Diversification of Amidyl Radical Intermediates Derived from C–H Aminopyridylation

Abstract

The N-activating substituents typically encountered in C–H amination chemistry are challenging to remove and have limited scope for synthetic elaboration. Here, we demonstrate that N-benzylaminopyridinium species provide a platform for synthetic elaboration via reductive N–N bond activation to unveil electrophilic N-centered radicals. These reactive intermediates can be trapped either via anti-Markovnikov olefin carboamination to provide access to tetrahydroisoquinolines or via aza-Rubottom chemistry with silyl enol ethers to provide α-amino ketones.

Graphical Abstract

The presence of amines and other nitrogen-based functional groups can profoundly impact the chemical and biological properties of organic small molecules and thus C–N bonds are ubiquitous in pharmacologically active organic scaffolds.¹ In both biology and synthetic chemistry, installation of C–N bonds typically requires substrate pre-oxidation, which inherently limits the efficiency and versatility of synthetic approaches to these important molecules.² A variety of C–H amination methods, based on either nitrene or nitrogen-centered radical intermediates, have been advanced to install N-containing functional groups without the need for substrate prefunctionalization (Figure 1a).^3,4 In practice, electron-withdrawing groups, such as N-sulfonyl substituents, are typically required to activate aminating reagents for C–H functionalization and methods to elaborate the resulting sulfonamides to more complex nitrogen-containing molecules are limited.^{5, 6}

Figure 1.

(a) Direct C–H amination via nitrene transfer or radical-mediated processes typically requires activation of the amine fragment with electron withdrawing substituents, which can be removed to ultimately generate free amines. (b) Here, we demonstrate C–H amination with N-aminopyridinium which provides the opportunity to diversify the products of C–H amination via amidyl radicals generated by reductive N–N cleavage.

We recently introduced N-aminopyridinium salts as bifunctional reagents in C–H amination chemistry.⁷ The combination of a nucleophilic N-amino group and a reductively activatable N–N bond⁸ provided a platform to couple C–H amination with C–N cross coupling to achieve formal nitrene transfer to benzylic C–H bonds. Here, we demonstrate that reductive activation of the same N–N bonds allows derivatization of the products of C–H amination via electrophilic N-centered radicals (Figure 1b).⁹ We highlight the amination/derivatization sequence in (1) the synthesis of tetrahydroisoquinolines, which are important heterocycles in medicinal chemistry and can be challenging to prepare by existing methods,¹⁰ and (2) the synthesis of α-aminoketones via formal aza-Rubottom chemistry.¹¹ These protocols enable conversion of benzylic C–H bonds to an array of nitrogen-containing products and significantly expand the utility of N-aminopyridiniums as lynchpins of molecular synthesis.

During our initial studies of C–H aminopyridylation, we developed conditions that promoted selective benzylic C–H functionalization of a variety of ethyl and alkylbenzene derivatives.⁷ We envisioned that oxidative quenching of the excited state of an appropriate photoredox mediator would promote reductive cleavage of the N–N bond of these compounds to release pyridine and unveil an electrophilic aminyl radical. The generated aminyl radical could be engaged with exogenous substrate, such as an olefin, with the potential for additional C–C bond formation through cyclization in the presence of pendant phenyl moiety (vide infra). Initial attempts to photolyze a solution of 1a in the presence of aryl olefins and a variety of photoredox mediators were unsuccessful. We observed complete recovery of starting materials with no desired N–N cleavage. We reasoned that the inability to achieve N–N cleavage may arise from the instability of the aminyl radicals that would result from reductive extrusion of pyridine from 1a and hypothesized that the installation of a sulfonyl group would stabilize the incipient N-centered radical (Figure 2). Tosylation of 1a by treatment with TsCl, K2CO3, and DMAP (10 mol%) afforded sulfonamide 2a. Consistent with the hypothesis that tosylation would enable reductive activation of the N-benzylaminopyridinium: The cyclic voltammograms (CVs) of compound 1a and 2a reveal that onset potential for reduction for compound 1a and 2a are −1.31 V and −0.86V vs. Ag/AgNO3, respectively (Figure S1).

Figure 2.

