α-Functionalization of Cyclic Secondary Amines: Lewis Acid Promoted Addition of Organometallics to Transient Imines

Abstract

Cyclic imines, generated in situ from their corresponding N-lithiated amines and a ketone hydride acceptor, undergo reactions with a range of organometallic nucleophiles to generate α-functionalized amines in a single operation. Activation of the transient imines by Lewis acids that are compatible with the presence of lithium alkoxides was found to be crucial to accommodate a broad range of nucleophiles including lithium acetylides, Grignard reagents, and aryllithiums with attenuated reactivities.

Graphical Abstract

Saturated nitrogen heterocycles remain one of the most important classes of compounds in drug discovery.¹ C─H bond functionalization of the parent heterocyclic frameworks represents an attractive strategy for accessing more complex saturated amines from simple ones, and remains a topic of widespread interest.² Particularly well-studied are α-C─H bond functionalizations of cyclic amines (Scheme 1).³ However, despite considerable advances, the vast majority of the various activation modes developed to date are incompatible with the presence of an N─H bond, limiting their utility to 3° (often N-aryl) or protected 2° amines. Directing groups are frequently required and can be difficult to remove, hampering the use of the underlying methods. As an alternative, condensation-based methods involving α-C─H bond functionalization of 2° cyclic amines have recently emerged.^2m,2o While attractive for a number of reasons, the products of these transformations are necessarily 3° amines. Methods for the direct synthesis of α-functionalized 2° cyclic amines from their corresponding parent amines remain limited. Hydroaminoalkylation enables the introduction of α-branched aliphatic substituents and is relatively well-developed for acyclic amines.⁴ However, applications to the functionalization of 2° cyclic amines remain underdeveloped and typically require elevated temperatures and prolonged reaction times (Scheme 1, eq 1).⁵ An interesting recent advance is the electrochemical α-cyanation of NH-piperidines (Scheme 1, eq 2).⁶ Here we report a generalizable method for the α-C─H bond functionalization of 2° cyclic amines, utilizing a broad range of easily accessible organometallic nucleophiles (Scheme 1, eq 3).

Scheme 1.

Overview and Strategy

Inspired by seminal studies on the hydride donor ability of lithium amides by Wittig et al.,⁷ we recently developed a new strategy for amine α-C─H bond functionalization (Scheme 1, eq 3).⁸ In the process, an N-lithiated amine 1 reduces a ketone to form a lithium alkoxide and cyclic imine 3, presumably via a transition state related to 2.⁹ Imine 3 subsequently engages an organolithium reagent, providing an α-functionalized amine 4.¹⁰ While applicable to a relatively broad range of amines, our original procedure is limited to the use of highly reactive organolithium nucleophiles. Organolithiums with attenuated reactivities (e.g., lithium acetylides) and, importantly, Grignard reagents, failed to effectively engage the transient imine species. We hypothesized that a Lewis acid may serve to activate cyclic imines towards nucleophilic addition. While there is precedent showing that such a strategy can be successful with acyclic imines and nonenolizable cyclic imines,^11–13 it was not obvious whether previously developed methods would be applicable to enolizable cyclic imines such as 1-pyrroline and 1-piperideine. These species are known to be unstable and prone to trimerization,¹⁴ a process that could potentially be accelerated by Lewis acids. Imine trimers tend to be stable under basic conditions and don’t react with organolithium compounds even at elevated temperatures. Conversion of the imine trimers to the corresponding monomers is possible but requires protic conditions and/or heating, conditions that are incompatible with strong nucleophiles.¹⁵ Further, while Lewis acid activation of an enolizable cyclic imine should serve to increase its electrophilicity, it also increases the acidity of the β-proton and may thus further enhance the known propensity of these imines to undergo deprotonation.⁷ Finally, it was unclear whether any Lewis acid with sufficient activity would be compatible with the lithium alkoxide produced in the imine-generating step. Needless to say, having to first remove said alkoxide from the reaction mixture would diminish the attractiveness of the method.

