Martine Largeron

Patrick Deschamps

Karim Hammad

Maurice-Bernard Fleury

A dual biomimetic process for the selective aerobic oxidative coupling of primary amines using pyrogallol as a precatalyst. Isolation of the [5+2] cycloaddition redox intermediates

A bioinspired organocatalytic cascade reaction mimicking both purpurogallin biosynthesis and copper amine oxidases (CuAOs) activity is described, at room temperature under ambient air, for the activation of the -C-H bond of primary amines. The reaction sequence uses low-cost commercially available pyrogallol as a precatalyst which undergoes an in situ oxidative self-processing step, resulting in its conversion into natural purpurogallin, a [5 + 2] cycloaddition redox intermediate. This is further involved in the CuAOs-like transamination mechanism for producing, under single turnover, the active biomimetic organocatalyst which mediates the selective oxidative coupling of primary amines, including the nonactivated substrates of CuAOs. Without any metal cocatalyst or additives, the protocol gives access to cross-coupled imines as well as 1,2-disubstituted benzimidazoles. The isolation of not easily accessible [5+2] cycloaddition redox intermediates provides direct and clear evidence for the proposed dual biomimetic process.

Introduction

The concept of waste prevention is central, influencing all aspects of modern society. Due to the harmful effects of chemical waste on the environment, catalysis plays a major role in chemistry for achieving both environmental and economic objectives. By using catalysts to perform chemical transformations, the amounts of both reagents and waste generated are considerably reduced. In particular, biocatalysis, which refers to the use of enzymes for synthetic applications, and bioinspired catalysis, which involves chemical species mimicking certain features of enzymes, have been identified as green methodologies by taking the benefits of catalysis with significant improvements. [START_REF] Marchetti | For selected reviews or perspectives[END_REF] These naturally derived catalysts are generally highly active under mild conditions, at ambient temperature and pressure, and exhibit high selectivity. Given that they are found in biological systems, biocatalysts are relatively renewable, nontoxic and biodegradable. However, they may not catalyse the reaction with non-natural substrates or not yield the desired products. This activity gap has inspired chemists to introduce artificial cofactors into protein scaffolds leading to the development of artificial enzymes, 2 but also to design bioinspired catalysts. [START_REF] Piera | For selected reviews[END_REF] These small molecules, which are devoid of protein scaffolds, have some advantages over naturally occurring biocatalysts as they may expand the scope of possible substrates and increase the scale of production. They are also useful for environmentally friendly catalytic chemistry, where it is important to avoid the use of toxic or expensive metal reagents, energy-consuming processing steps and undesirable solvents.

Copper amine oxidases (CuAOs) are a family of metalloenzymes which is involved in the metabolism of amines. [START_REF] Klinman | For selected reviews[END_REF] CuAOs couple the selective oxidation of unbranched primary amines to aldehydes with the reduction of dioxygen to hydrogen peroxide, through the synergistic action of a quinone-based organic cofactor, 2,4,5trihydroxyphenylalanine quinone or topaquinone (TPQ) and a copper ion, which is not directly implicated in the amine oxidation step (Scheme 1). [5][START_REF] Suzuki | Cofactors of amine oxidases. Copper ion and its substitution and the 2,4,5trihydroxyphenylalanine quinone[END_REF][7] Scheme 1 Selective aerobic oxidation of primary amines to aldehydes mediated by CuAOs cofactors.

