Divergent Mechanisms of the Banert Cascade with Propargyl Azides

Abstract

Triazoles are privileged heterocycles for a variety of applications. The synthesis of 1H-triazoles can be accomplished by the Banert cascade from propargylic azides. Depending on the substrate and conditions, the Banert cascade can proceed by either a sigmatropic or prototropic mechanism. This report describes the first detailed kinetic analysis of the Banert cascade proceeding by both pathways including substituent effects and KIE. The analysis identified the inflection point in the divergent pathways, allowing future work to predict which Banert products are accessible.

Graphical Abstract

INTRODUCTION

The triazole heterocycle is a common motif found in a wide variety of materials and biologically active molecules.^1–6 The triazole ring is recognized as an amide bond surrogate and an effective peptidomimetic.⁷ Alternatively, triazole linked poly-saccharides are known to possess a variety of desirable functional properties.⁸ The most common synthesis of 1,2,3-triazoles is via the copper-catalyzed alkyne–azide cycloaddition (CuAAC) reaction.^9–12 The major triazole product of a CuAAC reaction is substituted at the 1 and 4 positions (Figure 1). Typically, CuAAC is ineffective at directly affording triazole products with a carbon substituent at the 5 position because the mechanism is proposed to proceed through a copper acetylide complex,^13–15 although exceptions have been reported with specifically functionalized alkynes.^16–19 Alternatively, the ruthenium-catalyzed alkyne–azide cycloaddition (RuAAC) results in an isomeric 1,5-disubstituted 1,2,3-triazole (Figure 1).^20,21 Therefore, CuAAC and RuAAC reactions are considered complementary. However, the synthesis of 1H- triazoles with substituents at the 4 and 5 positions is much less straightforward.^22–28 Conceptually, a 1H-triazole may be more analogous to a native peptide due to the presence of both a hydrogen bond donor and acceptor and because it can adopt tautomeric structures.²⁹ One potentially efficient 1H-triazole synthesis is via the Banert cascade (Figure 1 and Scheme 1).^30,31 The Banert cascade has been used for this purpose in several synthetic contexts.^32–43

Figure 1.

Isomeric triazoles and corresponding synthesis.

Scheme 1.

Divergent Mechanisms of the Banert Cascade

Banert reported a synthesis of 1H-triazoles in 1989 that arose from propargylic azides (Scheme 1).³⁰ Initially, a sigmatropic cascade was reported that proceeds through an initial [3,3] rearrangement, resulting in an allenyl azide (Scheme 1a).^44,45 Banert found that the rate of electrocyclization (step i, Scheme 1) of allenyl azides could be fit to the Taft equation.⁴⁵ This sigmatropic reaction is reminiscent of the Winstein rearrangement, which is known for allylic azides.^46–48 In the Banert cascade, the allenyl azide is thought to undergo a rapid electrocyclization to generate a triazafulvene (step i).⁴⁵ The triazafulvene is highly electrophilic, similar to an o-quinone methide, and can polymerize, be trapped by solvent, or captured by another nucleophile (step ii).^31,49 Shortly after the initial report, Banert disclosed that a prototropic pathway could be mediated by base (Scheme 1b).⁵⁰ Interestingly, this process provides a regioisomeric triazole from the same starting material (Scheme 1a vs b).

Due to our ongoing interest in triazole synthesis^51,52 and allylic azides,^53–55 we were interested in investigating the reactivity of propargylic azides in the Banert cascade. We endeavored to quantify how various substituents would affect the rate of rearrangement and to understand the prototropic vs sigmatropic dichotomy. Reported herein is a detailed kinetic study of substituted 1-aryl-3-azido-1-butynes, which identified the break point in the divergent mechanisms.

RESULTS AND DISCUSSION

Our study began with the synthesis of the requisite azide substrates (Scheme 2), which was accomplished from commercially available aryl-acetylenes 1a–i. Lithiation with ⁿBuLi and subsequent addition to acetaldehyde afforded propargylic alcohols 2a–i. Derivatization was accomplished with MsCl and Et₃N followed by nucleophilic substitution with NaN₃. This afforded propargylic azides 3a–i, which were stable to silica gel purification and prolonged storage at −20°C.

Scheme 2.

