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COMMUNICATION
Cite this: DOI: 10.1039/c7cy00882a
Received 4th May 2017,Accepted 3rd July 2017
DOI: 10.1039/c7cy00882a
A five coordination CuIJII) cluster-based MOF andits application in the synthesis of pharmaceuticalsvia sp3 C–H/N–H oxidative coupling†
Thuan V. Tran,a Hanh T. N. Le,b Hiep Q. Ha, a Xuan N. T. Duong,a
Linh H.-T. Nguyen,c Tan L. H. Doan,cd Ha L. Nguyen *c and Thanh Truong *a
rsc.li/catalysis
Herein, a copper metal–organic framework, termed as VNU-18,
containing penta-coordinated sites was successfully synthesized
and fully characterized. This material was demonstrated to be an
efficient heterogeneous catalyst for the oxidative C–H activation
via N–H bonds. The optimized conditions are applicable for the
synthesis of pharmaceuticals constructed by α-amino carbonyl
skeletons.
α-Amino carbonyls are the skeletons that are often found in avariety of valuable compounds such as amino acids,pharmaceuticals, and biologically active natural products.1
Therefore, the development of a methodology to synthesizeα-aminated carbonyls has gained significant attention. In par-ticular, the traditional strategy involved the utilization of pre-functionalized α-halogenated carbonyls in nucleophilicFinkelstein substitution reactions.2 Metal-free or organo-catalytic routes suffer from limited scope, and additionalsteps are required to prepare the starting materials or/andgenerate the desired products.3 Reports on transition metalcatalysis have disclosed the two-step catalytic pathway startingwith the electrophilic 2π-electrophile aza-substrates andenolates followed by reduction.4 Recently, a novel direct intro-duction of an amine nitrogen adjacent to a carbonyl in a cata-lytic manner was disclosed by MacMillan group.5 Moreover,the reaction scope is limited to secondary amines. The useof homogeneous catalysts, especially in pharmaceutical indus-try, often represents major problems regarding removal of
contaminated metal from the final product.6 Therefore, thedevelopment of more practical protocols catalyzed by hetero-geneous catalysts is in great demand. It can be reasoned thatincreased efficiency makes the chemical processes greener byreducing the amount of steps in the purification process andrecycling of the catalyst.7
Metal–organic frameworks (MOFs) serve as a new class ofporous materials, which possess versatility in connectingmetal-containing nodes with a variety of organic bridges.8
Consequently, these materials have emerged as promisingheterogeneous catalysts for valuable organic reactions due totheir pore size controllability, facile modification of startingcomponents, and fine tunable structure.9 In particular,copper-based MOFs with open metal sites have been com-monly utilized as catalysts for various transformations.10 Inall the reported Cu-MOF catalysts synthesized using only cop-per salt and carboxylate organic linkers, Cu-oxo clusterexisted in either tetrahedral, distorted tetrahedral, or squareplanar structure with 4 coordination sites.11 This resulted inlow chemical stability of these Cu-MOFs towards moistureand harsh chemical environment especially with high chelat-ing affinity reagents and strong oxidants.12 To partially over-come this limitation, an aromatic or tertiary nitrogen-containing ligand, such as 1,4-diazabicycloij2.2.2]octane(DABCO) or 4,4′-bipyridine (BP), was often introduced to formthe vulnerable and thermally reversible fifth coordination.13
Although remarkable improvement in chemical durabilityhas been reported, ligand exchange between these ligandsand strong chelating starting materials, such as ketones orprimary/secondary amines, has been observed during the re-actions.14 Based on literature precedents, we hypothesizedthat copper-oxo clusters possessing 5 permanent bound mol-ecules would own higher chemical resistance.15 In this re-gard, herein, the synthesis and characterization of a copper-based MOF, termed as VNU-18, constructed using a 3,5-pyridinedicarboxylic acid (PDC) linker, has been presented.Furthermore, the chemical stability and catalytic activity ofVNU-18 possessing a copper cluster with five coordination
Catal. Sci. Technol.This journal is © The Royal Society of Chemistry 2017
a Faculty of Chemical Engineering, Bach Khoa University, VNU-HCM, 268 LyThuong Kiet, District 10, Ho Chi Minh City, Vietnam.E-mail: [email protected] Institute of Public Health, 159 Hung Phu, District 8, Ho Chi Minh City, VietnamcCenter for Innovative Materials and Architectures (INOMAR), VNU-HCM, Ho ChiMinh City, Vietnam. E-mail: [email protected], [email protected] Faculty of Chemistry, University of Science, VNU-HCM, Ho Chi Minh City,Vietnam† Electronic supplementary information (ESI) available: Synthesis and characteri-zation of VNU-18, additional catalytic data, and recycling studies. CCDC1515280. For ESI and crystallographic data in CIF or other electronic format seeDOI: 10.1039/c7cy00882a
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sites was investigated in the oxidative C–H/N–H couplings be-tween ketones and amines. Indeed, high efficiency in con-junction with excellent heterogeneity of VNU-18 was detected,whereas other Cu-MOFs with 4 coordination sites were struc-turally damaged or/and inactive.