Upon extensive evaluation of a range of reaction parameters, conditions were identified that allowed for the one-pot α-alkynylation of various amines with lithium acetylides (Scheme 2).¹⁶ Briefly, following the generation of the cyclic imine, Li-acetylide was added, immediately followed by addition of BF₃ etherate. The order of addition and the timing was found to be crucial.¹⁶ Regardless of ring size, 2° cyclic amines readily underwent substitutions with Li-phenylacetylide. A range of alkynes participated in this reaction. 4-Methyl piperidine and a bicyclic pyrrolidine derivative underwent alkynylation to provide products in highly diastereoselective fashion. Little or no product formation was observed in the absence of BF₃ etherate.

Scheme 2. α-Alkynylation of Amines^a.

^a All yields correspond to isolated yields of purified products. The Li-acetylide was prepared in a 4:1 mixture of PhMe and THF. ^b Benzophenone was used as the hydride acceptor ^c The Li-acetylide was prepared in THF.

Similar reaction conditions were successfully applied to substitution reactions of amines with aryllithium compounds possessing attenuated nucleophilicities, enabling the introduction of furan, benzofuran, and various substituted indole moieties (Scheme 3). Several of the nucleophiles had previously been evaluated in the absence of a Lewis acid. For instance, 2-furyllithium failed to provide any product without added BF₃ etherate. Others, such as 2-lithiated N-methylindole provided only trace amounts of products in the absence of a Lewis acid.

Scheme 3. α-Arylation of Amines With Heteroaryllithiums^a.

^a All yields correspond to isolated yields of purified products. Yields in parenthesis correspond to results obtained in the absence of BF₃ etherate. ^b Trifluoroacetophenone was used as the hydride acceptor.

Grignard reagents, an important class of easily accessible organometallic nucleophiles, failed to provide notable yields in the addition to cyclic imines in the absence of Lewis acids. While BF₃ etherate also enabled the use of these nucleophiles, trimethylsilyl trifluoromethanesulfonate (TMSOTf) provided the best results in the α-substitution of amines with Grignard reagents.¹⁶ The scope of this transformation is summarized in Scheme 4. Phenyl- and benzyl substituents were readily introduced into amines with different ring sizes. To obtain easily isolable nonvolatile products in the introduction of lower molecular weight substituents, these reactions were evaluated with azacyclotridecane. Linear, α-branched, and β-branched alkyl groups, as well as vinyl, allyl, and ethynyl groups were readily introduced. Notably, while methyllithium was previously found to be a poor nucleophile for cyclic imines, methylmagnesium chloride in combination with TMSOTf readily provided product 7g. High levels of diastereoselectivity were achieved in the α-phenylation of a bicyclic amine (product 7o), the introduction of an α-homoallyl substituent in 4-benzylpiperidine (product 7p), and the α-n-butylation of an intermediate used in the synthesis of the commercial drug risperidone (product 7q).¹⁷ Notably, the preparation of 7q failed with n-butyllithium as the nucleophile, presumably due to the incompatibility of this reagent with the benzisoxazole moiety. Further expansion of scope was achieved with active nucleophiles obtained via the turbo Grignard method (Scheme 5).¹⁸

(4)

(5)

Scheme 4. α-Functionalization of Amines With Grignard Reagents^a.

^a All yields correspond to isolated yields of purified products.

Scheme 5. α-Functionalization of Amines With Activated Grignard Reagents^a.

^a All yields correspond to isolated yields of purified products.

Products derived from the Lewis acid promoted α-C─H bond functionalization of 2° cyclic amines could be further functionalized regioselectively on the α′-position. For instance, piperidine 6f underwent α′-phenylation to provide product 9 in 60% yield (eq 4), whereas 10 was obtained in 64% yield via the α′-n-butylation of 7d (eq 5).

In summary, we have achieved the α-C─H bond functionalization of 2° cyclic amines with a broad range of organometallic nucleophiles. This method significantly improves the availability of valuable building blocks for synthesis.