Synthesis and Explosion Hazards of 4-Azido-l-phenylalanine

Abstract

A reliable, scalable, cost-effective, and chromatography-free synthesis of 4-azido-l-phenylalanine beginning from l-phenylalanine is described. Investigations into the safety of the synthesis reveal that the Ullman-like Cu(I)-catalyzed azidation step does not represent a significant risk. The isolated 4-azido-l-phenylalanine product, however, exhibits previously undocumented explosive characteristics.

Figure 1

Literature precedents for the construction of the phenyl azide in 4. Azidodediazoniation involves the use of explosive diazonium salts, and poisonous and explosive hydrazoic acid. A detonation involving the diazotransfer reagent, imiadazole-1-sulfonyl azide, has been reported by the Stick laboratory.^, A safety appraisal for the Ullman-like synthesis of phenyl azides has not previously appeared in the literature.

Figure 2

A heuristic proposal for understanding the mechanism of iodination by Suzuki’s reagent. The mechanism likely involves the formation of a polarized iodine intermediate, which then participates in S_EAr reactions.

Figure 3

Potential explosion hazards associated with the synthesis of 4. Roman numerals (i–viii) denote the eight discreet chemical mixtures chosen for explosion risk evaluation by DSC; hazards v–viii were further evaluated by ARC.

Figure 4

Mosher amide analyses. The ¹H NMR spectra of 9 (blue trace) and 10 (red trace) exhibit distinct Δδ^SR values at the ester CH₃, the α-proton, and both β-protons of the amino acid portion of the molecule. The Mosher acyl group also exhibits an unusually high Δδ^SR value at its etheric -OCH₃, apparently caused by diamagnetic shielding from the phenyl ring of the amino acid. The exquisite sensitivity of ¹⁹F NMR also provides high confidence in the optical purity, as no significant overlap is observed between the blue and red traces.

Figure 5

ORTEP representation of the molecular structure of Boc-Oxyma determined by single-crystal X-ray crystallography. Ellipsoids are shown at the 50% probability level. All hydrogens were discovered and are drawn as fixed-size spheres of radius 0.15Å.

Figure 6

Comparison of IR spectra of Boc-Oxyma in the carbonyl stretch region. A) IR spectrum of Boc-Oxyma (FT-IR/ATR); B) Previously reported IR spectrum of the same compound (FT-IR/KBr disc). The image has been reproduced from ref. and has been altered as follows: the spectrum has been reflected left-to-right.

Figure 7

The base-catalyzed formation of activated esters with Boc-Oxyma. The final step of the mechanism eliminates a tert-butoxide anion, allowing efficient activated ester generation in the presence of sub-stoichiometric quantities of the added base.

Figure 8

Menthyl ester analyses. The ¹H NMR spectra of 13 (blue trace) and 14 (red trace) exhibit subtle Δδ^LD values at the three methyl groups on the menthyl portion of the molecule, and the tert-butyl of the Boc protecting group. These slight differences are clearly apparent in the sample comprising a ~1:1 mixture of both stereoisomers (grey trace). The ¹³C NMR spectrum is less crowded, and the signals assigned to the carbons of the menthol isopropyl group, and a neighboring ring methylene, display the greatest Δδ^LD values. The lack of common peaks between the blue and red traces indicates that no epimerization at the amino acid α-carbon has occurred during the synthesis of 2 and 3, or during the esterification reaction.

Scheme 1

Synthesis of 4-azido-L-phenylalanine. Conditions: a) i) NaIO₃, I₂, AcOH/H₂SO₄, 70 °C, ii) NaIO₄; b) Boc₂O, Et₃N, H₂O/MeOH, 55 °C; c) N,N′-dimethylethylenediamine, CuI, NaN₃, KOH, sodium ascorbate, EtOH/H₂O, 25 °C; d) H₂SO₄/H₂O, 1,4-dioxane, 25 °C.

Scheme 2

Mosher amide synthesis. Conditions: a) SOCl₂, MeOH, 50 °C, 2 h; b) (S)- or (R)-MTPA-Cl, iPr₂NEt, DMAP, DMF, rt, 16 h.

Scheme 3

Synthesis of Boc-Oxyma. Conditions: a) Boc₂O, iPr₂NEt (cat.), THF, 35 °C, 3.5 h.

Scheme 4

Synthesis of menthyl esters using Boc-Oxyma as coupling agent. Conditions: a) Boc-Oxyma, iPr₂NEt, DMAP, D- or L-menthol, EtOAc, rt, 24 h.