Electrochemical Vicinal C–H Difunctionalization of Saturated Azaheterocycles

Abstract

A method to functionalize two vicinal C–H bonds of saturated azaheterocycles is described. The procedure involves subjecting the substrate to a mixture of hydrochloric acid, acetic acid, and acetic anhydride in an undivided electrochemical cell at constant current, resulting in stereoselective conversion to the corresponding α-acetoxy-β-chloro derivative. The α-position can be readily substituted with a range of other groups, including alkyl, aryl, allyl, alkynyl, alkoxy, or azido functionalities. Furthermore, we demonstrate that the β-chloro position can be engaged in Suzuki cross-coupling. This protocol thus enables the rapid diversification of simple 5-, 6-, and 7-membered saturated azaheterocycles at two adjacent positions.

Graphical Abstract

Cyclic amines are common motifs in bioactive compounds, agrochemicals, and natural products. For example, piperidines and pyrrolidines rank among the most commonly occurring ring structures in FDA-approved drugs¹ and bioactive natural products, a selection of which is shown in Figure 1A.² Accordingly, a wide variety of approaches have been developed to synthesize cyclic amines, often by cyclization of an acyclic precursor.³ An attractive alternative approach that has garnered much attention entails the selective C–H bond functionalization of simple cyclic amine derivatives. Owing to the unique reactivity of the α-sites in such compounds, numerous methods that achieve functionalization of the 2-position have been reported using Lewis acid catalysis,⁴ α-metallation,⁵ transition metal catalysis,⁶ photochemical oxidation,⁷ and electrochemical “Shono-type” oxidation.⁸ Functionalization of other C–H bonds in these rings is more challenging, however. While several catalytic approaches have been developed to selectively introduce β-functionality, most strategies have been limited to the installation of aryl⁹ or benzyl¹⁰ groups. Notably, photoredox catalysis has recently been employed to introduce a variety of functional groups at the β-position of saturated azacycles.^11,12 Less explored have been reactions that achieve the functionalization of multiple C–H bonds, which could lead to highly efficient synthetic strategies. While electrochemical approaches towards difunctionalization have been known since 1984,¹³ these reactions are prone to significant amounts of side product formation.¹⁴ It remains an outstanding challenge to develop methods that derivatize multiple positions of ring systems efficiently with a diverse array of functionalities (Figure 1B).

Figure 1.

Vicinal C–H difunctionalization of saturated azaheterocycles.

We recently reported the C–H triacetoxylation of various trifluoroacetamides using an electrophotocatalytic approach.¹⁵ We anticipated that a similar strategy could lead to other multiple C–H derivatization reactions. In particular, we hoped to develop a strategy that would enable the introduction of a wider range of functionality, especially including carbon substituents. After some experimentation, we found an electrochemical vicinal C–H functionalization reaction that uses simple reagents. Specifically, when a suspension of 1-(phenylsulfonyl)pyrrolidine, acetic acid, acetic anhydride, HCl, and Et₄NBF₄ in CH₂Cl₂ was subjected to a constant current of 5 mA, a single difunctionalized product, trans-3-chloro-1-(phenylsulfonyl)pyrrolidin-2-yl acetate, was formed in 88% yield as determined by ¹H NMR. Although the α-OAc moiety was unstable at room temperature, we found that the crude intermediate could be directly converted to a range of functionalized products. Thus, addition of the crude mixture to a variety of silyl or diorganozinc reagents in the presence of BF₃•OEt₂ readily converted the acetoxy group to a variety of carbon, heteroatom, or hydrogen-containing derivatives (Figure 1C).

