C–H functionalization of cyclic amines: redox-annulations with α,β-unsaturated carbonyl compoundsChem. Commun.


YoungKu Kang, Matthew T. Richers, Conrad H. Sawicki, Daniel Seidel
Chemistry (all) / Ceramics and Composites / Electronic, Optical and Magnetic Materials / Materials Chemistry / Metals and Alloys / Surfaces, Coatings and Films / Catalysis


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Richers, C. H. Sawicki and D. Seidel, Chem. Commun., 2015, DOI: 10.1039/C5CC03390J.

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Department of Chemistry and Chemical Biology, Rutgers, The State University of

New Jersey, Piscataway, New Jersey, 08854, USA. † These authors contributed equally.

Electronic Supplementary Information (ESI) available: Experimental procedures and characterization data. See DOI: 10.1039/x0xx00000x

Received 00th January 20xx,

Accepted 00th January 20xx

DOI: 10.1039/x0xx00000x www.rsc.org/

C–H Functionalization of Cyclic Amines: Redox-Annulations with α,β-Unsaturated Carbonyl Compounds

YoungKu Kang, a,†

Matthew T. Richers, a,†

Conrad H. Sawicki a and Daniel Seidel a, *

Cyclic amines such as pyrrolidine and 1,2,3,4tetrahydroisoquinoline undergo redox-annulations with α,βunsaturated aldehydes and ketones. Carboxylic acid promoted generation of a conjugated azomethine ylide is followed by 6πelectrocylization, and, in some cases, tautomerization. The resulting ring-fused pyrrolines are readily oxidized to the corresponding pyrroles or reduced to pyrrolidines.

Electrocyclic ring-closures of conjugated azomethine ylides enable efficient access to 5- and 7-membered azacycles. 1,2

A number of mechanistically distinct methods for the generation of the required dipolar intermediates have been developed, the most common of which involve decarboxylation or the deprotonation of a preformed iminium salt. 1,2

In contrast, the direct generation of conjugated azomethine ylides via redox-neutral amine α-C–H functionalization 3,4 as an avenue for 1,5- and 1,7-electrocyclizations has been explored to only a limited extent. 1

Previous examples include the reaction of enamines or related compounds with dimethyl acetylenedicarboxylate (DMAD) (e.g., eq 1) 5 or intramolecular rearrangements of dienamines bearing multiple electron-withdrawing groups (e.g., eq 2). 6

Oxidative C–H functionalization methods for the generation of conjugated azomethine ylides have also emerged. 7–9

Here we report a carboxylic acid facilitated method for the in situ generation of conjugated azomethine ylides and their subsequent 1,5electrocyclizations. Simple cyclic amines such as pyrrolidine or 1,2,3,4-tetrahydroisoquinoline (THIQ) and α,β-unsaturated aldehydes/ketones serve as the starting materials in these cascade reactions (eq 3).

Table 1. Evaluation of Reaction Conditions. entry X solvent (M) additive (equiv) time [h] yield (%) 1 5 PhMe (0.25) - 15 trace 2 5 PhMe (0.25) BzOH (0.5) 5 65 3a 5 PhMe (0.25) BzOH (0.5) 5 58 4 5 PhMe (0.1) BzOH (0.5) 5 74 5 5 PhMe (0.1) AcOH (0.5) 5 65 6 5 PhMe (0.1) 2-EHA (0.5) 5 69 7 5 PhMe (0.1) HCO2H (0.5) 5 trace 8 5 PhMe (0.1) BzOH (0.2) 6 68 9 5 PhMe (0.1) BzOH (1.0) 3 77 10 5 n-BuOH (0.1) BzOH (1.0) 5 23 11 5 1,2-DCE (0.1) BzOH (1.0) 12 trace 12 3 PhMe (0.1) BzOH (1.0) 3 62 13 2 PhMe (0.1) BzOH (1.0) 15 64 a Without molecular sieves. 2-EHA = 2-ethylhexanoic acid.

Our group has recently advanced a general amine α-C–H bond functionalization concept to access reactive azomethine ylide intermediates via the condensation of a secondary amine with an aldehyde or a ketone. 3u, 10

This enabled the development of a range

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COMMUNICATION Journal Name 2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx of new reactions in which azomethine ylides are transformed in non-pericyclic ways. 11,12

Carboxylic acids were found to be essential additives in many of these processes as they substantially lower the barriers for azomethine ylide formation. In addition, carboxylic acids serve to readily protonate azomethine ylides to form iminium ions or related N,O-acetal intermediates that undergo further transformations. Thus, the presence of a carboxylic acid, while required to access azomethine ylides, appears to be incompatible with well-established pericyclic azomethine ylide chemistry.

However, we could recently show that azomethine ylides, accessed via a benzoic acid catalyzed process, readily undergo intramolecular [3+2]-cycloadditions. 13

To test whether this strategy is compatible with other types of pericyclic reactions, we decided to explore 1,5electrocyclizations using pyrrolidine and chalcone as model substrates.

As summarized in Table 1, reactions between pyrrolidine and chalcone proceeded under a range of conditions. No formation of 1a was observed in the absence of a carboxylic acid additive (entry 1). Instead, analysis of the crude reaction mixture by 1

H-NMR indicated the presence of the conjugate addition product (not shown) in addition to unmodified chalcone. 14