Traceless Benzylic C–H Amination via Bifunctional N-Aminopyridinium Intermediates

Abstract

C–H amination reactions provide the opportunity to streamline the synthesis of nitrogen-containing organic small molecules. The impact of intermolecular C–H amination methods, however, is currently limited by typical requirement that the amine precursors bear activating groups, such as N-sulfonyl substituents, that are both challenaging to remove and not useful synthetic handles for subsequent derivatization. Here, we introduce traceless nitrogen activation for C–H amination—which enables application of selective C–H amination chemistry to the preparation of diverse N-functionalized products—via sequential benzylic C–H N-aminopyridylation followed by Ni-catalyzed C–N cross coupling with aryl boronic acids. Unlike many C–H amination reactions that provide access to protected amines, the current method installs an easily diversifiable synthetic handle that serves as a lynchpin for C–H amination, deaminative N–N functionalization sequences.

Graphical Abstract

Here we report C–H amination chemistry via traceless bifunctional nitrogen activation. Sequential C–H aminopyridylation followed by Ni-catalyzed cross coupling with aryl boronic acids affords the products of aryl nitrene insertion into C–H bonds. These products are unavailable by direct nitrene insertion due to the intrinsic instability of aryl nitrenes. The described method can be applied in the context of pharmacologically active molecules.

Direct C–H amination provides a platform to radically simplify the synthetic logic of nitrogen-containing small molecules by obviating the need for substrate pre-oxidation. In response to the synthetic utility of direct C–H amination, a wide variety of transition metal-based and metal-free catalytic protocols have been developed.^1,2 The promise of direct C–H amination is tempered, however, by the typical need for nitrogen-activating groups, such as N-sulfonyl substituents, that are both challenging to remove and not easily converted to the diverse array of N-substituents present in molecular targets of interest (Figure 1a).^3,4 Thus, while C–H amination simplifies the introduction of nitrogen content, additional synthetic manipulations are required to remove the vestigial activating groups before further N-functionalization can be accomplished.

Figure 1.

Current C–H amination methods with nucleophilic (a) and electrophilic (b) amine precursors provide access to protected nitrogen-containing products. (c) Here we describe benzylic C–H amination with bifunctional N-aminopyridinium reagents that enable sequential nucleophilic amination and electrophilic N–N functionalization to access the products of formal aryl nitrene insertion into benzylic C–H bonds.

Nucleophilic amine precursors (i.e., functionally N^– sources), such as sulfonamides, carboxamides, and carbamates have found application in C–H amination reactions that proceed through C-centered radicals or carbocation intermediates (Figure 1a).⁵ Electrophilic amine precursors (i.e., functionally N⁺ sources), such as iminoiodinanes, azides, hydroxylamine derivatives, and nitro compounds, have found application in both metal-catalyzed C–H amination as well as direct amination of organometallic nucleophiles (Figure 1b).⁶ The requisite electrophilic nitrogen sources are themselves typically derived from pre-oxidized reagents and not from C–H bonds. In both nucleophilic and electrophilic modalities, electron withdrawing N-substituents are typically required to prevent N-oxidation or to increase N-centered electrophilicity.

Here we introduce N-aminopyridinium reagents as bifunctional⁷ lynchpins (i.e., N^–/N⁺ reagents) for traceless⁸ N-activation chemistry (Figure 1c). N-functionalized pyridinium reagents have previously been employed as bifunctional platforms for olefin difunctionalization,⁹ amidyl radical precursors,¹⁰ and functional group transfer chemistry^11,12 but have not found application as bifunctional reagents in amination chemistry. We harness the innate bifunctionality of N-aminopyridinium species by 1) engaging the nucleophilic N-amino moiety in selective benzylic C–H amination chemistry, and 2) utilizing the reducible N–N bond of the generated N-aminopyridinium derivatives as an electrophilic partner in subsequent Ni-catalyzed C–N cross-coupling reactions. This sequence provides selective access to the products of formal aryl nitrene insertion into a benzylic C–H bond, which are unavailable from either free, or transition metal-stabilized nitrene fragments.

