Lyna Torzuoli

Assil Bouzid
email: assil.bouzid@unilim.fr

Philippe Thomas

Olivier Masson

An enhanced core-shell interatomic potential for Te-O based oxides

We present a new parametrization of the core-shell Buckingham interatomic potential (IAP) of Te-O oxides which allows to accurately reproduce experimental structural properties of various Te-O based systems including α-, β -, and γ-TeO 2 . Based on this IAP, we generate high temperature model of TeO 2 and find that it features a liquid-like dynamical behaviour in contrast to previous models. Furthermore, we generate an amorphous TeO 2 model by quenching from the melt and study its structural properties in comparison with those available in the literature. We find that our model improves upon existent data and leads to a total pair correlation function in close agreement with the one measured through X-ray diffraction. These results open the way to systematic studies of binary and ternary complex Te-O based oxides by relying on a cheap, yet transferable and accurate IA potentials.

Introduction

TeO 2 -based materials occurs either in crystalline or amorphous phases allowing for a wide range of applications encompassing photonics, optical devices, medical devices and telecommunications. [START_REF]Technological Advances in Tellurite Glasses: Properties, Processing[END_REF][START_REF] Barbosa | Photonic Applications of Tellurite Glasses Technological Advances in Tellurite Glasses: Properties, Processing[END_REF] In particular, TeO 2 -based compounds find a high interest in telecommunication technologies thanks to their good linear and non-linear properties, low melting temperature (below 1000 • C) and large optical transmission window. [START_REF] El-Mallawany R A H | Tellurite Glasses Handbook: Physical Properties and Data[END_REF] For exemple, their 3 rd order non linear susceptibilities are the highest among the known oxide glasses and reach 50 to 100 times higher than that of glassy SiO 2 [START_REF] Blanchandin | [END_REF] allowing for applications in Raman amplification [5,6], ultra fast optical switches, and electro optic modulators [7,8].

In spite of these outstanding properties, pure TeO 2 glass suffers from a low stability that requires the incorporation of modifier elements such as rare-earth atoms. This procedure allows one to tailor its mechanical properties, chemical stability window, refractive index, and optical response in order to target a given application. A better control of the macroscopic properties of binary and ternary TeO 2 based materials requires a deep understanding of their structural properties at the atomic scale. Hence, identifying the atomic scale origins of the measured properties will enable the design of efficient materials with desired properties. We note that TeO 2 -based glasses were thoroughly investigated through several techniques including: x-ray diffraction [9,10,11], neutron diffraction [11,12], NMR [13,14,15], EXAFS [16], and Raman scattering [17,18,19,20,21,22]. While the experimental input to the atomic scale picture of TeO 2 -based materials remains limited, modelling based on molecular dynamics simulations allows one to access the intimate details of the atomistic structures of this material. [23,24,25,18,26] In particular, classical molecular dynamics, based on empirical interatomic potentials, is an efficient tool to model the glassy structure at a low computational cost, while keeping a good accuracy.

The first TeO 2 interatomic potential (IAP) has been developed by Gulenko et al. [27] based on a core-shell Buckingham potential and allowed to model the structure of TeO 2 . The resulting model fairly reproduced the lattice parameters of various crystalline TeO 2 phases as well as the experimental pair correlation function of glassy TeO 2 . Nevertheless, at high temperatures the core-shell potential failed to converge and the authors had to use a rigid ion model and only include the shells at room temperature. While, the obtained amorphous model agrees well with experiments, it is of paramount importance to have a new parametrization of the IAP that allows one to properly simulate high temperature systems. Reproducing a correct dynamical behaviour of the investigated system is a prerequisite to model binary and ternary oxide glasses by relying on an unbiased parent high temperature model.

In this paper, we focus on modelling pure TeO 2 oxide through classical IAPs. First, we refine the core-shell Buckingham potential developed by Gulenko et al. [27] and reproduce the experimental lattice parameters of α-, β -, and γ-TeO 2 within less than 1% mean absolute error. Second, the obtained IAP is used to generate high temperature model of TeO 2 featuring a correct liquid-like dynamical properties. Finally, amorphous TeO 2 is generated by quenching from the melt. The obtained total pair correlation function shows a better agreement with experiments compared to that obtained in Ref. [27].

Refinement of the interatomic potential

Buckingham potential for crystalline TeO 2

In order to refine the IAP of TeO 2 we resort to the α-, β -, and γpolymorphic structures of TeO 2 . In the paratellurite form, or α-TeO 2 , each tellurium atom is coordinated with four oxygen atoms forming TeO 4 disphenoids, with 2 equatorial bonds (1.879 Å) and two longer axial bonds (2.121 Å). The three-dimensional network is composed of corner-sharing TeO 2 disphenoids leading to asymmetric Teeq O ax -Te bridges. [28] β -TeO 2 is the natural form of TeO 2 . In this phase, each tellurium atom is coordinated with four oxygen atoms forming two equatorial bonds (1.877 and 1.927 Å) and two longer axial bonds (2.070 and 2.196 Å). The crystal lattice of β -TeO 2 has a layered structure with weakly bonded layers where the TeO 4 disphenoids share alternately corners and edges. In this polymorph, the tellirum atoms are connected via double bridges. [29] The last of the main polymorphs of TeO 2 is the metastable γ-TeO 2 . This structure can be described with corner-sharing TeO 4 disphenoids, however, the disphenoids have a much more distorted geometry where one Te-O axial bond is longer than the other three (1.839 and 1.906 Å for the equatorial bonds and 2.048 and 2.241 Å for the axial bonds). Thus, the polyhedron is referred to as TeO 3+1 . The chain-like network organization can be described as an infinite zigzag chain of TeO 3 units along the c axis. In this polymorph, one can distinguish two types of Te-O-Te bridges: highly asymmetric Teeq O( 1) ax -Te and nearly symmetric Teeq O(2) ax -Te bridges. [30] Fitting these quite various structures ensures that our IAP will be efficient and transferable.

In practice, our theoretical procedure is based on the empirical IAPs within the Buckingham scheme for describing the short-range interaction as given by:

U i j (r) = A i j e -r/ρ i j -C i j r -6 + q i q j 4πε 0 1 r (1)
where A i j , ρ i j and C i j are the Buckingham potential parameters, and q i is the charge of ion i. Furthermore, we use a core-shell model to reproduce the polarisibilities of Te and O as given by:

U cs = 1 2 k cs 2 x 2 + 1 24 k cs 4 x 4 , (2)
where x is the distance between the core and the shell. In this model, the shell and the core are coupled through a harmonic spring constant (k cs 2 ) in the case of O. In the particular case of Te, it has been shown that adding an anharmonic term (k cs 4 ) leads to a better description of its various asymmetric local environments in TeO 2 -based oxides. [27] We start our potential refinement by considering the parameters (A i j , ρ i j and C i j , k cs 2 , k cs 4 and q) of Ref. [27] and perform a simultaneous fit of the potential on 44 experimental observables including the atomic positions, lattice parameters and dielectric constants for α-, β -, γ-TeO 2 using the general utility lattice program (GULP) program. [31] This procedure differs from that of Ref. [27], where a sequential fit was performed on the crystalline phases of TeO 2 . We here consider all three phases together and repeat the fitting until convergence of all potential parameters is Ref. [27].

Compared to the old potential [27], we here find smaller A (O-O) and C (Te-O) values which lead to a lower electronic and van der Waals interactions on the O-O and Te-O bonds, respectively. We note that k cs 4 is found to be insensitive to the fit. Consequently, the experimental lattice parameters of crystalline TeO 2 are better reproduced with an overall mean absolute error of 0.9% compared to 2.2% obtained previously (see table 2).

Potential transferability

The transferability of the obtained IAP is checked against a large family of Tellurium oxides containing 13 TeO 2 -based structures featuring different and various local environments around the Te atom. The obtained results are presented in table 3 and compared to experiments and to those obtained using the IAP of Ref. [27]. Overall, our IAP reproduces the experimental lattice parameters of all the considered systems with a mean absolute error of 1.48%. These results validate the new parametrization of the IAP which can be now used to investigate the structures of Te-O disordered systems.

Liquid and Amorphous TeO 2

We resort to classical molecular dynamics simulations (MD) as implemented in the DL POLY program [45] together with the obtained IAP to generate high temperature model of TeO 2 . We consider a 768 atoms system (256 Te + 512 O) and 768 shells in a cubic box of side length 23.00 Å corresponding to the experimental density. [27] The temperature is controlled through a Berndson thermostat and a time step of 1 fs is used to integrate the equations of motion. The system has been equilibrated in the NVT ensemble for 60 ps at T=2100 K. For comparison, we also generate a second model based on the rigid-ion IAPs of Ref. [27]. Figure 1 shows the mean square displacement of Te and O as obtained from both models. We find that the new parametrization of the IAP leads to high mobility of both Te and O with a liquid-like diffusion coefficients amounting to 1.2 10 -5 cm 2 /ps and 3.3 10 -5 cm 2 /ps, respectively. However, in the case of the rigid-ion model the atomic mobility remains low even for simulation times reaching 150 ps and leads to diffusion coefficients one order of magnitude lower than the that obtained through the present parametrization (1.1 10 -6 cm 2 /ps and 6.2 10 -6 cm 2 /ps, for Te and O respectively). This result highlights the importance of including the shells when modelling oxides at high temperatures.

Next, we generate an amorphous TeO 2 model by gradually lowering the temperature to 1000 K, 600 K and 300 K. The system is equilibrated during 60 ps at each temperature plateau. Residual pressure effects are removed by further relaxing the glass at 300 K in the NPT ensemble for 500 ps yielding a slightly higher density (22.66 Å side length). Similarly, we produce a second amorphous system based in IAPs of Ref. [27] where the shells are only added at room temperature.

Figure 2 shows the total pair distribution function as obtained from our model and compared to experiments. Furthermore, we also display the results of the model generated using IAPs of Ref. [27]. We find that our new IAP model allows one to accurately reproduce the shape of the total pair correlation function measured experimentally. Compared to the previous model of Gulenko et al, our model reproduces slightly better the depth of the first minimum at 2.3 Å and the intensity of the peak at about 3.7 Å.

Conclusions

In summary, we provide a new parametrization of the core-shell Buckingham potential of Te-O oxides. Our parametrization allows one to accurately reproduce the structures of crystalline phases of α-, β -, and γ-TeO 2 and its transferability was tested against a large family of Te-O based oxides showing a good accuracy. We then took advantage of the new parametrization to generate a high temperature model of TeO 2 and find that it features a liquid like dynamical behaviour. In addition, we showed that amorphous TeO 2 could be obtained by quenching from the melt and features a very good agreement with experiments, while slightly improving upon previously published models. Overall, we are convinced that the present parametrization will be a valuable tool to tackle the study of complex Te-O based glassy systems.

