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Copper(I)-Catalyzed 1,3-Dipolar Cycloaddition of Ketonitrones to Dialkylcyanamides: A Step toward Sustainable Generation of 2,3-Dihydro-1,2,4-oxadiazoles

CuI-catalyzed cycloaddition (CA) of the ketonitrones, Ph2C=N+(R′)O– (R′ = Me, CH2Ph), to the disubstituted cyanamides, NCNR2 (R = Me2, Et2, (CH2)4, (CH2)5, (CH2)4O, C9H10, (CH2Ph)2, Ph(Me)), gives the corresponding 5-amino-substituted 2,3-dihydro-1,2,4-oxadiazoles (15 examples) in good to moderate yields. The reaction proceeds under mild conditions (CH2Cl2, RT or 45 °C) and requires 10 mol % of [Cu(NCMe)4](BF4) as the catalyst. The somewhat reduced yields are due to the individual properties of 2,3-dihydro-1,2,4-oxadiazoles, which easily undergo ring opening via N—O bond splitting. Results of density functional theory calculations reveal that the CA of ketonitrones to CuI-bound cyanamides is a concerted process, and the copper-catalyzed reaction is controlled by the predominant contribution of the HOMOdipole–LUMOdipolarophile interaction (group I by Sustmann’s classification). The metal-involving process is much more asynchronous and profitable from both kinetic and thermodynamic viewpoints than the hypothetical metal-free reaction.


■ INTRODUCTION
Although 2,3-dihydro-1,2,4-oxadiazoles 1 (DHODs; Scheme 1) are relevant to 1,2,4-oxadiazoles with broad application of the latter in material and medicinal chemistry, 2 it is still an almost unexplored class of heterocyclic systems because synthetic routes to DHODs are poorly elaborated. In the context of known DHOD properties, platinum(II) species featuring ligated DHODs are of biological importance, exhibiting antitumor properties. 3 In addition, NR 2 substituents in 5amino-substituted DHODs could be potentially considered as a useful tool for design of bioisosteres (e.g., carboxylic acid, amide, and esters) based on this type of heterocycles. 4 Hence, novel synthetic approaches to DHODs warrant investigation.
The first group of reactions leading to DHODs includes metal-free cycloaddition (CA) of nitrones to nitriles (Scheme 1, A), and this reaction proceeds under harsh conditions. 1b,c,5 Although this atom-economic method is perhaps the simplest route to obtain DHODs, it is restricted exclusively to electrondeficient nitriles bearing strong acceptor substituents, such as CCl 3 , and it also utilizes quite reactive nitrones. The reaction of nitriles employing oxaziridines (B), which serve as a hidden and reactive form of nitrones, allows high-yield syntheses of DHODs, but even these reactions involve only rather electron-deficient nitriles, in particular, those with R = Ar. 6 CA between oxazol-5-ones and nitrosobenzene gives 3carboxylic-substituted DHODs (R 3 = CO 2 H) (C). 7 Another group of reactions leading to DHODs utilizes metal centers to promote CA of nitrones to nitriles (Scheme 1, right).
Metal-mediated processes gradually lose their initial popularity because metals serve as a potential toxic waste source. However, in many instances, metal-involving syntheses (particularly metal-catalyzed) are still preferred over relevant metal-free routes because metal centers could strongly activate reactants and/or substantially reduce the number of steps leading to target compounds. These metal-involving methods were applied for generation of DHODs, and it appeared that some metals act as efficient activators of RCN dipolarophiles in the CA (D). 8 The preparation of metal-free DHODs via routes (D)−(E) requires an additional step (E) of ligand liberation. 1d, 8a−i,9 This method (D−E), despite its generality, employs rather expensive platinum and palladium species.
Recently, we have demonstrated (F) that disubstituted cyanamides, NCNRR′, being coordinated to a Zn II center, can be employed in the CA with acyclic N-alkyl ketonitrones Ph 2 CN + (O − )R′ (R′ = Me, CH 2 Ph), and this reaction proceeds easily achieving the respective metal-free heterocycles. 10 We succeeded in replacing platinum and palladium in the CA with more favorable zinc(II), but the developed method employs stoichiometric rather than catalytic amounts of Zn(OTf) 2 .
