Modular construction of multifunctional ligands for the enantioselective ruthenium-catalyzed carbenoid N–H insertion reaction: an enzyme-like and substrate-sensitive catalyst system

Abstract

It was found for the first time that cinchonine- and BINOL-derived multifunctional ligands bearing a silicon-based bulky group exhibited promising enantioselective control in the ruthenium-catalysed carbenoid N–H insertion reaction, in which the Ru–L26 system with multiple stereogenic centers was proved to be an enzyme-like catalyst because it exhibited a narrow substrate scope and size-sensitive discrimination in this reaction.

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Introduction

Chiral ligands generally play a critical role in numerous stereoselective or chemoselective transformations in asymmetric organometallic catalysis. Thus, in the past decades, the catalytic asymmetric synthesis of chiral molecules with an organometallic complex focused on extending the scope of chiral ligands to better control enantioselectivity in this field.¹ Over the past years, our group has been interested in the design and preparation of multifunctional ligands with multiple stereogenic centers because of their powerful potential for catalytic asymmetric application in organic transformations.² For example, our group recently reported a novel multifunctional N,O,P-ligand (HZNU-Phos) with multiple stereogenic centers that was prepared from a chiral binaphthol (BINOL)-derived aldehyde and a primary amine bearing a phosphine moiety for the copper-catalyzed conjugate addition and palladium-catalyzed allylic alkylation,^2a,b in which the novel ligand was demonstrated to be highly effective in these reactions. Inspired by previous work on catalytic carbenoid N–H insertion reactions, we hypothesized that the concept of modular synthesis of multistereogenic ligands by combining axial chiral BINOL derivatives with sp³-carbon stereogenic amines would be applicable to the development of a novel ruthenium catalyst system and corresponding enantioselective carbenoid N–H insertion reactions.

The carbenoid N–H insertion reaction, one of the most attractive carbon–nitrogen bond-forming transformations, has recently attracted considerable interest because it allows for the synthesis of biologically active nitrogen-containing molecules, including α-amino acids and their derivatives.³ In particular, the versatile products of N–H insertion reactions have found wide utility both as precursors in the synthesis of complex natural products, and as building blocks for proteins and peptides.⁴ Therefore, the development of highly efficient and enantioselective methods for the construction of α-amino acids or their derivatives by the carbon–nitrogen bond-forming insertion reaction is a valuable and fundamental goal in organic synthesis.⁵ Since the early work on the copper bronze catalyzed N–H insertion reaction was reported in 1952 by Yates,⁶ transition-metal-catalyzed carbenoid N–H insertion reactions by means of amines and diazocarbonyls have proved to be an extremely simple approach for the synthesis of α-amino esters in an efficient and atom-economical way.⁷ Especially since 1996, the investigation of catalytic asymmetric versions of the carbenoid N–H insertion reaction has attracted considerable attention.⁸ However, whereas the catalytic carbenoid insertion has been developed into an extremely powerful tool in organic synthesis,⁹ the enantioselective insertion of an α-diazocarbonyl compounds into an N–H bond is still in its infancy in comparison to the catalytic asymmetric hydrogenation. For example, as two representative and seminal advances, the chiral rhodium(II) carboxylates reported by McKervey^8a and the chiral copper- and silver-based catalysts reported by Jørgensen^8c only gave low to moderate enantioselectivities (up to 48% ee).

Recently, other copper complexes have been found by Zhou and other groups to be highly enantioselective catalyst systems in this reaction,^10,11 in which the catalytic enantioselective insertion of α-diazoesters into N–H bonds using the copper complexes of chiral spirobisoxazoline ligands as catalysts, is a particularly impressive advance in this context. This work also further supported the highly important role of chiral ligands in enantioselective metal-catalyzed transformations. In view of synthetically useful N–H insertion reactions, further investigations and breakthroughs have been made by the groups of Fu,¹¹ Feng,¹² and Zhou¹³ in the past years, in which several interesting copper and rhodium complexes have been successfully achieved for such carbenoid N–H insertion reactions. Despite previous achievements in this field,¹⁴ there is no report on ruthenium-catalyzed asymmetric carbenoid N–H insertion reactions, possibly because of the different mechanistic procedure in chiral ruthenium chemistry. In addition, the effort of exploring alternative approaches with easily achievable ligands as well as the development of a novel catalyst system and concept with high catalytic activity and perfect stereochemistry are also highly desirable.

