Copper malonamide complexes and their use in azide-alkyne cycloaddition reactions

Article abstract of DOI:10.1039/c5dt01312g

We report a rare example of the malonamide functionality being used as a ligand in copper catalysis. We have ligated a homologous series of these O,O-chelating architectures to copper, investigated their structure and exploited them in azide-alkyne cycloa

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Copper malonamide complexes and their use in azide-alkyne
cycloaddition reactions
Received 00th January 20xx,
Accepted 00th January 20xx
S. J. Bent, M. F. Mahon and R. L. Webster*
We report a rare example of the malonamide functionality being used as a ligand in copper catalysis. We have ligated a
homologous series of these O,O-chelating architectures to copper, investigated their structure and exploited them in
azide-alkyne cycloaddition reactions for the step-growth synthesis of oligo(triazoles) and in the synthesis of small organic
azoles.
DOI: 10.1039/x0xx00000x
www.rsc.org/
opted to test the potential of our new complexes in these
cycloadditions.
Introduction
The development of new ligands is an important undertaking in
synthetic chemistry, providing access to untapped facets of classical
coordination chemistry and providing us with the opportunity to
enhance known catalytic transformations or even to develop
entirely new catalytic reactions. The malonamide motif to is known
to act as an O,O-chelating ligand for Cu(II),1 and we extended the
reactivity of malonamides to include the step growth synthesis of
polymalonates.2 As a consequence we were intrigued by the further
potential of the malonamide motif and whether its novel use as a
ligand could be developed for important catalytic transformations.
To the best of our knowledge this class of simple copper (I) O,O-
chelate have never been used in a catalytic process;3 this is
somewhat surprising given the levels of steric and electronic
variance that can be achieved along with the flexibility to ligate as a
neutral donor or as an ionic donor (analogous to the ubiquitous
acac motif). The tuneable nature of this pro-ligand makes it ideal
for catalysis. We herein report our initial results in this area, where
Cu(I) malonamide complexes have been synthesised and their
catalytic competency in azide-alkyne cycloaddition reactions
studied, both for the synthesis of small organic triazoles and in the
step growth cycloaddition synthesis of oligo(triazoles).
Results and discussion
We initiated our research by synthesising a small library of pro-
ligands with a range of steric and electronic properties. This was
achieved in generally good yields (up to 56%) and on a large scale
(up to 0.1 mol). Two principal routes can be used; due to steric
hindrance, 1 can only be accessed using Mukaiyama’s reagent to
couple malonic acid to diisopropylamine7 (Scheme 1a) whereas
synthesis of 2 to 4 is possible using aminolysis,8 by reacting
dimethylmalonate with the appropriate amine (Scheme 1b).
Scheme 1. Pro-ligand synthesis using Mukaiyama’s reagent or aminolysis.
The azide-alkyne cycloaddition reaction (or Huisgen 1,3-dipolar
cycloaddition reaction) is undoubtedly of universal importance,
being exploited under exacting ‘click’ conditions in the synthesis of
small organic motifs, with 1,4-regioselectivity being observed
preferentially using copper catalysts.4 The utility of this reaction is
further highlighted in the synthesis of poly(triazoles) for use in
polymer chemistry and materials science.5 The transformation has
also found applications in medicinal chemistry and biochemistry.6
Given the prevalence and importance of this transformation, we
Reaction of the pro-ligands with [Cu(MeCN)4]BF4 gives the desired
Cu(I) complexes (1-Cu to 3-Cu) in high yield as lilac solids (Scheme
2). These solids are air stable in the solid state for several days but
become air-sensitive when suspended in solvent or with prolonged
exposure to moisture in the atmosphere. Use of 4 as a ligand results
in decomposition and precipitation of a black nano-particulate side-
product. No copper complex was isolated. This is presumably due to
steric hindrance limiting product formation, reflecting the poor
yield obtained when preparing the pro-ligand, 4. Elemental analysis
of 1-Cu, 2-Cu and 3-Cu indicates the presence of one MeCN per
metal centre. The Cu(I) complexes (1-Cu to 3-Cu) are insoluble in
standard deuterated solvents and thus the chemical composition is
proven by elemental analysis and by controlled oxidation to the
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Cu(II) congener (5, 6 and 7 respectively) by exposure to air and then however, in this case they interact with the N–H protons on the
recrystallisation in CH2Cl2/pentane or THF/pentane to yield the ligand. Both six-membered cupracycles exhibit ring-puckering.