CuAOs have inspired considerable efforts to mimic their reactivity with synthetic quinone catalysts, earlier to demonstrate the transamination mechanism by which these enzymes operate, 8 while recent studies have focused on synthetic applications. [START_REF]For reviews or perspectives[END_REF] Thus, the aerobic oxidation of amines has been achieved with biomimetic or bioinspired quinone-based catalysts to accomplish crossimination, [START_REF]For selected recent examples[END_REF] oxidative -C-H functionalization, 11 crossdehydrogenative coupling, 12 deaminative cross-coupling and Nnitrosation of amines. 13 Biomimetic catalytic systems promote selective aerobic oxidation of unbranched primary amines, at room a Université de Paris, CiTCoM, UMR 8038, CNRS, F-75006 Paris, France. E-mail : martine.largeron@parisdescartes.fr. https temperature, without reacting with secondary and tertiary amines and follow a transamination mechanism reminiscent of that reported for natural CuAOs (Scheme 2), [START_REF]For selected recent examples[END_REF] while bioinspired catalysts surpass the activity of natural CuAOs by increasing the scope of substrates to -branched, 12a,14 secondary 12a, 13,15 and tertiary amines 12,13 following abiological pathways. Nevertheless, the procedures still suffer some drawbacks: 1) the majority of biomimetic catalysts has to be synthesized prior use affecting the economics as well as the ecofriendly nature of the methods; 2) when commercially available, the quinone catalysts are often expensive or require the cooperative action of additives such as metal co-catalyst. This may constitute a problem in the synthesis of medicinally relevant compounds due to the contamination of the final products by metal residues; 3) very few quinone-catalysed amine oxidation protocols are applicable to non-activated primary aliphatic amines, the natural substrates for CuAOs.

Recently, the concept of "second-order" biomimicry has been defined to describe a system in which in situ modification or processing of pre-catalyst components affords the active biomimetic catalyst, as opposed to "first-order" biomimicry, in which the active biomimetic catalyst is synthesized directly. 16 Obviously, "secondorder" biomimicry introduces new opportunities for the discovery of efficient active biomimetic organocatalysts generated in situ from simple and low-cost precursors, without turning to chemical synthesis.

In a preliminary communication, we have recently reported the first example of "second-order" biomimicry for the selective aerobic oxidation of unbranched primary amines to imines under exceptionally mild conditions (Scheme 3). 17 Scheme 3 Proposed "second-order" biomimicry for the aerobic oxidative cross-coupling of primary amines to imines. This one-pot cascade reaction sequence, which mimics both purpurogallin biosynthesis and CuAOs activity, starts from commercially available low-cost pyrogallol 10red as a precatalyst, allowing in situ formation of not easily accessible natural

R NH 2 R NH 2 R N R R N R' R'-NH 2 R 1 NO 2 R 1 NO 2 R Ar O N Ar Ar R X N R H 2 N XH N N Ar R = CH 2 Ar O O OH 1 1) 2)
3)

4)

Stahl et al 10a Please do not adjust margins Please do not adjust margins purpurogallin (2,3,4,6-tetrahydroxy-5H-benzocyclohepten-5-one) 11red. This is further engaged in the CuAOs-like transamination mechanism affording, under single turnover, the active biomimetic organocatalyst 12ox, which mediates the oxidative coupling of primary amines under ambient air. However, the proposed reaction pathway was only based on control experiments and we were aware that a real proof of the transient presence of purpurogallin was highly desirable. In this full paper, we present the results of new experiments aimed at validating the "second-order" biomimetic process, through the isolation of [5+2] cycloaddition redox intermediates including purpurogallin.

Results and discussion

The limited availability of natural purpurogallin 11red led us to examine its well-established biosynthesis, which involves the oxidative dimerization of pyrogallol 10red generated from gallic acid 13. Two molecules of o-quinone are engaged in a [5 + 2] cycloaddition reaction affording, after tautomerization reaction, the benzotropolone scaffold 14 (Scheme 4). Attack of water on the carbonyl bridge of 14 yields a carboxylic intermediate, which is prone to further oxidation and decarboxylation, leading to purpurogallin 11red. 18 Accordingly, we chose to utilize 10red as a precatalyst for generating 11red in situ.

Scheme 4 Established biosynthesis of purpurogallin 11red.