To date, there are no examples of C–H amination using N-aminopyridinium reagents and the synthetic chemistry of these species has historically been limited to hydrazine addition to pyrrilium precursors.¹³ We initiated the development of C–H N-aminopyridylation by examining the amination of ethylbenzene (1a) with N-aminopyridinium triflate and we identified two sets of reaction conditions that provide efficient access to benzylic amination products (Figure 2; DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, NIS = N-iodosuccinimide).^14,15 Thermolysis of a CH₂Cl₂ solution of 1a and N-aminopyridinium triflate in the presence of DDQ in a sealed tube afforded N-benzylaminopyridinium triflate 2a in 72% yield. Alternately, photolysis of a CH₂Cl₂ solution of 1a and N-aminopyridinium triflate in the presence of NIS afforded 2a in 65% yield. See the Supporting Information, Section C.2 for optimization details.

Figure 2.

Summary of the scope and limitations of benzylic C–H aminopyridylation reactions to access N-benzylaminopyridiniums 2. Conditions: (a) 1 (1.3 equiv), N-aminopyridinium triflate (1.0 equiv), DDQ (2.3 equiv), CH₂Cl₂, 110 °C, 40 h; (b), 1 (1.3 equiv), N-aminopyridinium triflate (1.0 equiv), NIS (2.2 equiv), CH₂Cl₂, 23 °C, 30 h, blue LEDs. * 1 (5.0 equiv), N-aminopyridinium triflate (1.0 equiv), NIS (2.2 equiv), CH₃NO₂, 23 °C, 30 h, blue LEDs; yields are isolated.

The two sets of C–H amination conditions display complementary substrate preferences (Figure 2). DDQ-promoted benzylic amination provided access to halogenated N-benzylaminopyridiniums (2b-2e) in 61–68% yield; in the case of the amination of 4-chloroethylbenzene (1d), the NIS-promoted condition proved superior and afforded 2d in 78% yield (Table S1). Electron-rich substrates, such as 4-methylethylbenzene (1f), 4-ethyl-1,1’-biphenyl (1g), 3-methylethylbenzene (1h), and 2-ethylthiophene (1i) afford the corresponding N-benzylaminopyridinium 2f-2i in moderate yields (44, 59, 62, and 58%, respectively). Ortho-substitution is tolerated as 1-ethylnaphthalene (1j) provided the corresponding aminated product 2j in 79% yield. Finally, the DDQ-promoted condition tolerates a boronic ester substituent (2k), which can be utilized as an additional handle for substrate functionalization via cross-coupling reactions. While the DDQ-promoted benzylic C–H amination method can be accomplished for gram-scale synthesis without any loss in the yield (see Supporting Information Section B.1.1), it was inefficient to provide access to aminated products when applied to 1,1-diphenylmethane derivatives (1l-1m), and substrates with strongly electron withdrawing substituents (1n-1o). In comparison, the NIS-promoted conditions afforded the N-benzylaminopyridinium derivatives of these substrates in greater efficiency. 1,1-Diphenylmethane derivatives (2l and 2m) were accessed in 71%, and 69% yields, respectively. Electron-deficient substrates 1n-1p are functionalized more efficiently, albeit still in modest yield, with the NIS promoted conditions (for additional electron deficient substrates and further discussion of substrate limitations, see the Supporting Information, Section C.5). Reaction with acyl and phenyl protected phenols (1q and 1r) under NIS-promoted conditions provided corresponding aminated products 2q and 2r in 68% and 56% yields, respectively. Similarly, protected amines, such as N-(4-ethylphenyl)acetamide (1s), afforded 2s in 65% yield under the NIS-promoted conditions. Longer chain alkyl groups are selectively aminated in the benzylic position (i.e., propylbenzene (1t) and n-hexylbenzene (1u)) and isochroman (1v) undergoes amination at the weaker benzylic C–H bond. In the context of more complex molecular settings, amination of isatin analogue 1w proceeds in 46% yield. In addition to the benzylic substrates described, C–H amination can also be achieved in aliphatic contexts such as adamantane, which undergoes amination of the methine position to afford 2x in 31% yield.