Visible-light promoted functionalization of N-benzylaminopyridiunium 2a in presence of styrene afforded carboamination product 5a while analogous functionalization of N–H substrate 1a was not productive. The dichotomous observations are presumably due to stabilization of incipient N-centered radical via tosyl substitution. Conditions: [Ir(ppy)₂(dtbbpy)][PF₆] (4, 1 mol%), blue LED, CH₂Cl₂, 0 °C.

Photolysis (λ= 463 nm) of sulfonamide 2a with [Ir(ppy)₂(dtbbpy)][PF₆] (4, 1 mol%) in the presence of styrene (3a) resulted in the evolution of tetrahydroisoquinoline 5a in 71% yield (1.4:1 ratio of cis:trans diastereomers). Tetrahydroisoquinoline 5a represents the product of anti-Markovnikov carbonamination of styrene. Control reactions in the absence of light and/or photocatalyst did not yield any deaminative product. For details of the carboamination optimization, including the impact of solvent, photocatalyst, reaction stoichiometry, and reaction temperature, see the Supporting Information (Tables S1–S4).

The developed carboamination chemistry tolerates substitution on both the aminopyridinium and styrene reaction partners. Reaction of 4-fluorostyrene with differently substituted aminopyridinium salts resulted in the formation of tetrahydroisoquinolines 5b-5d. Reaction of differently substituted halostyrenes with 2a affords the corresponding tetrahydroisoquinolines (5e-5g) as diastereomeric mixtures in 68–78% yield. The relative stereochemistry of the tetrahydroisoquinoline products was assigned based on single-crystal X-ray diffraction analysis of chlorinated tetrahydroisoquinoline 5e (for crystallographic details, see Figures S2–S3 and Tables S5–S6 in the Supporting Information). Electron-donating substituents such as 4- and 3-methylstyrenes afforded tetrahydroisoquinolines 5h and 5i with trans- and cis-diastereomers being major products, respectively. Deaminative carboamination of 4-acetoxystyrene provided tetrahydroisoquinoline 5j in 76% yield with the trans diastereomer being major product. Tetrahydroisoquinolines 5k-5n, derived from electron-deficient styrenes, were accessed in 47–61% yield with cis diastereoselectivity. Reaction with weakly withdrawing 4-vinyl-1,1’-biphenyl afforded tetrahydroisoquinoline 5o in 48% yield with a mixture of 1:2.2 cis: trans diastereoisomers. Deaminative carboamination of 4-(chloromethyl)styrene yielded 5p in 76% yield with cis isomer as the major product. It should be noted that no significant side-reaction via hydrogen atom abstraction (HAA) at the benzylic position of 4-(chloromethyl)styrene was observed. Bulky olefinic substrate such as 2-vinylnaphthalene yielded 5q in 53% yield with trans isomer as the major component. The reaction is also tolerant to substitution on the N-benzylaminopyridinium coupling partners. For example, coupling of 2d, the N-benzylaminopyridinium derived from 1-ethylnaphthalene, with 4-fluorostyrene yielded the corresponding benzo-fused tetrahydroisoquinoline 5r in 51% yield with a mixture of 1:1.5 cis: trans diastereomers. The diastereoselectivity does not appear to vary systematically with the electronic properties of the substituents on the olefin partners. Bulky substituents on the N-aminopyridinium partner give rise to preferential formation of the trans diastereomer (i.e., 5r). Reaction with non-aromatic olefins such as 1-octene or cyclohexene resulted in the formation of imines, presumably via H-atom abstraction by N-centered radical 10 (see the Supporting Information for additional details).

In addition to olefinic substrates, the electrophilic radicals generated by reductive activation of the N–N bonds in N-benzylaminopyridiniums engage in amination reactions with nucleophilic heterocycles, such as N-Boc-indole 6 to afford 2-aminated indole 7 in 47% yield (Figure 4a), and silyl enol ethers (8) to afford α-amino carbonyls 9 (Figure 4b). The amination of silyl enol ethers via N-aminopyridiniums,¹² which represents a formal aza-Rubottom reaction, tolerates both substitution of the nucleophilic partner 8 (i.e., preparation of 9a-9e) as well as variation of the benzylic substituents on the N-benzylpyridinium partner 2 (i.e., preparation of 9f and 9g). Synthesis of 9a could be performed on a 1 mmol scale with 61% isolated yield (see Supporting Information of additional details).