Early attempts to isolate 11red as a key intermediate in the proposed dual bioinspired organocatalytic process were performed using benzylamine 15 as the amine substrate. Previous optimization studies had revealed that a combination of one equivalent of benzylamine with 0.04 equivalent of 10red (4 mol% allowing the generation of 2 mol% of 11red) was ideal for the reaction. Complete conversion of 15 into N-benzylidene-benzylamine 16 (see Scheme 7) was then observed after 24h, at room temperature, under ambient air, using MeOH as the solvent. 17 Under these experimental conditions, the reaction medium could contain no more than 2 mol% of 11red which contrasted with the large excess of benzylamine utilized. Obviously, the low amount of 11red susceptible to be formed in situ, combined with its very low solubility in organic media, would create serious problems in the course of the isolation procedure, especially during the column chromatography. So, we envisioned some modifications of our initial protocol. First, we changed 10red to 17red, because the isolation of the corresponding purpurogallin analogue 18red should be facilitated by the presence of two benzyl groups (Scheme 5). To ensure that 17red and 10red behaved similarly, the aerobic catalytic oxidation of benzylamine 15 was performed under the optimal reaction conditions, 17 using 17red as the starting material. The reaction proceeded smoothly and full conversion into imine 16 could be attained after a prolonged reaction time of 36h. Second, we decided to modify the molecular ratio between 17red and amine 15 to facilitate the isolation of purpurogallin-like intermediate 18red from the bulk solution. Accordingly, the reaction was carried out in MeOH, at room temperature, under ambient air, in the presence of one equivalent of 15 and 0.25 equivalent of 17red. When 30% of 15 was converted to imine 16, the reaction was stopped by addition of dry ice. After evaporation of the solvent and column chromatography, two [5 + 2] cycloaddition new redox products 18red and 19red were isolated in 5 and 15% yields, respectively (Scheme 5).

Scheme 5 [5 + 2] cycloaddition redox products 18red and 19red isolated during the aerobic oxidation of benzylamine mediated by 17red. Ortep view of 19red. Displacement ellipsoids are drawn at the 50% probability level. 2012,00,123This journal is © The Royal Society of Chemistry 20xx

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The structure of 18red was established on the basis of extensive spectroscopic data including 2D NMR experiments (See Experimental and ESI), while the X-Ray crystallographic data undoubtedly confirmed the proposed structure 19red as a single diastereomer of relative configuration 6R,9R (Scheme 5 and Table S1).

From these results, it could be deduced that [5+2] cycloaddition redox intermediates could be formed in MeOH, under ambient air, starting from a pyrogallol derivative, in the presence of benzylamine. Note pyrogallol 17red was stable in methanol under ambient aerobic conditions and did not produce spontaneously the aerobic dimerization product, purpurogallin 18red. The presence of benzylamine was required for producing the monoanionic form of pyrogallol 17red (pKa around 9) which was further oxidized to the orthoquinone redox species. Two molecules of orthoquinone were further engaged in the [5+2] cycloaddition reaction initiating the formation of purpurogallin 18red. The latter would result from a nucleophilic attack of intermediate 20 (Scheme 5) by water, oxidation and decarboxylation steps, following a way which parallels that established for purpurogallin biosynthesis (Scheme 4). Interestingly, another [5+2] cycloaddition reaction product 19red was also isolated. Its formation very likely would arise from a competitive nucleophilic attack of benzylamine 15 on the carbonyl group in the five-membered ring of intermediate 20, resulting in a ring-opening reaction. 19 Subsequent oxidation step involving amide intermediate 21 would afford 22 which would rearrange into compound 19red as proposed in Scheme 6.

Scheme 6 Proposed reaction mechanism for the formation of compound 19red.

At this stage, note that both compounds 18red and 19red displayed two features that we have previously observed with redox precursors of bioinspired quinone-based catalysts of the same series: first, the presence of a carbonyl group adjacent to the pyrogallol moiety; second, the presence of an active hydroxyl group (red OH in Scheme 7). This was found to be an essential component of the catalytic activity associated with enzymatic 7a,7d,8 and non-enzymatic catalytic systems 9c,10a-d,20 through the formation of a highly reactive H-bonded cyclic transition state (CTS) (see Scheme 8). Note we had also shown that the aerobic oxidation of 2-aminoresorcinol (4 mol%) produced a poorly reactive o-iminoquinone catalyst, that mainly decomposed to melanin-like polymers, giving only 5% of imine 16. 17 When compared to highly reactive o-iminoquinone 2 (Scheme 2), this result confirmed the essential role of the acetyl group for successful operation of the catalytic process. 20c

Scheme 7 Structural analogy between the redox precursors of bioinspired active quinone-based catalysts and products 18red and 19red.

