Synthesis of Structurally Diverse 3-, 4-, 5-, and 6-Membered Heterocycles from Diisopropyl Iminomalonates and Soft C-Nucleophiles

Abstract

Herein, we present a general synthetic strategy for the preparation of 3-, 4-, 5-, and 6-membered heterocyclic unnatural amino acid derivatives by exploiting facile Mannich-type reactions between readily available N-alkyl- and N-aryl-substituted diisopropyl iminomalonates and a wide range of soft anionic C-nucleophiles without using any catalyst or additive. Fully substituted aziridines were obtained in a single step when enolates of α-bromo esters were employed as nucleophiles. Enantiomerically enriched azetidines, γ-lactones, and tetrahydroquinolines were obtained via a two-step catalytic asymmetric reduction and cyclization sequence from ketone enolate-derived adducts. Finally, highly substituted γ-lactams were prepared in one pot from adducts obtained using acetonitrile-derived carbanions. Overall, this work clearly demonstrates the utility of iminomalonates as highly versatile building blocks for the practical and scalable synthesis of structurally diverse heterocycles.

Figure 1.

Exploring the reactivity of hard and soft nucleophiles with iminomalonates.

Figure 2.

Comparison of achievable structural diversity in known Mannich reactions and this study.

Figure 3.

Proposed synthesis of chiral nonracemic azetidines, tetrahydroquinolines, and lactones from iminomalonates via enantio- merically enriched secondary alcohols (28).

Figure 4.

Proposed synthesis of aziridines and lactams from iminomalonates (25).

Figure 5.

Natural products and active pharmaceutical ingredients that contain 3-, 4-, 5-, and 6-membered heterocycles.

Figure 6.

Scope of substrates using iminomalonates as electrophiles. All iminomalonates were prepared from the corresponding amines by simple condensation with ketomalonate hydrate. The enolate addition reactions were conducted on a 1–5 mmol scale with 0.2 M concentration of the iminomalonate at the indicated temperature and were considered complete upon the full consumption of the individual iminomalonates as determined by TLC analysis.

Figure 7.

Scope of substrates for the reduction of ketone adducts. All chiral and racemic alcohols were prepared from the corresponding ketone adducts by simple reduction using BH₃·DMS in the presence of CBS catalyst. The reductions were conducted on a 0.5–3 mmol scale with 0.2 M concentration of the ketone adduct at the indicated temperature and considered complete upon full consumption of the individual ketone adducts as determined by TLC analysis.

Figure 8.

M06–2X/def2-TZVP//M06–2X/6–31G(d,p) transition-state structures and energies (Gibbs energy, enthalpy at 298 K) for (a) acetophenone-derived enolate and phenyl isopropyl ketone-derived enolate addition to N-Bu and N-Ph iminomalonates and (b) potassium-coordinated enolate addition to N-Bu and N-Ph iminomalonates. Energies are relative to separated reactants and in kcal/mol.

Figure 9.

Cyclization of chiral alcohols to corresponding azetidines and tetrahydroquinolines. The chiral alcohols obtained by reduction of ketone adducts were subjected to the above-mentioned conditions with 0.05 M concentration of starting material for cyclization to corresponding azetidines and tetrahydroquinolines considered complete upon full consumption of the individual chiral alcohols by TLC analysis.

Figure 10.

Cyclization of chiral alcohols to corresponding lactones. The chiral alcohols, obtained by the reduction of ketone adducts, were subjected to the conditions A or B for cyclization with 0.2 M concentration of alcohol to the corresponding lactones and considered complete upon the full consumption of the individual alcohols by TLC analysis.

Figure 11.

Cyclization of chiral alcohols to the corresponding lactones. The enantiomerically enriched and racemic 2° alcohols, obtained by reductions of ketone adducts, were subjected to the conditions A or B for cyclization with 0.2 M concentration of alcohol to corresponding to lactones and considered complete upon the full consumption of the individual chiral and achiral alcohols by TLC analysis.

Figure 12.

Scope of substrates using aryl/alkyl iminomalonates as electrophiles. All of the aromatic as well as aliphatic iminomalonates have been prepared from the corresponding amines by simple condensation with ketomalonate hydrate. The aziridination reactions were conducted on a 1 mmol scale with 0.1 M concentration of iminomalonate at the indicated temperature and considered complete upon full consumption of the individual iminomalonates by TLC analysis.

Figure 13.

Scope of substrates using iminomalonates as electrophiles. All iminomalonates were prepared from the corresponding amines by simple condensation with ketomalonate hydrate. The carbanion addition reactions were conducted on a 1–4 mmol scale with 0.13 M concentration of the iminomalonate at the indicated temperature and considered complete upon full consumption of the individual iminomalonate as determined by TLC analysis.

Figure 14.

Scope of substrates for cyclization using nitrile adducts. All of the nitrile adducts were prepared by carbanion addition to the iminomalonate. These nitrile adducts were reduced and subsequently cyclized to the corresponding lactams using the above-mentioned conditions and considered complete upon the full consumption of the individual nitrile adducts by TLC analysis.

Figure 15.

//M06–2X/6–31G(d,p)[LANL2DZ for Br] calculated reaction pathway structures and energies (Gibbs free energy, enthalpy at 298 K) for 46-derived enolate addition to N-Ph iminomalonate.