VNU-18 was solvothermally synthesized via the reaction of3,5-pyridinedicarboxylic acid (PDC) with copper nitratetrihydrate (CuIJNO3)2·3H2O) in N,N-dimethylformamide (DMF)at 100 °C in 24 h (Scheme 1). The blue single crystal of VNU-18 was isolated for crystal structure elucidation via singlecrystal X-ray measurement. The crystal structure of VNU-18revealed that this material crystallized in the monoclinic P21/m space group with a = 14.9611(7) Å, b = 18.8833(9) Å, c =15.2457(8) Å, and β = 102.2435IJ18)°. The three-dimensionalstructure of VNU-18 was composed by the connection be-tween 3,5-pyridinedicarboxylate linker units, in which the or-ganic components acted as a 3-connected point of extension,and copper building blocks.
Note that the copper building blocks of VNU-18 are inter-estingly found with three kinds of geometrical cluster units,which has been unprecedentedly reported in MOF chemistrybased on Cu-oxo cluster (Scheme 1).11,16 Especially, two car-boxylate groups of PDC were alternatively connected to theCu-paddle wheel cluster, generating the infinitive undulationof paddle wheel blocks. A copper atom of Cu-paddle wheellinks to 2 carboxylates of PDC and one guest molecule, whichis evacuated via solvent exchange and activation to form anopen copper site. This border of paddle wheel blocks coversthe 1D channel of the pore of VNU-18, whose size is found tobe 11 Å in diameter. Moreover, two PDC linking units werelocated perpendicular to the undulate paddle wheels,resulting in single octahedral Cu-building blocks via the con-nection of carboxylate functionalities, pyridine-based phenylrings on PDC, which was connected by forming an undulatechain of Cu-paddle wheel, and copper atom. In addition,three pyridine-based phenyl rings of PDC linkers were orthog-onal at the penta copper site that was directly linked to twohydroxyl groups to balance the charge (Fig. 1).
The powder X-ray diffraction (PXRD) analysis further con-firmed the pure phase of VNU-18, indicated by the coinci-
dence between the as-synthesized, the activated and the sim-ulated PXRD pattern (Fig. 2a). The thermogravimetricanalysis (TGA) supported the formation of VNU-18 via the re-sidual coincidence of CuO residue between experimental(35.2%) and theoretical (37.0%) values (see ESI,† section S2).The potential solvent accessible void, as calculated byPLATON,17 was 58.8%. This was supported by the N2 adsorp-tion isotherm measured at 77 K, in which VNU-18 exhibitedsignificant uptake in the low-pressure regions, resulting incalculated the Brunauer–Emmett–Teller (BET) and Langmuirsurface areas of 900 and 1200 m2 g−1, respectively (Fig. 2b).The topological analysis for VNU-18 was then conducted byTOPOS 4.0 package.18 The linking of pentanuclear Cu singlesite and two organic linker-based PDC was simplified as asquare planar connection. Another square linking unit wasalso identified based on the connection of two PDC unitswith Cu metal clusters, in which the carboxylate functionali-ties were chelated to Cu-paddle wheel at the center, whereaspyridine components generated the octahedral block (see ESI,†section S4). These 4-connected points combined to each otherto result in the three-dimensional topology of 4, 4, 4 T10.