requisite Cu(II) malonamide complexes. Conversion from Cu(I) to
the pale blue-turquiose Cu(II) complexes occurs in moderate yield
(11 to 47%), where the yield is limited to 50% due to sequestration
of an extra BF4 anion to allow oxidation. Presumably the remaining
copper disproportionates into Cu(0), similar to observations made
by Lei and co-workers on the disproportionation of Cu(I) β-keto
enolate analogues.9
Scheme 2. Synthesis of Cu(I) complexes 1-Cu to 3-Cu.
Fig. 2. Structure of complex 6, formed in 16% yield from 2-Cu. Selected bond
lengths (Å): Cu-O1 1.947(1), Cu-O2 1.977(1), C1-N1 1.318(2), C3-N2 1.315(3),
Complex 510 exists in a square pyramidal geometry in the solid
state. Crystallisation in hydrous solvent allows ligation of H2O to the
metal centre, which is subsequently able to hydrogen bond to both
BF4- counterions. An interesting feature of this Cu(II) complex is the
ring-puckering at C9, which is not observed at C1; this ring
maintains an almost planar geometry around the metal-centre. Ring
puckering at C9 results in a narrow C10-C9-C10 bond angle
(112.3(3)°) and widening of the O2-Cu-O2 angle (92.47(7)°)
compared to the planar ring which exhibits an angle of 118.2(3)°
around C1 and a close to right-angle connectivity for O1-Cu-O1
Cu-O3 2.378(2). Selected bond angles (°): O1-Cu-O2 92.16(6), C1-C2-C3
109.9(2). Carbon bound hydrogen atoms omitted for clarity. Primed labels
related to those in the asymmetric unit by the –x, 1 – y, –z symmetry
operation. Thermal ellipsoids set at the 30% probability level.
With our Cu(I) malonamide complexes, 1-Cu, 2-Cu and 3-Cu in hand
we began to explore their synthetic utility as catalysts in the azide-
alkyne cycloaddition reaction. We started our investigation in this
area by comparing the reactivity of 1-Cu, 2-Cu and 3-Cu in the
azide-alkyne cycloaddition of phenylacetylene and benzylazide
(Table 1). The control experiments gave very poor yields of
cycloaddition product (compare Entries 1 to 4). With 2.5 mol%
loading of pre-catalyst 1-Cu we observe 87% spectroscopic yield of
the cycloaddition product (8a) after one hour at RT. This is modest
in comparison to other 1,3-dipolar cycloaddition reactions under
neat conditions,4 where state-of-the-art examples using a Cu(I)
complex as the pre-catalyst include, but are not limited to, highly
active NHC systems developed by Nolan,12 Sarkar’s abnormal NHC
systems13 and Díez-González’s phosphine-based pre-catalyst.14
Using 1-Cu as the pre-catalyst, the reaction has an initial turnover
frequency of 167 h-1 for the first five minutes of the reaction, which
drops to 60 h-1 after 25 minutes and after 40 minutes the reaction is
incredibly sluggish, with little turnover observed. Reaction
monitoring under an inert atmosphere in C6D6 for ease of NMR
studies shows that the reaction is much slower in this solvent (only
10% complete after 1 h at RT using 2.5 mol% 1-Cu). Stirring is also
vital for the reaction to proceed; in an NMR tube saturation kinetics
are observed when the catalyst loading is increased to 3.75 mol%.
When the benzyl adduct 2-Cu is used in neat conditions, only 55%
spectroscopic yield is obtained and 43% with the aniline-derived
complex, 3-Cu (Table 1, Entries 5 and 6). Pleasingly, the reaction can
also be carried out on water (Entry 7) and in situ catalyst
preparation continues to give modest yield of product (Entry 8). In
situ reduction of the air-stable Cu(II) congenor, 5, using sodium
ascorbate15 gives 21% 8a after 1 h at RT and 69% after 4 h at RT
(Entry 9), thus offering a viable alternative to the air-sensitive
handling conditions required when using the Cu(I) pre-catalysts.
(89.28(7)°).