Meanwhile, previous studies on the general mechanism of metal-catalyzed carbenoid insertion reactions revealed that the rate-determining step (RDS) of the copper catalysis was different from that of rhodium(II); according to theoretical calculations and experimental results, steps A, B, and D were crucial for the copper(I) catalysis (Fig. 1).^3c,15 The mechanism of the ruthenium catalysis in this N–H insertion reaction is unclear, therefore further experimental investigations need to be carried out to clarify the mechanistic pathway. In addition, in comparison to the copper and rhodium-based catalyst systems, a ruthenium catalyst, such as [RuCl₂(p-cymene)]₂, has also been found as a highly reactive catalyst for carbenoid N–H insertion reactions.¹⁶ For example, Che and Xu^16a has found that only 1 mol% of [RuCl₂(p-cymene)]₂ was effective enough for the intermolecular carbenoid N–H insertion reaction of aniline within 30 min. Unfortunately, to our knowledge, there is no successful report on the design and synthesis of chiral ligands for the enantioselective ruthenium-catalyzed N–H insertion reaction to date.

Fig. 1 General mechanism for metal-catalyzed carbenoid N–H insertion reactions: steps A, B, and D are crucial for the copper catalysis and step B is the rate-determining step (RDS) for the rhodium catalyst system.^3c

Herein, we want to report the first example of an enantioselective ruthenium-catalyzed N–H insertion reaction of α-diazoesters into the N–H bond of aromatic amines in the presence of a multifunctional N,N,O-ligand bearing a silicon-based bulky group which was obtained from a chiral BINOL- and cinchona alkaloid-coupled backbone, providing the prospect that the concept of modular construction of novel multifunctional ligands with multiple stereogenic centers can mimic the catalytic model of artificial metalloenzymes. However, there are no general methods or concepts for the design and preparation of chiral ligands for ruthenium-catalyzed carbenoid N–H insertion reactions. We hypothesized that multifunctional N,N,O-ligands with different coordination points as well as a tuneable cavity would be beneficial to the enantioselective activity of a ruthenium-based chiral catalyst (Fig. 2). In brief, we considered two design criteria on the basis of a possible mechanism of ruthenium-catalyzed carbenoid N–H insertion reactions proposed in previous work¹⁶ as well as that of the copper and rhodium catalysis.¹⁵ One requirement was that the ligand should contain a Lewis basic nitrogen center (Schiff base or secondary amine) that, through ligand association, can increase the nucleophilicity of aromatic amine reagents. The other criterion, used previously in the BINOL-based ligand development, involves the use of a Brønsted acidic phenol moiety to form a Ru–O bond, which would be a stable enough Ru-complex linked with the chiral backbone during the carbenoid N–H insertion reaction.

Fig. 2 The design of N,N,O-groups containing multifunctional ligands for the ruthenium-catalyzed N–H insertion reaction.

Results and discussion

Initially, on the basis of our hypothesis, a series of BINOL-derived multifunctional ligands or phosphine ligands have been designed (Schemes 1 and 2, see ESI†).^17,18 These multifunctional ligands were easily prepared from a chiral BINOL-derived aldehyde. As shown in Scheme 2, for the synthesis of the ligands L1 and L2, we developed an efficient approach to prepare an Ar-BINMOL-derived aldehyde (SL-a) through the key step of a neighbouring lithium-assisted [1,2]-Wittig rearrangement (NLAWR).¹⁷ After the subsequent transformations of SL-a via classic condensation, reduction, and deprotection, we then furnished the introduction of trans-1,2-diaminocyclohexane and proline-derived motifs to the molecule SL-a which led to the formation of the multifunctional N,N,O-ligands L1 and L2.