As discussed, Cu-oxo clusters in distorted tetrahedralexisted in all the reported Cu-MOFs with open Cu sites oftenshowing lower stability under highly chelating environmentssuch as N–H amines or carbonyls. This was herein supportedby the results of the oxidative cross coupling reactions be-tween ethyl phenyl ketone and morpholine using various Cu-MOFs with 4 coordination sites under reported homogeneousconditions and KBr as a bromine source (Table 1, entries 2–6). Although several promising yields were obtained, on mea-suring the soluble copper content in reaction the filtrate, we
Scheme 1 Synthetic scheme depicting the generalized formation ofVNU-18 (c) via the combination of 3,5-pyridinedicarboxylate unit (PDC)(a) and three kinds of Cu building blocks (b). Color code: Cu, blue; O,red; C, black; N, green; and H atoms have been omitted for clarity. Theyellow balls display the pore size of 14 Å as calculated for VNU-18.
Fig. 2 (a) PXRD analysis showing the experimental pattern (red), as-synthesized (blue), and simulated pattern (black). (b) N2 adsorption iso-therm of VNU-18 at low pressure and 77 K.
Fig. 1 Asymmetric unit of VNU-18 drawn by ORTEP with thermal el-lipsoids styled at 50% probability.
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observed that all the tested Cu-MOF catalysts were eitherdissolved or partially leached. Gratifyingly, VNU-18maintained its structure after identical reaction with 42%yield. Therefore, optimization of the catalytic activity with re-spect to solvent, type of bromine sources, and catalyst wasfurther investigated. Unlike the homogeneous counterpart,reactions in dimethylformamide (DMF) as an optimal solventoffered 86% yield (entry 9). In particular, <60% yields wereobtained when 1,4-dioxane, acetonitrile, and toluene wereemployed (entries 11, 8, and 12, respectively). Studies of Mac-Millan postulated that the bromine atom in CuBr2 partici-pated in the formation of transient α-bromo carbonyl.5 WithVNU-18, the presence of KBr bromine source was found to becrucial (entry 10). The replacement of KBr with other haloge-nated salts, such as LiBr, CsBr, KI, or KCl, did not technicallyor economically improve the efficiency (entries 13–16). Notethat reactions carried out using the metal salt CuIJNO3)2 cata-lyst afforded lower yields than those carried out using VNU-18 (entry 17), whereas contribution of sole organic linkerPDC was unlikely (entry 18). This supported the synergeticand cooperative effect of linkers on metal clusters within theVNU-18 structure. Furthermore, other commonly used hetero-geneous systems provided lower catalytic activity or stability(entries 19–21), whereas other transition metal bromide saltsfailed to afford acceptable yields (entries 22–24).
To investigate the activity of VNU-18 over wide range ofsubstrates, optimized conditions were applied for a variety of
C–H and N–H bonds. The isolated product yields arepresented in Table 2. In particular, aromatic and especiallyaliphatic ketones efficiently undergo coupling without the ad-dition of co-catalyst, as reported under homogeneous condi-tions (entries 1–4).5 Ester functionality can also be used asC–H bond starting materials (entries 2, 3, and 5). Reactionswere not limited to morpholine. Subsequently, amination by1-methylpiperazine, piperidine and its derivatives, methylbenzyl amine, and pyrrolidine afforded desired products ingood yields (entries 6–11). Acyclic amine such as dimethylamine was also observed to be active (entry 12). Interestingly,aromatic amine and primary amine, which were not activeunder CuBr2 protocol, were successfully introduced into C–Hbonds (entries 13 and 14), demonstrating excellent activity ofVNU-18 towards oxidative C–H/N–H couplings.
To confirm the stability and heterogeneity of VNU-18 dur-ing the reaction process, control experiments were subse-quently conducted to ensure that the catalysis under leachedmetal was unlikely (see ESI,† section S7). When the catalystwas removed from the reaction mixture, no further formationof the desired product was observed, supported by the con-centration of Cu2+ in the reaction filtrate. Subsequently, therecycling studies were performed for 6 consecutive timeswithout remarkable loss in catalytic activity. Note that all thetested Cu-MOFs were vulnerable, and leaching of metal spe-cies was observed in all the cases (Table 1). Furthermore, thecrystallinity of the catalyst after reuse was maintained.
