Found: 423.1911. C24H27N2O5 requires:
m/z = 423.1914. (Found: C, 68.20; H, 6.42; N, 6.64. C24H26N2O5 requires: C, 68.23; H, 6.20; N,
6.63.); νmax (ATR) 2936, 1734 (C=O), 1621, 1596, 1565, 1318, 1129, 1001, 725 cm–1.
4.3.9.
Methyl
7,7-dimethyl-1-(4-nitrophenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]-
pyrazole-2-carboxylate 3{3; 1}. Prepared from 1{3} (123 mg, 0.5 mmol) and methyl propiolate
1
2{1} (50 μL, 0.6 mmol), 24 h. Yield: 154 mg (93%) of yellow solid; mp 118–120 °C. H NMR
(500 MHz, CDCl3): δ 1.14 (s, 3H); 1.25 (s, 3H); 2.44 (d, J = 16.0 Hz, 1H); 2.89 (d, J = 16.0 Hz,
1H); 3.64 (s, 3H); 5.58 (d, J = 1.5 Hz, 1H); 7.54 (d, J = 1.5 Hz, 1H); 7.69 (d, J = 8.5 Hz, 2H);
8.22 (d, J = 8.5 Hz, 2H). m/z (HRMS) Found: 332.1238 (MH+). C16H18N3O5 requires: m/z =
332.1241. Physical and spectral data are consistent with the literature data.14c
4.3.10. tert-Butyl (2-(7,7-dimethyl-1-(4-nitrophenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]-
pyrazol-2-yl)-2-oxoethyl)carbamate 3{3; 2}. Prepared from 1{3} (123 mg, 0.5 mmol) and tert-
butyl (2-oxobut-3-yn-1-yl)carbamate 2{2} (112 mg, 0.6 mmol), 24 h, FC (EtOAc/hexanes = 1:1).
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Yield: 190 mg (89%) of yellow solid; mp 160–166 C. H NMR (500 MHz, CDCl3): δ 1.15 (s,
3H); 1.23 (s, 3H); 1.41 (s, 9H); 2.49 (d, J = 16.0 Hz, 1H); 2.92 (d, J = 16.0 Hz, 1H); 4.01 (dd, J =
18.0, 4.8 Hz, 1H); 4.25 (dd, J = 18.0, 5.5 Hz, 1H); 5.12–5.14 (m, 1H); 5.67 (s, 1H); 7.64 (s, 1H);
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7.68–7.70 (m, 2H); 8.19–8.21 (m, 2H). C NMR (126 MHz, CDCl3): δ 19.1, 25.1, 28.4, 47.1,
49.2, 64.0, 64.8, 80.1, 122.0, 123.8, 129.0, 129.7, 147.7, 148.9, 155.7, 167.1, 190.2. m/z (HRMS)
Found: 431.1920 (MH+). C21H27N4O6 requires m/z = 431.1925. (Found: C, 57.69; H, 6.20; N,
12.69. C21H26N4O6·½H2O requires: C, 57.39; H, 6.19; N, 12.75.); νmax (ATR) 2971, 1702 (C=O),
1660 (C=O), 1516, 1347, 1158 cm–1.
4.3.11. 6-Acetyl-3,3-dimethyl-5-(4-nitrophenyl)-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-
1-one 3{3; 3}. Prepared from 1{3} (123 mg, 0.5 mmol) and but-3-yn-2-one 2{3} (48 μL, 0.6
mmol), 24 h. 100%; Yield: 115 mg (91%) of yellow solid; mp 136–140 °C. 1H NMR (500 MHz,
CDCl3): δ 1.15 (s, 3H); 1.22 (s, 3H); 2.21 (s, 3H); 2.46 (d, J = 16.0 Hz, 1H); 2.91 (d, J = 16.0 Hz,
1H); 5.62 (d, J = 1.5 Hz, 1H); 7.54 (d, J = 1.5 Hz, 1H); 7.69 (d, J = 8.5 Hz, 2H); 8.19 (d, J = 8.5
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Hz, 2H). C NMR (126 MHz, CDCl3): δ 18.9, 24.9, 26.7, 49.0, 63.7, 64.7, 123.5, 125.4, 128.8,
129.8, 147.4, 149.1, 167.3, 192.5. m/z (HRMS) Found: 316.1292 (MH+). C16H18N3O4 m/z =
316.1292. (Found: C, 60.80; H, 5.48; N, 13.16. C16H17N3O4 requires: C, 60.94; H, 5.43; N,
13.33.); νmax (ATR) 3077, 1722 (C=O), 1644, 1573, 1514, 1428, 1347, 1211, 823, 702 cm–1.