Therefore, we were encouraged to consider that not only 18red but also 19red, could be involved in the aerobic catalytic oxidation of benzylamine 15 to imine 16. Consequently, to clarify their respective role in supporting the catalytic efficiency, each compound (2 mol%) was separately tested in the presence of 15, under the optimal reaction conditions.

After 36h, almost full conversion (87%) of 15 into 16 could be observed starting from 18red, while the benzylamine conversion did not exceed 40% using 19red. As a consequence, 18red proved to be the better candidate for generating the quinone-based catalyst responsible for the high catalytic efficiency observed when compound 17red was used as the starting material (full conversion after 36h). Then, the continuously low concentration of the in situ generated o-quinone species 18ox (see Scheme 8) should protect it against the competitive formation of melanin-like polymers. Finally, 18red exhibited a behaviour close to that already observed with natural purpurogallin 11red. 17 Taking all together, 18red was considered as the most effective [5+2] cycloaddition intermediate in the bioinspired aerobic oxidative cascade reaction sequence allowing the oxidation of primary amines to imines.

The second part of the reaction sequence concerns the CuAOs activity mimicry. Once again, we showed that -branched primary amines such as sec-benzylamine were poor substrates for the biomimetic catalytic process (5-10% conversion), while secondary amines were not reactive at all. These results were fully in agreement with the enzymatic transamination mechanism which has been well 8,10,14a,20a,c Scheme 8 Proposed transamination mechanism for the aerobic oxidation of primary amines to imines mediated by o-iminoquinone active organocatalyst 12ox or 23ox.

The presence of the benzotropolone scaffold not only favoured attack of the amine at the 3-position of the generated o-quinone species 11ox or 18ox (Scheme 8, step 1), but also facilitated -proton abstraction and the subsequent electron flow from the -carbon to the o-quinone moiety, which aromatizes to a Schiff base intermediate (Scheme 8, step 2). Crucial also was the presence of an active hydroxyl group at the 4-position, which was previously proved to be an essential requirement for the successful operation of the catalytic process in the studied series. 9c,10a-d,20 The activation of the imine function for further nucleophilic attack by the amine 15, leading to the extrusion of imine 16 (Scheme 8, step 3), was provided by the intramolecular hydrogen bond between the 4-hydroxyl group and the imine nitrogen, generating a highly reactive H-bonded CTS. 9c,20c Similar effects of phenolic hydroxyl groups on the reactivity of ketimine derivatives have been previously reported. 21 Aerobic oxidation of the generated aminophenol form 12red or 23red after single turnover generated the active o-iminoquinone organocatalyst (Scheme 8, step 4), which can undergo transamination with benzylamine substrate (Scheme 8, step 5) and close the catalytic cycle by passing 11ox or 18ox.

The bioinspired organocatalytic cascade reaction reported here allows the selective oxidation of primary amines to imines under ambient air, at room temperature, without any metal cocatalyst or additives. These environmentally mild conditions are particularly favourable for using the imine in situ for further reactions. Accordingly, we have focused on two synthetic applications, first, the oxidative cross-coupling of primary amines, second, the synthesis of 1,2-disubstituted benzimidazoles.