Figure 1 .

 1 Figure 1. Mean square displacement as a function of the simulation time. The brown lines indicate the diffusive regime used to extract the diffusion coefficients.

Figure 2 .

 2 Figure 2. Neutrons total pair correlation function of the obtained glassy TeO 2 models compared to experiments from Ref. [27].

Table 1 .

 1 Refined parameters of the Buckingham potential for the Te 4+ -O 2-and O 2--O 2- interactions and for the shell model for Te and O atoms. Values between parenthesis are the parameters from Ref.[27].

		A (eV)	ρ ( Å)	C (eV. Å6 )
	Buckingham potential
	Te 4+ c -O 2-sh O 2-sh -O 2-sh	1631.810731 (1595.266748) 47902.536233 (82970.688434) 0.175930 (0.16099) 33.029759 (31.361954) 0.346336 (0.345867) 0.020139 (1.0)
		k cs 2 (eV. Å-2 )	k cs 4 (eV. Å-4 )	q s (e)
	Shell model
	Te 4+	30.827429 (35.736418)	90.0 (90.0)	-1.975415
	O 2-	61.600546 (61.776616)	0.0 (0.0)	-3.122581

Table 2 .

 2 The calculated lattice parameters of α-TeO 2 , β -TeO 2 and γ-TeO 2 compared to experiments[28,29,30] and previous modelling from PCCP 2014[27]. The numbers between parenthesis represent the absolute error compared to experiments.

	Parameter	Expt.	PCCP 2014 (error %) This work (error %)
	α-TeO 2	[28]
	a, b ( Å)	4.810	4.831 (0.44)	4.841 (0.64)
	c ( Å)	7.613	7.349 (3.46)	7.498 (1.51)
	Volume ( Å3 ) 176.135	171.548 (2.60)	175.692 (0.25)
	α, β , γ	90.0	90.0 (0.0)	90.0 (0.0)
	β -TeO 2	[29]
	a ( Å)	12.035	11.550 (4.03)	12.090 (0.45)
	b ( Å)	5.464	5.473 (0.17 )	5.482 (0.33)
	c ( Å)	5.607	5.549 (1.03)	5.559 (0.86)
	Volume ( Å3 ) 368.712	350.814 (4.85)	368.449 (0.07)
	α, β , γ	90.0	90.0 (0.0)	90.0 (0.0)
	γ-TeO 2	[30]
	a ( Å)	4.898	5.084 (3.79)	4.999 (2.06)
	b ( Å)	8.576	8.312 (3.08)	8.581 (0.06)
	c ( Å)	4.351	4.196 (3.55)	4.285 (1.51)
	Volume ( Å3 ) 182.765	177.326 (2.98)	183.831 (0.58)
	α, β , γ	90.0	90.0 (0.0)	90.0 (0.0)

reached. The final parameters are listed in table 1 and compared to the old parameters from

Table 3

 3

		: The calculated lattice parameters of various
	TeO 2 -based oxides compared to experiments and previous
	modelling from PCCP 2014 [27]. The numbers between
	parenthesis represent the absolute error compared to
	experiments.
	Parameter	Expt.	PCCP 2014 (error %)	This work (error %)
	Ag 2 Te 4 O 11	[32]
	a. ( Å)	7.287	7.201 (1.19)	7.261 (0.35)
	b. ( Å)	7.388	7.304 (1.14)	7.332 (0.75)
	c. ( Å)	9.686	9.619 (0.69)	9.677 (0.09)
	α	95.670	95.82 (0.16)	95.645 (0.03)
	β	94.100	96.38 (2.42)	95.647 (1.64)
	γ	119.400	119.50 (0.09)	119.356 (0.04)
	BaTe 2 O 6	[33]
	a. ( Å)	5.569	5.5378 (0.56)	5.582 (0.22)
	b. ( Å)	12.796	13.285 (3.82)	13.266 (3.67)
	c. ( Å)	7.320	7.279 (0.55)	7.317 (0.04)
	α. β . γ	90.0	90.0 (0.0)	90.0 (0.0)
	Bi 2 Te 4 O 11	[34]
	a. ( Å)	6.991	6.797 (2.78)	6.818 (2.47)
	b. ( Å)	7.959	7.836 (1.55)	7.822 (1.72)
	c. ( Å)	18.896	18.299 (3.16)	18.390 (2.68)
	α. γ	90.0	90.0 (0.0)	90.0 (0.0)
	β	95.176	93.049 (2.23)	93.557 (1.70)
	CaTe 2 O 5	[35]
	a. ( Å)	9.382	9.376 (0.07)	9.434 (0.55)
	b. ( Å)	5.709	5.679 (0.53)	5.688 (0.38)
	c. ( Å)	11.132	11.055 (0.70)	11.081 (0.45)
	α. γ	90.0	90.0 (0.0)	90.0 (0.0)
	β	115.109	114.764 (0.30)	115.710 (0.52)
	Co 6 Te 5 O 16	[36]
	a. ( Å)	11.032	11.146 (1.03)	11.188 (1.42)

Acknowledgments

We used computational resources provided by the computing facilities MCIA (Mésocentre de Calcul Intensif Aquitain) of the Université de Bordeaux and of the Université de Pau et des Pays l'Adour.


Keywords: biomimetics, cross-coupling, imines, organocatalysis, primary amines

A Bioinspired Organocatalytic Cascade for the Selective Oxidation of Amines under Air

Martine Largeron,* and Maurice-Bernard Fleury Abstract: We describe a bioinspired organocatalytic cascade reaction for the selective aerobic oxidative cross-coupling of primary amines to imines. This approach takes advantages of commercially available pyrogallol monomeric precursor to deliver in situ, under air, low loadings of natural purpurogallin. This is further engaged in a catalytic process with the amine substrate affording under single turnover the active biomimetic quinonoid organocatalyst and the homocoupled imine intermediate which is then converted into crosscoupled imine after dynamic transimination. This organocatalytic cascade inspired by both purpurogallin biosynthesis and copper amine oxidases activity allows the aerobic oxidation of non-activated primary amines that non-enzymatic organocatalysts were not able to accomplish alone.

Oxidation reactions play an important role in biology and are recognized as key transformations in organic synthesis. [1] As a result of current evolution, the use of ambient air as the sole oxidant fulfills the requirements of "green chemistry" because it is inexpensive and does not rise to any waste products. However, the direct aerobic oxidation of organic substrates is scarce because the energy barrier for electron transfer from the organic substrate to the oxidant is generally high. To solve this problem, nature has evolved a certain set of synthetic strategies and uses an impressive array of enzyme catalysts. Excellent examples are naturally occurring iron or copper-containing metalloenzymes which have revealed their efficiency as catalysts to perform controlled aerobic oxidations under very mild conditions. [2] Hence, the development of biomimetic methods that utilize environmentally benign oxidants is one of the most important goals in oxidation chemistry today.

Among metalloenzymes, copper amine oxidases (CuAOs) promote selective aerobic oxidation of primary amines to aldehydes, coupled with the reduction of O2 to H2O2 through the cooperation of a quinone-based organic cofactor 2,4,5trihydroxyphenylalanine quinone (TPQ) and a copper ion. [3] The presence of the copper ion is essential for the production of TPQ from the autocatalytic post-translational oxidation of a tyrosine residue, while the oxidation of the amine substrate is mediated by TPQ without direct involvement of the copper ion. [4] Yet it could play a second role in orienting the TPQ ring correctly in the active site and in facilitating the reduction of O2 to H2O2. [5] Although quinone models that mimic the active site of CuAOs have yielded important insight into the transamination mechanism by which these enzymes operate with benzylamine as the amine substrate, [6] surprisingly the synthetic scope of such reactions had received little attention for a long time.

Recently, there has been a boost in the development of various catalytic methods for the aerobic oxidation of amines to imines given the widespread importance of imines as pivotal intermediates in the synthesis of fine chemicals and pharmaceuticals. [7] As a consequence, the use of CuAOs-like catalytic systems has emerged in synthetic planning, [8] and organic chemists have designed biomimetic quinone-based catalysts (Scheme 1) with two objectives: [9] 1) to achieve sustainable aerobic amine oxidation reactions; 2) to expand the scope of possible substrates. For example, Wendlandt and Stahl have reported the aerobic oxidation of various primary benzylic amines to imines, at room temperature under 1 atm of O2, using 5-tert-butyl-2-hydroxybenzoquinone organocatalyst Q1, [10] a quinone initially developed for biochemical model studies. [6d] Recently, Luo and co-workers have shown that 4-methoxy-5tert-butyl-o-quinone organocatalyst Q2 enables effective aerobic oxidation, at room temperature under an O2 atmosphere, of branched primary benzylic amines considered as poor substrates for CuAOs enzymes. [11] Scheme 1. Bioinspired quinone-based organocatalysts and cooperative catalytic sytems for the aerobic oxidation of amines to imines.

More challenging, the possibility of expanding the scope to the oxidation of secondary amines, a reaction type that natural CuAOs are not able to accomplish, was also explored. This reaction was possible through the development of cooperative catalytic systems including a quinone-based organocatalyst.

For example, the group of Kobayashi has reported that a block copolymer-incarcerated bimetallic Pt/Ir alloy catalyst combined with 4-tert-butyl-o-quinone Q3 as the redox-active organic cofactor allowed the aerobic oxidation of secondary amines to imines, at 30°C under 1 atm of O2, [12] while Doris and coworkers have described a similar synergistic action of Rh nanoparticles, supported on carbon nanotubes as co-catalysts with 4-tert-butyl-o-quinone Q3 for the aerobic dehydrogenation of N-heterocycles, at room temperature under ambient atmosphere. [13] Although these two reaction systems share common characteristics with CuAOs such as the use of a quinone-based organocatalyst together with a metal co-catalyst, mechanistic studies revealed divergence in the reaction pathways because secondary amines are not compatible with the enzymatic transamination mechanism and often serves as inhibitors through the formation of irreversible covalent adducts. [14] Accordingly, Wendlandt and Stahl have brought definitive evidence for a non-biomimetic addition-elimination pathway involving a hemiaminal intermediate which was characterized by NMR spectroscopy. For this purpose, they used 1,10phenanthroline-5,6-dione Q4 in combination with ZnI2 as an efficient cooperative system to promote, under 1 atm of O2 at room temperature, dehydrogenation of secondary amines and a diverse range of N-heterocycles. [15] In contrast, the biomimetic aerobic catalytic oxidation of non-activated primary alkylamines, that are natural substrates for CuAOs, [16] has received little attention, probably because the generated alkylimines very easily isomerize into the unstable enamine tautomers. In 2012, we reported the first biomimetic aerobic catalytic oxidation of non-activated primary alkylamines through the synergistic combination of two redox couples: the oiminoquinone organocatalyst IMQ, previously discovered from electrochemical investigations, [17] is the substrate-selective catalyst and the biocompatible copper salt serves as an electron transfer mediator. [18] Although this system was capable to work under ambient air with high atom economy and was compatible with both activated benzylic and non activated aliphatic primary amines, some challenges still remained to be tackled. In particular, the use of a commercially available quinone-based organocatalyst would offer enhanced practicality. In this vein, novel strategies using simple low-cost precursors for quinone cofactor mimetics have been recently reported by the groups of Doris (Q5), [19a] Carbery (Q6) [19b] and Oh (Q7), [19c] but these cooperative systems still require transition noble or non-noble biocompatible metal co-catalyst and, in most cases, they failed to oxidize non activated aliphatic primary amines. [19b,c] Since the oxidation of the primary amine substrates by CuAOs is mediated by TPQ without direct involvement of the copper ion, [4] we thought that a more eco-friendly biomimetic organocatalytic method, avoiding contamination of the final products by metal residues, would be highly desirable but still challenging. In this paper, we describe an unprecedented bioinspired organocatalyzed cascade reaction, which allows the oxidative coupling of both activated and non activated primary amines to imines under ambient air.