Although CA with stoichiometric amounts of cheap zinc is an obvious development in the generation of DHODs, our goal was to find a catalytic system for the CA and synthesis of these heterocycles. At first glance, this task may seem simple, but it proves surprisingly challenging as the dominant part of useful catalytic systems utilizes Pearson's "hard" metal centers.
These centers, in turn, preferably coordinate with the hard oxygen center of nitrones, thus blocking these dipoles toward the CA, and also promote nitrone hydrolytic and/or deoxygenation decomposition (Scheme 2). 8d,11 Taking into account our general interest in metal-mediated reactions of substrates bearing a CN triple bond (for our reviews, see refs 9c and 12) and, in particular, in their metalcatalyzed organic transformations (for recent works, see ref 13), we focused our efforts on the search for a practically useful catalytic system for generation of DHODs. After many unsuccessful attempts, we found that copper(I) exhibits catalytic properties in the CAs of ketonitrones to push−pull nitriles, such as cyanamides, giving 5-amino-substituted DHODs, and all our results disclosing the first catalytic system for generation of DHOD's are consistently disclosed in sections that follow.  (Table S1, entry 15), which are soluble in the used organic solvents. The complex [Cu(NCMe) 4 ](BF 4 ) was found to be the best choice, and no reaction occurred without copper species (Table S1, entries 1, 2, and 14). Variation of load of catalyst (Table S1, entries 3−6) revealed that the highest yield was obtained when 10 mol % of [Cu(NCMe) 4 ](BF 4 ) was employed. The lowering of the yield of 1 upon decreasing the load of catalyst is probably due to decreased concentration of activated substrates. More unusual is the yield reduction upon increasing the load of catalyst above 10 mol %. This phenomenon can be rationalized by the occurrence of some side reactions at a higher catalyst concentration, for instance, Cu I -mediated reduction of the ketonitrone. The reaction proceeds in the temperature range from 20 to 80°C (Table S1, entries 7−11 and 17, in CH 2 Cl 2 or toluene), and increasing the temperature leads to an enhancement of the reaction rate. Effects of concentration (Table S1, entry 12) and microwave irradiation (Table S1, entries 13 and  14) were also studied, but they only slightly affected the reaction rate. The yield was decreased when dimethylcyanamide was taken in 10-fold excess compared with the nitrone (Table S1, entry 16), and the optimal molar ratio between these substrates is 1:1. We believe that a large excess of NCNMe 2 could lead to transformation of the copper catalyst to its less active form. Solvent variation was studied for the system Ph 2 CN + (Me)O − :NCNMe 2 in the presence of 10 mol % of the copper(I) catalyst (Table S1, entries 4 and 18−22). The yields of 1 are based on NMR integration with 1,4dimethoxybenzene taken as an internal standard. Only a small increase in the yield of 1 (from 60 to 68%) upon increasing the reaction time from 2 to 24 h (Table S1, entries 4 and 8−11) is probably explained by the consumption of the catalyst in the reaction. In summary, the results of these preliminary tests demonstrate that the optimal conditions for the model reaction include [Cu(NCMe) 4 ](BF 4 ) (10 mol %), molar ratio between the reactants 1:1, temperature 45°C and application of CH 2 Cl 2 as the solvent. The order of addition of the reactants is important, and the highest yield (68%; 45°C, 24 h) of 1 was achieved when NCNMe 2 was added to a solution of

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Article [Cu(NCMe) 4 ](BF 4 ) followed by addition of Ph 2 C N + (Me)O − . If the ketonitrone was added to a solution of the catalyst followed by addition of dimethylcyanamide, the yield of the target heterocycle was substantially lower (ca. 10%). This behavior could be explained taking into account the competition of the ketonitrone and NCNMe 2 for the copper(I) coordination site. We studied the reaction of ketonitrones with Cu I in a separate experiment and found that their interaction leads to oxidation of copper(I) and coordination of the nitrone O atom followed by decomposition of the complexes thus formed (see later). Hence, a combination of coordinated dimethylcyanamide and free dipole leads to the CA; 1a,14 therefore, the order of reactant addition indicated above is preferable. Our theoretical calculations (see later) agree with the experimental data and they support group I by Sustmann's classification 15 of CA.
