A copper(I)-complexed magnetic nanoparticle catalyst for enaminone synthesis

Article abstract of DOI:10.1016/j.catcom.2017.08.022

The synthesis of a copper(I)-complexed magnetic nanoparticle catalyst is described. The catalyst was characterized using Fourier transform infrared spectroscopy (FT–IR), energy-dispersive X-ray spectroscopy (XPS), atomic absrobtion spectroscopy (AA), thermogravimetric analysis (TGA), vibrating sample magnetometery (VSM), X-ray photoelectron spectroscopy (XPS), scanning electron miscroscopy (SEM) and transmission electron microscopy (TEM). The catalyst coupled thioamides and diazocarbonyl compounds to produce diverse enaminones. The catalyst reduced the reaction times and temperature and provided enaminones in high yields and selectivity. Moreover, the catalyst can be separated by a magnet and recycled.

Full text of DOI:10.1016/j.catcom.2017.08.022

Accepted Manuscript
A copper(I)-complexed magnetic nanoparticle catalyst for
enaminone synthesis
Leila Mohammadi, Mohammad Ali Zolfigol, Mahsa Ebriminia,
Kenneth P. Roberts, Samira Ansari, Tahereh Azadbakht, Syed R.
Hussaini
PII:
DOI:
Reference:
S1566-7367(17)30353-9
doi: 10.1016/j.catcom.2017.08.022
CATCOM 5171
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Catalysis Communications
Received date:
Revised date:
Accepted date:
4 July 2017
31 July 2017
15 August 2017
Please cite this article as: Leila Mohammadi, Mohammad Ali Zolfigol, Mahsa Ebriminia,
Kenneth P. Roberts, Samira Ansari, Tahereh Azadbakht, Syed R. Hussaini , A copper(I)-
complexed magnetic nanoparticle catalyst for enaminone synthesis. The address for the
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appropriate. Catcom(2017), doi: 10.1016/j.catcom.2017.08.022
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ACCEPTED MANUSCRIPT
A Copper(I)-Complexed Magnetic Nanoparticle Catalyst for Enaminone
Synthesis
Leila Mohammadia,b, Mohammad Ali Zolfigolb*, Mahsa Ebriminiaa, Kenneth P. Robertsa, Samira
Ansaric, Tahereh Azadbakhtb and Syed R. Hussainia*
aDepartment ofChemistry andBiochemistry,The University ofTulsa,800S TuckerDr,Tulsa,Oklahoma 74104,USA
bFaculty ofChemistry, Bu-Ali SinaUniversity,Hamedan 6517838683,Iran
cCinnaGen Medical Biotechnology ResearchCenter,AlborzUniversity ofMedical Science,Karaj,Iran

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The synthesis of a copper(I)-complexed magnetic nanoparticle catalyst is described. The catalyst was characterized using
Fouriertransforminfrared spectroscopy (FT–IR), energy-dispersiveX-ray spectroscopy(XPS), atomic absrobtion spectroscopy
(AA), thermogravimetric analysis (TGA),vibrating sample magnetometery(VSM), X-ray photoelectron spectroscopy (XPS),
scanning electron miscroscopy (SEM) and transmission electron microscopy (TEM). The catalyst coupled thioamides and
diazocarbonyl compounds to produce diverse enaminones. The catalyst reduced the reaction times and temperature and
provided enaminones in high yields and selectivity. Moreover, the catalyst can be separated by a magnet and recycled.
Keywords:
Copper-complexed magnetic nanoparticles
Enaminone
Diazocarbonylcompounds
Cross-coupling
1. Introduction
Scheme 2. Synthesis of enaminones using catalyst 1
Magnetic nanoparticles (MNPs)have been usedin many fields such as magnetic recordingdevices, targeted drug delivery,
biomedicine,biosensors,magnetic fluids and bioprobes.[1, 2] The synthesis and applications of MNPs are in great demand
because of their recyclability, reusability, high activity and selectivity in chemical processes.[2-5] In continuance of our
investigation onthe design,synthesisand use ofmagnetic nano-catalysts,[6, 7] we designed, synthesized and characterized a
novelCu(I) catalyst complexed with magnetic nanoparticles (1)(Scheme 1). Next, we tested 1 as a catalyst forthe formation of
Scheme 1. Synthesis of catalyst 1. TEOS = Tetraethyl orthosilicate