At the beginning of our investigations, we were aware that commercially available quinone-based organocatalysts reminiscent of TPQ would not be sufficiently reactive to promote the aerobic oxidation of non activated primary amines without any additives. [9] Based on our recent studies, [17,18] we were drawn to the structure of natural purpurogallin (2,3,4,6-tetrahydroxy-5Hbenzocyclohepten-5-one) 2red as a potential precursor of a highly reactive o-quinone-based organocatalyst 2ox because of the presence of the tropolone scaffold which should direct attack of the amine substrate at the 3-position of the generated o-quinone species 2ox (Scheme 2). Even more crucial was the presence of an active hydroxyl group at the 4-position which had been proved to be an essential component of the catalytic activity associated with enzymatic [4,6] and non enzymatic catalytic systems [17,20] through the formation of a highly reactive H-bonded cyclic transition state (CTS). However, the limited availability of purpurogallin 2red led us to concentrate on its well established biosynthesis which involves the oxidative dimerization of pyrogallol 1red generated from gallic acid. [21] Scheme 2. Proposed bioinspired cascade reaction for the organocatalyzed aerobic oxidation of primary amines to imines under air Based on this insight, we designed a double biomimetic reaction pathway for the chemoselective organocatalytic oxidative coupling of primary amines to imines under air as described in Scheme 2. The cascade reaction would involve aerobic oxidation of commercially available pyrogallol 1red to form the corresponding o-quinone 1ox which should then suffer homodimerization to yield the 6/7-fused bicyclic compound intermediate. The latter would afford purpurogallin 2red after decarboxylation and oxidation steps. Aerobic oxidation of 2red would then generate a highly reactive o-quinone species 2ox which should be intercepted by the primary amine substrate to produce the reduced o-aminophenol form 3red and homocoupled imine through the transamination process reported for CuAOs enzymes. The final step under single turnover would be the reoxidation of 3red to generate o-iminoquinone 3ox which would react directly with the amine substrate leading to the Schiff-base H-bonded CTS by passing 2ox. [5,6g] To evaluate the validity of this bioinspired cascade reaction sequence, we performed optimization studies by using 4methylbenzylamine 4 as the amine substrate. If our hypothesis is right, part of the reaction conditions should be identical to that required for the Cu II /IMQ-catalyzed cooperative process. [18b] Accordingly, a combination of one equivalent of amine 4 with 0.04 equivalent of pyrogallol 1red (corresponding to the generation of 2 mol% of purpurogallin 2red) gave optimal results. As expected, after 24h, under ambient air, complete conversion into imine 5 (Scheme 3) was observed only in MeOH, because strong solvation of the o-quinone 2ox or o-iminoquinone 3ox by MeOH was necessary to enhance the electrophilicity of its quinonoid moiety, thereby favoring the nucleophilic attack of the amine substrate. Then, N-(4-methylbenzyl)-1-(ptolyl)methanimine 5 was obtained in 90% isolated yield.

Scheme 3. Control studies

Control studies revealed that no reaction occurred under the same experimental conditions when 1red was fully omitted from the reaction mixture. Interestingly, as for natural CuAOs, branched amines such as sec-benzylamine were found to be poor substrates for the biomimetic organocatalyzed reaction with less than 5% conversion into imines, whereas secondary amines were not reactive at all (Scheme 3). These results were fully consistent with the enzymatic transamination mechanism and ruled out an addition-elimination process. Note that the transamination process could engage only 1ox by passing 2ox.

To gain more insight into the cascade reaction, we examined the catalytic efficiency of o-iminoquinone 6ox generated in situ from 2-aminoresorcinol 6red under the optimal reaction conditions. As previously reported from electrochemical studies, [17] aerobic oxidation of 6red produced a poorly reactive o-iminoquinone catalyst 6ox which mainly decomposed to melanin-like polymers, giving only 5% of imine 5. In contrast, when purpurogallin 2red was utilized as the starting material for producing 2ox, high catalytic activity was observed at the early stages of the reaction. Nevertheless, under aerobic conditions, the instability of the highly reactive o-quinone 2ox which slightly decomposed finally led to a decreased yield of imine 5 (75%) when compared to that obtained when 1red was used as the starting material (90%). Most likely, when starting from 1red, the continuously low concentration of the in situ generated o-quinone 2ox should protect it against the polymerization reaction.

We further explored the scope of this cascade reaction by focusing on the oxidative cross-coupling of primary amines which is known to be a challenging transformation [10,18,19] as selfcoupling is usually preferred. For this reason, the catalytic oxidative coupling of alcohols and amines reigns supreme although, with few exceptions, [22] this method generally requires elevated temperature, oxygen pressure or expensive metals. Optimization of the reaction parameters showed that mixing 4methylbenzylamine 4 and sec-benzylamine in the ratio 1:1 upon increasing pyrogallol loading [10, 19b] to 10 mol% (8 mol% followed by 2 mol% after 24h) thus generating 5 mol% of 3ox, in MeOH, at 25°C, under ambient air, gave exclusive formation of the desired cross-coupled imine 7 in 90% isolated yield after 60h (Table 1). The real-time monitoring of the cross-coupling reaction by 1 H NMR spectroscopy indicated that the homocoupled product 5 was initially formed and accumulated during the first hours of the reaction. Then, it gradually converted into the cross-coupled product 7 to become the exclusive product. These observations indicated that 7 was obtained through the transamination process reported in Scheme 2, which leads to the homocoupled imine intermediate 5, followed by dynamic transimination. [10,18,19] Just one equivalent of each primary amine was sufficient to achieve exclusive transformation into the cross-coupled imine 7 through the well-known oxidative self-sorting process which has widely been exploited to obtain thermodynamically disfavored products. [10,23] As shown in Table 1, a broad range of substituted benzylic amines were tolerated, including those bearing electron-donating groups (products 11-13), electron-withdrawing groups (products 14, 15, and 19) or fluorine (product 17). A thiophene moiety was also tolerated (product 20), as was furfurylamine which allowed the exclusive formation of the crosscoupled imine 21. Both branched and linear aliphatic amines could be efficiently coupled with benzylic amines in high isolated yields, within 24-60h depending on the basicity of the crosscoupled amine R'-NH2. Complete selectivity was observed except for aminomethylcyclohexane (product 10) and nhexylamine (product 13), for which small amounts of homocoupled imine (7%) were also isolated. As observed earlier, [10, 18b] poor nucleophilic 4-methoxyaniline afforded crosscoupled imine in only 55% isolated yield (product 9) as the conversion did not exceed 68% after 60h.

The synthesis of aliphatic imines was intrinsically more challenging because of their relative instability and isomerization into the enamine tautomer which decomposes under ambient air. [18b, 24] Nevertheless the reaction conditions used through this bioinspired cascade reaction sequence were favorable for trapping the generated unstable alkylimines in situ for further reactions. So, in a second series of experiments, we examined the aerobic oxidative cross-coupling of a range of non-activated primary aliphatic amines with N-methyl-o-aminoaniline as an in situ imine trap (Table 1). [25] This was not a trivial exercise because this reaction had proved to be unsuccessful in the absence of Cu II co-catalyst when IMQ (Scheme 1) was used as the sole organocatalyst. [25b] Pleasingly, at 60°C (See Table S1 in the Supporting Information), the organocatalyst 3ox was sufficiently reactive to activate, under ambient air, the -CH bond of diverse primary aliphatic amines to give 1,2disubstituted benzimidazoles 22-27 in good yields, except for sterically constrained -branched alkylamine for which the yield did not exceed 52% (product 28).

Recently, it has been reported that the evolutionary selection of viable quinone-based redox cofactors appears strongly linked to the ability of the catalytically produced quinols to undergo facile reoxidation back to their starting quinones. [4] Accordingly, the results of this study clearly highlight the ability of 3red to undergo oxidation to 3ox which occurs under ambient air, without the assistance of electron transfer mediator. In addition, its catalytic efficiency is enhanced through the participation of both tropolone scaffold and 4-hydroxy substituent in directing the nucleophilic attack of the amine substrate at the 3-position of 3ox. Also, the presence of the active 4-hydroxy group, which is engaged in an intramolecular hydrogen bond with the imine nitrogen to form a highly reactive Schiff base CTS (Scheme 2) is of overriding importance for the development of the catalytic process. [20] The combination of all these elements allows the oxidation of non-activated primary aliphatic amines that until now remained challenging substrates for nonenzymatic organocatalysts.

90%) [a,b] 8 (90%) [a,b] 9 (55%) [b,c] 10 (93%) [a,d] N 11 (85%) [a,b] O O N 14 (80%) [a,b] Cl Cl CH3O N 12 (89%) [a,b] F3C N 15 (90%) [a,b] CH 3 O N 13 (93%) [a,d] N 17 (88%) [a,b] F N 18 (84%) [a,b] N 16 (85%) [a,b] N 19 (87%) [a,b] Cl Cl N 20 (83%) [a,b] N 21 (89%) [a,d] S O N N 22 (76%) [b,e] N N 23 (64%) [b,e] N N 24 (63%) [b,e] N N 28 (52%) [b,e] N N 27 (74%) [b,e] N N 26 (67%) [b,e] N N 25 (62%) [b,e] self-sorting In summary, we have developed a bioinspired organocatalytic cascade reaction for the activation of the -C-H bond of primary amines which are converted to cross-coupled imines under exceptionally mild conditions. The reaction sequence starts from inexpensive commercially available pyrogallol 1red and allows, under ambient air, the in situ formation of not easily accessible natural purpurogallin 2red which is further engaged in the CuAOs enzymatic transamination process for producing, under single turnover conditions, the active biomimetic organocatalyst 3ox and the homocoupled imine intermediate, followed by dynamic transimination. Noteworthy, the present organocatalytic cascade reaction, which has been inspired by both purpurogallin biosynthesis and copper amine oxidases activity, would not be easily conceivable at this level of complexity from first chemical concepts.

