The metal-catalyzed carbene-transfer reaction of diazo compounds has become an important synthetic tool in organic synthesis [1, 2]. In this field, the reactions of cyclopropanation, X-H (X = C, N, O, Si, S) insertion, and carbonyl/imine ylide cycloaddition have been extensively investigated in the past decades. In 2003, Hu and his colleagues described a new type of reaction, in which the seemingly unstable ammonium ylides could be trapped with imine, giving 1, 2-diamines with a high diastereoselectivity (Eq. (3), Scheme 1) [3-7]. In their subsequent research, ammonium ylides and oxonium ylides intermediates [8, 9] were found to undergo nucleophilic addition onto a series of suitable electrophiles, such as ketone [10], aldehyde [11, 12], β, γ-unsaturated α-ketoester [13, 14], and azodicarboxylate [15]. These diazo compound reactions were usually mediated through rhodium (Ⅲ) catalysis [16-19].

Our group have recently reported that silver salts could be utilized as a catalyst to mediate the carbene transfer reaction of diazo compounds for the synthesis of oxirane molecules through the [2+1] cycloaddition of the diazo compounds with aldehydes (Eq. (1), Scheme 1) [20], and of 2, 5-dihydrofurans/tetrahydrofurans through the [2+2+1] cycloaddition of the diazo compounds with aldehydes and alkyne/olefin dipolarophiles (Eq. (2), Scheme 1) [21]. As a continuation of our previous research, we herein explore the silver (Ⅰ)-catalyzed three-component reactions of phenyl diazoacetate with arylamine and imine, which provide a series of polysubstituted 1, 2-diamine derivatives in moderate to good yields [22-25].

The reaction of methyl phenyldiazoacetate 1a with phenylamine 2a and 4-nitrophenyl-N-phenylmethanimine 3a was chosen as the model system for our initial investigation. Following our previous procedure, the combination IPrAgCl/AgOTf was utilized as the catalyst. As shown in Table 1, a mixture of 1a (0.1 mmol), 1.2 mol equiv. of 2a and 6 mol equiv. of 3a in CH₂Cl₂ was treated with 5 mol% equiv. of IPrAgCl/AgOTf using 50-mg 4-Å molecular sieves. We found that the diamine product 4aa could be obtained in 33% yield, together with the N-H insertion product 5a (26% yield, Table 1, entry 1). The diastereoselectivity of 4aa was very high (dr = 20/1).

The relative stereochemistry of 4aa was found to be a (2S^*, 3S^*) configuration, as determined by its X-ray chromatograph, shown in Fig. 1 [26].

Further optimization of the reaction conditions was then performed. It was found that the removal of IPrAgCl (no IPr ligand condition) would reduce the yield of 4a (Table 1, entry 2). After solvent screening (Table 1, entries 3-6), DCM was found to be the best reaction medium. The effect of molecular sieves was tested, 10 mg of the 4-Å molecular sieve additive was the optimal amount (Table 1, entry 7and 8). Except for IPr, other ligands were explored. Both PPh₃ and the dioxazoline ligand L1 proved to be inferior to IPr (Table 1, entries 9 and 10). Luckily, L2-ligated silver salts afforded the desired product 4aa in a high yield (Table 1, entry 11). However, the tricoordinated L3 proved to be a poor ligand (Table 1, entry 12). Utilizing L2 as the ligand, various silver salts were scrutinized, in which the AgOTf activity is much better than those of the other silver salts (Table 1, entries 13-19). In addition, raising or lowering the reaction temperature was found to be ineffective (Table 1, entries 20 and 21).

With the optimized reaction conditions determined, the various substrate scopes were then explored. As shown in Table 2, a series of diazo esters were investigated by using phenylamine 2a and 4-nitrophenyl-N-phenylmethanimine 3a as the ammonium ylide trapping partner. The ethyl phenyldiazoacetate ester 1b behaved like methyl ester 1a, giving 4ba in 83% yield with dr = 25/1 (Table 2). Different phenyl substitution patterns were tested, in which the electro-rich substituents (Table 2, 4ca-4ea) performed better than the electro-poor analogs (Table 2, 4fa). The bulky 2-naphthalenyl diazoester and heteroaromatic 2-thiophenyl diazo ester were also investigated, providing the desired diamine products 4ga and 4ha in moderate yields with high diastereoselectivities (Table 2) [27].

