Cobalt-catalyzed arylation and alkenylation of alpha-bromo eneformamides and enecarbamates by cross-coupling with organic bromides: Application to the synthesis of functionalized piperidines and azepanes

One-shot access to α,β-difunctionalized azepenes and dehydropiperidines by reductive cross-coupling of α-selenonyl-β-selenyl enamides with organic bromides

“…The improved efficiency of lithiation of the enecarbamate substrates (relative to the eneformamides) is probably a reflection of the robustness and/or superior directing ability of the Boc-group in such directed lithiations. 68 Congruous with our previous disclosure on the inertness of aryl chlorides under these reaction conditions, 55 we find that o-chlorobenzyl bromide selectively affords the benzylated product over the arylated product (see 4h). Instructively, while conditions for lithiation/trapping with carbon electrophiles are currently being fine-tuned, central among our objectives in the current study was the goal of preparing substrates bearing two pendant leaving groups, in view of utilizing them in one-pot vicinal carbo-functionalization protocols.…”

“…9 The importance of the α-selenonyl group in this reaction manifold is highlighted by the observation that α-carbo-functionalized enecarbamates such as 2a/b/d (see Scheme 2) fail to react under the specified conditions. 55,69 Of note, α-selenonyl-β-bromo eneformamides such as 3b appear to be recalcitrant coupling partners under the conditions described in Scheme 4. Having noticed that the Fe-catalyzed conditions employed in Scheme 2 for substitutive deselenonation were non discriminative when twopronged electrophiles such as 3b/e were utilized, and cognizant of the high tolerance for a diverse range of functional groups in reductive cross-couplings, 63 we sought efficient conditions for vicinal reductive cross-coupling of 3 with cheap feedstock chemicals such as organic bromides.…”

“…54 Additionally, we have recently disclosed that cyclic α-bromo eneformamides and enecarbamates are amenable to cobalt-catalyzed reductive cross-coupling with cheap feedstock chemicals such as organic bromides or α-bromo enones. 55 In this electrophile-electrophile coupling mode, [56][57][58][59][60] traditionally difficult functional groups (e.g., ester, ketone, nitrile, or alcohol groups) are impressively tolerated and the need for pregeneration of expensive or difficult-to-handle organometallic reagents (e.g., boronic esters) is obviated. [61][62][63] Seeking complementary and unifying strategies for accessing differentially-substituted azaheterocycles, especially those bearing vicinal disubstitution, it was surmised that α-selenonyl eneformamides or enecarbamates such as 1 (Fig.…”

“…In the event, we were pleased to find that readily available piperidine enecarbamates 6a/b, 65 undergo satisfactory vinyl lithiation 66 / selenation and subsequent m-CPBA-induced oxidation of the crude selenide to the desired α-selenonyl piperidine enecarbamates (Scheme 1, see 1a/b). Encouragingly, bromo eneformamide 7a (available in one step from δ-valerolactam 55 ) affords selenone 1c in reasonable yield, following selenation and oxidation. Furthermore, the identified conditions are applicable to α-bromo azepene 7b 52 (see 1d).…”

Trapping of carbolithiation-derived tertiary benzylic α-lithio piperidines with carbon electrophiles: Controlling the formation of α-amino quaternary and vicinal stereocenters

“…1). Accordingly, our interest in these functionalized azaheterocycles 11,[24][25][26][27][28][29][30][31] has recently led us to the discovery that α′-lithiation/trapping of α-alkyl-α-aryl disubstituted piperidines such as 1 (Fig. 2A) proceeds satisfactorily to afford the corresponding trisubstituted products (i.e., 2), in good to excellent diastereoselectivities.…”