Regio- and Diastereoselective Synthesis of 2-Arylazetidines: Quantum Chemical Explanation of Baldwin's Rules for the Ring-Formation Reactions of Oxiranes†

Abstract

A general, scalable two-step regio- and diastereoselective method has been described for the synthesis of versatile alkaloid-type azetidines from simple building blocks with excellent overall yields. In the kinetically controlled reaction, only the formation of the strained four-membered ring can be achieved instead of the thermodynamically favorable five-membered rings under appropriate conditions. Remarkable functional group tolerance has also been demonstrated. In this paper, we give a new scope of Baldwin's rules by density functional theory (DFT) calculations with an explicit solvent model, confirming the proposed reaction mechanisms and the role of kinetic controls in the stereochemical outcome of the reported transition-metal-free carbon-carbon bond formation reactions.

Scheme 1. Chemical Skeleton of 2-Arylazetidine-3-ylmethanol Derivatives (1) and Selected Examples for Bioactive 2-Arylazetidines

(LG: leaving group.).

Scheme 2. Synthesis and isolated Yields of the Key Intermediate Oxiranylmethyl-benzylamine Derivatives (2) from Epichlorohydrine (4) or Tosylates (5–7)

Scheme 3. Scope of the LiDA-KOR-Induced Azetidine Formation

Isolated yields of the products are also given. See Scheme 4. Other products were also formed; see the Experimental Section.

Scheme 4. Formation of the Allylic Side Product (9) in the Case of N-Boc Protection of the Amine

Figure 1

Conversion of the epoxide (2d-H⁺) into the four possible products (1d and 10d) via the four TSs (above), together with the bimolecular reaction (below). For the corresponding thermodynamic values, see Table 1.

Figure 2

Transition states (TS-1d-H⁺ and TS-10d-H⁺) of the four- and five-membered rings (without explicit ions and molecules), representing their HOMOs leading to the azetidine (1d) and pyrrolidine derivatives (10d) derived from the oxirane derivative 2d-H⁺. Black lines show the bond angles between the C1–C2–O and C1–C3–O atoms, corresponding to α (orange). Δα = 180° – α (blue). The carbon, hydrogen, nitrogen, and oxygen atoms are marked in gray, white, blue, and red, respectively.

Figure 3

Correlation between the Δα (Δα = 180° – α.) (blue) of TS-1d-H⁺, TS-10d-H⁺, and TS-13 and the related ΔG^‡ values.