Scheme 1 BINOL-derived chiral ligands L1–L11 used in this work.

Scheme 2 Synthesis of multifunctional N,N,O-ligands based on an Ar-BINMOL-derived backbone.

With the multifunctional ligand L1 in hand, we firstly investigated the catalytic activity of various transition metal catalysts in this reaction. In this study, the insertion of α-diazo-α-phenylacetate (1a) into the N–H bond of aniline (2a) was initially performed in dichloromethane at room temperature. As shown in Table 1, it was clearly revealed that the multifunctional ligand L1 is a good match in combination with [RuCl₂(p-cymene)]₂ in terms of enantioselectivity and conversion.

Table 1 Effect of various metal salts on the catalytic asymmetric N–H insertion reaction in the presence of the multifunctional ligand L1

Entry	Metal catalyst^a	Yield^b (%)	ee^c (%)
a Reaction conditions: 1 mol% metal catalyst, 2 mol% ligand (L1), substrate 1a (0.3 mmol), and substrate 2a (0.3 mmol) in THF at room temperature.b Isolated yields. NR is no reaction.c The ee values were determined by chiral HPLC.
1	AgSbF6	<20	8
2	Pd(dba)2	NR	—
3	Cu(CH3CN)4PF6	50	8
4	Ru(NO)Cl3	<20	—
5	[RuCl2(p-cymene)]2	>90	17
6	Pd(OAc)2	<20	0

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To investigate the enantioselective control of the BINOL-derived multistereogenic ligands shown in Scheme 1, we then used the N–H insertion reaction of α-diazo-α-phenylacetate (1a) with aniline (2a) as a model Ru-catalyzed carbenoid insertion reaction under the established reaction conditions (Table 1). As shown in Fig. 3, when these multifunctional ligands L1–L11 were used in this reaction, the corresponding ee values varied largely from 0 to 33% ee. The examples in Fig. 3 illustrated that the Schiff base and phenol moieties on the BINOL backbone were useful building blocks to guarantee promising enantioselectivities. Notably, the presence of a phosphine moiety on the multifunctional ligand leads to almost no reaction (L5, L9, and L10),¹⁷ and interestingly, the position of the Schiff base moiety on the multifunctional ligand is also important for achieving enantioselective control in this reaction. For example, the difference between L3 and L6 relied on modulations of the Schiff base, secondary amine, and the Ar-BINMOL-based building block. As a result, L6 gave a better enantioselectivity in comparison to that of L3 in this reaction. Although Ar-BINMOL-derived salen L7 and salen L8 exhibited excellent enantioselectivities in the copper-catalyzed fluorination and cobalt-catalyzed Henry reaction, respectively,¹⁸ these ligands were not effective in the enantioselective ruthenium-catalyzed carbenoid N–H insertion reaction. Then, the solvent effect on the Ru-catalyzed carbenoid N–H insertion was evaluated in the presence of ligand L6 (Table 2). Most solvents such as toluene, methanol, hexanes, etc., exhibited a negative effect on the catalytic asymmetric ruthenium-catalyzed insertion reaction. Thus, it was found that a higher enantioselectivity (57% ee) but a low yield (30%) could be obtained in THF. We hypothesized that the further modification of multifunctional ligand L6 would lead to the establishment of a suitable ligand for the ruthenium-catalyzed N–H insertion reaction.

Fig. 3 Enantioselective activities of the ligands L1–L11 for the Ru-catalyzed carbenoid N–H insertion reaction in DCM. The yields of the product 3a using L1–L11 in this reaction are: 90% (L1), 75% (L2), 91% (L3), 70% (L4), 0% (L5), 92% (L6), 80% (L7), 35% (L8), 0% (L9), 0% (L10), 93% (L11).