  [*] Dr. Martine Largeron, Prof. Dr. Maurice-Bernard Fleury UMR 8638 CNRS-Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie de Paris, 4 avenue de l'Observatoire 75270 Paris Cedex 06, France E-mail:martine.largeron@parisdescartes.fr Supporting information for this article is given via a link at the end of the document.

  25°C, 100% conversion, reaction times: 24h for 10, 12, 13, 15, 16, 19 and 20; 48h for 21 and 60h for 7-9, 11, 14, 17 and 18; additional aliquot of 1red (2 mol%) was added after 24h. [b] isolated yields after column chromatography. [c] 68% conversion. [d] yields of the cross-coupled imine were determined by 1H NMR. In the case of 10 and 13, analysis of the reaction mixture indicated the presence of 7% of the corresponding homocoupled imine. [e] 60°C, 100% conversion, reaction time 60h; additional aliquot of 1red (2 mol%) was added after 24h.

Table 1 .

 1 Insight into the substrate scope of the 3ox-mediated aerobic oxidative cross-coupling of amines.

			OCH 3
	N	N	N
	7
	N

Entry for the Table of Contents


Khac Minh

Huy Nguyen

Martine Largeron
email: martine.largeron@parisdescartes.fr

Dr K M H Nguyen

Catalytic Oxidative Coupling of Primary Amines under Air: A Flexible Route to Benzimidazole Derivatives

Benzimidazoles are of fundamental importance in chemistry and biology, and the development of efficient environmentally benign methods for their preparation remains a key challenge for organic chemists. In a biomimetic approach inspired by copper amine oxidases, we disclose herein the scope and factors influencing the success of the cooperative action of CuBr2 electron transfer mediator and topaquinone-like substrate-selective catalyst in the oxidative cyclocondensation of primary amines with oaminoanilines. This one-pot atom-economical multistep process, that works under green conditions with ambient air as the terminal oxidant, low loadings of catalysts together with equimolar amounts of commercially available amine substrates, is particularly suitable for the preparation of 1,2-disubstituted benzimidazoles. Furthermore, it allows the functionalization of non-activated primary aliphatic amines that are known to be challenging substrates for non-enzymatic catalytic aerobic systems.

Introduction

Benzimidazoles are recognized as essential chemical motifs present in a variety of natural products, agrochemicals and bioactive molecules. [START_REF] Basu | Mandal in Green Synthesis Approaches for Biologically Relevant Heterocycles, Chapter 9 Sustainable Synthesis of Benzimidazoles, Quinoxalines, and Congeners[END_REF] The most prominent benzimidazole derivative in nature is N-ribosyl-dimethylbenzimidazole which serves as an axial ligand for cobalt in vitamin B12. [START_REF] Barker | [END_REF] More importantly, benzimidazoles are privileged targets in drug discovery, as shown by the profusion in the market of pharmaceutical products such as telmisartan and candesartan as antihypertensives, omeprazole as proton pump inhibitor or astemizole, clemizole, and bilastine as antihistaminic agents. [3] Over the years, massive efforts have been dedicated to the synthesis of functionalized benzimidazole derivatives which are commonly prepared from o-aminoanilines by condensation with carboxylic acid derivatives under harsh dehydrating conditions or oxidative couplings with aldehydes. [4] Although the oxidative condensation of o-aminoanilines with aldehydes has received unabated attention from chemists, a major limitation of this strategy is the competitive formation of 2-substituted and 1,2disubstituted benzimidazoles. [START_REF] For A Book | Benzimidazoles in The Chemistry of Heterocyclic Compounds[END_REF] Subsequent advances have been dominated by the development of improved procedures that selectively synthesize either 2-substituted benzimidazoles [6] or 1,2-disubstituted benzimidazoles [7] as the sole product. Regiocontrolled syntheses of 1,2-disubstituted benzimidazoles have also been achieved by catalytic amination of 2haloacetanilides or catalyzed intramolecular C-N cross-coupling reactions starting from amidines. [8] However, these routes require special efforts to prepare the desired starting materials.

Recently, catalytic oxidative reactions, using molecular oxygen or air as the terminal oxidant, have received much attention because of their green chemistry and atom economy aspects. [START_REF] Que | For selected recent reviews or perspective[END_REF] Meanwhile, considerable progress has been made in developing catalytic aerobic oxidation of alcohols and amines to imines. [10] Taken together, the use of primary alcohols or amines as easily available substrates for the synthesis of benzimidazoles has emerged in synthetic strategies (Scheme 1). Interestingly, these routes are attractive to produce selectively 2substituted benzimidazoles (R 1 = H), without the concomitant formation of 1,2-disubstituted benzimidazoles. However, except for a few exceptions, [11] catalytic aerobic reactions suffer drawbacks such as elevated temperature (90-160°C) a nd/or oxygen pressure. In addition, non-activated primary alcohols or amines are generally ineffective starting materials for this cascade reaction sequence. [12] Catalyst-free aerobic oxidative condensation reactions of o-amino anilines with primary alcohols or amines have also been described, but the scope is limited to benzylic-type substrates thus limiting the potential applications of these methods. [13] Scheme 1. Catalytic aerobic oxidative condensation of o-aminoanilines with primary alcohols or amines.

In this vein, we recently described a bioinspired catalytic oxidative coupling of a diverse range of primary amines with oaminoanilines, under ambient air, that leads to N-phenyl-2substituted benzimidazoles through multistep oxidation and nucleophilic addition reactions. [14] The catalytic process, inspired by the copper amine oxidases activity, associates two redox couples in a way reminiscent of other biomimetic catalytic systems: [9b,15] low loadings of biocompatible CuBr2 electron transfer mediator and topaquinone-like substrate-selective catalyst 1ox (Scheme 2), are sufficient to activate the α-C-H bond of aliphatic primary amines which are converted, in the presence of o-aminoanilines, to cross-coupled imines B through a transamination process that leads to the homocoupled imine intermediate A, followed by dynamic transimination. [16] Further intramolecular cyclization to benzimidazoline C and subsequent oxidation afford the N-phenyl-2-substituted-benzimidazole derivatives under environmentally benign conditions. Of particular note, this one-pot atom-economical multi-step process allows the oxidative C-H functionalization of non-activated primary amines, which are known to be challenging substrates leading to 1,2-disubstituted benzimidazoles in moderate to good yields.

At this stage, mainly N-phenyl-o-aminoaniline had been engaged in the oxidative condensation with a range of primary amine substrates to produce N-phenyl-2-substituted benzimidazoles. [14] For a more comprehensive investigation of the potential of the bioinspired cooperative catalytic system, the variation of the o-aminoaniline substrate proved to be essential. In this prospect, there were several challenges inherent to this cascade reaction sequence which needed to be addressed. In this full paper, we present the results of new experiments aimed at exploring further the synthetic potential of this atom-economical cascade reaction sequence. Scheme 2. Bioinspired CuBr2/1ox-mediated cascade reaction sequence leading to N-phenyl-2-substituted benzimidazole derivatives.

Results and Discussion

CuBr2/1ox-catalyzed aerobic condensation of a range of primary aliphatic amines with N-methyl-o-aminoaniline

First, we examined the aerobic oxidative cross-coupling of a range of primary amines 2 with N-methyl-o-aminoaniline 3a as in situ imine trap (Table 1). This promised to be a trivial exercise due to the related chemistry we had recently reported from its Nphenyl congener. [14] However, applying the conditions that had proven most effective (6 mol% 1ox, 0.4 mol% CuBr2, MeOH, 45°C, under air), the oxidative condensation of N-methyl-oaminoaniline 3a with a range of primary amines 2 was not selective affording, in addition to the desired 1,2-disubstituted benzimidazole product 4, N-methylbenzimidazole 5a as the minor product. Its formation, with up to 28% isolated yield, was favored when the rate of the main reaction was affected either by steric effects in the case of benzylic amines (Table 1, entry 7), or by the decreased reactivity for β-branched alkylamines (Table 1, entries 17 and18). Because 5a was detected regardless of the nature of the condensed primary amine, the carbon source for the construction of the benzimidazole core seemed to have arisen from the solvent itself through the formation of a formaldehyde intermediate. [17] To verify this hypothesis, oaminoaniline 3a was reacted in MeOH under the same experimental conditions, in the absence of the primary amine substrate 2. Then, 5a was isolated in 15% yield after 24h. Note 5a could not be detected in the absence of CuBr2, which proved to be essential for MeOH dehydrogenation to formaldehyde. Moreover, as the yield of 5a was lower than several data reported in Table 1, it could not be excluded that the primary 13 [b] 14 [b] 34:27 [d] 58:18

15 [b] 2o 4oa 60:15

16 [b] 17 [b] 18 [b] 2p 2q 2r 4pa 4qa 4ra 62:18 42:24 [d] 38:28 [d,e] [a] The reactions were carried out using equimolar amounts of primary amines 2 and N-methyl-o-aminoaniline 3a on a 1.25 mmol scale, in the presence of 4 mol% of 1red and 0.4 mol% of CuBr2, in 25 mL of MeOH, under ambient air for 24h. After 6h, an additional aliquot of 1red (2 mol%) was added; [b] the reaction was conducted at 60°C to facilitate the cycloconden sation reaction, thus avoiding the competitive isomerisation of the generated alkylimine intermediate to the enamine tautomer; [14,18,19] [c] yield of isolated products; [d] yield after 48h; an additional aliquot of 1red (2 mol%) was added after 24h; [e] as volatile alkylamines 2l and 2r were lost at 60°C, an additional 0.5 equiv of alkylamine was added after 6h (entries 12 and 18).

amine substrate 2 could participate in MeOH dehydrogenation to formaldehyde through a base catalysis. At this stage, the formation of 5a was an unexpected complication and efforts were pursued to obtain selectively the desired 1,2-disubstituted benzimidazoles 4. Since CuBr2 was required for the formation of the side product 5a, we targeted a close catalytic oxidative process in the absence of CuBr2 catalyst. After 24h, the aerobic oxidative condensation of benzylamine 2a with o-aminoaniline 3a produced 1,2benzimidazole 4aa in 66% yield (70% conversion), owing to the spontaneous aerobic oxidation of 1red to organocatalyst 1ox. This result indicated that N-methyl-o-aminoaniline 3a was much more reactive than its N-phenyl congener, as only 30% (45% conversion) of the related 1,2-benzimidazole was isolated under the same experimental conditions. [14] Full conversion of 3a could be achieved after 48h leading to benzimidazole 4aa in 86% yield (Scheme 3). We attempted to reduce the reaction time by increasing the temperature to 60°C but, after 24h, the yield of benzimidazole 4aa decreased to 37% yield (45% conversion) due to the slow decomposition of the o-iminoquinone organocatalyst 1ox to melanin-like polymers. These encouraging results led us to envisage a metal-free 1ox-mediated strategy to produce selectively N-methyl-2substituted-benzimidazoles 4. With the optimized reaction conditions in hand (8 mol% 1ox, MeOH, 45°C, under air), we examined the reaction of a series of primary amine substrates (See Table in the Supporting Information). After 48h, variously substituted benzylamines were converted to the corresponding 1,2-benzimidazoles in high yields (77-86%), regardless of the electronic character of the substituents. However, heterocyclic compounds such as 2-thiophenemethylamine 2i and furfurylamine 2j were found to be inferior substrates, leading to roughly 65% yield of benzimidazoles 4ia and 4ja, with a 72h prolonged reaction time, while non-activated primary amines such as aminomethylcyclohexane 2k proved to be poor substrates for the organocatalyzed reaction, affording the desired benzimidazole 4ka in only 10% yield (44% conversion after 48h).