Substrate Variation. As the next step, we extended the scope of the substrate to various disubstituted cyanamides and two aryl ketonitrones (Scheme 3), and the obtained results are summarized in Table 1.
For most combinations of cyanamides and ketonitrones, the corresponding 2,3-dihydro-1,2,4-oxadiazoles were obtained and isolated in 28−73% yields. In all reaction mixtures, unreacted ketonitrone was identified, and this reflects an incomplete conversion of substrates. The target product was not isolated for the NCNR 2 /Ph 2 CN + (CH 2 Ph)O − (R = Me, Et) systems, whereas signals corresponding to 4 were determined by HRESI + -MS monitoring of the reaction mixtures. Product 4 was not obtained, probably due to steric restriction of the NEt 2 group that prevents cyanamide−nitrone CA.
When the reaction with conventional nitriles RCN (R = Me, Ph, 4-Cl-C 6 H 4 , 4-CF 3 C 6 H 4 ) was attempted under the same conditions (Ph 2 CN + (Me)O − , 10 mol % [Cu(NCMe) 4 ]-(BF 4 ), CH 2 Cl 2 , 45°C), no CA products were detected in the reaction mixture after 2 days. This observation additionally demonstrates the greater reactivity of cyanamides toward CA as compared to that of conventional nitriles; this trend was highlighted previously in our review. 1a Aldonitrone, 4-MeC 6 H 4 CHN + (Me)O − , did not react with NCNMe 2 under the reaction conditions (10 mol % [Cu(NCMe) 4 ](BF 4 ), CH 2 Cl 2 , 45°C, 2 days), which additionally confirmed the previously established greater reactivity of C,C-diaryl ketonitrones than that of C-aryl aldonitrones. 8b The higher reactivity of ketonitrones is related to the different electronic effect of phenyl groups in aldo-and ketonitrones. In aldonitrones, the aromatic substituent at the C atom is involved in the conjugation and acts as an electron-acceptor substituent, decreasing the reactivity of the 1,3-dipoles. In C,C-diaryl ketonitrones, both aromatic substituents are out of the CNO plane and are not involved in the conjugation and therefore, could not act as electron acceptors.
Characterization of 6 and 8−16. Heterocycles 1−3, 5, and 7 were identified by comparison of their 1 H NMR and high-resolution ESI + -MS spectra with those known from the

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Article 16 appear as a singlet located between 3.37 and 3.64 ppm. The 13 C{ 1 H} NMR spectra display resonances in the interval 94.7− 96.0 ppm corresponding to the quaternary C 3 atoms of the heterocycles and signals at 158.0−160.6 ppm attributed to the C 5 atom from the CN moiety. In the 13 C{ 1 H} NMR spectra, the peaks from the CPh 2 moiety emerge as one broad singlet due to a dynamic process.
Heterocycles 9, 12, and 16 were characterized by X-ray crystallography (Figures 1, S1, and S2, see the Supporting Information). Bond distances and angles for these structures are close to those in the previously reported structures of DHODs (Table S2). 10 Generation of Nitrone Complexes [Cu{ON(R′′)CPh 2 } 4 ]-(BF 4 ) 2 (17). If the reaction of copper(I) centers with nitriles are well known, 17 those of nitrones are poorly studied. Copper(II) nitrone complexes documented in the literature feature bidentately coordinated ligands with the nitrone moiety 18 and the monodentate 2,5,5-trimethyl-1-pyrroline-N-oxide. 18c For a deeper understanding of the copper(I)-catalyzed CA, we studied the reaction between the nitrone dipoles Ph  19 The resulting mixture was diluted with hexane and concentrated in vacuo at RT giving a dark greenish oily residue that, on the next day, solidified furnishing a few black needle-like crystals (R″ = Me) that were studied by X-ray diffraction (17; Figure 2; for description of the X-ray structure, see the SI).
