Zeo-click synthesis: Copper-zeolite-catalyzed synthesis of ynamides

Article abstract of DOI:10.1002/adsc.201400189

Copper(I)-zeolites, especially copper(I)- ultra stable Y zeolite (USY), are very efficient heterogeneous catalysts for the coupling of functionalized 1-bromoalkynes and various nitrogen derivatives. Under these conditions, sulfonylated alkyl- or aryl- ACHTUNGTRENUNGamines and various N-heterocycles, such as oxazolidinones or indoles, could be efficiently transformed into the corresponding N-alkynyl derivatives. However, imidazoles gave addition products rather than coupling products. The reaction conditions proved compatible with a variety of functional and protecting groups. Such zeolitic catalysts can be recycled and reused at least five times without significant deactivation. Low catalyst loading could be used (4 mol%) and as low as 0.8 mol% of this heterogeneous copper catalyst still gave good conversion and yields.

Full text of DOI:10.1002/adsc.201400189

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DOI: 10.1002/adsc.201400189
Zeo-Click Synthesis: Copper-Zeolite-Catalyzed Synthesis of
Ynamides
Hassina Harkat,a Sophie Borghꢀse,b Matteo De Nigris,b Serguei Kiselev,b
Valꢁrie Bꢁnꢁteau,b and Patrick Paleb,*
a
Faculty of Sciences, University of Batna, Batna, Algeria
Laboratoire de Synthꢀse, Rꢁactivitꢁ Organiques & Catalyse, Institut de Chimie de Strasbourg, associꢁ au CNRS,
b
University of Strasbourg, 4 rue Blaise Pascal, 67070 Strasbourg, France
Fax : (+33)-(0)3-6885-1517; phone: (+33)-(0)3-6885-1517; e-mail: ppale@unistra.fr
Received: February 20, 2014; Revised: June 21, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400189.
Abstract: Copper(I)-zeolites, especially copper(I)- compatible with a variety of functional and protect-
ultra stable Y zeolite (USY), are very efficient heter- ing groups. Such zeolitic catalysts can be recycled
ogeneous catalysts for the coupling of functionalized and reused at least five times without significant de-
1-bromoalkynes and various nitrogen derivatives. activation. Low catalyst loading could be used
Under these conditions, sulfonylated alkyl- or aryl- (4 mol%) and as low as 0.8 mol% of this heterogene-
ACHTUNGTRENNUNGamines and various N-heterocycles, such as oxazoli- ous copper catalyst still gave good conversion and
dinones or indoles, could be efficiently transformed yields.
into the corresponding N-alkynyl derivatives. How-
ever, imidazoles gave addition products rather than
coupling products. The reaction conditions proved Keywords: copper; coupling; ynamides; zeolites
Introduction
access to ynamides from bromoalkynes and deactivat-
ed amines (Scheme 2).
The last decade has witnessed the emergence of yn-
Hsung and co-workers were the first to develop
ACHTUNGTRENNUNG
amides[1] as a powerful and versatile tool in organic such copper-catalyzed couplings, but the use of N,N’-
synthesis.[2] Ynamides exhibit high reactivity due to dimethyl-1,2-ethanediamine (DMEDA) as ligand and
the strong polarization of the triple bond induced by high temperatures led to limitations in terms of sub-
ynamine conjugation, while the electron-withdrawing strate scope, especially with sulfonamides and some
group carried by the nitrogen atom modulates this re- heterocycles (Scheme 2a).[4] Danheiser and co-work-
activity (Scheme 1). Ynamides thus exhibit enhanced ers in part solved this problem by using stoichiometric
stability compared to ynamines,[3] and their reactivity amounts of copper iodide and potassium hexamethyl-
can be tuned depending on the nature of the nitrogen disilazane.[5] These reagents allowed the reaction to
substituent.
proceed at room temperature, but the strong base
Although ynamines were not easily obtained,[3] yn- also led to limitations (Scheme 2b). After an exten-
ACHTUNGTRENNUNG
Scheme 1. Ynamides: stability and reactivity.
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Hassina Harkat et al.
applied as catalysts in the synthesis of ynamides, pro-
viding a useful and interesting alternative to current
methods (Scheme 2f).