Table 2 Effect of solvent on the ruthenium-catalyzed N–H insertion in the presence of multifunctional ligand L6

Entry	Solvent	Isolated yield^a (%)	ee (%)
a NR is no reaction.
1	Toluene	36	0
2	THF	30	57
3	MeOH	NR	—
4	DCE	73	34
5	DMF	NR	0
6	n-Hexane	NR	—
7	TMSOTMS	NR	—
8	PhOMe	48	0
9	Et2O	52	32
10	t-BuOMe	45	40

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Encouraged by these results, we continued to modify and synthesize novel multifunctional ligands containing a chiral BINOL-derived backbone and an amine-based group (see ESI†). As shown in Scheme 3 and Fig. 4, the ligands L12–L26 showed different catalytic activities in the enantioselective Ru-catalyzed carbenoid N–H insertion reaction, providing the product with 0–59% ee. The best result was achieved by ligand L26 which was prepared from a BINOL-derived aldehyde and a cinchonine-derived primary amine. Next, the modularity of the multifunctional ligand structures was exploited through the combinatorial linkage of the cinchonine-derived primary amine with various aldehydes (Scheme 4). These studies indicated that it is very difficult to yield excellent enantioselectivity in Ru-catalyzed carbenoid N–H insertion reactions. Besides, the phenomenon of chirality matching or mismatching in this work was found to be very important for the ligand-assisted asymmetric Ru-catalyzed N–H insertion reaction. For example, ligand L25, obtained from a quinidine-derived primary amine, almost resulted in no reaction, which might result from the instability of such a ruthenium complex. Further studies, summarized in Fig. 5, established that L26 bearing a silicon-based bulky group was the best multifunctional ligand in the enantioselective carbenoid N–H insertion reaction in terms of enantioselectivity (59% ee) and yield (98%). Notably, the direct use of all the commercially available cinchona alkaloids and their primary amine derivatives yielded no enantioselectivity in this reaction.

Scheme 3 BINOL- and chiral amine-derived multifunctional ligands L12–L26.

Fig. 4 Enantioselective activities of the ligands L12–L26 for the Ru-catalyzed carbenoid N–H insertion reaction in THF. The yields of the product 3a using L12–L26 in this reaction are: 93% (L12), 93% (L13), 93% (L14), 93% (L15), 93% (L16), 92% (L17), 92% (L18), 90% (L19), 90% (L20), 70% (L21), 63% (L22), 80% (L23), 30% (L24), <10% (L25), 95% (L26).

Scheme 4 Combination of aromatic aldehydes with the cinchonine-derived primary amine for the in situ formation of the Schiff base ligands L27–L35.

Fig. 5 Enantioselective activities of the ligands L27–L35 for the Ru-catalyzed carbenoid N–H insertion reaction in THF. The yields of the product 3a using L27–L35 in this reaction are: <10% (L27a), <10% (L27b), 25% (L27c), 90% (L28), 90% (L29), 90% (L30), <10% (L31), 80% (L32), 93% (L33), <10% (L34), <10% (L35).

With L26 as the optimal multifunctional ligand, a broad range of substituted anilines was reacted with α-diazo-α-phenylacetate under the standard reaction conditions. As shown in Table 3, all of the N–H insertion reactions proceeded smoothly and afforded the desired products in good yields (up to 98%). Although varied enantioselectivities (up to 82.5 : 17.5 er) were obtained for most substrates (Table 3), the multifunctional ligand L26 still exhibited promising activity during the generation of the ruthenium carbine intermediate. Moreover, two α-diazoesters with a Me- or Et-ester were also examined under the same reaction conditions. The desired α-amino esters were also obtained in high yields. Although the present ruthenium-catalyzed N–H insertion reaction resulted in only moderate enantioselectivities in the presence of a multifunctional N,N,O-ligand, to our knowledge, these are the best results for an asymmetric ruthenium-catalyzed carbenoid N–H insertion in terms of enantioselectivity.