Synthesis of Propargylic Azides

To investigate the Banert cascade under sigmatropic conditions, azides 3a–3i were dissolved in MeOH and heated to 60 °C for 24 h, which resulted in near quantitative formation of triazoles 4a–4i (see Supporting Information for details). The same reaction was conducted in MeOD and monitored by ¹H NMR using trimethoxybenzene as an internal standard. The reaction time course was fit using Copasi software⁵⁶ for a simple, single step, first order reaction (azide 3 to triazole 4). This simplified kinetic model for the Banert cascade provided a satisfactory fit. Alternatively the conversion of azides 3a–3i could be fit using the classical linear transform (ln([3]/[3₀]) vs t). Both methods provided similar values for the rate constant (e.g., for 3a to 4a the Copasi fit was 1.48 × 10⁻⁴ s⁻¹ and the linear transform was 1.23 × 10⁻⁴ s⁻¹). The ability to use a simplified kinetic model for the complex cascade process is consistent with Banert’s observation that there is minimal buildup of allenyl azide during the reaction.⁴⁵ For the azides investigated here, neither the allenyl azide nor the triazafulvene intermediate were directly observed as an intermediate by ¹H NMR. This is consistent with a computational model of this cascade, which predicts a rate determining barrier for the initial sigmatropic process (Scheme 1, [3,3]) and a fast electrocyclization (Scheme 1a, step i).⁵⁷

For a series of azides 3a–3i, the rate of the sigmatropic Banert cascade could be correlated to the Hammett values σ (R² = 0.86, ρ = −0.15), σ⁺ (R² = 0.89, ρ = −0.13), and σ⁻ (R² = 0.69, ρ = −0.09).⁵⁸ The best correlation was to σ⁺ (Figure 2), which is consistent with prior observations that the rate of the Winstein rearrangement is slightly accelerated with electron donating groups.^46,48,53 It should be noted that the ρ value is quite small (−0.13), which indicates that this process is largely unaffected by substituent effects (k_rel for 4-Me vs 4-CN is less than 1.5). This is loosely consistent with the broad substrate scope previously reported for the sigmatropic Banert cascade.^30,31,49

Figure 2.

Hammett correlation for sigmatropic cascade. Plot of log(k/ k_H) vs σ⁺ for substituent effects on the sigmatropic Banert cascade of azides 3a–3i in MeOD at 60 °C. Rates were determined by ¹H NMR spectroscopy and measured in duplicate. The average of two replicates is shown. The error bars reflect the difference between the two trials.

Having determined parameters for the sigmatropic pathway, the prototropic pathway was investigated. Azides 3a–3i were heated to 60 °C under basic conditions (10 equiv of NaOMe in MeOH). Unlike the sigmatropic reaction, the prototropic reaction showed a striking qualitative dependence on the aryl substituent. For azides 3a–3d, the prototropic product was not observed, likely because the sigmatropic pathway was faster, and only triazoles 4a–4d were isolated. On the other hand, azide 3i produced only triazole 5i (R = CN) in high yield via the prototropic pathway.

Given the qualitative differences observed, the reaction was queried by conducting the cascade of azide 3f at different concentrations. The product ratio of triazoles 5f:4f was determined. The 5f:4f ratio was taken as k_rel for the prototropic vs sigmatropic pathways, which demonstrated a first order dependence on the concentration of NaOMe (see Supporting Information). This prompted a detailed kinetic analysis. A quantitative assay was established by HPLC-UV to monitor the reaction progress. Attempts at using ¹H NMR analysis, as was done for the sigmatropic reaction, did not afford high quality data. A number of factors complicated the ¹H NMR analysis including partial triazole ionization under basic conditions (signal broadening) and the presence of adventitious water, which could trap the cascade competitively with methanol. The HPLC assay was therefore found to be more reliable. The rate of the reaction for azide 3g to triazole 4g was determined by both methods and only a minimal difference was observed (see Table S1). The reaction conditions used a 10-fold excess of NaOMe relative to the azide substrate to ensure pseudo-first order reactions at 60 °C. The reaction time course data was fit using Copasi software for a simple kinetic model for parallel first order reactions (azide 3 to triazole 4 and azide 3 to triazole 5), which provided k_obs for the prototropic pathway. The conversion of azide 3 could also be fit using the classical linear transform (ln([3]/[3₀]) vs t), providing the sum of the two rates.