Fig. 1. Structure of complex 5, formed in 47% yield from 1-Cu. Selected
bond lengths (Å): Cu-O1 1.936(2), Cu-O2 1.947(2), Cu-O3 2.217(3), O1-C2
1.256(3), O2-C10 1.258(3), N1-C2 1.330(3), N2-C10 1.322(3). Selected bond
angles (°): O1-Cu-O1 89.28(7), O2-Cu-O2 92.47(7), C2-C1-C2 118.2(3), C10-
C9-C10 112.3(3). Disorder and carbon bound hydrogen atoms omitted for
clarity. Primed labels related to those in the asymmetric unit by the – x, – y,
z symmetry operation. Thermal ellipsoids set at the 30% probability level.
Complex 611 is obtained from a wet THF/pentane recrystallising
solution and in contrast to 5, preferential ligation of THF is
observed. An octahedral geometry around the metal centre is
-
obtained, with THF coordinating in the axial positions. The BF4
counter ions are, once again, involved in hydrogen bonding,
2 | J. Name., 2012, 00, 1-3
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Table
1.
Optimisation
We then proceeded to investigate alkenes and the potential of
reacting more challenging alkynes. Unfortunately reaction of
styrene with benzyl azide in the presence of 2.5 mol% 1-Cu, even at
60 °C for 24 h, shows only unreacted starting materials by 1H NMR.
Likewise, activated alkenes such as methyl- and butylacrylate do not
react even with prolonged heating at 60 °C. No reaction is observed
with the internal alkyne methyl-2-butynoate, however,
dimethylacetylene dicarboxylate does give good yield of the
corresponding triazole after 1 h at RT.16 It should be noted that this
transformation is in fact not a catalytic one and the cycloaddition
occurs readily at RT catalyst-free (Scheme 3).17 In the presence of
2.5 mol% 1-Cu, 73% 9a and 61% 9b is obtained.
of
azide-
alkyne
cycloaddition.
Entry Pre-catalyst
Conditions
Spec. Yield
8a, %a
trace
12
1
2
3
4
5
6
7b
8
9
Cu-free
Cu(MeCN)4BF4
1
-
2.5 mol%
5 mol%
trace
87 (84)
55
1-Cu
2.5 mol%
2.5 mol%
2.5 mol%,
2.5 mol%, H2O
2-Cu
3-Cu
43
1-Cu
76
1 + Cu(MeCN)4BF4 5 mol% 1, 2.5 mol% [Cu]
5 + Na ascorbate 2.5 mol% [Cu], 25 mol% [Na]
51
15, 69c
Scheme 3. Cycloaddition of internal alkyne dimethylacteylene dicarboxylate. Reaction
conditions: azide (0.5 mmol), alkyne (0.5 mmol), RT, 1 h, N2.
General reaction conditions: benzylazide (63 μL, 0.5 mmol), phenylacetylene (50
μL, 0.5 mmol), 1 h, RT, N2. aDetermined by 1H NMR spectroscopy using 1,2-DCE as
an analytical standard (isolated yield shown in brackets). bDegassed H2O,
performed under N2. c4 h, RT.
Finally the competancy of 1-Cu at catalysing the polymerisation of
diazides and diynes was explored (Table 2). The oligomeric pre-
polymers are insoluble in organic solvents but DSC analysis shows
that both products have good thermal stability, where 10b has a Tg
of 80.1 °C and a Tm of 248.4 °C. In comparison 10a has a much
reduced Tg (18.1 °C), but this is contrasted by a high Tm of 283.2 °C.
Analysis by MALDI-ToF indicates both products form pre-polymer
with very similar molecular weights (1,800 gmol-1). This is the first
time these oligo(triazole) structures have been reported and we are
currently investigating the potential of high molecular weight
polymer synthesis through vacuum condensation and subsequent
post-polymerisation functionalisation.
Using pre-catalyst 1-Cu, a range of alkynes are tolerated in this
transformation (Figure 3) including propiolates (8c and 8d), nitriles
(8e), unactivated alkynes (8f) and halo-substituted alkynes (8g). The
azide coupling partner can also be varied (8i, 8j, 8k and 8l) and all
reactions can still be undertaken at RT with only a modest increase
in reaction time necessary in some cases. Synthesis of 8c and 8k can
be achieved thermally in the absence of 1-Cu; heating at 70 °C for 1
h gives 68% and 21% of 8c and 8k respectively. However, no
reaction is observed in the absence of a catalyst after 3 h at RT.