The oxidative cross-coupling of primary amines is known to be a challenging transformation as self-coupling is usually preferred. Recently, selective formation of cross-coupled imines has been reported, but the procedures generally require elevated temperature, oxygen pressure, metal cocatalyst, additive or problematic solvent. [START_REF]For selected recent examples[END_REF]22 Our dual bioinspired cascade reaction sequence proved to be effective for producing cross-coupling imines. The optimized reaction conditions we had previously reported 17 were applied by mixing two primary amines in a ratio 1:1 upon increasing pyrogallol 11red loading to 10 mol% (generating 5 mol% of active organocatalyst 12ox), in MeOH, at room temperature, under ambient air. Note MeOH was found to be the best solvent for the aerobic oxidative coupling of primary amines to imines because it provided the ideal balance of 11ox (or 12ox) solvation by enhancing the of the quinonoid moiety and reaction rate. 20,[START_REF] Anson | For another example where MeOH was shown to be an efficient solvent for enhancing the quinone reactivity[END_REF] Although MeOH was initially considered as problematic according to Safety, Health and Environment (SH&E) criteria, it was finally ranked as recommended in the CHEM21 solvent guide. 24 The result of the 12ox-mediated aerobic cross-coupling of primary amines is illustrated in Table 1 (See Experimental). The reaction is quite effective for various sec-primary amines 24a-l and unbranched aliphatic primary amines 24m and 24n. A single colourless crystal of imine 24j suitable for X-ray diffraction analysis was obtained from MeOH (Chart 1 and Table S1). Complete selectivity was observed except for cross-coupled imines 24m and 24n since the analysis of the reaction mixture by 1 H NMR revealed the presence of 7% of the corresponding homocoupled imine (See ESI). However, with poor nucleophilic 4-methoxyaniline, the conversion did not exceed 68% after 60h, leading to the cross-coupled imine 24o in only 55% isolated yield.

More challenging, the possibility of expanding the reaction scope to the synthesis of scarcely stable aliphatic imines has also been explored. Due to their isomerization into enamine tautomer, which decomposes under ambient air, the generated alkylimines have been generally trapped in situ for further reactions. 10d,11g So, we have performed the aerobic oxidative cross-coupling of a range of nonactivated primary aliphatic amines with N-substituted-oaminoanilines as in situ imine trap. This reaction led to 1,2disubstituted benzimidazoles which are privileged and significant structural components of pharmaceuticals. 25 For this reason, numerous strategies have been developed for the regiocontrolled synthesis of 1,2-disubstituted benzimidazoles. 26 In particular, the catalytic oxidative coupling of amines has provided a straightforward protocol to synthesize substituted benzimidazoles derivatives through the variation of both commercially available cyclocondensation partners. 11a,c,d,f,27 However, with only few exceptions, 11a,c,d the molecular diversity is limited to derivatives bearing benzylic or allylic substituents at the 2-position of the benzimidazole framework, because of the difficulty of oxidizing nonactivated primary amines. Please do not adjust margins Please do not adjust margins

Amine A Amine B 1,2-Benzimidazole Yield (%) b NH 2 H N H 2 N N N 25a 76 NH 2 H N H 2 N N N 25b 75 NH 2 H N H 2 N Ph N N Ph 25c 61 NH 2 H N H 2 N Ph N N Ph 25d 70 NH 2 H N H 2 N p-Cl-Ph N N p-Cl-Ph 25e 71 c NH 2 H N H 2 N N N 25f 64 NH 2 Ph H N H 2 N N N Ph 25g 63 NH 2 H N H 2 N N N 25h 67 NH 2 H N H 2 N N N 25i 62 NH 2 H N H 2 N N N 25j 74 NH 2 H N H 2 N N N 25k 52 NH 2 H N H 2 N N N 25l 40 NH 2 H N H 2 N N N 25m 75 NH 2 S H N H 2 N N N S 25n 76 c NH 2 O H N H 2 N N N O 25o 73 c
a 8 mol% of 10red affording 4 mol% of 12ox,100% conversion, reaction times 60h, 60°C for 25a-l; 45°C for 25m-o; additional aliquot of 10red (2 mol%) was added after 24h. b Yields of the isolated product. c 72h.