The rate of the prototropic Banert cascade with azides 3e– 3i could be correlated to the Hammett values σ (R² = 0.87, ρ = 4.1), σ⁺ (R² = 0.85, ρ = 3.1), and σ⁻ (R² = 0.95, ρ = 2.7). The best correlation was to σ⁻ (Figure 3) and the ρ value of 2.7 is consistent with an anionic intermediate, as would be expected for deprotonation by NaOMe. The modest correlation for the formation of triazole 5f may be due to the competing acidity of the terminal CC–H bond. The difference in Hammett value correlation and ρ value for the sigmatropic and prototropic pathways clearly indicate divergent mechanisms for these competing processes (Figure 2 vs Figure 3).

Figure 3.

Hammett correlation for the prototropic cascade. Plot of log(k/k_Cl) vs σ⁻ for substituent effects on the prototropic Banert cascade of azides 3e– 3i in MeOH at 60 °C. Rates were measured by HPLC-UV and measured in duplicate. The average of two replicates is shown. The error bars reflect the difference between the two trials. For error bars not visible, the difference was smaller than the point marker.

To substantiate the observed divergence in mechanism, a deuterated substrate (3j) was prepared from tetradeutero-acetaldehyde to measure a kinetic isotope effect (KIE, see Experimental Section for synthesis). The reaction with azide 3j could be compared to the cascade with azide 3g (Scheme 3). The formation of both triazoles was monitored simultaneously in the presence of NaOMe by HPLC-UV. The sigmatropic reaction (azides 3 to triazoles 4) proceeded with a minimal KIE = 1.03, which is likely within error of unity based on the HPLC assay. The α-azido deuterium label remained intact in the product as well. The observed KIE is consistent with a sigmatropic process for the formation of triazoles 4, where no C–H bond breaking/making is required. However, a distinct primary KIE = 1.81 was observed for the prototropic cascade (azides 3 to triazoles 5). Furthermore, ca. 50% of the α-azido deuterium label was washed out during the formation of triazole 5j. Both of these observations are expected in the prototropic reaction where the α-C–H/D bond is broken.

Scheme 3.

Kinetic Isotope Effect for Banert Cascades

CONCLUSION

This study has provided definitive evidence that the Banert cascade can proceed via two divergent mechanisms. Both processes show distinct correlations to either the Hammett value σ⁺ or σ⁻, and these correlations provide ρ values of opposite sign. Furthermore, the sigmatropic reaction shows a minimal KIE, whereas the prototropic reaction shows a primary KIE. Significantly, a 4-Cl-C₆H₄ group defines the inflection point in the two mechanisms, which can be used for predictive purposes to identify substrates that should be susceptible to the prototropic mechanism.

EXPERIMENTAL SECTION

Azide Safety.

Azides are known to be high energy materials, and explosions have been reported when working with azides.⁵⁹ In the course of this work, no issues were encountered. All of the azides synthesized in this report have C/N ratios equal to or above the recommended guideline of 3. Precautionary safety shields were used for all reactions using or producing more than 1 mmol of azide. Safety shields were used both in the fume hood and during rotary evaporation. All waste and aqueous solution that could be contaminated with azide were kept in individually labeled containers and were kept strictly free of acid to avoid the accidental production of HN₃. Caution! Do not use aqueous HCl during work up of any of the reactions reported herein. Further reading on azide safety is available.^60,61

General Methods.

All reactions conducted at elevated temperature used aluminum heating blocks with magnetic stirring (500 rpm). Reported temperatures were based on an external thermal couple. All commercially available chemicals were used without further purification. Dry tetrahydrofuran and dimethylformamide were obtained from a commercial solvent system utilizing activated alumina columns under a positive pressure of argon. Thin-layer chromatography (TLC) was used for monitoring reaction progress. Visualization was conducted by using UV light, KMnO₄, or PMA stains. Organic solutions were concentrated using rotary evaporator under reduced pressure at or below 40 °C. Flash chromatography was performed on a Teledyne Isco CombiFlash R_f system utilizing normal phase precolumn load cartridges and gold high performance columns. All proton (¹H) nuclear magnetic resonance spectra were recorded at 400 or 500 MHz. All carbon (¹³C) nuclear magnetic resonance spectra were recorded at 100 or 125 MHz. The fluorine (¹⁹F) nuclear magnetic resonance spectra were recorded at 376 or 470 MHz with proton decoupling. Chemical shifts are expressed in parts per million and are referenced to residual solvent (CDCl₃: 7.27 ppm), to the central carbon in the NMR solvent (CDCl₃: 77.0 ppm). Data are presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, ad = apparent doublet–para disubstituted pattern, t = triplet, q = quartet and m = multiplet), integration, and coupling constant in Hertz (Hz). Infrared (IR) spectra were taken in a Nicolet Nexus 670 FT-IR with salt plates. IR spectra were reported in cm⁻¹.