Moreover, we also found that the nitrones are unstable in the presence of a catalytic amount of the copper(I) complex. The heating of Ph 2 CN + (O − )Me with [Cu(NCMe) 4 ](BF 4 ) (10 mol %) under optimized conditions (45°C, 2 h) leads to a partial hydrolytic decomposition of the dipole giving benzophenone Ph 2 CO (preparative yield 22%).
Thus, upon treatment of ketonitrones with Cu I we observed that the reactant interplay leads to oxidation of copper(I) and a broad spectrum of products. In the context of the copper(I)catalyzed CA, these synthetic experiments give an idea that the generation of 2,3-dihydro-1,2,4-oxadiazoles is likely to proceed via ligation of the nitriles to the Cu I center, followed by the reaction of the metal-bound dipolarophiles with the nitrones. This assumption is fully supported by theoretical calculations whose results are presented below.
Theoretical Study of the Cu I -Catalyzed CA of Ketonitrones to Cyanamides. To understand the mechanism of the copper-catalyzed CA of ketonitrones to cyanamides we have carried out quantum-chemical calculations at the density functional theory (DFT) level of theory of model CA of Me 2 CN + (Me)O − to uncomplexed and copper-bound NCNMe 2 . We have successfully used this approach in studies of similar metal-assisted and metal-free 1,3-dipolar CA reactions of nitrones to isocyanides 20 and nitriles, 21 and metal-assisted coupling of oximes and nitriles. 22 We proposed three types of mechanisms for CA of Me 2 C N + (Me)O − to NCNMe 2 , two of them are stepwise (Scheme 5 A,C) and the third is concerted (B). CA is initiated by the endoergonic formation of the orientation complex OC (+4.2 and +2.3 kcal/mol for metal-free and Cu I -catalyzed reactions, respectively). Stepwise pathways involve the formation of acyclic zwitterionic intermediates INTa or INTb (via TSs1a or TSs1b), which then undergo the cyclization (via TSs2a or TSs2b, respectively) giving the cyclic product P, whereas the

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Article concerted CA proceeds via a cyclic transition state (TSc). For both metal-free and metal-involving processes no minima for structures corresponding to any acyclic intermediates were located upon a detailed search for the potential energy surface. Despite numerous attempts, in all cases, optimization led to the formation of initial species, which are separated from each other, or to product P. Thus, stepwise pathways have been excluded from consideration. On the other hand, the TSc structures, corresponding to concerted CA, were successfully found for both metal-free and metal-involving reactions (TSc free and TSc Cu , respectively). The cyclic nature of these transition states (TSs) has been confirmed by the topological analysis of the electron density distribution within the formalism of the quantum theory of atoms in molecules (QTAIM) method 23 (we successfully used this approach in studies of noncovalent interactions and properties of coordination bonds in various transition metal complexes 20,24 ).
The Poincare−Hopf relation in both cases is satisfied, thus all critical points have been found. The contour line diagrams of the Laplacian distribution ∇ 2 ρ(r), bond paths, and selected zero-flux surfaces are shown in Figure S48. The ring critical point (3, +1) for the 2,3-dihydro-1,2,4-oxadiazole cycle and five suitable bond critical points (3, −1; BCPs) were determined. For TSc Cu , the electron density value ρ(r) at the O···C cyanamide BCP is significantly higher than that at the C nitrone ···N cyanamide BCP, but for TSc free , these parameters at both BCPs are comparable (Table S4). The energy density H b at the O··· C cyanamide and C nitrone ···N cyanamide BCPs in TSc free and at O··· C cyanamide BCP in TSc Cu is clearly negative demonstrating some covalent contribution in these interactions, whereas H b at the C nitrone ···N cyanamide BCP in TSc Cu is virtually zero and hence, no covalent contribution in this contact was detected. These observations reveal that the concerted metal-involving CA reaction is significantly more asynchronous as compared to the metal-free process, which is consistent with the general trend:  Table S6) indicates, first, that the activation barrier for the Cu-catalyzed CA is significantly lower than that for the metal-free coupling (by 5.4 kcal/mol in terms of Gibbs free energies in solution). Second, metal-involving process is more preferably from a thermodynamic viewpoint.