Table 2. Oligo(azide-alkyne) cycloaddition to give products 10a and 10b.
Property
Mn (gmol-1)a 1800
10a
10b
1800
1.07
7
PDIa
DP
1.06
6
Tg (°C)b
Tm (°C)b
Tc (°C)b
18.1
80.1
283.2 248.4
-
188.5,
207.4
Measurements: aMALDI-ToF. b DSC.
Conclusions
In summary, we have presented initial investigations into the use of
the malonamide motif as a neutral ligand in Cu(I) catalysis. The
complexes prepared prove to be competant pre-catalysts for the
synthesis of triazoles using azide-alkyne cycloaddition methodology.
The Cu(I) complexes are readily oxidised in hydrous solvent to
furnish the Cu(II) analogues in good yield. Catalysis with the Cu(I)
complexes has also been extended to include preliminary studies in
oligo(azide-alkyne) cycloadditions, with the pre-polymers prepared
demonstrating good thermal stability and in one case a high Tg of
Fig. 3. Substrate scope for azide-alkyne cycloaddition reaction using complex 1-Cu.
Reaction conditions: azide (0.5 mmol), alkyne (0.5 mmol), 1-Cu (2.5 mol%, 8 mg), RT, 1
h, N2, isolated yield. a3h, RT. b24h, RT.
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80.1 °C is observed. Overall, we have demonstrated that the 143.5 (Arq), 129.5 (Ar), 127.8 (Arq), 127.2 (Ar), 41.2 (C(O)CH2C(O)),
malonamide is a good ligand for copper catalysis and hints at the 37.13 (CH3); IR ν 3064, 2941, 1644, 1593, 1494 cm-1; m.p. 108 °C.
potential of this ligand in other transformations, where we envisage
that it could be further exploited as neutral donor or developed as General method for the synthesis of Cu(I) complexes.
an anionic ligand similar to the ubiquitous acac motif; these studies For example, complex 1-Cu: manipulations carried out under an
are on-going.
inert atmosphere. [Cu(MeCN)4]BF4 (200 mg, 0.64 mmol, 1 eq),
diisopropyl malonamide 1 (343 mg, 1.27 mmol, 2 eq) and toluene (2
mL) were combined in a J-Young reaction tube and stirred at room
temperature for 3 hours. Using a metal cannula with a glass paper
frit, the reaction solution was filtered away from the precipitate
leaving a lilac solid which was then washed with toluene (3 x 1 mL).
The solid was then dried under vacuum before storing in a
glovebox. See ESI for analytical data.
Experimental
General considerations
Reagents were purchased from Sigma Aldrich and used without
further purification. Laboratory grade solvents were purchased
from Fisher Scientific and used without further purification. NMR
data was collected at 250, 300, 400 or 500 MHz on Bruker
instruments in CDCl3 at 298 K and referenced to residual protic
solvent. Heated and anhydrous reactions were undertaken in
Schlenk tubes or J-Young reaction tubes.
General procedure for the synthesis of triazoles 8a to 8l and 9a
and 9b.
Alkyne (0.5 mmol) was added to azide (0.5 mmol) and the
appropriate copper malonamide complex (2.5 mol%) in a small
Schlenk tube and stirred for one hour at room temperature. The
reaction was quenched with water and the product extracted into
EtOAc. The extractions were filtered through a pipette fitted with
glass paper and MgSO4 before being dried under nitrogen. 1,2-DCE
(0.5 mmol) was then added to optimisation reactions for the
synthesis of 8a and the sample analysed by 1H NMR prior to
purification. Spectroscopic yield was obtained by integrating the
CH2 product peak relative to 1,2-DCE. Products could be isolated
recrystallisation from EtOAc/pentane as necessary. See ESI for
analytical data. The procedure to synthesise 9a and 9b was
identical, but can be carried out in the absence of catalyst.
Method for the preparation of 1.