Results and Discussion
Catalyst and Condition Screening
In a first set of experiments, we looked for the best
combination of reagents and catalysts as well as for
the best conditions. This study was performed starting
from the readily available N-tosylbenzylamine and 1-
bromo-4-phenyl-1-butyne as model substrates, and
with copper(I)-ultra stable Y zeolite [Cu(I)-USY] as
catalyst due to its high performance in other Cu(I)-
zeolite-catalyzed reactions (Table 1).[9–12]
Under homogeneous conditions, these starting ma-
terials gave, as reported, the corresponding ynamide,
but with 1,10-phenanthroline as ligand and potassium
carbonate as base – the best conditions achieved with
Cu(I)-zeolite catalyst (vide infra) – high yields were
obtained without complete conversion (entries 1 and
2). With Cu(I)-USY as catalyst and without additive
or with just a base, no reaction occurred whatever the
solvent (entry 3 or 4). Upon addition of various li-
gands, the expected transformation could be achieved
depending on the nature of the ligand (entries 5–9),
but only N,N’-dimethyl-1,2-ethanediamine and 1,10-
phenanthroline gave full conversion and satisfactory
high yields of ynamide (entries 8 and 9). Shifting from
potassium carbonate to the phosphate or to cesium
carbonate led to a sharp decrease in conversion and
thus in yields (entries 10 and 11). Similarly, variations
in the relative amounts of either base or ligand also
reduced conversion, but less drastically giving still
reasonable yields (entries 12 and 13). Interestingly,
decreasing the amount of catalyst (and accordingly of
ligand) did not dramatically influence the reaction
Scheme 2. Known ynamide syntheses and our proposal.
conditions have been proposed from terminal alk- (entries 14–16). Only a slight conversion lowering was
ACHTUNGTRENNUNG
amides and bases, non-convenient solvents and high copper catalyst, around 70% of ynamide could still be
temperatures (Scheme 2d–e) in order to limit the isolated (entry 16).
Glaser homo-coupling reaction.
The reaction could also be performed in various
Our interest in metallated zeolites,[8] especially solvents (entries 17–19), among which THF and DMF
Cu(I)-zeolites, as catalyst in organic synthesis led us proved almost as efficient as toluene (entries 17 and
to consider applying copper(I)-zeolites as convenient 18 vs. 9). These interesting results provided thus ex-
and recyclable catalysts for ynamide synthesis. As suc- cellent alternative conditions in case of solubility
cessfully shown for the “click” Huisgen reaction,[9] the problems with one or the other coupling partner. It is
cycloaddition of azomethine imines,[10] multicompo- worth mentioning that such flexibility in solvent use is
nent Mannich-type reactions,[11] and alkyne homocou- not so common in homogeneous conditions.
pling,[12] the zeolite frame could act as ligand toward
Control experiments showed that the native H-
copper(I) stabilizing this inherently labile species. USY, with or without additive, was unable to promote
Furthermore, the inherent heterogeneous nature of any transformation (entries 20 and 21).
zeolites should greatly facilitate product recovery
For comparison purposes, we prepared other Cu(I)-
(through simple filtration) and recycling. We demon- zeolites with different internal shapes, sizes and Si/Al
strate here that such Cu(I)-zeolites could indeed be ratio, and we examined their behaviour as catalyst
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Table 1. Screening of conditions for the Cu(I)-zeolite catalyzed ynamide synthesis.