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enaminones. Enaminone derivatives have great potential as synthetic intermediates because of the existence of three
electrophilic and two nucleophilic sites existing within its molecular structure.[8] Enaminones are enamines of a ketoester,
1,3-diketone or similar 1,3-difunctionalmolecules.[9]One reason fortheirgeneralapplication is their multipurpose reactivity,
as both nucleophiles and electrophiles.[8-10] Furthermore, enaminones are versatile therapeutic pharmacophores.[11]
The enaminone functional group can be found in compounds with anti-inflammatory, anticonvulsive and antibiotic
activity.[9, 11] Because oftheirimportance,numerousapproacheshavebeendeveloped forthe synthesis ofenaminones.[8-13]
Some common methods include:the Eschenmosercoupling reaction,[13-15] the imino ester (imidate) approach,[16, 17] amine
condensationwith dicarbonylcompounds [8, 9, 18, 19] and the metal-catalyzed coupling of α-diazocarbonyl compounds with
thioamides.13,[20]
AlthoughCu(I)-catalyzed coupling ofthioamide and diazo compoundsfor the formation of enaminones has been reported
recently,[21]there are no reports ofthe use ofnanocatalystsin this transformation.In this paper,we addressthis deficiency and
report the use of1 as an efficient catalystforthe formation ofenaminones via the cross-coupling reaction between thioamides
and -diazocarbonylcompounds(Scheme 2). Furthermore,the catalyst can be removedeasily by an external magnet. This can
be important for industrial applications as the removal of transition metals is one of the biggest costs associated with the
production of drugs.[22]
2. Experimental
2.1 Synthesis ofcatalyst 1
Fe3O4@SiO2(CH2)3NH2 (Scheme 1) was synthesized according to the literature procedure[7] (experimental details are
provided in the supplementary data). 3.00 g of Fe3O4@SiO2@(CH2)3NH2 in 50.0 mL of dry methanol was sonicated for 30
min. 1.35 g (5.00 mmol) of 2-[2-(2-formylphenoxy)ethoxy]-benzaldehyde 2 and 20.0 mL toluene were added and the
reaction mixture was heated at 70 ⁰C for five hours. The temperature was lowered to 50 ⁰C and the reaction was stirred for
43 hours. The reaction was allowed to come to room temperature and the particles were separated using a magnet. The
particles were washed three times with dry methanol (30.0 mL  3), and dried in an oven at 70 ⁰C for 24 h to provide the
MNPs- Schiff base ligand.[7]
Copper(I) iodide (5.00 mmol, 0.950 g) was added to 4.35 g of MNPs- Schiff base ligand and the suspension was refluxed
at 110 ⁰C for 48 hours. The particles were washed with dry methanol and dried for 48 h at 100 ⁰C in a vacuum oven giving
5.10 g of MNPs-Cu catalyst 1 (0.0918 mmols gm–1 of Cu based AAS).

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2.2 General procedure forthe synthesisofenaminones
Thioamide (0.13–0.22 mmol) was dissolvedin dry dichloroethane (0.50mL) and the solutionwas transferredto a vial
containing the diazo compound (1.2–1.6 eq). The well-mixed solution was transferred to a pressure vessel containing the
MNPs-Cu catalyst(2.3–3.5 mol% based on Cu).The vials containingthe thioamide and the diazo compoundwere washed with
0.25 mL of dry dichloroethaneusing the above transferprotocoland thesolutionwas added to thereactionvessel. The mixture
was heated in a 70 ⁰C oil bath for 2–6 hours. An external magnet was used to separate the MNPs-Cu catalyst 1 fromthe
reaction mixture. The crude product was purified using column chromatography (details are provided in the supplementary
data).
3. Results andDiscussion
3.1 Characterization ofcatalyst1
The structure of 1 was characterized by FT-IR, EDX, AA, TGA, VSM, XRD, SEM, and TEM. The FT-IR spectra of the
blankFe3O4 MNPs,Fe3O4@SiO2 core-shellMNPs and the other core-shell surface modified samples showed the absorption
band near630–650 cm−1. This indicates the presence ofthe Fe–O bond (Fig. 1, supplementary data (SD)). The IR bands near
1105–112 cm−1 and 980–993 cm−1 showthe presence ofthe Si–Obond.The broadbandat 3246 cm−1 shows the presence ofthe
NH2 group.The absorption band appearing at 1634 cm–1 in Fig. 1d (SD) is due to the C=N group. The bands appears at 1627
cm–1 in Fig. 1e (SD) because of the presence of copper in the structure.[7]
The energy-dispersive X-ray spectroscopy(EDX) of catalyst1 displayed thepresence ofcarbon(C),nitrogen (N), Iron (Fe),
oxygen (O), silicon (Si), copper (Cu) and Iodine (I) (Fig. 2, SI). The atomic absorption spectroscopy (AA) indicated the
presenceof1.8% of Cu in catalyst 1.The TGA of the catalystshowedhigh thermalstability and negligible organic compound
leaching up to 220 °C (Fig. 3, SI). Magnetic measurements of Fe3O4 nanoparticles, Fe3O4@SiO2 and 1 showed that Fe3O4
nanoparticles have thegreatest magnetization and 1 has the lowest magnetization (Fig. 4, SD). This supports scheme 1. The
surface ofcoating ofFe3O4 nanoparticlesincreases in each step of scheme 1, which in turn, should result in the reduction of
magnetization after each step.