Despite the presence of the electron-withdrawing N-pyridinium substituent, N-benzylaminopyridiniums 2 are sufficiently nucleophilic at the benzylic nitrogen to participate in substitution chemistry with alkyl halides: Treatment of N-benzylaminopyridinium 2a with CH₃I or hexyl iodide in the presence of K₂CO₃ affords alkylation products 2aa and 2ab, respectively (Equation 1). Compounds 2 also readily participate in reductive N–N bond cleavage reactions to afford free amines: Exposure of N-benzylaminopyridinium 2g to Mg in methanol or to Zn in AcOH resulted in reductive N–N cleavage to yield 1-[1,1’-biphenyl]-4-yl)ethan-1-amine in 89% and 83% yield, respectively (Equation 2).^16,18

With access to a large family of N-benzylaminopyridiniums (2) we sought to develop conditions to engage compounds 2 in C–N bond-forming cross-coupling chemistry. These efforts were guided by the hypothesis that low-lying pyridinium-centered LUMO in 2 provides the opportunity to promote N–N cleavage by electron transfer from a transition metal catalyst (LUMO = lowest unoccupied molecular orbital).¹⁷ Based on the success of Ni-catalyzed C–C cross-coupling of alkylpyridinium electrophiles,¹² we initiated the development of a new C–N bond-forming reaction by examining the activity of various Ni catalysts in the presence of chelating nitrogen-based ligands. Combination of N-benzylaminopyridinium 2a with (4-(ethoxycarbonyl)phenyl)boronic acid (3g) in the presence of Ni(OAc)₂·4H₂O (10 mol%) and 1,10-phenanthroline (13 mol%) in CH₃CN afforded arylamine 4g, the product of C–N cross coupling, in 38% yield. Optimization of Ni catalyst (and loading), ancillary ligand and temperature resulted in the identification of optimized conditions (see Supporting Information Section C.4 for details): Combination of 2a and 3g in the presence of NiBr₂(dme) (10 mol%), 1,10-phenanthroline (13 mol%), and K₃PO₄ at 65 °C in CH₃CN afforded 4g in 89% yield (Figure 3).

Figure 3.

Summary of the scope and limitations of Ni-catalyzed cross-coupling of N-alkylaminopyridinium electrophiles 2 with aryl boronic acids 3 to generate secondary and tertiary amines 4. Conditions: 2 (1.0 equiv), 3 (1.5 equiv), NiBr₂(dme) (0.10 equiv), 1,10-phenanthroline (0.13 equiv), K₃PO₄ (2.5 equiv), CH₃CN, 65 °C, 16 h; yields are isolated.

The optimized conditions for C–N cross coupling of N-aminopyridiniums (2) and aryl boronic acids (3) to access aryl amines 4 is compatible with diverse substitution of both coupling partners (Figure 3). In the context of the boronic acid partner, hydrocarbyl and halide substituents are well tolerated (i.e., 4b-4d and 4e-4f, respectively). Electron deficient aryl boronic acids were generally found to be efficient coupling partners (i.e., 4g-4i) while electron-rich boronic acids are significantly less efficient; e.g., the coupling of 4-methoxyphenylboronic acid with N-aminopyridinium 2a proceeds to afford aryl amine 4j in 40% yield. Substitution at the meta-position is compatible with efficient cross coupling (i.e., 4k-4n), but ortho-substitution of the boronic acid is not tolerated (i.e., 4o and 4p). Heterocyclic boronic acids, such as 4-pyridyl- and 2-thienyl boronic acid are compatible with the developed conditions and afford heteroarylated products 4q and 4r in 65% and 26% yield, respectively. In the context of the N-benzylaminopyridinium coupling partner, both N-substitution and functionalization of the aryl ring can be accommodated. Cross-coupling of alkylated N-aminopyridiniums 2aa and 2ab provides access to tertiary amines 4s and 4t in 74 and 48% yield, respectively. More electron-withdrawing N-substituents, such as N-tosyl or N-acyl derivatives of 2a, do not participate in C–N cross coupling under the developed conditions (see Supporting Information Section C.5 for additional substrates that do not participate in productive C–N coupling). All substitution patterns of the aryl ring of the N-aminopyridinium are compatible with efficient coupling (i.e., 4u-4z), but cross-coupling efficiency is diminished in the case of doubly benzylic substrate 2l (40% yield of 4z).