These data confirmed that organocatalyst 1ox and CuBr2 must work cooperatively to facilitate the aerobic oxidation of non-activated primary amines to imines under air. [14] Therefore, the unique possibility to avoid the formation of byproduct 5a which originated with MeOH was to change the nature of the solvent. So, we performed optimization studies of the CuBr2/1oxmediated aerobic oxidative condensation of o-aminoaniline 3a with non-activated aminomethylcyclohexane 2k as the amine substrate (Table 2). Taking into account our previous investigations, [14] alcohols were retained as the best efficient solvents because strong solvation of the o-iminoquinone 1ox by MeOH had been shown to enhance the electrophilicity of its quinonoid moiety, thereby favoring the nucleophilic attack of the amine substrate. [16b,20] As expected, in EtOH attempts to isolate 1,2benzimidazole 4ka as the single product were thwarted by the occurrence of the solvent as reactant, providing 1,2dimethylbenzimidazole 6 as the side product in 37% isolated yield (Table 2, entry 2). In contrast, exclusive formation of 4ka could be achieved in 2-propanol that was unable to produce an aldehyde species, but the yield of 4ka was limited to 40% under the standard experimental conditions as the cascade reaction sequence proceeded too slowly (70% conversion after 24h). When the oxidative condensation reaction was conducted at higher temperature, the yield of 4ka remained almost unchanged (Table 2, entry 3). [14] Previous studies on metal-free aerobic oxidative condensation of o-aminoanilines with aldehydes had demonstrated that water significantly accelerated the conversion to benzimidazoles by changing the disfavored 5endo-trig cyclization of imines to the favored 5-exo-tet cyclization through a tetrahedral intermediate (Scheme 4). [6h] NH 2 Accordingly, addition of 10% water was found to facilitate the formation of benzimidazole 4ka (Table 2, entry 4) which was isolated in 58% yield (70% conversion after 24h). Increasing the amount of water to 50% led to complete conversion after 24h, but the yield of 4ak decreased to 46% (Table 2, entry 5), presumably due to the partial hydrolysis of the cross-coupled imine intermediate B to give the aldehyde, a side reaction that would interfere with the cyclization to benzimidazoline C. [18] As we had previously shown that CuBr2 also mediated the ultimate oxidation step yielding the benzimidazole product, [14] we chose to increase the amount of CuBr2 to 0.8 mol% (Table 2, entry 6). Then, full conversion was observed after 24h and the yield of 4ak attained 66%. These optimized reaction conditions were further applied to the oxidative condensation of a diverse range of activated and non-activated primary amines with N-methyl-oaminoaniline 3a (Table 3). Not surprisingly, high yields of 1,2benzimidazoles were obtained from variously substituted benzylamines 2a-f (Table 3, entries 1-4), except for sterically constrained benzylamine 2g, which gave benzimidazole 4ga in 66% yield despite a prolonged reaction time (Table 3,entry 5).

Table 3. CuBr2/1ox-catalyzed aerobic oxidative cross-coupling of primary amines 2 with o-aminoaniline 3a in iPrOH:H2O 9:1 v/v. 11 [b] 12 [b] 13 [b] 14 [b] 15 [b] 16 [b] p-tBu-C6H4 78 75 [d] 74 [d] 66 75 [e] 32 [d] 60 65 72 44 17 [d,e] [a] The reactions were carried out using equimolar amounts of primary amines 2 and o-aminoaniline 3a on a 1.25 mmol scale, in the presence of 4 mol% of 1red and 0.8 mol% of CuBr2, in 25 mL iPrOH:H2O 9:1 v/v, under ambient air for 24h. After 6h, an additional aliquot of 1red (2 mol%) was added; [b] the reaction was conducted at 60°C; [c] yield of isolated produc ts; [d] yield after 48h; an additional aliquot of 1red (2 mol%) was added after 24h; [e] As volatile alkylamine 2l and 2r were lost at 60°C, additional 0.5 equiv of alkylam ine was added after 6h (entries 10 and 16).

Likewise, 1-naphthylmethylamine 2h could also be used as the amine substrate affording benzimidazole 4ha in 78% yield (Table 3, entry 6), while heterocyclic amines 2i and 2j, containing sulfur or oxygen atoms, gave 1,2-benzimidazoles 4ia and 4ja in roughly 75% yields after 48h (Table 3, entries 7 and 8). More challenging, the reaction scope could be expanded to the non-activated primary aliphatic amines (Table 3, entries 9-16). This type of experiments has generally been reported as unsuccessful. [11][12][13] Except for tetrahydrofurfurylamine (Table 3, entry 11) and β-branched alkylamines (Table 3, entries 15 and 16), non-activated primary amines were converted to the desired 1,2-benzimidazoles in acceptable yields ranging from 60 to 75%. Therefore, changing MeOH to a 9:1 mixture of 2-propanol and water proved to be efficient to prepare selectively the 1,2disubstituted benzimidazole derivatives. Note that undesired byproduct arising from the reaction of MeOH had not been observed when N-phenyl-o-aminoaniline was used instead of Nmethyl-o-aminoaniline. [14] CuBr2/1ox-catalyzed aerobic condensation of benzylamine or aminomethylcyclopropane with a range of diverse o-amino anilines.

To further investigate the substrate scope of this bioinspired cascade reaction sequence, variation in the structure of the condensed o-aminoaniline was also explored using benzylamine as the primary amine substrate (Table 4). The process was effective with N-substituted o-aminoanilines 3a-e, leading to the corresponding 1,2-benzimidazoles 4aa-ae in high yields ranging from 70 to 84% (Table 4, entries 1-5). In MeOH, oxidative condensation of benzylamine with N-propyl-o-aminoaniline 3b led to the desired 1,2-benzimidazole 4ab in 77% yield (Table 4, entry 2), along with N-propylbenzimidazole byproduct 5b in 12% yield (Scheme 5), a result close to that reported from its Nmethyl analog 3a (Table 4, entry 1). Similarly, the formation of 5b could be prevented by working in a 9:1 mixture of 2propanol:H2O giving exclusive formation of 4ab in 81% yield (Table 4, entry 2 [d] ) . It is noteworthy that appreciable amounts of byproduct 5 were only detected with the more reactive N-alkyl-oaminoanilines, whereas exclusive formation of 1,2-disubstituted benzimidazoles was observed using N-benzyl or N-aryl-oaminoaniline substrates (Table 4, entries 3-5). Consequently, MeOH was selected for further experiments because it provided the ideal balance of 1ox solvation and reaction rate.

In a second series of experiments, we focused on the preparation of 2-substituted benzimidazoles using a range of oaminoanilines 3f-l. Oxidative coupling of benzylamine 2a with electron-rich o-aminoanilines 3f-h afforded the 2-substituted benzimidazoles 4af-ah in suitable yields ranging from 60 to 70% (Table 4, entries 6-8). These yields were slightly lower than those obtained from more reactive N-substituted o-aminoanilines 3a-e, but the decreased yield could not be assigned to the formation of the benzimidazole byproduct originated from MeOH itself since no change was observed by working in a 9:1 mixture 1 3a 4aa 81 [c] 86 [d] 77 [c] 81 [d] 68 70 [d] 82 84 60 62 [d] 61 70 70 [d] 70 [e] 63 [e] 56 [e] 25 [e] [a] The reactions were carried out using equimolar amounts of benzylamine 2a and o-aminoaniline 3 on a 1.25 mmol scale, in the presence of 4 mol% of 1red and 0.4 mol% of CuBr2, in 25 mL of MeOH, under ambient air for 24h. After 6h, an additional aliquot of 1red (2 mol%) was added; [b] yield of isolated products; [c] byproducts 5a (10%, entry 1) and 5b (12%, entry 2) arising from MeOH as carbon source were also isolated; [d] the reaction was conducted in iPrOH:H2O 9:1 v/v; [e] yield after 72h; an additional aliquot of 1red (2 mol%) was added after 24h.

of 2-propanol:H2O (Table 4, entries 6 [d] and 8 [d] ).

Haloaminoanilines 3i-k work very slowly affording the desired 2substituted benzimidazoles 4ai-ak in decent yields only after a 72h prolonged reaction time (Table 4, entries 9-11). Regarding the use of o-aminoaniline 3l which is a strongly electron-deficient substrate, a poor yield (25%) of benzimidazole product 4al was obtained because the rate of the reaction was adversely affected by the electronic withdrawing effect of the nitro group (Table 4,entry 12).