An interaction between the frontier MOs of the reactants is the driving force of CA reactions. Our calculations indicate that the CA reaction of Me 2 CN + (Me)O − to free NCNMe 2 belongs to group II processes in the Sustman classification (energy gaps between HOMO dipole −LUMO dipolarophile and HOMO dipolarophile −LUMO dipole are 0.26 and 0.25 au, respectively, see Figure 4).
The coordination of NCNMe 2 to the copper(I) metal center results in a decrease of both HOMO π(CN) and LUMO π*(CN) energies and leads to significant contraction of the HOMO dipole −LUMO dipolarophile energy gap and expansion of the HOMO dipolarophile −LUMO dipole energy gap. Thus, the simple qualitative MO consideration suggests that (i) the coordination of NCNMe 2 should accelerate the nitrone CA and (ii) the metal-involving CA belongs to normal electron demand processes (group I by Sustmann's classification).
Literature data confirm our observations and, indeed, CAs of nitrones often belong to group II reactions, 28 but it is easily possible to change the type of reaction by the variation of substituents in the reactants or its coordination to the metal center. Thus, CA of nitrones to electron-deficient dipolarophiles (namely, acrylonitrile, 29 acrolein, 30 methyl propiolate, 31 methyl acrylate, 32 nitroalkenes, 33 fluoroalkenes, and fluoroalkynes 34 ) as well as metal-involving processes 35 is determined by the interaction of HOMO dipole −LUMO dipolarophile (group I, normal electron demand reactions), whereas usage of dipolarophiles with electron-donating substituents (e.g., methyl vinyl ether) 26a leads to switching of the type of reaction to inverse electron demand (HOMO dipolarophile −LUMO dipole , group III by Sustmann's classification).

■ CONCLUDING REMARKS
We found a novel synthetic approach to 2,3-dihydro-1,2,4oxadiazoles that includes Cu I -catalyzed CA of ketonitrones to disubstituted cyanamides and gives 5-amino-substituted ring systems. The reaction proceeds under mild conditions (RT or 45°C) and requires 10 mol % of [Cu(NCMe) 4 ](BF 4 ) as the catalyst. The application of the developed method furnishes the heterocycles in good to moderate yields. The somewhat reduced yields are due to the individual properties of 2,3dihydro-1,2,4-oxadiazoles, which easily undergo ring opening via the NO bond splitting.
All previous approaches to 2,3-dihydro-1,2,4-oxadiazoles bearing donor substituents at the fifth position of the ring were based on the usage of stoichiometric amounts of activating metal centers (Zn II , Pt II , Pd II , or Pt IV ) and these methods included a two-step procedure followed by (for platinum and palladium) conventional recycling of these expensive metals. The discovery of a simple catalytic system for generation of 2,3dihydro-1,2,4-oxadiazoles is certainly a step toward sustainable synthesis of this yet unexplored class of heterocycles.
Inspection of our experimental data indicates that the combination of coordinated cyanamide dipolarophile and uncomplexed nitrone dipole, not vice versa, leads to the CA. Theoretical calculations are agreeable with this conclusion. Results of the DFT calculations reveal that the CA of ketonitrones to Cu I -bound cyanamides is a concerted process

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Article and the copper-catalyzed reaction is controlled by the predominant contribution of the HOMO dipole −LUMO dipolarophile interaction (group I by Sustmann's classification). The metalinvolving process is much more asynchronous and favorable from both kinetic and thermodynamic viewpoints than the hypothetical metal-free reaction.

■ EXPERIMENTAL SECTION
Materials and Instrumentation. The dialkylcyanamides, NCNR 2 (R = Me, Et, 1/2(CH 2 ) 5 , 1/2(CH 2 ) 4 O, 1/2(CH 2 ) 4 ; Aldrich), and solvents were obtained from a commercial source and used as received. The dialkylcyanamides NCN(CH 2 Ph) 2 , NCN(Me)Ph, and NCNC 9 H 10 , 36 the copper(I) complex [Cu(NCMe) 4 ](BF 4 ), 37 and the nitrones 38 were synthesized in accord with the published recipes. The HRESI mass spectra were obtained on a Bruker micrOTOF spectrometer equipped with an electrospray ionization source, and MeOH was employed as the solvent. The instrument was operated in positive ion mode using an m/z range of 50−3000. The capillary voltage of the ion source was set at −4500 V (ESI + MS) and the capillary exit was set at ±(70−150) V. In the isotopic pattern, the most intensive peak is reported. Infrared spectra were recorded using a Bruker FTIR TENSOR 27 instrument in KBr pellets. 1 H and 13 C{ 1 H} NMR spectra were measured using a Bruker Avance III 400/100 MHz spectrometer at ambient temperature.
