γ-Amino Alcohols via Energy Transfer Enabled Brook Rearrangement

Abstract

In the long-standing quest to synthesize fundamental building blocks with key functional group motifs, photochemistry in the recent past has comprehensively established its attractiveness. Amino alcohols are not only functionally diverse but are ubiquitous in the biologically active realm of compounds. We developed bench-stable bifunctional reagents that could then access the sparsely reported γ-amino alcohols directly from feedstock alkenes through energy transfer (EnT) photocatalysis. A designed 1,3-linkage across alkenes is made possible by the intervention of a radical Brook rearrangement that takes place downstream to the EnT-mediated homolysis of our reagent(s). A combination of experimental mechanistic investigations and detailed computational studies (DFT) indicates a radical chain propagated reaction pathway.

Figure 1

(A) γ-Amino alcohols highlighting dual chemical functionality and their prevalence in bioactive compounds, (B) conventional methods to synthesize 1,3-amino alcohols, (C) σ-bond homolysis coupled with concurrent radical rearrangement, (D) radical Brook rearrangement, and (E) working hypothesis (this work).

Figure 2

(A) Reagent synthetic pathway and (B) reagent library; triplet energies (kcal·mol^–1) are calculated using uB3LYP-D3/def2-svp-CPCM (DCM) level of theory. DMF = N,N-dimethylformamide.

Figure 3

Scope table and sensitivity screen. Standard conditions: 0.2 mmol of 1, 0.3 mmol of 2, Ir−F (1.0 mol %), and CH₂Cl₂ (0.05 M). Crude ¹H NMR yields are given in parentheses unless otherwise mentioned. ^aYield after isolation of deprotected salts (0.2 mmol)—deprotection with 2.5 mL of MeOH and 2.5 mL of 1.0 M HCl solution under air for 1 h. ^b1H NMR yields are reported.

Figure 4

Product diversifications. ^aCrude ¹H NMR yield was determined using CH₂Br₂ as an internal standard. CDI = 1,1′-Carbonyldiimidazole; DIPEA = N,N-Diisopropylethylamine.

Figure 5

Mechanistic investigations. (A) Cyclic voltammetry studies, (B) UV/vis spectroscopy, (C) direct excitation experiments, (D) employment of thermal radical initiators as control (AIBN: Azobis(isobutyronitrile), BPO: Benzoyl peroxide, DTBP: di-tert-butyl peroxide), (E) Stern–Volmer quenching analysis, (F) TEMPO-trapping experiments, and (G) quantum yield analysis.

Figure 6

Proposed mechanism was supported by computational studies. Calculated free Gibbs energies [CPCM(DCM) uB3LYP-D3/def2-svp] are given in kcal·mol^–1. For details, see the Supporting Information.