Table 1 Optimization of conditionsa
Entry Catalyst Solvent Br− source GC yield (%) [Cu]b (ppm)
1 CuBr2 DMSO — 78 3082 Cu2IJBTC)3 DMSO KBr 62 563 Cu(BDC) DMSO KBr 65 1054 Cu2IJBDC)2 (BPY) DMSO KBr 35 925 Cu2IJBDC)2 (DABCO) DMSO KBr 56 876 Cu2IJBPDC) (BPY) DMSO KBr 35 987 VNU-18 DMSO KBr 42 <58 VNU-18 CH3CN KBr 56 <59 VNU-18 DMF KBr 86 <510 VNU-18 DMF — 6 <511 VNU-18 1,4-Dioxane KBr 40 <512 VNU-18 Toluene KBr 28 <513 VNU-18 DMF LiBr 21 <514 VNU-18 DMF CsBr 76 <515 VNU-18 DMF KI 84 <516 VNU-18 DMF KCl 26 <517 CuIJNO3)2 DMF KBr 71 31518 PDC DMF KBr <2 n.d19 Cu/zeolite X DMF KBr 48 16220 Cu/ZSM-5 DMF KBr 31 7521 CuFe2O4 DMF KBr 22 2322 FeBr3 DMF KBr 723 CoBr2 DMF KBr <224 NiBr2 DMF KBr 5
a Volume of solvent, 2 mL; 0.5 mmol scale.; BDC, benzene-1,4-dicarboxylate; BTC, 1,3,5-benzene tricarboxylate; BPY, 4,4′-bipyridine; BPDC,biphenyldicarboxylate; DABCO, 1,4-diazabicycloij2.2.2]octane. b In reaction filtrate. See ESI for more details.
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Subsequently, the reaction mechanism was proposed(Scheme 2). α-Bromination of carbonyl compounds undercopper catalysis occurred to generate α-bromo carbonylsfollowed by nucleophilic substitution by N–H amines. In fact,the synthesized α-bromo ethyl phenyl ketone facilely reacted
with morpholine to afford the desired product in excellentyield (see the ESI†).
To highlight the generality of VNU-18 within oxidativeamination, the synthesis of high-profile relevant medicinalagents was carried out utilizing the optimized conditions.
Table 2 Reaction scope with respect to coupling partnersa
Entry N–H C–H Product Yield (%)
1 81 (76)b
2 48
3 73
4 77
5 76
6 76
7 78
8 2-Me: 453-Me: 744-Me: 80
9 82
10 65c
11 51
12 62
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The use of heterogeneous catalysts in pharmaceutical indus-try is highly preferred due to the avoidance of removal oftoxic contaminated metals in final products and cost reduc-tion.19 Particularly, racemic mixtures of Clopidogrel (Plavix),an agent that prevents blood clot, Amfepramone, an appetitesuppressant, and α-pyrrolidinovalerophenone (α-PVP), dopa-mine transporters (DAT) were achieved in reasonable yieldsin one-step manner using VNU-18 catalysis protocol fromcommercially available starting materials (eqn (1)–(3),Scheme 3). The utility of air atmosphere instead of oxygen, li-gand-free, ambient temperature, and heterogeneous catalystmakes the method more operational.
In summary, we have presented the synthesis of a copper-based metal–organic framework, VNU-18, with copper clusterpossessing three kinds of geometrical cluster units, whichhas been unprecedentedly reported in MOF chemistry based
Cu-oxo cluster. A complete characterization including singlecrystal and powder X-ray diffraction analyses, thermo-gravimetric analysis, and N2 adsorption measurement at lowpressure and 77 K for VNU-18 was also disclosed. Further-more, this material was demonstrated as an active catalystfor direct coupling of wide range of carbonyls and N–Hamines. Leaching test and recycling studies indicated theheterogeneity of VNU-18, whereas other reported Cu-MOFs orcommon heterogeneous materials were inefficient. Gratify-ingly, the synthesis of prominent pharmaceutical agents wasalso performed under optimized conditions. More studies tosupport the chemical resistance and excellent activity of thiscopper-oxo cluster possessing 5 permanently bound mole-cules are currently undergoing.
We would like to acknowledge Vietnam NationalUniversity-Ho Chi Minh City (VNU-HCM) for financial sup-port via grant No. B2015-20-04. H. L. N dedicates this work toProf. Dzung Hoang on the occasion of his 65th birthday.
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Table 2 (continued)
Entry N–H C–H Product Yield (%)
13 47d
14 31
a Reaction conditions: volume of solvent, 2 mL; 0.5 mmol scale. b Number in parenthesis indicated 5.0 mmol scale reaction. c Catalyst (10mol%). d Reactions were run at 40 °C.
Scheme 2 Tentative reaction mechanism.
Scheme 3 Schematic of the synthesis of medical agents conductedunder optimized conditions using the VNU-18 catalyst.
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