R NH 2 + R'NH 2 R N R' A (1 equiv) B (1 equiv) 24a-o air, MeOH, rt 10red (8 -10 mol%) R NH 2 + A (1 equiv) B (1 equiv) 25a-o air, MeOH, 45-60°C 10red (10 mol%) H N H 2 N R' N N R' R
Please do not adjust margins Please do not adjust margins Under the optimized reaction conditions previously reported, 17 but at a slightly more elevated temperature of 60°C, the organocatalyst 12ox was sufficiently reactive to activate the -C-H bond of diverse non-activated primary aliphatic amines to give 1,2disubstitued benzimidazoles 25a-j in good isolated yields (Table 2 and Experimental). A single colourless crystal of benzimidazole 25d suitable for X-ray diffraction analysis was obtained from the chloroform/petroleum ether solvent system (Chart 1 and Table S1). Note this reaction was unsuccessful in the absence of Cu (II) cooperative catalyst when 2 was used as the sole organocatalyst. 11c As previously reported for catalysed aerobic oxidation of nonactivated alcohol, 28 a decreased reactivity for sterically constrained -branched alkylamines was observed affording the benzimidazoles 25k and 25l in 52 and 40% yields, respectively. As expected, the procedure could also be applied to common benzylic amines including heterocyclic amines containing a sulphur or oxygen atom which gave 1,2-disubstituted benzimidazoles 25n and 25o in good yields, after a prolonged reaction time of 72h.

24j 25d

Chart 1 Ortep views of imine 24j and 1,2-benzimidazole 25d.

Displacement ellipsoids are drawn at the 50% probability level.

Finally, cross-coupled imines 24a-o were obtained through the transamination mechanism reported in Scheme 8, yielding the homocoupled imine intermediate, which was progressively consumed in favour of the cross-coupled imine through dynamic transimination (Scheme 9, path 1). [START_REF]For selected recent examples[END_REF]17 Its formation could be driven by continuous oxidation of the extruded primary amine R-CH 2 -NH 2 (self-sorting step) which was re-engaged in the transamination mechanism. So, just one equivalent of each amine was sufficient to achieve exclusive formation of the cross-coupled imine product. This oxidative strategy, known as oxidative self-sorting, has extensively been utilized to obtain thermodynamically disfavoured products. 29 In the presence of o-aminoanilines, the resulting cross-coupled imines were engaged in cyclocondensation and oxidation reaction steps to furnish 1,2-disubstituted benzimidazoles 25a-o (Scheme 9, path 2).