4.3.12. 6-Benzoyl-3,3-dimethyl-5-(4-nitrophenyl)-2,3-dihydro-1H,5H-pyrazolo[1,2-a]-
pyrazol-1-one 3{3; 4}. Prepared from 1{3} (123 mg, 0.5 mmol) and 1-phenylprop-2-yn-1-one
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2{4} (79 mg, 0.6 mmol), 24 h. Yield: 173 mg (92%) of yellow solid; mp 199–203 °C. H NMR
(500 MHz, CDCl3): δ 1.19 (s, 3H); 1.27 (s, 3H); 2.49 (d, J = 15.9 Hz, 1H); 2.95 (d, J = 15.9 Hz,
1H); 5.90 (s, 1H); 7.40–7.43 (m, 3H); 7.51–7.54 (m, 1H); 7.62–7.64 (m, 2H); 7.82–7.84 (m, 2H);
8.20–8.22 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 19.1, 25.1, 49.3, 64.8, 65.0, 123.8, 124.5,
128.3, 128.7, 129.0, 131.0, 132.7, 138.1, 147.6, 149.0, 167.0, 190.1. m/z (HRMS) Found:
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378.1445 (MH+). C21H20N3O4 requires: m/z = 378.1448. (Found: C, 66.01; H, 4.98; N, 10.89.
C21H19N3O4·¼H2O requires: C, 66.05; H, 5.15; N, 11.00.); νmax (ATR) 3101, 2973, 1749 (C=O),
1611, 1570, 1514, 1322, 1201, 1003, 718, 695 cm–1.
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4.3.13. Methyl 1-(4-chlorophenyl)-7,7-dimethyl-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]-
pyrazole-2-carboxylate 3{4; 1}. Prepared from 1{4} (116 mg, 0.5 mmol) and methyl propiolate
2{1} (54 μL, 0.6 mmol), 24 h. Yield: 134 mg (99%) of yellow solid; mp 110–116 °C (with
1
previous softening). H NMR (500 MHz, CDCl3): δ 1.14 (s, 3H); 1.23 (s, 3H); 2.41 (d, J = 15.8
Hz, 1H); 2.87 (d, J = 15.8 Hz, 1H); 3.63 (s, 3H); 5.45 (d, J = 1.5 Hz, 1H); 7.32 (d, J = 8.5 Hz,
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2H); 7.41 (d, J = 8.5 Hz, 2H); 7.50 (d, J = 1.5 Hz, 1H). C NMR (126 MHz, CDCl3): δ 19.1,
25.1, 49.5, 51.7, 64.0, 64.6, 116.6, 128.7, 129.4, 129.6, 133.8, 140.7, 164.1, 166.5. m/z (HRMS)
Found: 321.0997 (MH+). C16H18ClN2O3 requires: m/z = 321.1000. (Found: C, 59.37; H, 5.33; N,
8.46. C16H17ClN2O3 requires: C, 59.91; H, 5.34; N, 8.73.); νmax (ATR) 3075, 2946, 1740 (C=O),
1685 (C=O), 1598, 1378, 1322, 1192, 1087, 841 cm–1.
4.3.14. tert-Butyl (2-(1-(4-chlorophenyl)-7,7-dimethyl-5-oxo-6,7-dihydro-1H,5H-pyrazolo-
[1,2-a]pyrazol-2-yl)-2-oxoethyl)carbamate 3{4; 2}. Prepared from 1{4} (117 mg, 0.5 mmol) and
tert-butyl (2-oxobut-3-yn-1-yl)carbamate 2{2} (112 mg, 0.6 mmol), 24 h, FC (EtOAc/hexanes =
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1:1). Yield: 199 mg (95%) of yellow solid; mp 150–155 °C (with previous softening). H NMR
(500 MHz, CDCl3): δ 1.15 (s, 3H); 1.21 (s, 3H); 1.41 (s, 9H); 2.45 (d, J = 16.0 Hz, 1H); 2.89 (d, J
= 16.0 Hz, 1H); 4.01 (dd, J = 18.0, 4.6 Hz, 1H); 4.22 (dd, J = 18.0, 5.4 Hz, 1H); 5.18–5.20 (m,
1H); 5.54 (s, 1H); 7.29–7.32 (m, 2H); 7.39–7.42 (m, 2H); 7.61 (s, 1H). 13C NMR (126 MHz,
CDCl3): δ 19.1, 25.1, 28.4, 47.2, 49.4, 63.9, 64.6, 80.0, 122.7, 128.7, 129.3, 133.8, 140.4, 155.7,
167.1, 190.2. m/z (HRMS) Found: 420.1681 (MH+). C21H27ClN3O4 requires: m/z = 420.1685.
