Hydrazone Activation in the Aminocatalytic Cascade Reaction for the Synthesis of Tetrahydroindolizines

In this Letter, we demonstrate the usefulness of hydrazone activation for the synthesis of biologically relevant tetrahydroindolizines. A pyrrol-derived hydrazone bearing a Michael acceptor moiety in the N-alkyl side chain has been designed with the aim of participating in the aminocatalytic cascade reaction leading to the annulation of the new six-membered heterocyclic scaffold. The application of (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether as the aminocatalyst allows for the iminium ion–enamine-mediated cascade to proceed in a fully stereoselective manner.

N itrogen heterocycles constitute privileged structures present in many natural products and pharmacologically active molecules. 1Among them, compounds containing a substituted pyrrole ring are of particular importance to medicinal and synthetic chemists. 2Tetrahydroindolizine and its derivatives are a unique group of pyrrole-ring-containing heterocycles possessing an additional tetrahydropyridine with interesting biological properties.−6 In classical organic synthesis, polar reactions between an electron-rich nucleophile and an electron-poor electrophile constitute a common approach.Already in the 1960s, Corey and Seebach introduced a concept of umpolung, allowing new bond-forming processes to be obtained following the principle of polarity inversion of functional groups. 7One way to access umpolung of the carbonyl group relies on the application of the hydrazone activation phenomenon (Scheme 1, top). 8,9It should be noted that N,N-dialkyl hydrazones of aldehydes are isoelectronic with the corresponding enamines and therefore are considered as aza-enamines (Scheme 1, middle). 10 Moreover, the nucleophilicity enhancement provided by the hydrazone moiety can be effectively transferred over the conjugated double bond system, 11,12 with N,N-dialkyl hydrazones derived from heteroaromatic aldehydes being particularly useful group of vinylogous reactants (Scheme 1, bottom). 13−16 It was shown that such a strategy can be efficiently employed in the asymmetric Friedel−Crafts reaction, (3 + 2)-cycloaddition (for the synthesis of 2,3-dihydro-1H-pyrrolyzines), 15 or asymmetric [4 + 2]-cycloaddition with hydrazone derived from 9-carboxyanthracene, leading to the formation of the biologically relevant dihydro-9,10-ethaneanthracene scaffold. 16iven our interest in the hydrazone activation of (hetero)aromatic aldehydes and the particular usefulness of pyrrole derivatives for the development of new reaction pathways, we turned our attention to tetrahydroindolizine derivatives.It was anticipated that the introduction of a Michael acceptor moiety in the N-alkyl side chain present at the nitrogen atom of pyrrole-derived hydrazone would lead to an interesting reactant.It should be able to participate in a reaction cascade with the appropriately selected Michael acceptor, involving a Friedel−Crafts reaction followed by annulation of the new sixmembered heterocyclic ring via an intramolecular Michael reaction.
Herein, we present our studies on the application of asymmetric aminocatalysis in the synthesis of highly functionalized tetrahydroindolizines.The reaction of hydrazone derivative 1 bearing a Michael acceptor moiety in the sidechain with α,β-unsaturated aldehydes 2 realized under aminocatalytic conditions 17 proceeded in a cascade manner and resulted in the annulation of the new heterocyclic scaffold (Scheme 2).
Optimization studies were performed using hydrazone and cinnamaldehyde 2a as model substrates (Table 1).Initially, catalyst screening was performed (Table 1, entries 1−7) in dichloromethane at room temperature in the presence of trifluoroacetic acid as the cocatalyst (with the exception of the catalyst 3f that was employed as hydrochloride).The course of the reaction was controlled by analyzing 1 H NMR spectra of the crude reaction mixture after 24 h.For catalysts 3a, 3b, 3f, and 3g, only Friedel−Crafts alkylation took place, and no formation of the desired 4a was observed (Table 1, entries 1, 2, 6, and 7, respectively).The remainder of the tested prolinol derivatives 3c−e allowed us to obtain a mixture of compound 5a and its cyclization product 4a (Table 1, entries 3−5, respectively).Encouraged by the excellent diastereo-and enantiomeric excesses of the isolated compound 4a in the presence of the catalyst 3d, we decided to select it for further optimization studies that included the analysis of additive and solvents effects.Co-catalyst screening (Table 1, entries 7−9) indicated that both benzoic and acetic acid promoted the cyclization to 4a, with acetic acid providing better conversion (Table 1, entry 9).Subsequent solvent screening (Table 1, entries 9−14) performed in the presence of acetic acid as the cocatalyst indicated dichloromethane or toluene as the best reaction medium, with toluene providing higher diastereoselectivity (Table 1, entry 14).The use of molecular sieves increased the efficiency of the studied sample (Table 1 entries  15 and 16), with the effect being particularly pronounced in the case of toluene (Table 1, entry 16).