4-(p-Tolyl)but-3-yn-2-ol(2a).

A procedure was adapted from a known method.⁶² To a solution of 4-ethynyltoulene 1a (1.31 mL, 10.3 mmol) in THF (30 mL) cooled in an ice bath, n-butyllithium (5.2 mL, 2.5 M in hexanes, 13 mmol) was added dropwise. After 30 min, acetaldehyde (0.8 mL, 14 mmol) was added dropwise, and the ice bath was removed. After 30 min, the reaction mixture was poured onto NH₄Cl (15 mL, sat. aq.). The resulting mixture was extracted with EtOAc (3 × 15 mL). The combined organic phases were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure. Purification by column chromatography (0–40% EtOAc/ hexanes) afforded alcohol 2a (850 mg, 74%) as a yellow oil. Characterization data for this compound has been reported.⁶³ An image of the ¹H NMR spectrum is supplied in the Supporting Information.

4-(4-(tert-Butyl)phenyl)but-3-yn-2-ol(2b).

Following the procedure above for compound 2a using 4-tert-butylethynylbenzene 1b, the product (252 mg, 59%) was isolated as a colorless solid: ¹H NMR (500 MHz; CDCl₃) δ 7.38 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 4.78 (q, J = 6.6 Hz, 1H), 1.93 (br, 1H), 1.57 (d, J = 6.6 Hz, 3H), 1.33 (s, 9H); ¹³C{¹H} NMR (125 MHz; CDCl₃) δ 151.7, 131.4, 125.3, 119.5, 90.3, 84.1, 58.9, 34.8, 31.2, 24.5;IR (NaCl, thin film, cm⁻¹) 3286, 2960, 2902, 2886, 2250, 1505, 1365, 1097; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₄H₁₈NaO⁺ 225.1250, found 225.1243.

4-(4-(tert-Butyl)phenyl)but-3-yn-2-ol (2c).

Following the procedure above for compound 2a using phenylacetylene 1c, the product (415 mg, 64%) was isolated as a yellow oil. Characterization data for this compound has been reported.⁶² An image of the ¹H NMR spectrum is supplied in the Supporting Information.

4-(4-Fluorophenyl)but-3-yn-2-ol (2d).

Following the procedure above for compound 2a using 4-fluorophenylacetylene 1d, the product (481 mg, 59%) was isolated as a yellow oil. Characterization data for this compound has been reported.⁶² An image of the ¹H NMR spectrum is supplied in the Supporting Information.

4-(4-Chlorophenyl)but-3-yn-2-ol (2e).

Following the procedure above for compound 2a using (4-chlorophenyl)acetylene 1e, the product (722 mg, 80%) was isolated as a colorless solid. Characterization data for this compound has been reported.⁶⁴ An image of the ¹H NMR spectrum is supplied in the Supporting Information.

4-(4-Ethynylphenyl)but-3-yn-2-ol (2f).

The procedure above for compound 2a was modified by cooling a solution of 1,4-diethynylbenzene 1f (1.26 g, 9.96 mmol) in THF to −78 °C prior to the addition of ⁿBuLi (4.4 mL, 2.5 M in hexanes, 11 mmol) and acetaldehyde (236 mg, 5.37 mmol). After 2 h at −78 °C, the reaction was quenched. The product (513 mg, 56%) was isolated as a pale yellow solid: ¹H NMR (500 MHz; CDCl₃) δ 7.43 (d, J = 7.7 Hz, 2H), 7.38 (d, J = 7.7 Hz, 2H), 4.78 (q, J = 6.6 Hz, 1H), 3.19 (s, 1H), 2.38 (br, 1H), 1.57 (d, J = 6.6 Hz, 3H); ¹³C{¹H} NMR (125 MHz; CDCl₃) δ 132.0, 131.5, 123.1, 122.0, 93.0, 83.4, 83.2, 79.0, 58.7, 24.3; IR (NaCl, thin film, cm⁻¹) 3280, 2984, 2934, 2229, 1498, 1265, 1105, 1034; HRMS (EI-TOF) m/z [M]⁺ calcd for C₁₂H₁₀O⁺ 170.0726, found 170.0709.