NEt3 (1 mL, 7.17mmol) followed by diisopropylamine (1 mL, 7.14
mmol) each in CH2Cl2 (5 mL) were added dropwise to a stirred
solution of malonic acid (312 mg, 3 mmol, 1 eq) and Mukaiyama’s
reagent (2-chloro-N-methylpyridinium iodide, 1.61 g, 6.3 mmol, 2.1
eq) in CH2Cl2 (50 mL) at 0 °C. The solution was left to stir at 0 °C for
30 minutes and then allowed to warm to RT and stirred for a
further 4 hours. The resulting mixture was concentrated in vacuo
and the product was isolated by silica gel column chromatography
(40% EtOAc/pentane). White solid, 332 mg (41%). 1H NMR (400
MHz; 298 K; CDCl3) δ 4.32 (septet, 2H, J 6.8 Hz, CH(CH3)2), 3.40 (s,
2H, CH2), 1.39 (s, 12H, J 6.8 Hz, CH(CH3)2), 1.16 (d, 12H, J 6.8 Hz,
CH(CH3)2); 13C{1H} NMR (100 MHz; 298 K; CDCl3) δ 165.8 (C=O), 49.4
(C(O)CH2C(O)), 46.0 (CH(CH3)2), 20.6 (CH(CH3)2), 20.3 (CH(CH3)2); IR
(solid) ν 2962, 1734, 1614 cm-1; m.p. 146 °C.
General procedure for the step growth synthesis of 10a and 10b.
Diyne (0.5 mmol) was added to diazide (0.5 mmol) and the
appropriate copper malonamide complex (2.5 mol%) in a small
Schlenk tube and stirred for one hour at room temperature to give
low Mn pre-polymer. The pre-polymer was washed with CH2Cl2 (2 ×
2 mL) followed by MeOH (2 × 2 mL), before drying under a stream
of N2. Analysis by of the sample by carried out using MALDI-ToF,
with the sample loaded as a solid.
Method for the preparation of 2.
Dimethyl malonate (5.7 mL, 50 mmol, 1 eq) and benzylamine (10.9
mL, 100 mmol, 2 eq) were added to a round bottomed flask, heated
to 160 °C and stirred for 18 hours with distillation of methanol using
short-path distillation apparatus. The product crystallised on
cooling, it was then filtered, washed with ice cold ethyl acetate and
dried under vacuum. The same protocol can be used to prepare
ligands 3 and 4.
Acknowledgements
We thank the Royal Society of Chemistry for an Undergraduate
Summer Research Bursary (SJB) and the University of Bath for
additional financial support.
1
2: White solid, 7.87 g (56%). H NMR (250 MHz; 298 K; CDCl3) δ
7.38-7.26 (m, 12H, ArH), 4.45 (s, 4H, CH2Ar), 1.39 (s, 2H, CH2), 1.16
(d, 12H, J 6.8 Hz, CH(CH3)2); 13C{1H} NMR (63 MHz; 298 K; CDCl3) δ
167.3 (C=O), 137.7 (Arq), 128.6 (Ar), 127.6 (Ar), 127.4 (Ar), 43.5
(CH2Ar), 42.9 (C(O)CH2C(O)); IR ν 3281, 3064, 3033, 1655, 1624,
1542 cm-1; m.p. 144 – 145 °C.
Notes and references
3: White solid, 5.89 g (21%). Sparingly soluble in CDCl3. 1H NMR (250
MHz; 298 K; CDCl3) δ 8.74 (br. s, 2H, NH), 7.57 (d, 4H, J 7.6 Hz, ArH),
7.36 (d, 4H, J 7.6 Hz, ArH), 3.54 (s, 2H, CH2), 1.58 (s, 6H, CH3); IR ν
3268, 3150, 3115, 1645, 1596 cm-1; m.p. 231 °C.
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[I>2
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=
3822,
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85.
data/restraints/parameters = 3909/28/274. Observed data;
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1.54184 Å, triclinic, space group P-1, a = 9.6068(3), b =
10.6220(4), c = 11.5052(5) Å, α = 79.821(3), β = 77.423(3), γ =
o
73.676(3) , U = 1091.27(7) Å3, Z = 2, Dc = 1.440 g cm-3, μ =
1.454 mm-1, F(000) = 491. Crystal size = 0.22 × 0.15 × 0.13
mm, unique reflections = 4254 [R(int) = 0.0326], observed
reflections [I>2σ(I)] = 3948, data/restraints/parameters =
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DOI: 10.1039/C5DT01312G
A series of copper (I) malonamide complexes have been synthesised and their catalytic activity
explored in 1,3-dipolar cycloaddition reactions: the first time this ligand motif has been reported in a
catalytic transformation.