Oxidative coupling of non-activated aminomethyl cyclopropane 2l was similarly tested with a range of Nsubstituted o-aminoaniline 3a-e together with its parent oaminoaniline 3f (Table 5). The process works efficiently with Nsubstituted o-aminoanilines 3a-e affording the corresponding 1,2-disubstituted benzimidazole products 4la-le in suitable yields ranging from 68 to 75%, at the exclusion of N-benzyl oaminoaniline 3c that proved somewhat unstable during the oxidative process giving 1,2-benzimidazole 4lc in lower isolated yield (Table 5, entry 3). Much less reactive parent oaminoaniline 3f afforded 2-benzimidazole 4lf in only 30% isolated yield, because of the rapid isomerisation of the generated alkylimine intermediate into its enamine tautomer (Table 5,entry 6). [16b,18,19]

Conclusions

New insights into the scope and factors influencing the success of a bioinspired CuBr2/topaquinone-like catalytic oxidative coupling of primary aliphatic amines with oaminoanilines, that leads to benzimidazole frameworks, are disclosed through the variation of both solvent and coupling partners. MeOH proves to be the best solvent for this transformation because it provides the ideal balance of 1ox solvation and reaction rate, except when reactive N-alkyl oaminoanilines are used as in situ imine traps, due to the concomitant formation of a benzimidazole byproduct originated from MeOH itself. In these cases, exclusive formation of 1,2disubstituted benzimidazoles can be achieved in 2-propanol, in the presence of water (10%) which markedly accelerates the cyclization rate to the benzimidazoline intermediate. Our one-pot atom-economical multistep process, that works under green conditions with ambient air, low loadings of biocompatible CuBr2 and topaquinone-like organocatalyst, together with equimolar amounts of commercially available coupling partners, is wellsuited to the functionalization of unactivated primary aliphatic amines that are known to be challenging substrates for nonenzymatic catalytic aerobic systems. Further synthetic applications involving unstable alkylimine intermediates generated through this biomimetic environmentally benign protocol are envisioned.

Table 5. CuBr2/1ox-catalyzed aerobic oxidative cross-coupling of aminomethylcyclopropane 2l with a range of o-aminoanilines 3, in MeOH. [a] Entry o-aminoaniline 3 Benzimidazole Product 4

Yield

[%] [b] 1 3a 4la 73 [c] 75 [d] 72 [e] 30

[a] The reactions were carried out using equimolar amounts of aminomethylcyclopropane 2l and o-aminoanilines 3 on a 1.25 mmol scale, in the presence of 4 mol% of 1red and 0.4 mol% of CuBr2, in 25 mL of MeOH, under ambient air for 24h. After 6h, an additional aliquot of 1red (2 mol%) was added together with an additional 0.5 equivalent of 2l because of its volatility at 60°C; [b] yield of isolated products; [c] the corresponding by-product 5a (15%) arising from MeOH as carbon source was also isolated; [d] the reaction was conducted in iPrOH:H2O 9:1 v/v; [e] yield after 48h; an additional aliquot of 1red (2 mol%) was added after 24h.

Experimental Section

General considerations: 1 H NMR and 1D proton decoupled 13 C NMR spectra were recorded in CDCl3 on a Brucker AC-300 spectrometer operating at 300 MHz and 75 MHz respectively. Chemical shifts δ, are given in ppm relative to TMS and coupling constants J, in hertz. The measurements were carried out using the standard pulse-sequences.

The carbon type (methyl, methylene, methine, or quaternary) was determined by DEPT experiments. High-resolution mass spectra (HRMS) were performed on a Bruker maXis mass spectrometer operating in the positive ion mode. Chemicals were commercial products of the highest available purity and were used as supplied. Reduced catalyst 1red was synthesized in two steps from commercially available 2-nitroresorcinol. [21] General experimental procedure for the CuBr2/1ox-catalyzed aerobic oxidative coupling reaction that gives substituted benzimidazoles. Equimolar amounts of benzylamine 2 (1.25 mmol) and o-amino-aniline 3 (1.25 mmol) with reduced organocatalyst 1red [21] (0.05 mmol, 4 mol%), and copper (II) bromide (0.005 mmol, 0.4 mol%), were mixed in methanol (25 mL), in an air atmosphere. The reaction mixture was stirred at 45°C for 6h. Then, an additional aliquot of 0.025 mmol of 1red (2 mol%) was introduced into the reaction mixture and the reaction was continued for 18h. The solvent was then removed by evaporation under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether 50/50 v/v) to afford the desired benzimidazole 4, at the exception of 2-benzimidazoles 4af-4ai and 4lf which were directly recrystallized from the crude material (See the Supporting Information). The above procedure is generally representative for all the products shown in Tables 1 and4. Any deviations from this protocol are specified in the footnotes of the tables.

Representative experimental procedure for the CuBr2/1ox-catalyzed aerobic condensation of primary amines with N-alkyl-oaminoanilines. Equimolar amounts of n-octylamine 2n (1.25 mmol) and N-methyl-o-aminoaniline 3a (1.25 mmol) with reduced organocatalyst 1red [21] (0.05 mmol, 4 mol%) and copper (II) bromide (0.01 mmol, 0.8 mol%), were mixed in a 9:1 mixture of 2-propanol:water (25 mL) in an air atmosphere. The reaction mixture was stirred at 60°C for 6h. Then, an additional aliquot of 0.025 mmol of 1red (2 mol%) was introduced in the reaction mixture and the reaction was continued for 18h. The solvent was then removed by evaporation under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether 50/50 v/v) to give 1,2-benzimidazole 4na (60% yield) as a new compound.

Entry for the Table of Contents

Scheme 3 .

 3 Scheme 3. Metal-free 1ox-mediated aerobic oxidative condensation of Nmethyl-o-aminoaniline 3a with a range of benzylic amines 2.

Scheme 4 .

 4 Scheme 4. Postulated route for the oxidative cyclization of the cross-coupled imine intermediate B to 1,2-benzimidazole 4ka, in a 9:1 mixture of 2propanol:H2O according to reference 6h.

Scheme 5 .

 5 Scheme 5. CuBr2/1ox-mediated aerobic oxidative condensation of benzylamine 2a with N-propyl-o-aminoaniline 3b in MeOH.

1, 2 -

 2 Benzimidazole 4na: White solid (recrystallized from petroleum ether) m.p. 40-44°C; 1 H NMR (300 MHz, CDCl3, 25°C, TMS): δ = 0.86-0.89 (t, J = 6.7 Hz, 3H, CH3), 1.28-1.42 (m, 8H, CH2), 1.81-1.83 (m, 2H, CH2), 2.77-2.81 (t, J = 7.7 Hz, 2H, CH2), 3.60 (s, 3H, N-CH3), 7.19-7.2 (m, 3H, Ar), 7.69-7.71 (m, 1H, Ar); 13 C NMR (75 MHz, CDCl3, 25°C, TMS): δ =14.1 (CH3), 22.7 (CH2), 27.5 (CH2), 27.7 (CH2), 29.1 (CH2), 29.5 (CH2), 29.6 (CH3), 31.7 (CH2), 108.8 (CH, Ar), 119.1 (CH, Ar), 121.6 (CH, Ar), 121.8 (CH, Ar), 135.7 (Cq), 142.5 (Cq), 155.4 (Cq); HRMS (ESI+) m/z calcd for C15H23N2 [M+H] + 231.1861. Found 231.1872.

Layout 2 :

 2 Homogeneous catalysisFULL PAPERAtom Economical: Factors influencing the success of the biomimetic cooperative action of CuBr2 electron transfer mediator and topaquinone-like substrate-selective catalyst in the oxidative cyclocondensation of primary aliphatic amines with oaminoanilines are disclosed in order to provide a flexible route to benzimidazole derivatives under green conditions.

Table 1 .

 1 CuBr2/1ox-catalyzed aerobic oxidative coupling of a range of primary amines 2 with N-methyl-o-aminoaniline 3a in MeOH.[a]

	Entry	Amine	Benzimidazole	Yield
		Substrate 2	Product 4	4:5a
				[%]

Table 2 .

 2 Optimization of the CuBr2/1ox-catalyzed aerobic oxidative crosscoupling of aminomethylcyclohexane 2k with o-aminoaniline 3a.

Table 4 .

 4 CuBr2/1ox-catalyzed aerobic oxidative cross-coupling of benzylamine 2a with a range of diverse o-aminoanilines 3 in MeOH.

Acknowledgements

We would like to thank Dr M.-B. Fleury, Emeritus Professor at the Paris Descartes University, for fruitful discussions. We also thank ADRAPHARM (Association pour le Développement de la Recherche Appliquée à la Pharmacologie) for financial support.

Keywords: aerobic oxidation • amines • benzimidazoles • crosscoupling • homogeneous catalysis


Martine Largeron

Maurice-Bernard Fleury

A Metalloenzyme-Like Catalytic System for the Chemoselective Oxidative Cross-Coupling of Primary Amines to Imines under Ambient Conditions

Keywords: homogeneous catalysis, cross-coupling, primary amines, oxidation, cycloaddition

come     A Metalloenzyme-Like Catalytic System for the Chemoselective Oxidative Cross-Coupling of Primary Amines to Imines under Ambient Conditions

Introduction

Imines, commonly known as Schiff bases, represent a very important class of N-containing intermediates widely utilized as electrophiles in many organic transformations such as reduction, addition, condensation and cyclization. They are also essential pharmacophores in numerous biologically active compounds. Imines have traditionally been prepared through condensation of amines with aldehydes or ketones, but new mild and practical catalytic methods [1] including oxidative coupling of alcohols and amines [2] together with oxidation of secondary amines [3] have also been developed. For a long time, little attention had been given to the oxidation of primary amines probably due to poor product selectivity. [4] The discovery of homogeneous and heterogeneous catalytic systems that operate effectively with molecular oxygen as the sole oxidant has contributed to revitalize interest in this area. [5] Recently, non-noble transition-metal catalysis, [START_REF] Patil | For selected recent examples[END_REF] metal-free catalysis, [7] and photocatalysis [8] have led to homocoupled imines in high yields and selectivity. However, save for a few exceptions, [6b,6d] these catalytic systems require elevated temperature (70°----130°C)