Table 3 Ru-catalyzed carbenoid N–H insertion reaction of various aromatic amines with α-diazoesters in the presence of multifunctional ligand L26^a

Entry	R/R^1	Yield^b (%)	er^c	ee^c (%)
a Reaction conditions: 1 mol% [RuCl2(p-cymene)]2, 2 mol% ligand (L26), substrate 1 (0.3 mmol), and substrate 2 (0.3 mmol) in THF at room temperature.b Isolated yields.c The ee and er values were determined by chiral HPLC.d R′ = ethyl (1b).e Addition of 20 mol% of 1a as an additive in this reaction.
1	H/H	3a: 95	79.5 : 20.5	59
2	2-Me/H	3b: 85	66.5 : 33.5	33
3	3-Me/H	3c: 87	75.5 : 24.5	51
4	4-Me/H	3d: 80	70.5 : 29.5	41
5	2 F/H	3e: 83	59.5 : 40.5	19
6	3 F/H	3f: 82	82.5 : 17.5	65
7	2-Cl/H	3g: 79	56 : 44	12
8	3-Cl/H	3h: 85	76.5 : 23.5	53
9	4-Cl/H	3i: 87	79 : 21	58
10	2-Br/H	3j: 79	56.5 : 43.5	13
11	3-Br/H	3k: 88	72.5 : 27.5	45
12	4-Br/H	3l: 82	77 : 23	54
13	3-I/H	3m: 84	79.5 : 20.5	59
14	4-I/H	3n: 60	64.5 : 35.5	29
15	2-OMe/H	3o: 65	70 : 30	40
16	3-OMe/H	3p: 78	77 : 23	54
17^d	H/1b	3q: 87	76.5 : 23.5	53
18	H/3-Br	3r: 21	64.5 : 35.5	29
19	H/2-Br	3s: <5	—	—
20	H/4-Me	3t: <5	—	—
21	H/2-Me	3u: <5	—	—
22	H/2-OMe	3v: <5	—	—
23	H/1c	3w: <5	—	—
24	H/1d	3x: <5	—	—
25^e	H/3-Br	3r: 37	62 : 38	24

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It is well known that the previously reported chiral copper complex or other transition metal catalysts (Rh or Ag) controlled by various chiral ligands have been successfully used with various α-diazoesters in the catalytic asymmetric N–H insertion reaction,^8–13 with no obvious differences in reactivity of the aromatic or aliphatic diazo-substrates in the presence of a certain catalyst system. Especially for aromatic diazoesters, no obvious differences in reactivity and enantioselectivity between α-diazo-α-phenylacetate and other substituted diazoesters were observed. Unfortunately and unexpectedly, we found that the utilization of the ligand L26 in the N–H insertion reaction of substituted diazoesters led to almost no reaction. Thus, different from the copper or rhodium catalysis, the nature of the substituent on the benzene ring of diazoesters significantly influenced the conversion and enantioselectivity in the ruthenium-catalyzed N–H insertion reaction. As shown in Table 3, methoxy-, methyl-, and halide-substituted diazoesters resulted in poor or no conversion. These outcomes indicated that aromatic diazoesters bearing substituted groups at any position are unsuitable substrates. In addition, the catalytic N–H insertion reaction of aliphatic diazoesters was very sluggish, exhibiting poor reactivity with almost no conversion after 24 h. This pronounced effect indicated that the ruthenium–L26 complex is substrate-sensitive because of the narrow substrate scope, and it might be responsible for the preferential activation and interaction of α-diazo-α-phenylacetate in this reaction. Also, at that time, we believed that the L26–Ru complex might form a cage-shaped metal complex for size-sensitive discrimination of α-diazo-α-phenylacetate from various substituted diazoesters.

