N-Aminopyridinium reagents as traceless activating groups in the synthesis of N-Aryl aziridines

N-functionalized aziridines, which are both useful intermediates and important synthetic targets, can be envisioned as arising from the addition of nitrenes (i.e., NR fragments) to olefinic substrates. The exceptional reactivity of most nitrenes, in particular with respect to unimolecular decomposition, prevents general application of nitrene-transfer to the synthesis of N-functionalized aziridines. Here we demonstrate N-aryl aziridine synthesis via 1) olefin aziridination with N-aminopyridinium reagents to afford N-pyridinium aziridines followed by 2) Ni-catalyzed C–N cross-coupling of the N-pyridinium aziridines with aryl boronic acids. The N-pyridinium aziridine intermediates also participate in ring-opening chemistry with a variety of nucleophiles to afford 1,2-aminofunctionalization products. Mechanistic investigations indicate aziridine cross-coupling proceeds via a noncanonical mechanism involving initial aziridine opening promoted by the bromide counterion of the Ni catalyst, C–N cross-coupling, and finally aziridine reclosure. Together, these results provide new opportunities to achieve selective incorporation of generic aryl nitrene equivalents in organic molecules.

In this work, we describe the first example of olefin aziridination with N-aminopyridinium reagents (Fig. 1c). Inspired by the Nicatalyzed C-C coupling chemistry of N-alkylpyridinium electrophiles pioneered by Watson 57-60 and others [61][62][63][64][65][66] , we demonstrate that the resulting N-pyridinium aziridines are competent electrophiles for C-N bond-forming cross-coupling with aryl boronic acids to afford N-aryl aziridines. Analogous chemistry is unknown for N-tosyl or N-phthalyl aziridines. Moreover, in contrast to classical methods for functionalization of N-H aziridines based on N-centered nucleophilicity, the described protocol leverages Ncentered electrophilicity to provide access to the products of formal aryl nitrene transfer to olefinic substrates. Initial mechanistic experiments suggest that the cross-coupling proceeds via a noncanonical mechanism involving halide-promoted ring opening, C-N bond-forming cross coupling, and aziridine reclosure.

