Synthesis of Functionalised Piperidines Through a [3 + 3] Cycloaddition Strategy

Abstract

A novel approach to functionalised piperidines is described through a [3+3] cycloaddition reaction of aziridines with Pd-trimethylenemethane complexes. Importantly, the employment of enantiomerically pure aziridines (prepared in three steps from the appropriate amino acids) allows the corresponding piperidines to be furnished in enantiomerically pure form. Additionally, the application of this technique in the total synthesis of (-)-pseudoconhydrine is described.Cycloaddition reactions are amongst the most effective methods for the rapid synthesis of functionalised cyclic systems in a stereocontrolled manner. 1 Additionally, the application of transition metal catalysts in these processes provides added opportunity to exert further control over the efficiency and selectivity of these reactions. In the context of six membered ring formation, the Diels-Alder reaction holds a uniquely prominent position and formally comprises a [4+2] assembly strategy. 2 In contrast, the employment of a [3+3] cycloaddition approach has been much less widely studied. 3 In this context, the employment of Pd-catalysis has led to techniques for the assembly of pyran derivatives 4 whereas piperidine systems have been prepared by a formal [3+3] cycloaddition reaction of 1,3-cyclic sulfates with C,N-dianions, 5 vinylogous amides with a,b-unsaturated iminiums, 6 a,a'-dimethoxylated amides with allyltrimethylsilane 7 and Pd-trimethylenemethane (Pd-TMM) complexes with aziridines. 8 We anticipated that the latter approach represented a potentially efficient technique for the synthesis of enantiomerically pure nitrogen and oxygen containing heterocyclic products through the employment of readily available enantiomerically pure aziridines and epoxides (Figure). Despite the attractiveness of this approach, only a single reaction of this type is known in the literature whereby racemic Ntosyl and N-acyl 2-methylaziridines have been transformed to the corresponding piperidines. 8 We decided to undertake a study of the generality of this [3+3] cycloaddition process, particularly with a view to preparing enantiomerically pure piperidines. Accordingly, we report herein our initial results on the reaction scope and its use in a short enantioselective synthesis of (-)-pseudoconhydrine.Enantiomerically pure aziridines were prepared in 3 steps from the appropriate amino acids by the method of Craig. 9 We decided to employ the commercially available conjunctive reagent 2-[(trimethylsilyl)methyl]-2-propen-1-yl acetate as a convenient source for the in situ generation of the Pd-TMM complex, since it has been applied successfully in the presence of a range of palladium catalysts and has been shown to be an efficient partner for other cycloaddition processes. 10 With the requisite substrates in hand, we began our studies by investigating the effects of catalyst system on the efficiency of the [3+3] cycloaddition reaction. In our hands, the use of Pd(PPh 3 ) 4 following the procedure of Kemmitt et al. 8 was ineffective in promoting piperidine formation. Notably...

Highly Selective Palladium‐Catalyzed Intramolecular Chloroamination of Unactivated Alkenes by Using Hydrogen Peroxide as an Oxidant

“…In addition, it is interesting to note that X-ray structure determination of 2 m and 2 o shows that the substituents adjacent to the amine moiety prefer an axial orientation due to the steric bulky of sulfonyl group (Scheme 3, bottom). [13] However, the cyclization of alkenylamines like 1 a generally undergoes 5-exo model to give five-membered ring, which is opposite to our results. [8] Based on this consideration, there are three different mechanism manifolds to address the six-membered ring 2 a formation (Scheme 4): 1) the reaction yields five-membered product 3 a first, then a isomerization of 3 a occurs to give six-membered ring 2 a via an aziridinium intermediate III (path a); [14] 2) the formation of aziridinium intermediate III might be formed through in- www.chemeurj.org tramolecular nucleophilic attack at carbon center of Pd IV intermediate II by N moiety with concomitant Pd II release (path b); 3) alternatively, if a reversible 5-exo and 6-endo aminopalladation was involved, and the oxidative cleavage of C À Pd II bond of intermediate IV to generate the C À Cl bond was faster than that of I, the reaction might expect to generate six-membered product 2 a as sole or major product (path c).…”

Ring Expansions of Activated Aziridines and Azetidines

“…It is worth noting that optically pure aziridines provided the piperidines in enantiomerically pure form. The group published the first report on this chemistry in 2001 where they performed several [3 + 3]-annulation reaction employing various 2-alkyl/aryl-N-activated aziridines with the commercially available conjunctive reagent 2-[(trimethylsilyl)methyl]-2-propen-1-yl acetate 365 in the presence of 10 mol% Pd(OAc) 2 and 60 mol% P(O i Pr) 3 and 20 mol% n-BuLi in THF at 65 C for the in situ generation of the Pd-TMM complex 363 to obtain the corresponding piperidines derivatives 364 in high yields (Scheme 53) [160]. As a demonstration of the generality of their methodology, they synthesized hemlock alkaloid (À)-pseudoconhydrine 371 in enantiomerically pure form after a few steps of synthetic manipulation as depicted in Scheme 94.…”

Recent trends in the synthesis of O-glycosides of 2-amino-2-deoxysugars

“…As demonstrated above, nucleophilic ring opening 94 and cycloaddition reactions 95 have harnessed the synthetic utility of these intermediates. Although direct synthesis of 1,2-aziridines from glycal precursors has not yet emerged, it is believed that a variety of approaches, among which are products of amidation procedures described herein, proceed through aziridines.…”