In addition to benzylic N-aminopyridinium substrates (2), allylic N-aminopyridinium substrates (5) also participate in Ni-catalyzed cross-coupling to access the products on N-arylation (Figure 4). The requisite N-aminopyridinium allyl amines 5 are available by Rh-catalyzed aminopyridiylation of the corresponding allyl carbonates.¹⁸ Using the optimized coupling conditions identified for N-benzylaminopyridinium cross coupling in Figure 3, allylic aminopyridiniums 5 engage in productive cross coupling to afford allyl aryl amines 6. Both n-alkyl (6a and 6b) and α-branched alkyl allyl amines (6c) are available from this transformation.

Figure 4.

Ni-catalyzed cross-coupling of N-pyridinium allyl amines affords N-aryl allyl amines. Conditions: 2 (1.0 equiv), PhB(OH)₂ (1.5 equiv), NiBr₂(dme) (0.10 equiv), 1,10-phenanthroline (0.13 equiv), K₃PO₄ (2.5 equiv), CH₃CN, 65 °C, 16 h; yields are isolated.

The broad functional group tolerance of the developed Ni-catalyzed C–N cross-coupling enabled application to a variety of more complex, pharmaceutically relevant molecular scaffolds (Figure 5). C–N cross-coupling between N-aminopyridinium 2a and boronic acids derived from loratadine, nefazodone, estrone, and indomethacin proceeded in good yields to afford complex aryl amine 8a-8d, respectively. These examples highlight the compatibility of C–N bond construction with the presence of pharmaceutically relevant basic heterocycles, amides, carbamates, and basic amines. Similar to the cross-coupling reactions of simple substrates highlighted in Figures 3 and 4, the N-aminopyridinium coupling partner can also accommodate significant variation in these more complex settings: Coupling of N-allylpyridinium derivative 5c with indomethacin-derived boronic acid 7d affords complex allyl amine 8e in 63% yield and coupling methylated N-aminopyridinium 2aa with the boronic acid 7f affords thioflavin T derivative 8f, which features a tertiary amine in 41% yield.

Figure 5.

Application of deaminative C–N cross-coupling in complex molecules. Conditions: N-aminopyridinium derivative (1.0 equiv), 7 (1.5 equiv), NiBr₂(dme) (0.10 equiv), 1,10-phenanthroline (0.13 equiv), K₃PO₄ (2.5 equiv), CH₃CN, 65 °C, 16 h; *N-aminopyridinium derivative (1.5 equiv), 7 (1.0 equiv), NiBr₂(dme) (0.10 equiv), 1,10-phenanthroline (0.13 equiv), K₃PO₄ (2.5 equiv), CH₃CN, 65 °C, 16 h; yields are isolated.

In summary, here we demonstrate that N-aminopyridinium reagents represent traceless bifunctional activating groups for C–H amination chemistry. Selective benzylic C–H aminopyridylation coupled with Ni-catalyzed C–N cross-coupling provides direct access to aryl amines from benzylic C–H. These products have previously been unavailable via C–H amination because the aryl nitrene precursors that would be required are insufficiently long-lived to participate in intermolecular chemistry. By simultaneously providing the requisite nitrogen-activation for C–H functionalization and a chemically addressable N–N bond, N-aminopyridinium intermediates provide a new strategy to utilize C–H bonds as disconnections in the synthesis of nitrogen-containing small molecules.