Results
We began the development of a formal nitrene transfer sequence by developing robust conditions for olefin aziridination with N- Fig. 1 N-Activation strategies for aziridination. a Nitrene transfer to olefins provides access to aziridines but often requires the utilization of sulfonyl groups to activate the nitrogen. b N-H aziridines can be accessed directly from olefins and metal-catalyzed allylation methods enable functionalization of the N-H valence. c Here we advance N-pyridinium aziridines as platforms for C-N cross coupling to provide access to N-substituted aziridines. aminopyridinium reagents as nitrogen sources. Combination of styrene and N-aminopyridinium triflate in the presence of iodobenzene diacetate (PhI(OAc) 2 ) and MgO resulted in 1-(2-phenylaziridin-1-yl)pyridin-1-ium in 64% yield. Aziridination could also be accomplished using N-amino-2,4,6-triphenylpyridinium tetrafluoroborate (2) as the nitrogen source under these conditions (42% yield of the corresponding pyridinium aziridine (3a)). During subsequent studies of C-N cross coupling (vide infra), the triphenyl derivative was found to provide superior results and thus we optimized the aziridination reaction with compound 2 as the pyridinium source. Examination of the impact of various catalysts, solvents, reaction temperatures, and additives (see Supplementary Information Section C.1 for details) identified optimized aziridination conditions based on iodide catalysis in the presence of 4 Å molecular sieves, which affords aziridine 3a in 71% yield (Fig. 2).
With conditions in hand to efficiently access N-pyridinium aziridines, we turned our attention to engaging these species as electrophiles in C-N coupling reactions. We envisioned a C-N cross coupling of N-pyridinium aziridines would (1) provide access to the products of formal nitrene transfer to olefins, (2) provide a rare example of an aziridine cross-coupling in which the aziridine ring remains intact, and (3) represent the first application of pyridinium electrophiles in C-N cross-coupling chemistry. We initiated our investigations by examining potential Ni-catalyzed cross coupling of N-pyridinium aziridine electrophiles with appropriate organometallic nucleophiles (i.e., Grignard reagents, organolithiums, organostannanes, and boronic acids). We identified that treatment of N-pyridinium aziridine 3a with tolyl boroxine and NiCl 2 (dme) in MeCN afforded N-arylaziridine 5b in 36% yield. The coupling efficiency is extremely sensitive to the Ni(II) counter anion: Under identical conditions, NiCl 2 provided 5b in 36% yield while NiBr 2 afforded 5b in 60% yield. Ni(OAc) 2 , Ni(acac) 2 , and NiSO 4 salts were completely ineffective. Optimization of the cross-coupling reaction (see Supplementary Information Section C.2 for details) ultimately identified the use of NiBr 2 (phen) as catalyst in the presence of K 3 PO 4 and 2,4,6-collidine provided N-tolylaziridine 5b in 79% yield (Fig. 3). The catalyst loading could be reduced to 10 mol% without significant loss of yield, but further reduction to 5 mol% resulted in substantial reduction in reaction efficiency. For comparison, attempted cross-coupling reactions with N-phthalyl or N-sulfonyl aziridines under our optimized conditions or with N-H aziridines using C-N cross-coupling conditions described in the literature were unsuccessful (see Supplementary Information sections C.8 and C.9) 33,34 . We also examined potential Nicatalyzed cross-electrophile-coupling and found inferior results: Combination of 3a with 4-bromotoluene in the presence of NiCl 2 (30 mol%), 1,10-phenanthroline (30 mol%), and either Mn or Zn dust as terminal reductant afforded the product 5b at 50% and 11% NMR yield, respectively (see Table S7) 60 .
In addition to direct C-N coupling with boronic acids, the developed N-pyridinium aziridines participate in ring-opening chemistry to access 1,2-difunctionalization products (Fig. 4). Exposure of N-pyridinium aziridine 3a to halide sources (i.e. [TBA]Br, [TBA]Cl, or pyridine·HF) or H 2 O in the presence of BF 3 ·OEt 2 resulted in opening of the aziridine to afford 1,2haloamine derivatives 6a-6c or 1,2-hydroxyamine 6d. Attempts to isolate 6a and 6b resulted in low isolated yields due to aziridine reclosure to N-pyridinium aziridine 3a (vide infra). A variety of other oxygen-, nitrogen-, and sulfur-based nucleophiles participate in aziridine opening to afford isolable aminopyridinium derivatives 6e-6j. Indole can serve as a carbon nucleophile to provide 6k in 37% yield. These ring-opened compounds could be isolated as analytically pure materials and participate in efficient Ni-catalyzed cross coupling to generate 1,2-aminofunctionalized compounds 7e-7k (the products of p-tolylboronic acid coupling), respectively. The ring-opened product 6g and 6j also participated in cross coupling with more complex boronic acids, as highlighted by the synthesis of 7l and 7m, which are derived from cross-coupling of ring-opened compounds with the boronic acid derived from indomethacin. Metal-catalyzed cross-coupling of aziridine often results in ring opening products [16][17][18][19][20][21][22][23][24] . In contrast, we observed Ni-catalyzed C-N coupling to generate N-arylaziridines in which the aziridine ring is conserved in the product. To better understand this unusual reaction outcome, we were interested in evaluating the mechanism of C-N bond-forming chemistry that leaves the three-membered aziridine ring intact. These investigations were guided by (1) a desire to understand the bromide-specific activity noted in our original catalyst optimization studies and (2)   followed by cross-coupling of an open-chain aminopyridinium intermediates, and finally aziridine reclosure may be operative (Fig. 5a). Consistent with this hypothesis, treatment of aziridine 3a with NiBr 2 (dme) (with or without added phenanthroline) results in the observation of ring-opened compound 6a by 1 H NMR (Fig. 5b). While BF 3 ·OEt 2 was required for ring opening with [TBA]Br, spontaneous ring-opening is observed upon addition of NiBr 2 , which suggest that under these conditions Ni 2+ is serves as a cooperative Lewis acid activator and bromide source for aziridine opening. Finally, exposure of a sample of compound 6a to Ni(OTf) 2 or Ni(BF 4 ) 2 and p-ethoxylcarbonylphenylboronic acid results in the formation of N-arylaziridine 5j, which demonstrates the viability of cross-coupling and aziridine reclosure (Fig. 5c). For further discussion of the impact of added bromide on cross-coupling efficiency, see Section C.7 of the Supplementary Information.

Discussion
In summary, we report a strategy for the synthesis of N-aryl aziridines, which are the formal products of aryl nitrene addition to olefins. This method overcomes the inherent instability of free nitrene fragments by harnessing N-pyridinium aziridine intermediates that participate in Ni-catalyzed C-N cross-coupling. By decoupling the aziridination from installation of the N-substituent, this strategy overcomes the common requirement for difficult-to-remove N-substituents in aziridination chemistry. The observed C-N cross-coupling chemistry contrasts the typical reactivity pattern of N-sulfonylaziridine cross-coupling, which typically participate in ring-opening C-N activation, by taking advantage of a unique reversible ring opening/reclosure mechanism. These studies not only provide strategies to access products of formal nitrene transfer to olefins but significantly expand the synthetic scope of nitrene transfer by demonstrating N-aminopyridinium to be a bifunctional amination reagent.
General procedure for cross-coupling of pyridinium aziridines. A 20-mL scintillation vial was charged with Ni(Phen)Br 2 (20 mol%), base (2.8 equiv), aryl boronic acid (4, 2.4 equiv), pyridinium aziridine (3, 1 equiv) and a magnetic stir bar. In an N 2 filled dry box, a solution of 2,4,6-collidine in acetonitrile (0.08 M, 1.0 equiv) was added to the scintillation vial with the rest of the reaction components. The reaction vial was heated at 65°C for 36 h. After cooling to 23°C, the reaction mixture was transferred to a centrifuge tube and centrifuged at 3220×g (6000 rpm) for 10 min. The supernatant was decanted. The residue was washed with CH 2 Cl 2 and the combined supernatants were concentrated under reduced pressure and the crude mixture was purified as indicated in the Supplementary Information to afford the aziridine compound 5.
indicated temperature for indicated time. Solvent was removed under reduced pressure and the residue was purified by SiO 2 gel chromatography (eluent 2:1 ethyl acetate:hexane) to afford the compound 6.

Data availability
All data generated in this study are provided in the Supplementary