Letter pubs.acs.org/OrgLett
Regio- and Diastereoselective Cross-Dehydrogenative Coupling of Tetrahydropyridines with 1,3-Dicarbonyl Compounds Huan Long,†,§ Gang Wang,†,§ Ran Lu,† Mengmeng Xu,‡ Kelian Zhang,‡ Shutao Qi,‡ Yiheng He,‡ Yuxiang Bu,‡ and Lei Liu*,†,‡ †
School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
‡
S Supporting Information *
ABSTRACT: A regio- and diastereoselective cross-dehydrogenative coupling of N-carbamoyl tetrahydropyridines with a variety of 1,3-dicarbonyl compounds is described. The method exhibits good functional group tolerance, diastereoselectively generating cis-2,6- or cis-2,4-substituted tetrahydropyridines by using different types of 1,3-dicarbonyls. Moreover, a two-step sequence involving diastereoselective cross-dehydrogenative coupling followed by epimerization was also developed, allowing facile access to trans-2,6-substituted tetrahydropyridines as single isomers. Applications in natural product synthesis and divergent analogue preparation were further demonstrated.
F
rom the viewpoint of green and sustainable chemistry, constructing C−C bonds through bimolecular crossdehydrogenative coupling (CDC) of two readily available C− H components represents an ideal strategy that not only streamlines existing syntheses of valuable complex molecules but also unlocks opportunities for economical and topologically straightforward synthetic planning for both complex target molecules and their analogues for lead discovery.1,2 In particular, diastereoselective CDC is extremely fascinating because it would rapidly deliver increases not only in structural complexity but also in stereochemical diversity.3 However, development of diastereoselective bimolecular CDC reactions has been challenging, and the capabilities of the synthesis remain underdeveloped. Therefore, developing such methods bearing a utility-oriented mind-set is highly desired. Cis- or trans-2,6- or 2,4-substituted tetrahydropyridines and piperidines possessing a methylene carbonyl substituent at the C2 or C4 position are key units spread across numerous bioactive natural products and pharmaceuticals (Figure 1A).4 Prevalent strategies for preparing such skeleton bearing methylene carbonyl moieties typically require the prefunctionalization of both reaction components, and thus, the economy of the syntheses might be impaired.5 We envisioned that a regio- and diastereoselective bimolecular CDC of tetrahydropyridines 1 with 1,3-dicarbonyl compounds (2) followed by decarboxylation would provide a highly straightforward way to access the above complex molecules and their analogues (Figure 1B). Additionally, the potential ability of expected product 3 to undergo epimerization through retro-aza-Michael/ aza-Michael reactions might provide access to the opposite stereoisomer. 6 Herein, we report the first regio- and diastereoselective CDC of N-carbamoyltetrahydropyridines © XXXX American Chemical Society
Figure 1. (A) Representative 2,6- or 2,4-disubstituted tetrahydropyridines and piperidines. (B) Our retrosynthetic analysis.
with 1,3-dicarbonyl compounds. Applications in natural product and analogue syntheses are also demonstrated. Initially, the reaction of 1a with dimethyl malonate (2a) was selected for optimization (Table 1). No expected product was observed when TEMPO+BF4− (TEMPO oxoammonium Received: March 16, 2017
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DOI: 10.1021/acs.orglett.7b00787 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Reaction Condition Optimizationa
Scheme 1. Diastereoselective Cross-Dehydrogenative Coupling with Dialkyl Malonates
entry
additive
regioselectivityb (3a/ 4a)
3a, yieldc (%)
3a, drd
1 2e 3 4 5 6f 7g 8h
metal salt Cu(CH3CN)4PF6 Cu(OTf)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2
n.a. n.a. 10:1 1:8 13:1 n.a. 14:1 n.a.