and/or oxygen pressure. In addition, the condensation of amines is not an efficient way to prepare cross-coupled imines due to the concomitant formation of self-coupling products. [6a,7a,9] To the best of our knowledge, only two highly efficient and selective (>95%) oxidative cross-coupling protocols for various amines have been reported to date, but they require high reaction temperatures (100°C) together with oxygen pressure. [10] The general interest in amine oxidation has also stimulated efforts to mimic the biological activity of metalloenzymes, [11] in particular copper amine oxidases (CuAOs) that promote selective aerobic oxidation of primary amines to aldehydes in nature through the cooperation between a quinone-based cofactor (topaquinone) and copper. [12] Recently, metalloenzyme-like catalytic systems have been developed for the aerobic oxidation of primary amines to imines under mild conditions. [START_REF]For a recent perspective[END_REF] In particular, the topaquinone analog 5-tert-butyl-2-hydroxy-1,4-benzoquinone has been described as an efficient biomimetic organocatalyst for the chemoselective aerobic oxidative self-coupling of primary amines to imines, at room temperature, under 1 atm of molecular oxygen. The exclusive selectivity for primary benzylic amines allowed the preparation of various cross-coupled imines in high yields, from the oxidative condensation of benzylamine with anilines or with primary aliphatic amines. [13b] We have ourselves described a biomimetic homogeneous catalytic system for the aerobic oxidation of primary amines to imines, based on the synergistic combination of copper and a topaquinone-like organocatalyst 1ox, first discovered from electrochemical investigations. [14] Low catalysts loadings (2 mol% of 1red precursor of 1ox and 0.2 mol% of Cu I ) were sufficient to oxidize benzylic and aliphatic amines to self-coupled imines under ambient conditions. The oxidation process started with atmospheric oxygen and continued in a cascade-like manner by passing the oxidation potential of oxygen through the copper salt to the organic oiminoquinone mediator 1ox, that finally oxidized the amine substrate (Scheme 1). (2 mol %) This catalytic process that combines two redox couples where the oiminoquinone organocatalyst 1ox is the substrate-selective catalyst and the copper salt serves as an electron transfer mediator brings back other biomimetic catalytic systems that use transition metals as substrate-selective catalysts coupled with electron transfer mediators. [15] Interestingly, the oxidative condensation of 4-methyl benzylamine with several aliphatic amines produced the corresponding cross-coupled imine in good yields, together with N-(4-methylbenzyl)-1-(p-tolyl)methanimine derived from homo condensation as the minor product (5-30%). This expedient investigation of the performance of our bioinspired catalytic system led to a preliminary communication. [16] At this stage, only 4methylbenzylamine or benzylamine [9,10,13b,d] had been engaged in the oxidative cross-coupling with alkylating amines. So, the development of a more general method that would operate effectively with complete selectivity, under ambient conditions, would be highly desirable but still challenging.

1 ox 1 red 2 Cu (I) 2 Cu (II) (0.2 mol %) R NH 2 R N R NH 3 MeOH, RT 2
In this full paper, we have tried to achieve exclusive formation of cross-coupling imines and to expand the substrate scope. Diverse benzylic amines including heterocyclic amines containing sulfur and oxygen atoms could be converted, with complete selectivity, into the corresponding cross-coupled imines in high yields. The synthesis of aliphatic imines was inherently more challenging because of their instability resulting from subsequent tautomerization to the enamine form that decomposed under ambient air. Although the crosscoupled aliphatic imine could be formed with complete selectivity as shown through monitoring the 1 H NMR spectrum, we were not able to isolate it as such. So, we decided to engage the generated alkylimine in situ in Diels-Alder reaction with the Danishefsky's diene to produce N-alkylpyridin-4-one derivatives. Finally, all the results led us to revise the reaction pathway we had previously proposed for the oxidative cross-coupling of primary amines to imines. [16]

Results and Discussion

Choice of the optimal reaction conditions: First, we performed optimization studies of the Cu I /1ox-mediated aerobic oxidative crosscoupling process using 4-methylbenzylamine 2a and 1ethylpropylamine 3a as the amine substrates. Only the copper source and solvent were varied, while the use of o-aminophenol 1red precursor of the o-iminoquinone cooperative organocatalyst 1ox, room temperature and ambient air as the source of oxidant was retained throughout. As shown in Table 1, the initial oxidation state of the copper catalyst had not significant impact on the reaction efficiency (entries 1-5). The reaction progressed in all of the solvents used (entries 5-8), but, after 10h, complete conversion was observed only in MeOH likely because strong solvation of the oiminoquinone 1ox by MeOH was required to enhance the electrophilicity of its quinonoid moiety, thereby favoring the nucleophilic attack of 4-methylbenzylamine 2a. [14] Optimization of the reaction parameters showed that mixing 4methylbenzylamine 2a and 1-ethylpropylamine 3a in the ratio 1:1 with Cu(OAc)2 (0.4 mol%) and o-aminophenol 1red (4 mol%), in MeOH under ambient conditions, afforded the desired cross-coupled product 4a with 95% selectivity after 10h (entry 5). In addition, exclusive formation of 4a could be attained when an additional aliquot of o-aminophenol 1red (1 mol%) was introduced after 6h which corresponded to 95% conversion. Probably, the in situ generated oiminoquinone organocatalyst 1ox slightly polymerized. Control studies revealed that copper catalyst and organocatalyst 1ox worked cooperatively to facilitate the aerobic oxidation of amines to imines under ambient conditions. In the absence of copper, the reaction proceeded very slowly owing to the spontaneous aerobic oxidation of 1red to 1ox, whereas no reaction occurred at room temperature when copper salt was used as the sole catalyst. [a] The reactions were carried out using equimolar amounts of amines 2a and 3a on a 2.5 mmol scale, in the presence of 4 mol% of 1red and 0.4 mol% of copper salt, in 10 mL of solvent, at room temperature, under ambient air for 10h. [b] Molar ratio based on the 1 H NMR spectrum of the crude product. [c] After 6h, an additional aliquot of 1red (1 mol%) was added. CuMeSal : copper (I) 3-methylsalicylate.

Scope and functional group tolerance of Cu II /1ox-mediated oxidative cross-coupling of two primary amines: To explore potential applications of this method, the optimized reaction conditions (Table 1, entry 5) were first applied to the catalytic oxidative cross-coupling of 4-methylbenzylamine 2a with diverse primary amines 3 (Table 2). Both branched and linear aliphatic amines (entries 1-6) could be efficiently coupled with 4methylbenzylamine 2a in high yields, with complete selectivity, except for n-hexylamine 3e and aminomethylcyclohexane 3f for which small amounts of homocoupled imines (4-5%) were also isolated (entries 5, 6). 1-Phenylethan-1-amine 3g (entry 7) together with 2,3-dihydro-1H-inden-2-amine 3h (entry 8) reacted efficiently with 2a leading to cross-coupled imines that directly precipitated in the bulk solution. As has earlier been observed, [13b] anilines 3i-k (entries 9-11) were less reactive, but afforded cross-coupled imines with good levels of conversion after 48h, provided a second 2 mol% portion of o-aminophenol 1red was added after 24h (entries 9 and 10), with the exception of p-chloroaniline 3k for which the conversion could not exceed 60% (entry 11). Interesting, introduction of ether or alcohol groups (entries 12-14) allowed the synthesis of functionalized cross-coupled imines, especially without oxidation of the alcohol fragment (entry 14). 90 [d] 90 [d] 95 [e] 90 [e] 60 [e] 100 90 [d] 80 [d] 55 [d] 90 95 85

[a] The reactions were carried out using equimolar amounts of amines 2a and 3 on a 2.5 mmol scale, in the presence of 5 mol% of 1red (4 mol% + 1mol% added after 6h) and 0.4 mol% of Cu(OAc)2, in 10 mL of methanol, at room temperature, under ambient air for 10h. [b] Molar ratio based on the 1 H NMR spectrum of the crude product. [c] Yields of the cross-coupled imine refer to the isolated unpurified product, which, unless otherwise stated, was pure by 1 H NMR spectroscopy (see the Supporting Information). [d] cross-coupling imine product directly precipitated in the bulk solution. [e] conversion after 48h, provided a second 2 mol% portion of o-aminophenol 1red was added after 24h.

In a second series of experiments, diverse primary amine substrates 2 were screened in the presence of 1-ethylpropylamine 3a (Table 3). High yields of cross-coupled imines were obtained from substituted benzylamines 2a-j regardless of the electronic character and the position of the substituents (entries 1-10). The free amino group of p-aminobenzylamine 2g did not affect the cross-coupling reaction although the yield slightly decreased (75%, entry 7). Likewise, a sterically bulky group such as 1-naphthyl was well tolerated (entry 11). Furthermore, heterocyclic amines 2l and 2m containing sulfur and oxygen atoms could be cross-coupled with 3a in high yields with complete selectivity (entries 12 and 13).

Much more challenging, the possibility of expanding the reaction scope to the synthesis of scarcely stable aliphatic imines was also explored. The catalytic oxidative cross-coupling of aminomethylcyclopropane 6 and 4-methoxyaniline 3i was chosen as the example and monitored by 1 H NMR spectroscopy. In the reaction of equimolar amounts of both amines 6 and 3i, the time course revealed the formation of only heterocoupled product 7 at early stages of the reaction. Although 1-cyclopropyl-N-(4-methoxyphenyl) methanimine 7 could be observed through monitoring the 1 H NMR spectrum (see the Supporting Information), its instability with time did not permit to isolate it as such. Nevertheless, the mild conditions required for the generation of unstable cross-coupled aliphatic imine 7 proved to be useful for using it in situ as a dienophile in Diels-Alder reactions. After roughly 60% conversion of aminomethyl cyclopropane 6, the reaction mixture was mixed with Danishefsky's diene 8 to form the dihydro-4-pyridone derivative 9 in 45% isolated HO yield (Scheme 2). Similar acid-free tandem oxidative aza Diels-Alder reactions have been earlier reported for the synthesis of N-aryl and N-alkylbenzaldimines. [17] Beside dihydro-4-pyridone 9, (Z)enaminone 10 was also isolated in 52% yield. The formation of 10 indicated that both 1-cyclopropyl-N-(4-methoxyphenyl) methanimine 7 and Danishefsky's diene 8 hydrolyzed partially under our experimental conditions leading to benzaldehyde, 4-methoxyaniline 3i together with (3E)-4-methoxybut-3-en-2-one. The latter further reacted with 4-methoxyaniline 3i to generate the (Z)-enaminone 10 as previously reported. [18] As a proof of the partial hydrolysis of methanimine 7, when the same reaction was performed using 4methylbenzylamine 2a as the amine substrate that was oxidized to stable benzaldimine 4i, dihydro-4-pyridone 11 was isolated in 80% yield at the exclusion of (Z)-enaminone by-product 10 (Scheme 2). Mechanistic considerations: On the basis of only one example of cross-coupling reactions, we had previously proposed that both homo-and cross-coupling products would be produced competitively through the ionic transamination mechanism earlier described. [16] Our present investigation into the substrate scope of the Cu II /1ox- Cu(OAc) 2 /air,1 ox MeOH, RT mediated cross-coupling of two primary amines led us to revise our original proposals to the one depicted in Scheme 3. Indeed, in almost all of the cases, the real-time monitoring of the cross-coupling reactions by 1 H NMR spectroscopy indicated that the homocoupling product was initially formed and accumulated at early stages of the reaction. After roughly 30 min, the homocoupled imine gradually turned to the cross-coupling product that finally became the exclusive product after ten hours. Of particular note, only the reaction of 4-methylbenzylamine 2a with n-hexylamine 3e (Table 2, entry 5) or aminomethylcyclohexane 3f (Table 2, entry 6) revealed the simultaneous formation of homo-and cross-coupling products (4e or 4f) from the outset of the reaction, but with a preference for the homocoupling product 5. These observations indicated that the homocoupling product was first generated as the sole imine product through the transamination mechanism earlier reported. [14,16] This was further alkylated by the second primary amine R'-NH2 through a transimination process [19] to give the cross-coupling product whose formation could be driven by continuous oxidation of the extruded primary amine R-CH2-NH2 (self-sorting step) as shown in Scheme 3. As a consequence, just one equivalent of both primary amines was sufficient to achieve exclusive formation of the cross-coupling imine product. This oxidative strategy known as "oxidative self-sorting" has previously been exploited to obtain thermodynamically disfavored products. [13b,20] We have further validated our mechanistic process by subjecting the isolated homocoupled imine 5 with two equivalents of 1-ethylpropylamine 3a under the standard conditions (Table 1, entry 5). Then, full conversion of the homocoupled imine 5 into the crosscoupling imine 4a was observed after ten hours providing support for the two-step mechanism. The synthesis of cross-coupled aliphatic imines was found to be troublesome because of their instability. The main problem associated with these imines is related to the formation of the tautomeric enamine form which decomposed under ambient air. [21] Nevertheless, the fact that aliphatic imines can be engaged in situ for further reactions leading to N-alkylpyridin-4-one derivatives demonstrates that aliphatic amines are well oxidized to imines under our experimental conditions as previously reported. [16] Whereas transition-metal-catalyzed oxidations to dehydrogenate aliphatic amines to imines require vigorous reaction conditions, the synergistic action of our bioinspired homogeneous cooperative catalyst lowers the activation energy enabling high reactivity that neither catalyst can accomplish alone. Scheme 3. Proposed overall two-step mechanism for the Cu(OAc)2/1oxmediated cross-coupling of primary amines