Entry
Catalyst
Ligand
Base
Yieldb)
1
2
CuSO4
CuBr
K3PO4
K2CO3
68[c,d]
81[c,d]
3
4
Cu(I)-USY
Cu(I)-USY
–
–
–
0
0
K2CO3
5
6
Cu(I)-USY
Cu(I)-USY
K2CO3
K2CO3
0
0
7
8
Cu(I)-USY
Cu(I)-USY
K2CO3
K2CO3
3
89
9
Cu(I)-USY
Cu(I)-USY
Cu(I)-USY
Cu(I)-USY
Phen
Phen
Phen
Phen (10 mol%)
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
–
K2CO3
K3PO4
Cs2CO3
K2CO3
K2CO3 (1 equiv.)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
–
92
10
11
12
13
14
15
16
17
18
19
20
21
36[e]
45[e]
58[f]
68[f]
87
Cu(I)-USY
Cu(I)-USY (6 mol%)
Cu(I)-USY (4 mol%)
Cu(I)-USY (0.8 mol%)
Cu(I)-USY
Cu(I)-USY
Cu(I)-USY
87[g]
67
91[h]
87[i]
82[j]
0
H-USY
H-USY
0
[a]
Performed with Cu-zeo (8 mol%), ligand (L) (20 mol%) and base (2 equiv.) in toluene at 708C for 20 h, unless otherwise
noted.
[b]
[c]
[d]
[e]
[f]
Isolated pure product.
Homogeneous conditions.
83–87% conversion.
Modest conversion (40–50%).
65–70% conversion.
95% conversion.
In THF.
[g]
[h]
[i]
In DMF.
In dioxane.
[j]
(Figure 1). Surprisingly, Cu(I)-Y proved less effective
These results suggest that the zeolites’ internal sizes
than Cu(I)-USY despite its structural similarity (see and shapes did not play a large role since the largest
the Supporting Information). In contrast, the Cu(I)- cage-type Y and USY zeolites behave quite different-
doped mordenite proved almost as effective as Cu(I)- ly, while the smaller channel-type zeolites gave results
USY, despite structural differences, although conver- similar to those of Y. Such phenomena could be ex-
sion was lower. The Cu(I)-doped beta and ZSM5 zeo- plained both by the flexible molecular shapes of the
lites behaved similarly, giving reasonable but never- starting materials and products allowing them to fit
theless lower yields of ynamide and with a lower con- within either cages or channels,[13,14] and by mobility
version than with Cu(I)-USY.
differences in each zeolite (confinement effects).[15]
Nevertheless, a surface catalysis due to Cu(I) species
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Figure 2. Correlation of the zeolite Si/Al ratios with cou-
pling efficiency.
Figure 1. Comparison of various Cu(I)-zeolites as catalyst in
the ynamide synthesis, and shapes and sizes of their frame-
work. USY: cage – 7.4 ꢃ; Y: cage – 7.4 ꢃ; MOR: channels –
6.5ꢄ3.4; Beta: channels – 6.5ꢄ5.5; ZSM5: channels – 5.5ꢄ
5.3.
(agglomerates) can still be envisaged. The latter
could, however, be ruled out since EDX mapping re-
vealed a homogeneous distribution of copper in zeo-
lites.
It has been shown that the number and the position
of Al atoms in a zeolite framework play a crucial role
in determining the type of Cu coordination, inducing
different activation and confinement effects, both
acting on reactivity.[16] These phenomena have been
confirmed for acetylene binding to Cu(I)-zeolites.[17]
Therefore, we looked for a possible correlation be-
tween the different Si/Al ratios of the present Cu-zeo-
Figure 3. Recycling of the Cu(I)-USY catalyst in the yn-
AHCTUNGTREGaNNUN mide synthesis.
lites and their reactivity. Too low or too high ratios catalyst was reused for the next reaction run. As
indeed proved not appropriate for the present cataly- shown in Figure 3, the catalyst remained very efficient
sis with a clear optimum for ratios between 3 to 10 over at least five runs. A slight decrease was never-
(Figure 2). This observation suggests the value of theless observed after the three first runs, but the
tuning the zeolite structural and functional parame- yields of recovered ynamide after isolation were still
ters in order to improve the catalysis efficiency.[18]
high after the fifth reuse (78%).
The possible leaching of copper species was also
evaluated. After having heated mixtures containing
Cu(I)-USY and phenanthroline in toluene, with or
without potassium carbonate, filtration over Nylon
Recycling
With a heterogeneous and efficient catalyst in hand micromembranes provided a clear solution. To the
for the coupling of deactivated amines and 1-bro- latter were added N-tosylbenzylamine and 1-bromo-5-
moalkynes, it was worthwhile to look at its properties silyloxypent-1-yne, with or without further phenan-
as heterogeneous catalyst, and especially its recycla- throline and potassium carbonate. Upon heating
bility and stability. This was performed with the cou- again, NMR monitoring did not show any compounds
pling of N-tosylbenzylamine and 1-bromo-4-phenyl- other than the starting materials, supporting the true
but-1-yne under the conditions set out above.
heterogeneous nature of such catalysts.