Having an optimized synthesis procedure, we proceeded to determine the applicability range of the developed aminocatalytic reaction of the hydrazone pyrrole derivative 1 with α,βunsaturated aldehydes 2a−o (Table 2).It was found that regardless of the position and the electronic nature of the substituent on the phenyl ring of the aromatic α,β-unsaturated aldehydes 2a−k (Table 2, entries 2−11, respectively), all target compounds 4a−k were obtained in high yields and in a highly diastereo-and enantioselective manner.Furthermore, optimized reaction conditions were successfully applied to aliphatic enals 2l−o (Table 2, entries 12−15, respectively), with the reaction outcome being unbiased toward both the length of the aliphatic chain (Table 2, entries 12 and 13) as well as the presence of functional groups (Table 2, entries 14 and 15).The reaction proved readily scalable, with very good results obtained for aldehyde 2a at 1 mmol scale using only 5 mol % catalyst 3d (Table 2, entry 16).During further studies, morpholine-derived hydrazone 1b was employed, providing product 4p with comparable results (Table 2, entry 17).
In the course of further studies, cycloadduct 4a was subjected to chemoselective transformations (Scheme 3).Initially, unmasking of the hydrazone moiety using meta-Scheme 2. Presentation of Our Synthetic Goals chloroperoxybenzoic acid in dichloromethane was performed, affording nitrile 6a in 96% yield.Nitrile 6a was employed in the further transformations.Reductive amination of the aldehyde group in 6a gave product 7a in a good yield.The reaction was realized under mild conditions using sodium cyanoborohydride as the reduction reagent.Furthermore, products 8a and 9a containing an additional six-membered ring were efficiently obtained following a two-step protocol performed in a one-pot sequence.δ-Lactam 8a was obtained in 45% yield, while the reaction providing δ-lactone 9a was slightly more efficient (57% yield).All products were obtained as single diastereoisomers.
The absolute configuration of product 4g was confirmed by the X-ray structural analysis (for details, see the SI). 18The stereochemistry of compounds 4a−o has been assigned by analogy assuming the same reaction mechanism.The mechanism and stereochemical model of the studied reaction was proposed (Scheme 4).The catalytic cycle of the reaction is initiated with the condensation of aminocatalyst 3d with α,βunsaturated aldehydes 2, which results in the formation of the appropriate iminium ion 10.The Friedel−Crafts reaction of hydrazone 1a with iminium ion 10 is facilitated by the donating effect provided by the hydrazone moiety in 1a.The stereochemical outcome of the addition is governed by the steric shielding principle exerted by the bulky substituent present in the C-2 position of the pyrrolidine ring in 10.Subsequently, the cyclization of 11 takes place via the enamine-mediated Michael reaction.It is postulated that the reaction proceeds via a chairlike transition state the controls the diastereoselectivity of the process.Finally, the hydrolysis of intermediate 12 occurs, releasing the catalyst 3d with the restoration of the carbonyl moiety in 4.
In conclusion, a new aminocatalytic reaction of a pyrrolderived hydrazone bearing a Michael acceptor moiety in the N- Reactions were performed on a 0.1 mmol scale using 1 (1.2 equiv), 2a−o (1 equiv), catalyst 3d (20 mol %), and acetic acid (40 mol %) in toluene (0.4 mL) at room temperature for 24 h.b The isolated yield is given.c Determined by chiral stationary phase UPC 2 .d The reaction was carried out with five equivalents of aldehyde 2l at 0 °C for 2 days and overnight at room temperature.e The reaction was carried out with two portions of aldehydes 2l−o at 0 °C for 2 days and overnight at room temperature.f The reaction was proceeded on a 1 mmol scale using 1a (1.2 equiv), 2a (1 equiv), catalyst 3d (5 mol %), and acetic acid (40 mol %) in toluene (4 mL) at room temperature for 24 h.g The reaction was performed using 1b (1.2 equiv), 2a (1 equiv), catalyst 3d (20 mol %), and acetic acid (40 mol %) in toluene (0.4 mL) at room temperature for 96 h.

Scheme 3. Stereoselective Transformations of Tetrahydroindolizine 4a
Organic Letters alkyl side chain with α,β-unsaturated aldehydes was developed.The synthesis of the target products proceeded by Friedel− Crafts alkylation and subsequent cyclization via a Michael reaction.Target products were obtained with very good yields and excellent diastereo-and enantioselectivities.The possibility of using the obtained desired products for further modifications leading to useful polycyclic compounds was also demonstrated.

Table 1 .
Aminocatalytic Asymmetric Synthesis of Tetrahydroindolizine 4a: Optimization Studies a a Reactions were performed on a 0.05 mmol scale using 1a (1.2 equiv) and 2a (1 equiv) in 0.2 mL of the solvent for 24 h.bConversion was determined by 1 H NMR of a crude reaction mixture.Isolated yield is given in parentheses.cDeterminedby 1 H NMR of a crude reaction mixture.d Determined by chiral stationary phase UPC 2 .e Reaction carried out in the presence of 3 Å molecular sieves.

Table 2 .
Aminocatalytic Asymmetric Synthesis of Tetrahydroindolizines 4: Scope Studies a a