Conclusions

New insights into the scope and mechanism of the bioinspired Cu II /1ox-catalyzed aerobic oxidative cross-coupling of primary amines to imines have been delineated. Low loadings of biocompatible Cu II metal catalyst and topaquinone-like organocatalyst 1ox were sufficient to activate the α-C-H bond of various primary amines, which were converted to cross-coupled imines through a transamination process, that leads to the homocoupled imine intermediate, followed by dynamic transimination. This atom-economical process, that proceeds at room temperature, under ambient air, with equimolar amount of each coupling partners and tolerates diverse functional groups, generates with unprecedented selectivity cross-coupled imines which have been previously shown to have broad use in organic synthesis. The mild reaction conditions used in this work should be particularly favorable for using the unstable alkylimines in situ for further reactions.

Experimental Section

General considerations: 1 H NMR and 1D proton decoupled [START_REF]For a recent perspective[END_REF] C NMR spectra were recorded in CDCl3 on a Brucker AC-300 spectrometer operating at 300 MHz and 75 MHz, respectively. Chemical shifts δ are given in ppm relative to TMS and coupling constants J, in hertz. The measurements were carried out using the standard pulse-sequences. The carbon type (methyl, methylene, methine, or quaternary) was determined by DEPT experiments. Mass spectra were recorded on a ZQ 2000 Waters spectrometer, equipped with the positive electrospray mode (ES+). Chemicals were commercial products of the highest available purity and were used as supplied. Reduced catalyst 1red was synthesized in two steps from commercially available 2-nitroresorcinol. [22] General experimental procedure for Cu II /1ox-catalyzed aerobic oxidative cross-coupling of two primary amines. Equimolar amounts of 4-methylbenzylamine 2a (2.5 mmol) and 1ethylpropylamine 3a (2.5 mmol), reduced organocatalyst 1red (0.1 mmol, 4 mol%), and copper (II) acetate (0.01 mmol, 0.4 mol%) were mixed in methanol (10 mL) in an air atmosphere. The reaction mixture was stirred at room temperature for six hours. Then, an additional aliquot of 0.025 mmol of 1red (1 mol%) was introduced in the reaction mixture and the reaction was pursued during roughly four hours. The progress of the reaction was monitored by 1 H NMR spectroscopy. After completion of the reaction, the solvent was evaporated at room temperature to give the cross-coupling imine product 4a in 97% yield as an almost pure product as confirmed by The above procedure is generally representative for all the products shown in Tables 2 and3. Any deviations from this protocol are specified in the footnotes of the tables.

Representative procedure for Cu II /1ox-catalyzed aerobic oxidative synthesis of dihydro-4-pyridones derivatives. 1-Cyclopropyl-N-(4-methoxyphenyl)methanimine 7 was prepared in situ by mixing equimolar amounts of aminomethylcyclopropane 6 (1.25 mmol) and 4-methoxyaniline 3i (1.25 mmol), reduced organocatalyst 1red (0.05 mmol, 4 mol%), and copper (II) acetate (0.005 mmol, 0.4 mol%) in methanol (5 mL) under ambient conditions for six hours. Then, an additional aliquot of 0.0125 mmol of 1red (1 mol%) was introduced in the reaction mixture and the reaction was pursued during four hours. After roughly 60% conversion of aminomethylcyclopropane 6 into the cross-coupling imine product 7 (see the NMR spectrum in the Supporting Information), 2 mL of the resulting solution (that corresponds roughly to 0.3 mmol of 7) was taken and Danishefsky's diene 8 (0.6 mmol, 2 equiv) was added dropwise in 30 min. After stirring for 1 hour at room temperature, another equiv of Danishefsky's diene 8 (0.3 mmol) was added dropwise in 15 min to the reaction mixture which was stirred for 2h at room temperature. The reaction mixture was then quenched with 2 mL of 1.0 M HCl. The product was extracted with diethyl ether and the solvent was evaporated under reduced pressure. The crude material was purified by column chromatography with dichloromethane/ethyl acetate (4:1 v/v) as the eluent leading to dihydro-4-pyridone 9 in 45% yield together with (Z)enaminone 10 in 52% yield.

Dihydro-4-pyridone 9 : 1 ), 198.4 (Cq, C=O). 1 H and 13 C NMR spectral data are in agreement with those previously reported in the literature. [23] Entry for the

Scheme 1 .

 1 Scheme 1. Aerobic oxidation of primary amines to imines catalyzed by Cu I /1ox cooperative system

Table 3 . 1 HScheme 2 .

 312 Scheme 2. Tandem oxidative aza Diels-Alder reaction for the synthesis of dihydro-4-pyridones

1 H

 1 and 13 C NMR spectroscopy (See the Supporting Information). Imine 4a: 1 H NMR (300 MHz, CDCl3, 25°C, TMS): δ = 0.88 (t, J = 8 Hz, 6H, 2 × CH3), 1.70 (m, 4H, 2 × CH2), 2.43 (s, 3H, CH3), 2.91 (m, 1H, CH), 7.25 (d, J = 7 Hz, 1H, 2 × CH, Ar), 7.68 (d, J = 7 Hz, 1H, 2 × CH, Ar), 8.24 (s, 1H, CH=N); 13 C NMR (75 MHz, CDCl3, 25°C, TMS): δ = 11.1 (2 × CH3), 21.5 (CH3), 28.9 (2 × CH2), 75.2 (CH), 128.1 (2 × CH, Ar), 129.3 (2 × CH, Ar), 133.8 (Cq), 140.5 (Cq), 159.4 (CH=N); MS (ES+): m/z = 190 [MH + ].

  H NMR (300 MHz, CDCl3, 25°C, TMS): δ = 0.00 (m, 2H, CH2), 0.40 (m, 2H, CH2), 1.37 (m, 1H, CH), 2.62 (dd, J = 16 Hz, J = 4 Hz, 1H, CH), 2.98 (dd, J = 16 Hz, J = 6.7 Hz, 1H, CH), 3.24 (m, 1H, CH), 3.85 (s, 3H, CH3), 5.16 (d, J = 7.6 Hz, 1H, CH), 6.93 (d, J = 8.9 Hz, 2H, 2 × CH, Ar), 7.16 (d, J = 8.9 Hz, 2H, 2 × CH, Ar), 7.27 (d, J = 7.6 Hz, 1H, CH),; 13 C NMR (75 MHz, CDCl3, 25°C, TMS): δ = 1.7 (CH2), 5.6 (CH2), 12.1 (CH), 41.6 (CH2), 55.5 (CH3), 65.4 (CH), 99.6 (CH=), 114.6 (2 × CH, Ar), 125.2 (2 × CH, Ar), 138.6 (Cq), 150.7 (CH=), 157.8 (Cq), 191.5 (Cq, C=O); MS (ES+): m/z = 244 [MH + ]; elemental analysis cacld (%) for C15H17NO2 : C 74.07, H 6.99, N 5.76; found C 73.96, H 7.10, N 5.74. (Z)-enaminone 10 : 1 H NMR (300 MHz, CDCl3, 25°C, TMS): δ = 2.18 (s, 3H, CH3), 3.82 (s, 3H, CH3), 5.30 (d, J = 7.6 Hz, 1H, CH), 6.93 (d, J = 9.0 Hz, 2H, 2 × CH, Ar), 7.16 (d, J = 9.0 Hz, 2H, 2 × CH, Ar), 7.20 (m, 1H, CH), 11.65 (broad d, 1H, NH, D2O exchanged); 13 C NMR (75 MHz, CDCl3, 25°C, TMS): δ = 29.4 (CH3),), 55.6 (CH3), 96.6 (CH=), 114.9 (2 × CH, Ar), 117.7 (2 × CH, Ar), 134.0 (Cq), 144.1 (CH=), 156.1 (Cq

  The cooperative copper salt and topaquinone-like catalysts lower the activation energy enabling high reactivity toward the chemoselective oxidative cross-coupling of primary amines to imines that neither catalyst can accomplish alone.Martine Largeron*, Maurice-Bernard FleuryPage No. -Page No. ) 2 (0.4 mol%)/1 ox (5 mol%) ambient air, MeOH, RT

Table 1 .

 1 Optimization of the Cu

	Entry	Copper	Solvent	Conversion	Imine
		Catalyst		[%]	Selectivity
					4a:5

II /1ox-catalyzed aerobic oxidative crosscoupling of 4-methylbenzylamine 2a with 1-ethylpropylamine 3a

[a]

Table 2 .

 2 Cu

	Entry	Alkylating Amine 3	Imine	Conversion	Imine	Yield
			Product 4	(%)	Selectivity	[%]
					4:5 [b]

(OAc)2/1ox-catalyzed aerobic oxidative cross-coupling of 4methylbenzylamine 2a with diverse primary aliphatic and aromatic amines 3

[a]

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Acknowledgements

The authors would like to thank ADRAPHARM (Association pour le Développement de la Recherche Appliquée à la Pharmacologie) for financial support of this work.