Then, various amine and imine substrates were investigated. It was found that an amine exchange could occur between the amine and imine substrates. In order to avoid the formation of an amine-exchanging side product, the same amine subunit (Ar₁NH₂) was employed in the amine substrate 2 and imine substrate 3 (Table 3). It has been proposed that the imine substrates act as ammonium ylide trapping reagents. Thus, its electrophilicity might affect the result of this three-component coupling reaction. As shown in Table 3, when the highly electrophilic imines, derived from p-nitro benzaldehyde, were utilized, the reactions of 1a with different amine substrates, such as p-fluoro, p-chloro and p-trifluoromethyl amines, provided diamine products 4ab-4ad in moderate yields with high diastereoselectivities, which were higher than that of Rh(Ⅲ) catalysis (Table 3) [3].

However, when the less electrophilic p-trifluoromethyl phenyl substituted imine 3e was utilized, two diamine diastereomers 4ae and 4ae' could be obtained in 43% yield, with dr = 1.5/1 (Table 3) [28]. Similarly, the reaction of the unsubstituted diphenyl imine 3f afforded the two diastereomers 4af and 4af' with a relatively low diastereoselectivity (4af/4af'= 3/1, Table 3). In the reaction of the p-methyl diphenyl imine 3g, the corresponding diamine diastereomers 4ag and 4ag' were separated in 31% yield, with dr = 2/1 (Table 3).

Then, the amine-exchange process was explored in the silver-mediated ammonium ylide trapping reaction. As shown in Scheme 2, when the p-fluorophenyl amine 2b was utilized to react with the diazo ester 1a and imine 3a, two ammonium ylide trapping adducts 4ah and 4aa were synthesized, in which the normal coupling adduct 4ah was obtained in only 23% yield (Scheme 2, Eq. (3)). It was obvious that an amine exchange reaction occurred between 2b and 3a, which led to the formation of the amine exchange coupling product 4aa [29]. Similarly, in the reaction of the p-trifluoromethylphenyl amine 2d, both 4am and amine-exchange product 4aa could be separated from the Ag(Ⅰ)/L₂ mediated reaction (Scheme 2, Eq. (4)). As a comparison, the Rh(Ⅲ) catalyst was used to catalyze the reactions in Eqs. (3) and (4), in which an amine-exchange product 4aa could also be obtained, though with relatively low yields (Scheme 2).

Then, we explored the asymmetric three-component reaction by using the chiral ligand (R)-L2, however, no enantioselectivity was obtained in the reaction shown in Eq. (5) (Scheme 3). In the N-H insertion reaction, only 11% ee was obtained (Eq. (6), Scheme 3).

The mechanism of the Ag(Ⅰ)-catalyzed ammonium ylides trapping reaction was then discussed. Based on previous research, a process of the nucleophilic addition of ammonium ylides onto electrophilic imines would be involved, in which the product diastereoselectivities are determined by intermolecular hydrogen bonding between the ArNH₂ group and the imine nitrogen atom, and the π-π interactions of the phenyl group[3]. Because of the Lewis acidity of the Ag(Ⅰ) salt, we considered that an additional intermolecular silver coordination might be involved, which led to the high diastereoselectivity of p-nitrophenyl imine in the Ag(Ⅰ)-mediated reaction (favored transition state, Scheme 4). When other imine substrates, such as p-trifluoromethylphenyl, p-methylphenyl and unsubstituted phenyl imines, were tested, poor diastereoselectivities were observed, possibly because of the coordination of silver salts with the imine nitrogen atom (unfavored transition state, Scheme 4). In addition, the amine exchange process between the amine and imine substrates might also be a result of the Lewis acidity of the Ag(Ⅰ) salt, leading to the amine-exchange three-component reaction.

In summary, we have reported the first example of the Ag(Ⅰ)-catalyzed three-component reaction of a diazo ester with arylamine and diaryl imine by using dioxazoline L₂ as the ligand to synthesize a series of polysubstituted 1, 2-diamine compounds in moderate to good yields. The Lewis acidity of Ag(Ⅰ) affected the diastereoselectivities of the 1, 2-diamine molecule, and led to the formation of amine-exchange diamine adducts. Compared with the previously reported Rh(Ⅲ)-mediated reaction, the silver catalyst performed better for the reactions of the p-nitrophenyl imine substrates, while providing relatively lower enantioselectivities for the reactions of less electrophilic substrates. Moreover, it was found that the dioxazoline L₂ ligand greatly enhanced the Ag(Ⅰ) catalytic activities in the carbene transfer reaction. The detailed research of the silver-catalyzed ammonium ylide trapping reaction and its further application is ongoing in our laboratory and will be reported in due course.

Supplementary data associated with this article include: a brief experimental details, and spectral data for all new products and NOESY spectra for compound 4aa is available free of charge via the Internet.