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The X-ray photoelectronspectroscopy (XPS)indicated thatthe copperspecieson the sample is in +1 oxidation state (Fig.5,
SD). Even thoughCu metal and Cu(I) spectra are similar, the Cu 2p3/2 observed at ~932eV BE and the Augerpeakobservedat
~916 ev BE confirms that the copperin the catalyst is in the Cu(I) oxidation state.[23] Size, shape and morphology of 1 were
also studiedby comparing the X-ray diffraction (XRD) pattern of 1 with Fe3O4 nanoparticles and Fe3O4@SiO2 nanoparticles.
The XRD patterns of Fe3O4 nanoparticles showed characteristic peaks at 2θ = 30.10, 35.50, 43.10, 53.00, 57.00, 62.80,
corresponding to the reflections of (220), (311), (400), (331), (422) and (511). These peaks match with those from
the JCPDS card (no. 76-1849) for the spinelcubic structure of Fe3O4 (Fig. 6a, SD).[24] All of these peaks are were also found
in the XRD spectra of Fe3O4@SiO2 and catalyst 1, which confirms crystalline structures of Fe3O4@SiO2 and catalyst 1.
Furthermore, no broad peak pattern was observed between 2θ = 20–29 which is an indicator of non-crystallinity.[7]
Therefore, the spinalcube crystalline nature ofFe3O4 is retained during thesynthesis ofcatalyst 1. By analyzing the SEM and
the TEM images (Fig. 1) of catalyst1, we found that these particles have various morphologies and they are clearly smaller
than a micron in size with some particles as small as 30 nmin length (Fig. 7, SD).
Fig. 1. SEM and TEM images of catalyst 1
3.2 Use of catalyst 1 in the synthesis of enaminones

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The coupling of3 and 4 was selected asa modelto optimize the reaction conditions.We chose dichloroethane (DCE)as the
solvent because we have previously found it to be the most suitable solvent with the copper(I) catalyst in this
transformation.[21]Various amountsofcatalyst 1 fromroom temperature to 70 °C were tested (Table 1). The lowest catalyst
loading at 70 °C that gave complete conversion of 3 into 5 was 2.3 mol% of catalyst 1 (Table 1, entry 3). Increasing the
catalyst 1 loading to 2.7mol% did not allow conversion of 3 into 5 at a lower temperature (entry 5, Table 1). The use of even
30 mol% of CuI gave negligible quantities ofthe product (compare entry 3with 6, Table 1) and no reaction was observed with
just the magnetic part of catalyst 1 (i.e., Fe3O4, entry 7, Table 1).
To display the generalapplicability ofthis procedure, α-diazocarbonyl compounds were reacted with various thioamides.
As shown in Table 2, -diazoesters (enaminones 6, 8, 9, 11, 13 & 14),-diazoketoesters (enaminones 7, 10, 12 & 15) and -
diazodiketones (enaminones 16 & 17)all undergo this transformation with 2.3–3.5 mol% of catalyst 1. Primary (enaminone 11,
Table 2), secondary (enaminones 6–8, 10 & 12–17, Table 2) and tertiary (enaminone 9, Table 2) thioamides can all be
convertedinto the corresponding enaminones with 2.3–3.5 mol% catalyst 1. A comparison of catalyst 1 with Ru(II)[25] and
(CuOTf)2.Tol,[21] which highlights its efficiency is shownforenaminone 7 and 8 (Table 2). Catalyst 1 providedenaminones in
less time and in betteryields (Table 2). The catalyst also showed excellent diastereoselectivity and provided enaminones as
single diastereomers (enaminones 7, 10, 12 & 15). This diastereoselectivity is believed to be due to stronger intramolecular
hydrogenbonding betweenthe NH and the ketone carbonyl compared with the hydrogen bonding between the NH and the
estercarbonyl. Various otherreasonshave alsobeenpostulatedforsuch selectivity.[13]The stereochemistry of7, 10,and 15 is
assigned by comparing with literature values.[25, 26] The stereochemistry of 12 is assigned by comparing the NH chemical
shifts of12 with 13 and by comparing the NHchemicalshift of 14, 15 and the diketo isomer (two esters of 14 being replaced
by two acetylgroups)[27] of 14. The chemical shift of NH hydrogen is significantly downfield in the E isomer as a result of
stronger H-bonding with the ketone oxygen.[13]
3.3 Recyclability of catalyst 1 in the synthesis of enaminones
At the end ofeach reaction the catalyst could be easily separated fromthe reaction by an external magnet. After washing
with methanoland DCM and drying undera vacuum,the catalyst could be re-used.We alsotestedthe recyclability of catalyst
1 in the coupling reaction of 3 and 4 (Fig.2) for the synthesisof5.Results showedthatcatalyst 1 could be recycledand reused.
Even after five cycles,the catalyst showed robust activity and converted 84% of 3 into enaminone 5 after three hours. There
was a loss ofcatalyst 1 aftereach cycle (see supplementary data).The lossofthe catalystsuggests that the minimal amount of
catalyst 1 does remain in the reaction mixture after being separated by an external magnet.