Conclusion

New information about the reaction mechanism of an organocatalytic cascade reaction for the activation of the -C-H bond of primary amines are disclosed through the isolation of [5 + 2] cycloaddition purpurogallin-like intermediates. The one pot protocol, mimicking both purpurogallin biosynthesis and CuAOs activity, utilizes inexpensive commercially available pyrogallol precatalyst, for delivering in situ, under ambient air, at room temperature, low loadings of the active biomimetic organocatalyst, which mediates the oxidative coupling of primary amines. Without any metal cocatalyst or additives, the method gives access to diverse cross-coupling imines, or 1,2-disubstituted benzimidazole derivatives in the presence of o-aminoanilines. This method constitutes an appropriate illustration of the potential of "second order" biomimicry in terms of atom economy, while preserving the benefit of the eco-friendly nature of the bioinspired catalytic processes. A rational application of this concept should allow the discovery of efficient catalysts generated from simple, low-cost precursors, introducing new opportunities in green chemistry. Benzylamine 15 (2 mmol) and pyrogallol derivative 17red (0.5 mmol) were mixed in MeOH (25 mL), under ambient air. The reaction mixture was stirred at room temperature. The progress of the reaction was monitored by 1 H NMR spectroscopy. When 30% of benzylamine 15 was converted into N-benzylidene benzylamine 16, the reaction was stopped by addition of dry ice. After evaporation of the solvent under reduced pressure at 30°C, the residue was purified by column chromatography (toluene-acetone, 90/10 v/v) on silica gel, to afford the [5+2] cycloaddition redox intermediates 18red (0.025 mmol) and 19red (0.075 mmol) in 5 and 15% yields, respectively. Caution: particular attention is required during the column chromatography which has to be realized quickly to minimize the aerobic oxidation of products 18red and 19red to melanin-like polymers. Please do not adjust margins Please do not adjust margins 4, 39.1, 115.9, 117.3, 126.1, 126.7, 128.26 (x2), 128.33, 128.68, 128.74 (x2), 128.88 (x2), 129.1 (x2), 130.1, 130.8, 134.8, 140.1, 141.0, 150.5, 151.2, 152.6, 182 35.2, 43.2, 48.3, 87.8, 105.2, 118.6, 125.5, 125.9, 126.8, 127.5 (x2), 127.78 (x2), 127.82 (x2), 127.9 (x2), 128.0 (x2), 128.7, 128.8 (x2), 131.6, 131.8, 137.5, 137.6, 141.1, 145.6, 151.2, 153.5, 171.1, 191.9 Representative experimental procedure for the organocatalyzed aerobic oxidative cross-coupling of two primary amines Equimolar amounts of benzylamine (2.5 mmol) and 1ethylpropylamine (2.5 mmol), pyrogallol 10red (0.2 mmol, 8 mol%, corresponding to the generation of 4 mol% of purpurogallin 11red) were mixed in MeOH (10 mL), under ambient air. The reaction mixture was stirred at room temperature for 24h. 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 24a as an almost pure product, which was further purified by washing through a small pad of base-washed silica (eluent: 1/2 petroleum ether/ethyl acetate + 2% triethylamine). Caution: particular attention is required during the column chromatography which has to be realized quickly to avoid the hydrolysis of the cross-coupled imine to aldehyde. The above procedure is generally representative for all the products shown in Table 1. Any deviations from this protocol are specified in the footnotes of Table 1.

X-Ray analysis of imine

Table of contents entry

Low-cost pyrogallol precatalyst undergoes an oxidative selfprocessing step for delivering the active organocatalyst in situ through a dual biomimetic process.

  MeCN, O 2 stream, rt, 30min

  adjust margins established through the utilization of bioinspired quinone-based catalytic systems (Scheme 8).

6 |

 6 J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

Scheme 9

 9 Scheme 9 Biomimetic cascade reaction sequence affording crosscoupled imines 24a-o or 1,2-disubstituted benzimidazoles 25a-o.

8 |

 8 J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

  24j. A colorless crystal of 0.23  0.19 0.04 mm, crystallized from methanol was used. Empirical formula C 17 H 17 N, M = 235.1, T = 100(2) K. Triclinic system, space group P-1, Z = 2, a = 5.6742(2) Å, b = 8.7921(4) Å, c = 13.5713(5) Å,  = 103.259(1) °,  = 95.099(1)°,  = 95.624(1)°, V = 651.48(4) Å 3 , d calc = 1.200 g cm -3 , F(000) = 252,  = 0.526 mm -1 , (CuK) = 1.54178 Å. 21496 intensity data were collected with a VENTURE PHOTON100 CMOS Bruker diffractometer (Cu-Kα radiation) controlled by APEX3 software package, giving 2166 unique reflections. Refinement of 166 parameters on F 2 led to R 1 (F) = 0.0439 calculated with 1995 observed reflections as I ≥ 2 sigma (I) and wR 2 (F 2 ) = 0.1122 considering all the 2166 data. Goodness of fit = 1.072. CCDC deposition number: 1981805.