Figure 4.

Functionalization of N-benzylpyridiunium 4 with (a) nucleophilic heterocycles (conditions: 2a (1.0 equiv), 6 (3.0 equiv), CH₂Cl₂, 35 °C, 16 h), and (b) silyl enol ethers (conditions: 2a (1.0 equiv), 8 (2.0 equiv), CH₂Cl₂, 0 °C, 16 h). ^a 4 equivalents of 8e were used; with 2 equivalents the yield of 9e was 61%.

Reductive functionalization of N-benzylaminopyridiniums (2) can be envisioned as arising from the mechanism illustrated in Figure 5a (illustrated for olefin carboamination to generate tetrahydroisoqunolines).¹³ Electron transfer from an excited state of the Ir photocatalyst to 2 results in N–N cleavage to an amidyl radical (10), pyridine, and an Ir(IV) intermediate. Reaction of the generated amidyl radical 10 with olefin 3 generates benzylic radical 11. Oxidation of 11 by Ir(IV) would afford cationic intermediate 12 and regenerate the photocatalyst. Electrophilic addition to the arene to the cation in 12 furnishes tetrahydroisoquinoline 5. In support of this scheme, addition of N-tert-butyl-α-phenylnitrone (PBN) to the carboamination of 2a resulted in observation of the PBN adduct of amidyl radical 10 by both X-band EPR spectroscopy and high-resolution APCI-MS (Figure 5b and S4).¹⁴ In addition, deaminative functionalization of 2a in the presence of 1,1-diphenylethylene yielded the corresponding olefinic product 5s in 87% yield as opposed to the expected tetrahydroisoquinoline (Figure 3), which is presumably due to elimination from stabilized carbocation 12s in preference to arene alkylation to generate the corresponding tetrahydroisoquinoline. Similarly, benzylic carbocation 12 can be trapped with water as nucleophile in a mixed solvent of acetone/water to form the corresponding β-aminoalcohol (see Supporting Information). The quantum yield for the deaminative olefin functionalization was found to be 15.8%, which is consistent with a non-radical chain pathway for the generation of tetrahydroisoquinolines (see Supporting Information Section F for additional details).

Figure 5.

(a) Potential carboamination catalytic cycle. Electron transfer from the excited state of [Ir(ppy)₂(dtbbpy)][PF₆] to 2a results in reductive N–N cleavage to unveil amidyl radical 10 and Ir(IV). Addition to olefin 5 generates benzylic radical 11. Oxidation by Ir(IV) generates a benzylic cation 12, which alkylates the pendent arene to afford tetrahydroisolinolines 5. (b) EPR spectra for photo-chemical deaminative functionalization of 2a in presence of PBN was obtained in acetonitrile. The observed triplet of quartet in the photolyzed spectrum is attributed to PBN-trapped amidyl radical with a_N(PBN) = 13.85 G, a_H = 3.20 G, and a_N(amidyl) = 2.52 G; (—) experimental spectrum with blue light irradiation, and (—) simulated spectrum.

Figure 3.

Photocatalytic carboamination promoted by deaminative functionalization of 2 in presence of olefins provides access to a family of 1,4-subsituted tetrahydroisoquinolines 5. Conditions: 2 (1.0 equiv), 3 (1.6 equiv), CH₂Cl₂, 0 °C, 16 h. dr cis:trans

In summary, here we described utilization of benzyl C–H aminopyridylation products in olefin carboamination and formal aza-Rubottom oxidation of silyl enol ethers. The nucleophilicity of N-aminopyridinium allows these reagents to engage in C–H amination chemistry, and reductive N–N cleavage unveils electrophilic amidyl radical intermediates as diversifiable nitrogen synthons. The realization of C–H functionalization chemistry with N-aminopyridinium reagents both significantly expands the structural complexity that is available to this burgeoning class of bifunctional reagents and significantly expands the synthetic utility products accessible via C–H amination.