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4. Conclusion
In summary,a novelheterogeneousCu(I) catalyst complexed with magnetic nanoparticles (1) was designed, synthesized
and characterized by FT-IR, EDX, TGA, DTG, VSM, XRD, SEM, TEM and XPS. Catalytic applications of 1 were studied in
the syntheses of enaminones. The catalyst provided enaminones by coupling thioamides and d iazo compounds at lower
temperature and in less time than literature methods.[21, 25] It is the only example of the use ofa magnetic nanoparticle-based
catalyst in the synthesisofenaminones fromthe coupling ofthioamidesand diazo compounds. The catalyst can be separated
easily by a magnet and re-used. The recyclability of the catalyst was shown for the synthesis of enaminones. The ease of
separation and reusability of the catalyst can be important for industrial applications, especially where the removal of
transition metals is an issue. The catalyst furnishes enaminones as single diastereomers in excellent yields. As such, the
catalyst offers many advantages over previously published methods for the synthesis of enaminones.
Acknowledgments
Financial support was provided by The University of Tulsa. We thank Dr. Paulo Perez from the Surface Analysis and
Nanoscale Imaging Lab, which is sponsored by the College of Engineering, Health Science Center, Office of the Vice
President for Research, And the Utah Science and Technology and Research (USTAR) Initiative of the State of Utah, for
performing the XPS studies oncatalyst1.This workis supported by the National Science Foundation under Grant No. CHE-
1048784. The authorsthankthe Ministry ofScience,Iran for awarding Research Opportunity Award to Ms. Mohammadi for
conducting part of this work at The University of Tulsa. Bu-Ali Sina University provided funds for the characterization of
catalyst 1. Iran National Science Foundation (INSF) (The Grant Number: 940124) provided financial support to Zolfigol’s
research group.
Supplementary data
1
Experimental procedures, spectroscopic data and H and 13C spectra.
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Entry
Catalyst
Temperature
Time Yield (%)

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loading
(oC)
(hour)
10
10
3
1
2
3
4
5
6
7
1, 0.9 mol%
1, 1.8 mol%
1, 2.3 mol%
1, 2.7 mol%
1, 2.7 mol%
CuI, 30 mol%
Fe3O4, 28 mol%
70
70
70
r.t.
50
70
70
20b
50b
100b (93%)c
12
10
3
0b
40b
4b
3
0b
aAll reactions were performedin an argonatmosphere using a pressure
vessel. Reactionconditions: 3 (0.156 mmols), 4 (1.3eq), DCE 0.75 mL;
1
c
bPercent Conversion of 3 into 5 by H NMR. Isolated yield.

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100%
93%
90%
84%
84%
100
80
60
40
20
0
1
2
3
4
5
Number of Cycles

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Fig. 2. Recyclability of catalyst 1 in thecoupling reaction
of 3 and 4 under theoptimized reaction conditions. Percent
conversion refers to the conversion of 3 into 5 after 3 h as
determined by the 1H NMR.

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Graphical abstract

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Highlight



A new magnetically recoverable Cu(I)-complexed nanoparticle catalyst is prepared
The catalyst provides diverseenaminonesas single diastereomers in high yields
The catalyst provides enaminonesat lowertemperature and in less time than reportedmethods