Synthesis of Polycyclic Isoindolines via α-C–H/N–H Annulation of Alicyclic Amines

Abstract

Relatively unstable cyclic imines, generated in situ from their corresponding alicyclic amines via oxidation of their lithium amides with simple ketone oxidants, engage aryl lithium compounds containing a leaving group on an ortho-methylene functionality to provide polycyclic isoindolines in a single operation. The scope of this transformation includes pyrrolidine, piperidine, azepane, azocane, and piperazines.

Graphical Abstract

Given the prevalence of saturated azacycles as core structures of numerous bioactive materials,¹ the development of methods for the synthesis of more complex amines via the C–H bond functionalization of their parent heterocycles continues to inspire the development of diverse synthetic strategies.^2,3 Despite the tremendous progress that has been achieved in this area, there is a lack of available methods that enable direct amine annulation via concurrent N–H and α-C–H bond functionalization as an attractive entry to polycyclic amines (Scheme 1). While redox-annulations (Scheme 1a) are highly appealing in this regard, these transformations remain limited to aldehydes containing activated pronucleophiles.⁴ For instance, direct access to polycyclic isoindolines via redox-annulation of alicyclic amines and aryl aldehydes would be highly desirable (Scheme 1b), given the privileged nature of such compounds in drug discovery and the need for multiple-step sequences when accessing these materials via traditional approaches.^5,6 However, due to other, more facile reaction pathways, this transformation has remained elusive.⁷ Here we report a new approach to the synthesis of polycyclic isoindolines, proceeding in a single operation from commercial materials.

Scheme 1.

Overview of methods for amine α-C–H/N–H annulation

Capitalizing on the well-documented ability of lithium amides to serve as reductants,⁸ we recently developed a strategy to access relatively unstable enolizable cyclic imines in situ from lithium amides and simple ketone oxidants (Scheme 1c).⁹ This approach enabled the synthesis of various α-functionalized amines.⁹ In addition, we could show that transient imines undergo annulation with lithiated o-toluamides to form polycyclic lactams (Scheme 1d).^9f We reasoned that isoindolines may be accessible via the process outlined in Scheme 1e, utilizing an aryl lithium nucleophile containing a leaving group on an o-methylene functionality. This nucleophile was envisioned to be accessible via lithium–halogen exchange. This idea was evaluated with 1-bromo-2-(chloromethyl)benzene (1a)¹⁰ and 1-ethylpiperazine. Selected experiments are summarized in Table 1. Following significant optimization, the use of a mixed solvent system (ether/THF) in the lithiation of 1a was found to be critical. Under the optimized conditions, product 2e was obtained in 63% yield. Interestingly, performing the entire reaction sequence in just ether or THF as the only solvent led to dramatically reduced yields.

Table 1.

Reaction development.^a

entry	deviation from optimized conditions	yield (%)
1	none	63
2b	reaction performed at rt for 3 h	41
3c	reaction performed at −78 °C for 3 h	61
4d	amine as the limiting reagent	33
5e	1 equiv of LiCl used as additive	14
6	entire reaction performed in ether	23
7	entire reaction performed in THF	16

^aReactions were performed with 0.5 mmol of 1a. Yields correspond to isolated yields of chromatographically purified product. A mixture of ether (1 mL) and THF (1 mL) was used for the lithiation of 1a. Cyclic imine was prepared in situ by adding n-BuLi (2 equiv) to a solution of 1-ethylpiperazine (2 equiv) in ether (1 mL) at −78 °C, followed by the addition of trifluoroacetophenone (2.05 equiv).

^bReaction immediately warmed up to rt after the addition of the in-situ generated imine.

^cReaction was carried out at −78 °C throughout without warming to rt.

^d1.5 equiv of the 2-bromobenzyl chloride used with respect to the in-situ generated imine.

^eLithium chloride was added as a 0.5 M THF solution before the Li-halogen exchange reaction.

To evaluate the scope of this transformation, a series of readily available o-chloromethyl-arylbromides were subjected to Li–Br exchange with n-BuLi, followed by addition of cyclic imines generated in situ as described previously (Scheme 2). A range of polycyclic isoindolines 2 were obtained in acceptable to good yields. Substituents on the aryl ring were tolerated in any position. Amines with different ring sizes were readily accommodated. 4-Substituted piperidines and bicyclic amines underwent annulation to furnish products with high levels of diastereoselectivity (products 2h–j). Precedent for this type of reaction is extremely limited and all prior examples involve the use of stable, non-enolizable acyclic imines.¹¹

Scheme 2. Scope of the reaction.

Reactions were performed with 0.5 mmol of 1. Yields correspond to isolated yields of chromatographically purified product. A mixture of ether (1 mL) and THF (1 mL) was used for the lithiation of 1. Cyclic imines were prepared in situ by adding n-BuLi (2 equiv) to a solution of the corresponding cyclic amine (2 equiv) in ether (1 mL) at −78 °C, followed by the addition of trifluoroacetophenone (2.05 equiv). ^a A mixture of ether (1.8 mL) and THF (0.2 mL) was used for the lithiation of 1. ^b THF (1 mL) was used for the lithiation and cyclic imine was prepared in situ by adding n-BuLi (2 equiv) to a solution of cyclic amine (2 equiv) in ether (1.5 mL) at −78 °C, followed by the addition of trifluoroacetophenone (2.05 equiv) in 1 mL of ether.

In conclusion, we have achieved annulation reactions of o-chloromethyl-aryllithiums with enolizable cyclic imines, species that were prepared in situ via the oxidation of the corresponding lithiated amines with a ketone oxidant. This methodology allows for the facile construction of various polycyclic isoindolines in a single operation, dramatically simplifying access to these materials.