Using this approach, we found that a variety of phenylsulfonyl-protected¹⁶ pyrrolidine and piperidines could be derivatized to generate β-chloro azaheterocycles (Table 1). For example, subjecting N-benzenesulfonylpyrrolidine to the acetoxychlorination procedure followed by diethylzinc and BF₃•OEt₂ furnished the chloroethylated derivative 1 in 79% yield with 96:4 trans:cis stereoselectivity. The configuration of the major isomer was confirmed by single crystal X-ray analysis (1 X-ray). Use of diphenylzinc similarly led to compound 2, in this case as a single observable isomer. Alternatively, use of allyl or chloromethylallyl trimethylsilane enabled the production of 3 and 4 respectively in good yields and with high stereoselectivity. Use of the TMS silyl enol ether derived from cyclohexanone led to 5, albeit in low yield and as a mixture of diastereomers. On the other hand, TMSCN was used to form adduct 6 in 61% yield and as an 81:19 mixture of diastereomers. Silylated acetylenic partners enabled access to products such as 7-10, whereas heteronucleophiles such as methoxy (11) or azide (12) were also feasible. Notably, we also found that the β-chlorinated adduct 13 could be accessed by triethylsilane reduction of the acetate group. In a similar fashion, derivatives of the N-benzenesulfonyl-2-methylpyrrolidine 14-18 could be accessed in good yields, with a preference for the stereoisomers shown. In addition, phenylsulfonyl-protected piperidines were equally effective in producing the difunctionalized product. By subjecting the intermediate chloroacetate adduct to dimethylzinc or diisopropylzinc along with BF₃•OEt₂, we were able to access the corresponding chloromethylated 19 and chloroisopropyl 20 products. The presence of substituents on the substrate ring did not impede the transformations (21-27); however, diastereocontrol from this group ranged from poor (22-24) in the case of 3- or 4-substituents to exclusive in the case of 2-substituents (21, 25-27). We also found that N-phenylsulfonyl-protected azepane also participated in the acetoxychlorination and the subsequent substitution reaction with diisopropylzinc gave rise to the chloroisopropyl adduct 28 exclusively as the anti-isomer in 43% yield.

Table 1.

Scope of the vicinal C–H difunctionalization reaction.^a

^aYields based on 0.3 mmol scale (see SI). Isolated Yields. Isomeric ratios were determined by GC-MS.

^bIsomeric ratios were determined by ¹H NMR of the crude reaction mixture.

As a further demonstration of the complexity-building potential of this transformation, we subjected several of the products from Table 1 to Ni-catalyzed Suzuki coupling,¹⁷ thereby installing an aryl group in the 3-position (Figure 2A). In total, this procedure effectively transforms the two vicinal C–H bonds of a saturated azaheterocycle into C–C bonds, or in the case of 32, represents a formal β-C–H arylation reaction. Alternatively, adduct 13 could be subjected to nucleophilic substitution with sodium thiomethoxide to produce 33 representing a formal β-C–H thiolation reaction (Figure 2B).

Figure 2.

Derivatization of 3-chloropyrrolidine products.

We also found that this strategy could be used to achieve the vicinal C–H difunctionalization of oxoheterocycles. In this case, the standard conditions did not lead to acetoxychlorination, but addition of (NH₄)₂S₂O₈ generated the corresponding α-acetoxy β-chloro intermediates from tetrahydrofuran or tetrahydropyran, which, upon further functionalization, furnished the adducts 34 and 35 in modest yields (eq 1).

(1)

In terms of the mechanism of the acetoxychlorination procedure, we presume the process is initiated by anodic oxidation of chloride (1.36 V vs. SCE), which has a much lower oxidation potential than the substrate 29 (2.29 V vs. SCE).¹⁸ The thusly produced chlorine radical could effect H-atom abstraction from the substrate, to form radical 36 and then iminium 37 (Figure 3A). Loss of proton would lead to enamine 38, which could suffer chloride radical addition to generate radical 39. Finally, removal of another electron would furnish iminium 40 that could be trapped by acetic acid to generate the acetoxychlorinated product 41. In support of this pathway, we subjected putative intermediate 38 to our reaction conditions and observed a 43% yield of trans-3-chloro-1-(phenylsulfonyl)pyrrolidin-2-yl acetate (41) formation (Figure 3B).

Figure 3.

Mechanistic rationale for chloroacetoxylation reaction.

Lastly, we hypothesize that the regioselective functionalization of the less-hindered sites of 2-substituted substrates is a consequence of the conformational bias of cyclic sulfonamides. For example, for a 2-substituted piperidine sulfonamide, conformation 42a is strongly disfavored due to A^1,3 strain (Figure 3c), leading to a distribution heavily biased toward conformation 42b. In 42b, only the less-substituted carbon has a hydrogen stereoelectronically disposed for abstraction, thus leading to the observed regioisomeric products 43.¹⁹

In conclusion, we have developed an electrochemical approach to achieve the vicinal C–H bond difunctionalization of saturated heterocycles. A mixture of commercially available acids (AcOH/HCl) was used to introduce easily diversifiable functionalities, making this procedure highly practical. A further downstream diversification to forge vicinal C-C bonds demonstrates the power of this procedure.