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. 2022 Mar 16;144(10):4572-4584.
doi: 10.1021/jacs.1c13434. Epub 2022 Mar 1.

Asymmetric Azidation under Hydrogen Bonding Phase-Transfer Catalysis: A Combined Experimental and Computational Study

Jimmy Wang  1 , Matthew A Horwitz  1 , Alexander B Dürr  1 , Francesco Ibba  1 , Gabriele Pupo  1 , Yuan Gao  2 , Paolo Ricci  1 , Kirsten E Christensen  1 , Tejas P Pathak  3 , Timothy D W Claridge  1 , Guy C Lloyd-Jones  2 , Robert S Paton  4 , Véronique Gouverneur  1
Affiliations

Asymmetric Azidation under Hydrogen Bonding Phase-Transfer Catalysis: A Combined Experimental and Computational Study

Jimmy Wang et al. J Am Chem Soc. .

Abstract

Asymmetric catalytic azidation has increased in importance to access enantioenriched nitrogen containing molecules, but methods that employ inexpensive sodium azide remain scarce. This encouraged us to undertake a detailed study on the application of hydrogen bonding phase-transfer catalysis (HB-PTC) to enantioselective azidation with sodium azide. So far, this phase-transfer manifold has been applied exclusively to insoluble metal alkali fluorides for carbon-fluorine bond formation. Herein, we disclose the asymmetric ring opening of meso aziridinium electrophiles derived from β-chloroamines with sodium azide in the presence of a chiral bisurea catalyst. The structure of novel hydrogen bonded azide complexes was analyzed computationally, in the solid state by X-ray diffraction, and in solution phase by 1H and 14N/15N NMR spectroscopy. With N-isopropylated BINAM-derived bisurea, end-on binding of azide in a tripodal fashion to all three NH bonds is energetically favorable, an arrangement reminiscent of the corresponding dynamically more rigid trifurcated hydrogen-bonded fluoride complex. Computational analysis informs that the most stable transition state leading to the major enantiomer displays attack from the hydrogen-bonded end of the azide anion. All three H-bonds are retained in the transition state; however, as seen in asymmetric HB-PTC fluorination, the H-bond between the nucleophile and the monodentate urea lengthens most noticeably along the reaction coordinate. Kinetic studies corroborate with the turnover rate limiting event resulting in a chiral ion pair containing an aziridinium cation and a catalyst-bound azide anion, along with catalyst inhibition incurred by accumulation of NaCl. This study demonstrates that HB-PTC can serve as an activation mode for inorganic salts other than metal alkali fluorides for applications in asymmetric synthesis.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Molecular principles of catalysis and inhibition featuring hydrogen bonding interactions in natural enzymes; translational design strategies for synthetic organocatalysts. (A) Azide binding in natural enzymes. (B) Azidation with sodium azide under hydrogen bonding phase-transfer catalysis (this work).
Scheme 1
Scheme 1. Azidation of β-Chloroamine (±)-2a Using NaN3 in 1,2-Difluorobenzene with(out) Schreiner’s Urea 1a
Scheme 2
Scheme 2. Substrate Scope, Scale-up, and Derivatization
1.09 mmol scale. Absolute configuration of major enantiomer not determined.
Figure 2
Figure 2
Coordination diversity of achiral urea-azide complexes. M+ = tetrabutylammonium or Na[15-crown-5].
Figure 3
Figure 3
Achiral hydrogen bonded donor-azide complexes. Counter cations and crown ethers are omitted for clarity.
Figure 4
Figure 4
DFT computed conformers and relative Gibbs energies (kJ·mol–1) of the [(S)-1k·N3]− complex. N–H distances (Å) and natural charges on azide N atoms (au) also shown.
Figure 5
Figure 5
(A) Ka(1:1) and Ka(2:1) for the complexes of TBA·N3 with (S)-1k in CDCl3 (2 mM). (B) 14N spectra of and TBA·N3 complexed to 1 equiv of (S)-1k in CDCl3 (25 mM). (C) 1D and 2D 1H–15N HMBC spectra of (S)-1k·[1-15N]N3 (CDCl3, 25 mM, 213 K).
Figure 6
Figure 6
(A) Asymmetric unit of a Z′ = 2 crystal structure consisting of both (R)-1k and (S)-1k complexed to tetrabutylammonium azide. (B) View of (S)-1k complexed to azide. Distances provided in Ångstroms, displacement ellipsoids drawn at 50% probability level. (C) Overlay of [1k·N3]− (DFT vs X-ray).
Figure 7
Figure 7
In situ ATR-FTIR analysis of the reaction of 2a with {NaN3}s in 1,2-difluorobenzene, catalyzed by (S)-1k. Data, open circles. Kinetic model (eq 2), solid red lines/crosses. (A) Temporal growth of [3a] from [2a]0 = 0.25, 0.18, and 0.13 M, at [(S)-1k]0 = 0.025M. (B) Temporal growth of [3a] from [2a]0 = 0.25 M, at catalyst (S)-1k loadings (mol %) indicated. (C) Net enantiomeric excess of (S,S)-3a at catalyst (S)-1k loadings (0.6, 1.3, 2.6, 7.7, 10, and 20 mol %). Constants used for fitting eq 2: a = 0.081(±0.018) M–0.5 s–1; b = 2.1(±0.9); c = 1.8(±0.5) × 10–5 M0.5 s–1; r = {NaN3}s/{NaCl}s. Enantioselectivity employed in all fits as aS,S/aR,R = 7.94 (e.r. = 88.8:11.2) and cS,S/cR,R = 1.00 (e.r. = 50:50).
Figure 8
Figure 8
Two pathways for generation of 3a from NaN3 and 2a catalyzed by 1k, in competition with a racemic background reaction. The pathways are kinetically equivalent in the context of eq 2.xN3 is the mole fraction of {[1k·X]−[Na+]}in which X is azide.
Figure 9
Figure 9
DFT computed transition structures for aziridinium formation, azidation with 1a·N3–, and binding of azide vs chloride to catalysts 1a and 1k. Distances in Å and energies in kJ·mol–1.
Figure 10
Figure 10
Low-lying enantiodetermining azidation TSs with (S)-1k. Relative distortion energies of aziridinium and [(S)-1k·N3]− fragment in each TS shown. The reduced density gradient isosurface (RDG = 0.3) around the substrate is shown to indicate qualitatively the extent of substrate-catalyst noncovalent interactions in each TS.
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