The catalyst was recovered after the reaction by fil-
As mentioned above, the presence of Cu agglomer-
tration and washed to remove the added base and any ates on the zeolite surface can be excluded. Neverthe-
organic component. After drying and calcination, the less, one cannot exclude catalysis due to a release and
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Zeo-Click Synthesis: Copper-Zeolite-Catalyzed Synthesis of Ynamides
Table 2. Cu(I)-zeolite-catalyzed ynamide synthesis: screen-
catch mechanism. To try to get some clues on one or
the other catalysis mechanism, we investigated in
more detail the Cu(I)-zeolite before and after recy-
cling. Due to its high sensitivity and large element
coverage, X-fluorescence was finally selected, allow-
ing us to monitor to some extent the Cu concentra-
tion within the catalyst, and it turned out that a small
amount (1–2%) of copper is lost after recycling.[19]
Taken together, these results tend to support a re-
lease and catch mechanism. Indeed, incomplete catch-
ing of Cu species may explain the small erosion ob-
served upon recycling. Such phenomena have been
observed with other metals and supports,[20] and seem
related to hydrogen-bonding and acid sites.[20c,21] How-
ever, such a mechanism cannot account for the large
reactivity differences observed with the various zeo-
lites examined. It is nevertheless difficult to conclude
since the actual mechanism of ynamide coupling is
unknown. Related to the Ullmann reaction, it may in-
volve a Cu(I)/Cu(III) cycle.[22] Interestingly, it has re-
cently been shown that protonation should facilitate
the reductive elimination step, especially with nitro-
gen ligands.[23] Cu(I)-zeolites may act as such, since
they exhibit residual acidity due to incomplete ex-
change (~80%) of acid sites by Cu(I). This would be
in line with the correlation we observed upon Si/Al
ratios and thus zeolite acidity (see Figure 2).
ing of nitrogen derivatives as coupling partner.[a]
Scope
In order to make a comparison with the homogeneous
version, we then examined what partners could be en-
gaged in this Cu(I)-zeolite-catalyzed ynamide synthe-
sis. Different amines, amides, and various nitrogen
heterocycles, as well as various 1-bromoalkynes were
thus prepared (when necessary) and submitted to the
best conditions described above (Table 2 and Table 3,
respectively).
Various nitrogen derivatives were first evaluated as
possible substrates (Table 2). The nature of the elec-
tron-withdrawing group carried by the nitrogen atom
was first examined (entries 1–4). The more electron-
[a]
Performed with Cu(I)-USY (8 mol%), 1,10-phen
(20 mol%) and K2CO3 (2 equiv.) in toluene.
Isolated pure product.
Decomposition occurred.
[b]
[c]
Since some nitrogen heterocycles have been suc-
withdrawing this group, the more effective was the cessfully engaged in Hsung coupling, we also exam-
coupling, as shown by the quantitative coupling seen ined the behaviour of such heterocycles in the pres-
with the N-para-nitrophenylsulfonyl (nosyl; Ns) ben- ence of Cu(I)-zeolites. Oxazolidinone readily reacted
zylamine compared to its tosyl analogue (entry 2 vs. in the presence of Cu(I)-USY, giving the expected N-
1). Carbamates may not be electron-withdrawing alkynyloxazolidinone in very high yield, opening up
enough, since no reaction occurred despite higher the way to chiral ynamides (entry 8).[6] Indoles could
heating and longer reaction time (entries 3 and 4). In- also be engaged in such a coupling, as shown by the
terestingly, simple tosylated alkylamines readily react- very efficient formation of N-alkynylindole (entry 9).
ed under the optimized conditions. The tosylated n- However, imidazole gave the product resulting from
butylamine quantitatively gave the coupling product addition to the starting bromoalkyne (entry 10). Such
(entry 5), while its tert-butyl analogue only slowly re- addition products have already been observed.[24]
acted and moreover decomposed (entry 6). Arylated
sulfonamides also gave the expected coupling N-aryl- substrates in the presence of N-tosylbenzylamine as
ACHTUNGTRENNUNGynamide in high yields (entry 7). coupling partner (Table 3).