Inspired by previous results on additive-accelerated organic reactions¹⁹ and the concept of springboard chemistry that a highly reactive substrate acts as a “tractor” or “reactive springboard” to drive the catalytic reaction of a less reactive substrate (HDL catalysis),²⁰ we hypothesized that a highly reactive substrate might accelerate the ruthenium-catalyzed N–H insertion reaction of aromatic or aliphatic diazoesters with various substituents. Unfortunately, the enhancement of low-reactive diazoesters with HDL catalysis was not satisfying in yields and enantioselectivity (Table 3, entry 25).²¹

On the basis of the aforementioned experiments and previous reports,^22–24 we proposed a preliminary carbenoid N–H insertion reaction mechanism, as shown in Scheme 5. In the initial step, the reaction of [RuCl₂(p-cymene)]₂ with multifunctional ligand L26 resulted in the formation of a Ru–L26 complex that was detected by ESI-MS analysis (see Fig. S1 of ESI†). Then, the treatment with α-diazoester led to the generation of a chiral Ru-carbene intermediate (I),²² which reacted quickly with aniline to give a possible chiral metal ylide (II) similarly to the that in the Cu and Rh catalyst systems.^13,23 In the key step, trace HCl that generated from the catalyst system might possibly assist in a proton/hydrogen transfer to form the desired N–H insertion product, whereby the Ru–L26 complex and Brønsted acid are simultaneously regenerated for the next catalytic cycle. Notably, as shown in the schematic drawing of Fig. 6,²⁵ the Ru–L26 complex could have an unexpected cage structure that could discriminate between different aromatic α-diazoesters if these bear bulky and branched groups on the aromatic rings. Accordingly, the outcomes of enantioselective transformations with aromatic or aliphatic α-diazoesters provide direct evidence and information, based on possible molecular interactions between the substrates and the Ru–L26 complex.

Scheme 5 Proposed mechanism for the asymmetric ruthenium–L26 complex-catalysed carbenoid N–H insertion reaction.

Fig. 6 Views of the optimized structure of the Ru–L26 complex (top: top view; bottom: side view): the geometry of the Ru catalyst was optimized at the HF/LANL2DZ (Ru), 3-21G (C, H, O, N, Si) level of theory.²⁵ r(Ru⋯O) = 2.040 Å; r(Ru⋯N_sp²) = 2.048 Å; r(Ru⋯N_sp³) = 2.215 Å.

According to this proposed mechanism, the addition of a Lewis or Brønsted base could inhibit the formation of the desired product. As expected, we have found that almost no N–H insertion product was obtained in the presence of a base additive (see Table S2 of ESI†). In addition, with catalytic amounts of a Brønsted acid such as PhCOOH and CF₃COOH, the carbenoid N–H insertion reaction proceeded smoothly with the same level of enantioselectivity. Similar to the copper catalysis, we found that most multifunctional ligands evaluated in this work could slow down or even halt the ruthenium catalysis.^16,26 Although more detailed investigations need to be carried out to get direct evidence for elucidating the precise reaction mechanism, the new model established with multifunctional ligands for ruthenium catalysis will help with the further design and synthesis of novel and powerful ligands for enantioselective Ru-catalyzed organic reactions.