Table 1 12ox

 1 -mediated aerobic oxidative cross-coupling of amines a

	Amine A		Amine B	Cross-coupled imine		Yield
							(%) b
	NH 2					24a
			H 2 N	N			85
		NH 2					24b
	Cl	Cl	H 2 N		N		87
				Cl	Cl
	NH 2					24c
	S		H 2 N	N			83
				S
	NH 2					24d
	O		H 2 N	N			89
				O
		NH 2					24e
	MeO		H 2 N		N		89
				MeO
		NH 2					24f
	F 3 C		H 2 N		N		90
				F 3 C
		NH 2					24g
	F		H 2 N	Ph	N	Ph	88
				F
		NH 2					24h
			H 2 N	Ph	N	Ph	84
		NH 2					24i
				NH 2	N		90
		NH 2					24j
			H 2 N		N		90
		NH 2					24k
	Cl	Cl	H 2 N		N		80
				Cl	Cl
	O	NH 2					24l
	O		H 2 N	O	N		89
				O
		NH 2	H 2 N		N		24m
							93 c
		NH 2	H 2 N		N		24n
	MeO			MeO			93 c
		NH 2		OMe		OMe 24o
			H 2 N		N		55 d
	a 8 mol% of 10red affording 4 mol% of 12ox, rt, 100% conversion, reaction

times: 24h for 24a-c, 24e, 24f, 24m and 24n; 48h for 24d and 60h for 24g-l and 24o; additional aliquot of 10red (2 mol%) was added after 24h. b Isolated yields after column chromatography. c Yields of the cross-coupled imine were determined by 1 H NMR. d 68% conversion.

Table 2

 2 Representative isolated 1,2-disubstituted benzimidazoles 25a-o a

  (F 2 ) = 0.1045 considering all the 9064 data. Goodness of fit = 1.011. CCDC deposition number: 1965257. 1D and 2D NMR spectra for compound 19red are reported in the ESI. Key HMBC correlations are shown in Chart 3.

	; HRMS (ESI-) m/z calcd for C 33 H 27 NO 6 [M -H]  532.1760. Found 532.1772. X-Ray analysis: A yellow crystal of 0.27  0.22  0.05 mm, crystallized from a mixture toluene/methanol was used. Empirical formula C 33 H 27 NO 6 , M = 533.55, T = 100(2) K. Triclinic system, space group P-1, Z = 4, a = 12.6327(6) Å, b = 15.2434(7) Å, c = 15.9800(7) Å,  = 102.027(2)°,  = 105.432(2)°,  = 112.595(2)°, V = 2566.4(2) Å 3 , d calc = 1.381 g cm -3 , F(000) = 1120,  = 0.776 mm -1 , (CuK) = 1.54178 Å. 77250 intensity data were collected with a VENTURE PHOTON100 CMOS Bruker diffractometer (Cu-K radiation) controlled by APEX3 software package, giving 9064 unique reflections. Refinement of 743 parameters on F 2 led to R 1 (F) = 0.0375 calculated with 7934 observed reflections as I ≥ 2 sigma (I) and wR 2 Chart 3 Key HMBC correlations of compound 19red.

Published on 17 February 2020. Downloaded by Universite Paris Descartes on 2/17/2020 1:22:12 PM. View Article Online DOI: 10.1039/C9GC03992A

Acknowledgements

We thank CNRS and Paris Descartes University for financial support. Pascale Leproux is acknowledged for running high resolution mass spectra. The authors also wish to thank Regis Guillot (ICMMO -Université Paris Saclay) for collecting the crystallographic data.

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General experimental procedure for the organocatalyzed aerobic oxidative coupling reaction affording 1,2-disubstituted benzimidazoles Equimolar amounts of primary amine (1.25 mmol) and Nsubstituted-o-aminoaniline (1.25 mmol) with pyrogallol 10red (0.1 mmol, 8 mol%, which corresponds to the generation of 4 mol% of purpurogallin 11red), were mixed in MeOH (25 mL), in an air atmosphere. The reaction mixture was stirred at 60°C for 24h. Then, an additional aliquot of 0.025 mmol of 10red (2 mol%) was introduced into the reaction mixture and the reaction was continued for 36h. The solvent was then removed by evaporation under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: 1/1 petroleum ether/ethyl acetate) to afford 1,2-disubstituted benzimidazoles 25a-o. The above procedure is generally representative for all benzimidazoles shown in Table 2. Any deviations from this protocol are specified in the footnotes of Table 2.

X-Ray analysis

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