Electrophilic Activation of [1.1.1]Propellane for the Synthesis of Nitrogen-Substituted Bicyclo[1.1.1]pentanes

Abstract

Strategies commonly used for the synthesis of functionalised bicyclo[1.1.1]pentanes (BCP) rely on the reaction of [1.1.1]propellane with anionic or radical intermediates. In contrast, electrophilic activation has remained a considerable challenge due to the facile decomposition of BCP cations, which has severely limited the applications of this strategy. Herein, we report the electrophilic activation of [1.1.1]propellane in a halogen bond complex, which enables its reaction with electron-neutral nucleophiles such as anilines and azoles to give nitrogen-substituted BCPs that are prominent motifs in drug discovery. A detailed computational analysis indicates that the key halogen bonding interaction promotes nucleophilic attack without sacrificing cage stabilisation. Overall, our work rehabilitates electrophilic activation of [1.1.1]propellane as a valuable strategy for accessing functionalised BCPs.

Keywords: [1.1.1]propellane; amination; bicyclo[1.1.1]pentane; bioisostere; halogen bond.

Figure 1

A) Examples of bioactive nitrogen‐substituted BCPs in patents. B) Synthesis of N‐substituted BCPs from [1.1.1]Propellane 1 with anionic and radical reagents. C) Facile decomposition of BCP carbocations. D) Synthesis of N‐substituted BCPs from 1,3‐bis‐iodo‐BCP 2. E) Synthesis of N‐substituted BCPs by electrophilic activation of 1 in halogen bond complex 5. NIS: N‐iodosuccinimide.

Scheme 1

Contrasting reactivity of I₂ and NIS in their activation of propellane 1 for the alkylation of a model aniline substrate. NIS: N‐iodosuccinimide.

Scheme 2

Initial scope of 3‐iodo‐BCP‐anilines.

Scheme 3

Scope of the BCP‐anilines obtained by the N‐alkylation/C‐I reduction one‐pot sequence. All reactions were conducted on 0.2 mmol of aniline in 1 mL of solvent except otherwise noted; yields of pure isolated products. [a] In THF. [b] BEt₃ (0.2 equiv), HS(CH₂)₂OH (1 equiv); reduction reaction rapidly warmed to r.t and stirred for 1 h. [c] In Et₂O. [d] In acetone. [e] BEt₃ (1 equiv), HS(CH₂)₂OH (2 equiv). [f] Reduction reaction warmed to 0 °C slowly over 2.5 h. [g] Reduction reaction kept at −40 °C for 2 h. [h] ¹H NMR yield, volatile compound. [i] Reduction not attempted.

Scheme 4

Scope of 3‐iodo‐BCP‐azoles. [a] In Et₂O, 1‐ITMH. [b] In acetone, DIH. [c] Single regioisomer. [d] Ratio of regioisomers. DIH: 1,3‐diiodo‐5,5‐dimethylhydantoin. 1‐ITMH: 1‐iodo‐3,5,5‐trimethylhydantoin.

Figure 2

Bond distances from X‐ray crystal structures of 26 and 27 and the optimised geometry of 30 calculated at the SMD(Et₂O)‐B2GP‐PLYP‐D3BJ/def2‐TZVP level of theory. Average values for r _C1‐C2 and r _C3‐C2.

Scheme 5

Reaction of procaine.

Scheme 6

Further functionalisation of the BCP‐anilines and BCP‐azoles. a) 1 mol % [Rh₂(OAc)₄], PhC(=N₂)CO₂Me (2 equiv), CH₂Cl₂, 30 °C, 3 hours slow addition of diazo compound, then 20 h. b) 5 mol % [Pd(Pt‐Bu₃)₂], t‐BuONa (1.5 equiv), p‐BrC₆H₄CO₂ t‐Bu (1.2 equiv), toluene, 110 °C, 24 h. c) n‐Bu₃SnH (1.1 equiv), AIBN (0.3 equiv), methyl acrylate (8 equiv), benzene, 80 °C, 3.5 h. d) (Me₃Si)₃SiH (1.8 equiv), AIBN (0.2 equiv), water, 75 °C, 5 h. e) 3 mol % Pd(PPh₃)₄, t‐BuOK (2 equiv), isopropanol, blue light, r.t., 22 h. AIBN: azobisisobutyronitrile.

Figure 3

A) Optimised geometry and Hirschfeld charges (δ) of carbocation 3, and the energy profile of its fragmentation calculated at the SMD(Et₂O)‐DLPNO‐CCSD(T)/def2‐TZVPP//SMD(Et₂O)‐B2GP‐PLYP‐D3BJ/def2‐TZVP level of theory. B) Optimised geometries and Hirschfeld charges (δ) of halogen bond complex 5 and transition state 41. C) Energy profile of the reaction of propellane 1 with aniline and NIS. Parts B and C were calculated at the [SMD(Et₂O)‐DLPNO‐CCSD(T)/def2‐TZVPP, ma‐def2‐TZVPP on I//SMD(Et₂O)‐B2GP‐PLYP‐D3BJ/def2‐TZVP, ma‐def2‐TZVP on I] level of theory. D) Fukui dual descriptors (f ⁽²⁾(r)) for [1.1.1]propellane 1 and halogen‐bond complex 5, calculated at the B2GP‐PLYP‐D3BJ/def2‐TZVP level; f ⁽²⁾(r)<0 (red) and f ⁽²⁾(r)>0 (blue); isovalue=0.005 au.