Experimental

Typical procedure for the ruthenium-catalyzed N–H insertion reaction

RuCl₂(p-cymene)₂]₂ (1.8 mg, 0.003 mmol, 1 mol%) and L26 (50 mg, 0.06 mmol, 2 mol%) were introduced into an oven-dried Schlenk tube in an argon-filled glove box. After fresh THF (1 mL) was injected into the Schlenk tube, the solution was stirred at room temperature under argon atmosphere for 1 h. A solution of aniline 2a (27 mg, 0.3 mmol) and methyl 2-diazo-2-phenylacetate 1a (52.8 mg, 0.3 mmol) in 2 mL THF was injected into the reaction mixture at room temperature. The resulting mixture was stirred at room temperature for overnight. After filtrating and removing the solvent under vacuum, the product was isolated by flash chromatography (petroleum ether/ethyl acetate = 50 : 1, v/v) as a colorless solid. All the products are known and were confirmed by GC-MS, NMR, IR, and HRMS (see ESI†). For example, 3a: R_f = 0.30 (PE/EA = 10 : 1, v/v, PE = petroleum ether, EA = ethyl acetate); 89% yield; HPLC analysis with Chiralcel AD-H column (hexane/i-PrOH = 95 : 5 v/v, 1 mL min⁻¹, 254 nm), t_R = 10.6 min, t_R = 11.8. ¹H NMR (400 MHz, CDCl₃): δ = 7.49 (d, J = 7.7 Hz, 2H), 7.11 (t, J = 7.5 Hz, 2H), 6.69 (t, J = 7.3 Hz, 1H), 6.55 (d, J = 7.9 Hz, 2H), 7.31 (td, J = 13.8, 7.3 Hz, 3H), 5.06 (d, J = 12.8 Hz, 1H), 3.72 (d, J = 11.4 Hz, 3H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 172.3, 145.9, 137.6, 129.3, 128.9, 128.4, 127.3, 118.3, 113.5, 60.8, 52.8 ppm. HRMS (ESI) calcd for [C₁₅H₁₆NO₂, M + H]⁺: 242.1176; found: 242.1177.

Conclusions

In summary, it can be seen from this work and previous efforts that the development of the ruthenium-catalyzed carbenoid N–H insertion reaction is not an easy task at present. On the basis of this high-throughput screening of multifunctional ligands which combined BINOL-derived aldehydes with chiral primary amines, we have tried to demonstrate for the first time that the catalyst system of [RuCl₂(p-cymene)]₂ with multifunctional ligand L26 bearing a silicon-based bulky group could be used as an efficient catalyst in the catalytic asymmetric carbenoid N–H insertion reaction. The major findings in this work include: (a) the single phenol group of the chiral BINOL-based backbone was important for the enantioselective control of the Ru–L26 complex; (b) the cinchonine-derived primary amine that was used to form the Schiff base moiety was proved to be a crucial building block in the construction of the multifunctional ligands with promising enantioselectivities in this reaction. The experimental results supported that the chirality matching of the (S)-BINOL-derived aldehyde and cinchonine-derived primary amine would be beneficial to the formation of a stable ruthenium complex from [RuCl₂(p-cymene)]₂. Although the final results achieved in this work are not perfect, to our knowledge, it is the first example of a ruthenium-catalyzed carbenoid N–H insertion reaction with the aid of multifunctional N,N,O-ligands, which is complementary to the copper- or rhodium-catalyzed synthesis of amino esters through an intermolecular carbon–nitrogen bond-forming reaction of α-diazoesters with amines. The new chemistry in the asymmetric ruthenium-catalyzed N–H insertion reaction will possibly inspire researchers to explore more effective ligands in this field.

Acknowledgements

Financial support by the National Natural Science Foundation of China (NSFC Grant no. 21173064, 51203037, and 21472031), the Fundamental Research Funds for the Central Universities (GK201501005), and the Zhejiang Provincial Natural Science Foundation of China (LR14B030001) is appreciated.

Notes and references

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21. For most of the unreactive diazoesters (entries 19–24 of Table 3), the utilization of α-diazo-α-phenylacetate as an additive slightly improved the conversion of these diazoesters in this reaction. However, the desired products 3r–x were difficult to obtain by flash column chromatography because of the similarity to 3a in polarity.
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26. As shown in Fig. 3–5, the use of several ligands resulted in almost no reaction, and the reaction rate of the Ru–L26-catalyzed N–H insertion reaction was slower than that under ligand-free reaction conditions (see ref. 16a).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra05804j

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