Various 1-bromoalkynes were then examined as
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Table 3. Cu(I)-zeolite catalyzed ynamide synthesis: screen-
numerous functional groups are compatible with
these heterogeneous coupling conditions. Further-
more, the catalyst can be recycled at least five times
without dramatic loss of activity.
ing of 1-bromoalkynes as coupling partner.[a]
Experimental Section
General Procedure for the Formation of Ynamides
In
a 10-mL tube with a screw stopper, sulfonamide
(0.57 mmol) was added to a solution of bromoalkyne
(0.63 mmol, 1.1 equiv.) in dry and degassed toluene
(1.5 mL). Dry potassium carbonate (1.14 mmol, 2 equiv.)
was added, followed by 1,10-phenanthroline (0.114 mmol,
0.2 equiv.) and Cu-zeolite (mass corresponding to 8 mol% of
copper). The mixture was then stirred and heated at 65–
1108C for appropriate time (see the appropriate Tables).
After cooling to room temperature, the solid was filtered
over a pad of celite or a Nylon membrane (0.2 mm), and
washed with ethyl acetate. The filtrate was then evaporated
under vacuum. The product was purified by flash column
chromatography (cyclohexane/ethyl acetate).
Recycling Procedure
At the end of the run, the solid (mixture of Cu-zeolite and
inorganic salts from the base) was recovered by filtration
over a Nylon membrane (0.2 mm), washed with ethyl ace-
tate, water (20 mL), dried at 1008C for 4 h, and then calci-
nated at 3508C for 4 h.
Ynamides 2,[6b] 5,[25] 8a,[26] 8b,[27] 8c,[28] 9[29] and 11[30] are
known compounds and exhibit spectroscopic data identical
to those reported in the literature. Data of the other yna-
mides are provided in the Supporting Information.
[a]
Performed with Cu(I)-USY (8 mol%), 1,10-phen
(20 mol%) and K2CO3 (2 equiv.) in toluene.
isolated pure product.
2 equiv. of bromoalkyne were used for volatility reasons.
1.7 equiv. of bromoalkyne were used for volatility rea-
[b]
[c]
Acknowledgements
[d]
sons.
The authors thank the CNRS, the French Ministry of Re-
search and the French Agency of Research (ANR 13-BLAN-
CHOZE) for financial support. SB also thanks the Loker In-
stitute, Los Angeles, for a joined PhD fellowship. HH thanks
the Algerian Government and the University of Batna for
a short-term fellowship. MdN thanks the Italian Government
for a short-term fellowship. SK thanks the Russian Govern-
ment for a President fellowship. The authors thank Dr. G.
Laugel from the “Laboraoire de Rꢀactivitꢀ de Surface”, Uni-
versity P. & M.Curie, Paris for the X-ray fluorescence experi-
ments.
Bromides derived from phenylacetylene derivatives
gave the expected ynamides in high yields (entries 1–
3). The simple 1-bromo-1-octyne quantitatively gave
the corresponding ynamide (entry 4). Remarkably, an-
alogues functionalized at various positions could also
be readily coupled. Noteworthy are acetate, ketal, car-
bamate, ester and free or silylated hydroxy groups,
which even at propargylic positions, were well tolerat-
ed, giving the corresponding ynamides in very high,
sometimes quantitative yields (entries 5–9).
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Adv. Synth. Catal. 0000, 000, 0 – 0
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!

FULL PAPERS
8 Zeo-Click Synthesis: Copper-Zeolite-Catalyzed Synthesis of
Ynamides
Adv. Synth. Catal. 2014, 356, 1 – 8
Hassina Harkat, Sophie Borghꢀse, Matteo De Nigris,
Serguei Kiselev, Valꢁrie Bꢁnꢁteau, Patrick Pale*
8
asc.wiley-vch.de
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
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