X-ray Structure Determinations. Crystals of 9, 12, 16, and 17 were measured on a Agilent Technologies SuperNova diffractometer at a temperature of 100 K using monochromated Cu Kα radiation. All structures were solved by direct methods by means of the SHELX program 39 incorporated into the OLEX2 program package. 40 For crystallographic data and refinement parameters, see Table S3. The carbon-bound H atoms were placed in calculated positions and were included in the refinement in the "riding" model approximation, with U iso (H) set to 1.5U eq (C) and CH 0.98 Å for CH 3 groups, with U iso (H) set to 1.2U eq (C) and CH 0.99 Å for CH 2 groups, and with U iso (H) set to 1.2U eq (C) and CH 0.95 Å for CH groups. Empirical absorption correction was applied in the CrysAlisPro 41 program complex using spherical harmonics, implemented in the SCALE3 ABSPACK scaling algorithm. Supporting crystallographic data for this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC 1456546, 1456547, 1470262, 1468157) and can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/ cif.
Computational Details. The full geometry optimization of all structures and TSs has been carried out at the DFT level of theory using the M06 functional 42 with the help of the Gaussian-09 43 program package. No symmetry operations have been applied. The calculations were carried out using the multielectron fit fully relativistic energy-consistent pseudopotential MDF10 of the Stuttgart/Cologne group that described 10 core electrons and the appropriate contracted basis set for the copper atom 44 and the 6-31G(d) basis set for other atoms. The Hessian matrix was calculated analytically for the optimized structures to prove the location of correct minima (no imaginary frequencies) or saddle points (only one imaginary frequency) and to estimate the thermodynamic parameters, the latter being calculated at 25°C. The nature of all TSs was studied by the analysis of vectors associated with the imaginary frequency and by calculations of the intrinsic reaction coordinates using the Gonzalez−Schlegel method. 45 The total energies corrected for solvent effects (E s ) were estimated by single-point calculations on the basis of equilibrium gas-phase geometries at the same level of theory using the SMD continuum solvation model by Truhlar and coworkers 46 with CH 2 Cl 2 as the solvent. The entropic term in CH 2 Cl 2 solution (S s ) was calculated according to the procedure described by Wertz 47 (4) where S g is the gas-phase entropy of the solute, ΔS sol is the solvation entropy, S°, s liq , S°, s gas , and V s m,liq are the standard entropies and molar volume of the solvent in liquid or gas phases (173.84 and 270.28 J/mol K and 64.15 mL/mol, respectively, for CH 2 Cl 2 ), V m,gas is the molar volume of ideal gas at 25°C (24 450 mL/mol), V°m is the molar volume of the solution corresponding to the standard conditions (1000 mL/ mol).
The enthalpies and Gibbs free energies in solution (H s and G s ) were estimated by using expressions 5 and 6 where E s , E g , and H g are the total energies in solution and in the gas phase and gas-phase enthalpy, respectively. A topological analysis of the electron density distribution with the help of the QTAIM formalism developed by Bader 23 has been performed using the Multiwfn program (version 3.3.4). 49 The Wiberg bond indices were computed using the natural bond orbital partitioning scheme. 50 The synchronicity of concerted CAs (S y ) 27 was calculated using eqs 7−9 where n is the number of bonds directly involved in the reaction (n = 5 for 1,3-dipolar CAs) and δB i is the relative variation of a given Wiberg bond index B i at the TS relative to reactants (R) and products (P), and it is calculated as If the δB i value is negative, it is assumed to be zero. The average value of δB i (δB av ) is defined as S y is 0 for stepwise CAs and is 1 for the fully concerted reactions.
The Cartesian atomic coordinates of the calculated equilibrium structures are presented in the Table S7.