(Found: C, 59.93; H, 6.46; N, 9.94. C21H26ClN3O4 requires: C, 60.07; H, 6.24; N, 10.01.); νmax
(ATR) 3070, 1735 (C=O), 1721 (C=O), 1633, 1361, 1161, 1014 cm–1.
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4.3.15. 6-Acetyl-5-(4-chlorophenyl)-3,3-dimethyl-2,3-dihydro-1H,5H-pyrazolo[1,2-a]-
pyrazol-1-one 3{4; 3}. Prepared from 1{4} (117 mg, 0.5 mmol) and but-3-yn-2-one 2{3} (48 μL,
0.6 mmol), 24 h. Yield: 114 mg (89%) of yellow solid; mp 137–141 °C (with previous softening).
1H NMR (500 MHz, CDCl3): δ 1.15 (s, 3H); 1.19 (s, 3H); 2.20 (s, 3H); 2.42 (d, J = 16.0 Hz, 1H);
2.89 (d, J = 16.0 Hz, 1H); 5.49 (d, J = 1.5 Hz, 1H); 7.30 (d, J = 8.5 Hz, 2H); 7.41 (d, J = 8.5 Hz,
2H); 7.49 (d, J = 1.5 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 19.0, 25.1, 26.9, 49.4, 63.9, 64.7,
126.3, 128.9, 129.3, 129.5, 133.6, 140.8, 167.5, 192.9. m/z (HRMS) Found: 305.1058 (MH+).
C16H18ClN2O2 requires: m/z = 305.1057. (Found: C, 59.96; H, 5.49; N, 8.59. C16H17ClN2O2
requires: C, 63.06; H, 5.62; N, 9.19.); νmax (ATR) 2980, 1726 (C=O), 1655 (C=O), 1631, 1397,
1197, 1088, 830, 678 cm–1.
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4.3.16. 6-Benzoyl-5-(4-chlorophenyl)-3,3-dimethyl-2,3-dihydro-1H,5H-pyrazolo[1,2-a]-
pyrazol-1-one 3{4; 4}. Prepared from 1{4} (117 mg, 0.5 mmol) and 1-phenylprop-2-yn-1-one
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2{4} (79 mg, 0.6 mmol), 24 h. Yield: 140 mg (90%) of yellow solid; mp 181–184 °C. H NMR
(500 MHz, CDCl3): δ 1.18 (s, 3H); 1.24 (s, 3H); 2.45 (d, J = 16.0 Hz, 1H); 2.92 (d, J = 16.0 Hz,
1H); 5.77 (d, J = 1.5 Hz, 1H); 7.29–7.34 (m, 3H); 7.407.43 (m, 2H); 7.517.55 (m, 3H);
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7.647.65 (m, 2H). C NMR (126 MHz, CDCl3): δ 19.2, 25.2, 49.5, 64.6, 65.0, 125.4, 128.4,
128.68, 128.73, 129.4, 130.5, 132.6, 133.7, 138.3, 140.5, 167.0, 190.3. m/z (HRMS) Found:
367.1205 (MH+). C21H20ClN2O2 requires: m/z = 367.1208. (Found: C, 68.53; H, 5.48; N, 7.56.
C21H19ClN2O2 requires: C, 68.76; H, 5.22; N, 7.64.); νmax (ATR) 2982, 1725 (C=O), 1622, 1571,
1313, 1201, 1007, 722, 697 cm–1.
4.4. Procedure for the Cu–C-catalyzed CuAIAC reaction. Synthesis of compound 3{1;
1}. A mixture of dipole 1{1} (25 mg, 0.125 mmol), methyl propiolate 2{1} (12.5 μL, 0.15
mmol), 10% Cu–C (25 mg) and CH2Cl2 (2 mL) was stirred at r.t. for 24 h. The catalyst was
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