Free Amino Group Transfer via α‐Amination of Native Carbonyls

Abstract We report herein a straightforward transfer of a free amino group (NH2) from a commercially available nitrogen source to unfunctionalized, native carbonyls (amides and ketones) resulting in direct α‐amination. Primary α‐amino carbonyls are readily produced under mild conditions, further enabling diverse in situ functionalization reactions—including peptide coupling and Pictet–Spengler cyclization—that capitalize on the presence of the unprotected primary amine.

Nitrogen is the fourth most abundant element in smallmolecule drugs (Scheme 1A), [1,2] rendering the introduction of an amino group to a small molecule at a predetermined position a long-standing aim of synthetic chemists. [3]Methods for the installation of a primary amino group (NH 2 ) are particularly valuable, as they obviate the need to perform additional post-synthetic transformations to liberate the desired functionality.Notably, only few such methods exist for the preparation of primary α-amino carbonyls. [4]Moreover, owing to the mismatched electronic nature of the αcarbon of carbonyls and the nitrogen of amines, in many cases such an amination often requires prefunctionalization [5] of the carbonyl partner in the form of α-halogenation or similar (Scheme 1B).Conversely, and while amination with electrophilic aminating reagents is an important alternative strategy, [6] most of these methods typically lead to α-hydrazinyl or α-aminoxy products requiring further modification to unveil the NH 2 group.4d] Protocols for direct oxidative amination have been developed to circumvent this issue, in which the utilization of nucleophilic (often cyclic, secondary) amines as aminating reagents is crucial. [7]The direct installation of the NH 2 group onto native carbonyls therefore remains a challenging, unmet goal.
Charge-accelerated sulfonium rearrangement has emerged as a valuable strategy for the construction of CÀ C bonds and CÀ N bonds. [8]8i] Inspired by that work, we envisioned that deploying tertbutanesulfinamide [9] 1 in conjunction with an appropriate vinyl cation (I) [10,11] could enable CÀ N bond formation, installing the elusive NH 2 group in a single direct step.However, this plan was not without its possible caveats: intermolecular sulfidation [12a] or retro-ene reaction [12b] were potential side reactions (among others) of adduct II, leading to undesired α-sulfanyl carbonyls or starting materials respectively.Furthermore, conditions to cleave the expected NÀ S bond of sulfenamide III in the same pot were also to be unveiled (Scheme 1C).
We first set out to attempt the α-amination of amides employing N,N-dimethyl-4-phenylbutanamide (2 a) as a model substrate.12a] We sought to demonstrate the broad applicability of this amination protocol.Hence, various amides were subjected to the standard reaction conditions and afforded the desired primary amine products in good yields (4 b-h, Scheme 2).Here, it is worth highlighting morpholine-(4 d), Weinreb-(4 e) and indolinyl-amides (4 f), products amenable to transformation into other carbonyl derivatives.Moreover, the presence of a trifluoromethyl substituent near the reactive center was found not to negatively impact the reactivity (4 h).This protocol was found to also tolerate a large panel of functional groups, including alkenes ( 4

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the acidic conditions employed for cleavage of the NÀ S bond.Various heteroaromatic and aromatic motifs were also well-tolerated (4 q-t).Cyclopropyl substrate 3 u also smoothly converted to the desired product 4 u, exempt from any ring opening or decomposition of the strained 3membered ring.Remarkably, 13-membered ring lactam could also be efficiently aminated to afford 4 v.
Electron-rich aryl ketones are also candidates for electrophilic activation to form highly reactive intermediates, [11] a prerequisite for this α-amination reaction.In this case, the acidic work-up led to side reactions such as condensation of the generated primary amine with the ketone group.To circumvent this issue, in situ benzoylation of the free NH group was conducted throughout, enabling the isolation of a wide array of N-protected α-aminated ketones (5 a-f).
The work presented herein portrays a rare transformation deploying a free NH 2 group.Apart from its unique character, one of the benefits of such a process is the potential to directly capitalize on the rich chemistry of amines with in situ chemistry.For instance, free NH 2 groups are ideally suited for peptide coupling and indeed, generated amines 4 d, 4 v and 4 q could be successfully coupled in situ in a one-pot fashion with different amino acids.It is noteworthy that this amounts to a formal and unprecedented "α-peptidation" of previously unfunctionalized amides in a single step, to yield the corresponding peptides 6 a-d in excellent yields (Scheme 3A).Interestingly, compound 6 d was obtained in very good yield and a 9 : 1 mixture of diastereomers when enantiopure sulfonamide (R)-1 was employed.
In addition, primary amines such as 4 r were found to be prime substrates for Pictet-Spengler cyclization to directly generate piperidines 7 and 8, [13] employing paraformaldehyde or benzaldehyde as the carbonyl partner, respectively (Scheme 3B).This transformation allows the direct "stitching" of the α carbon of the amide in 2 r and the heteroarene CH, with the amino moiety serving as a linchpin-a potentially very useful transformation for drug discovery.Moreover, ketoamide 2 w was directly converted to piperidine 9 through a one-pot α-amination/reductive amination sequence (Scheme 3C), [14] whereas an amide bearing an ωchlorine atom on the side chain (2 x) could be successfully engaged in a tandem amination-cyclization process, furnishing piperidine 10 in excellent yield (Scheme 3D). [15]rom a mechanistic point of view, we believe that nucleophilic attack of tert-butanesulfinamide on the keteniminium I or its congener (I') generates adduct II (Scheme 4).This sulfonium species II is then thought to undergo a charge-accelerated [2,3]-rearrangement [16, 8j] to yield sulfenamide III. [17]Noteworthy, both sulfenamides of type III and primary α-aminated products were detected by LC/MS analysis before the acidic work-up, supporting this mecha- In conclusion, we have developed a facile method for the direct installation of primary amines (NH 2 ) into native carbonyls under mild conditions.Moreover, this strategy allows for a wide range of possible in situ derivatization reactions, including peptide coupling and Pictet-Spengler cyclization.We anticipate this method to provide a general platform towards the synthesis of unnatural α-amino acid derivatives, which we believe opens up exciting avenues for further research in the field of synthesis and medicinal study of peptidomimetics.