Initial screening studies were conducted on the N−H insertion of NH3·H2O with methyl phenyldiazoacetate 1 (table 1). After evaluating multiple reaction parameters, the desired N–H insertion product 2 was obtained under optimized conditions in 92% yield (in 12 hours from treating 1 with 8.0 equiv of NH3·H2O at 60 oC in 1,2-dichloroethane (DCE) in the presence of 10 mol % TpBr3Ag), along with 5% of O–H insertion product 3 (table 1, entry 8). All other tested transition‑metal catalysts failed to deliver even a trace amount of the insertion product 2, instead leading to products of side reactions of carbene or diazo compounds (entries 1-5).
The scope of substrate diazo compounds was then explored under the optimized conditions (Fig. 2A). The tested aryl and heteroaryl diazoacetates resulted in the desired α-amino acid esters (4-26) in 53–98% yield, regardless of electronic character or position of the substituents on the aromatic ring. In addition to the methyl and ethyl esters, benzyl (27), allyl (28), propargyl (29), 2-(trimethylsilyl)ethyl (30), tert-butyl (31), and cyclohexyl (32) phenyldiazoacetates also furnished the corresponding insertion products in good yield. The reaction is not limited to donor/acceptor diazo compounds, and can be successfully expanded to donor/donor diazo compounds. As depicted in Fig. 2B, a broad range of symmetric and unsymmetric diaryl diazomethanes afforded the target diaryl methylamines (33-39) in good to excellent yield.
Because the toxicity and potential explosivity of high-energy diazo compounds prevent scale-up of this transformation,24,25 we explored the possible use of easily-prepared, bench-stable N‑sulfonylhydrazones as carbene precursors.36,37,45-47 Another round of optimization studies with diphenyl N-triftosylhydrazone as model substrate resulted in the desired diaryl methylamine (33) being obtained in 85% yield, when the reaction was performed in DCE at 80 oC with Cs2CO3 as the base (table S2). In contrast, N-tosylhydrazone proved unsuitable substrate, as the same product was obtained in a much lower 33% yield under identical conditions (table S2, entry 11). Under these modified conditions, various diaryl N-triftosylhydrazones provided the desired diaryl methylamines in good to excellent yield along with a trace amount of O−H insertion products (33, 34, 37 and 40–60)—the electronic and steric effects did not impact the reaction efficiency and chemoselectivity. Heteroaryl methylamines, including benzofuryl (61, 64 and 65), benzothienyl (62 and 63), furyl (66) and thienyl (67) methylamines, were analogously isolated in moderate to good yield from the corresponding N-triftosylhydrazones. Donor/acceptor N-triftosylhydrazones could also undergo effective N−H insertion reactions (8, 28, 32, 68 and 69). Notably, this in situ diazo generation protocol proved to be equally effective as the corresponding diazo-initiated reactions (8, 28, 32–34 and 37). The reaction exhibited excellent functional group tolerance of a range of functional groups, including halogen, aniline, ketone, ester, nitro, olefin, alkyne, tert-butyl, methoxy, trifluoromethyl and trimethylsilyl groups, predominantly providing the desired N−H insertion products along with only trace amounts of O−H insertion products.
When the reaction of NH3·H2O with diphenyl N-triftosylhydrazone was conducted on a gram‑scale, hydrochloride 33·HCl was obtained pure, without chromatography, in a two-step 74% yield from diphenyl ketone (Fig. 3A). Our silver-catalyzed protocol could also be applied to late-stage modification of bioactive molecules (Fig. 3B). For instance, natural products containing a hydroxy group, such as phytol, tocopherol, vitamin D2, and (-)-β-citronellol, were first converted into the corresponding phenyldiazoacetates, then subjected to the optimized reaction conditions, affording the corresponding α-amino acid esters in moderate to good yield (70–73). Similarly, doxepin-1, a precursor of doxopin hydrochloride (a psychotropic drug) was easily converted into diarylmethylamine 74 in moderate yield through the corresponding diazo compound. The diarylmethylamine moiety is present in many agrochemical and pharmaceutical compounds, for example, the hydrochloride salts of cetirizine, hydroxyzine, and meclizine possessing the structural motif of 46,12 and the antimigraine drug lomerizine containing the structural motif of 40.13 Ketoprofen (an oral analgesic) and fenofibrate (an oral drug used to lower cholesterol levels) were converted to the corresponding primary amines 75 and 76, respectively, via the corresponding N-triftosylhydrazones. Compounds 77 and 78, intermediates in the synthesis of pharmaceutical compounds (GK-GKRP disruptor14 and DOR115 agonist, respectively), could also be obtained by this N−H insertion of NH3·H2O with N-triftosylhydrazones, showcasing the potential of our protocol for applications in drug discovery.