4-(4-(Trifluoromethyl)phenyl)but-3-yn-2-ol (2g).

Following the procedure above for compound 2a using 4-trifloromethylphenylacetylene 1g, the product (987 mg, 96%) was isolated as a yellow oil. Characterization data for this compound has been reported.⁶⁵ An image of the ¹H NMR spectrum is supplied in the Supporting Information.

Methyl 4-(3-hydroxybut-1-yn-1-yl)benzoate (2h).

The procedure above for compound 2a was modified by cooling a solution of methyl 4-ethynylbenzoate 1h (498 mg, 3.1 mmol) in THF to −78 °C prior to addition of ⁿBuLi (1.4 mL, 2.5 M in hexanes, 3.4 mmol) and acetaldehyde (0.21 mL, 3.7 mmol). After 1.5 h at −78 °C, the reaction was quenched. The product (322 mg, 51%) was isolated as a pale yellow solid. Characterization data for this compound has been reported.⁶³ An image of the ¹H NMR spectrum is supplied in the Supporting Information.

4-(3-Hydroxybut-1-yn-1-yl)benzonitrile (2i).

The procedure above for compound 2a was modified by cooling a solution of 4-ethynylbenzonitrile 1i (640 mg, 5.03 mmol) in THF to −78 °C prior to addition of ⁿBuLi (2.2 mL, 2.5 M in hexanes, 5.5 mmol) and acetaldehyde (0.34 mL, 6.0 mmol). After 2 h at −78 °C, the reaction was quenched. The product (573 mg, 67%) was isolated as a pale flash chromatography (gradient elution 40–100% EtOAc in hexanes) afforded the product 4a as a colorless solid (39 mg, 91%): ¹H NMR (500 MHz; CDCl₃) δ 10.95 (br, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 4.86 (q, J = 6.6 Hz, 1H), 3.33 (s, 3H), 2.42 (s, 3H), 1.60 (d, J = 6.6 Hz, 3H); ¹³C{1H} NMR (125 MHz; CDCl₃) δ 143.8, 142.7, 138.6, 129.5, 128.1, 126.9, 71.0, 56.1, 21.3, 19.9; IR (NaCl, thin film, cm⁻¹) 3162, 2983, 2932, 2825, 1454, 1115, 1094, 832; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₂H₁₅N₃NaO⁺ 240.1107, found 240.1113.

5-(4-(tert-Butyl)phenyl)-4-(1-methoxyethyl)-1H-1,2,3-triazole (4b).

Following the procedure above for compound 4a using azide 3b, the product (56 mg, 97%) was isolated as a colorless solid: ¹H NMR (500 MHz; CDCl₃) δ 12.43 (br, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.3 Hz, 2H), 4.90 (q, J = 6.6 Hz, 1H), 3.34 (s, 3H), 1.61 (d, J = 6.6 Hz, 3H), 1.37 (s, 9H); ¹³C{1H} NMR (125 MHz; CDCl₃) δ 151.6, 143.6, 142.7, 127.9, 127.0, 125.7, 71.1, 56.1, 34.7, 31.3, 20.0; IR (NaCl, thin film, cm⁻¹) 3162, 2983, 2932, 2825, 1454, 1115, 1093, 823; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₅H₂₁N₃NaO⁺ 282.1577, found 282.1578.

4-(1-Methoxyethyl)-5-phenyl-1H-1,2,3-triazole (4c).

Following the procedure above for compound 4a using azide 3c, the product (65 mg, 99%) was isolated as a colorless solid: ¹H NMR (500 MHz; CDCl₃) δ 10.90 (br, 1H), 7.78 (d, J = 7.8 Hz, 2H), 7.46 (dd, J = 7.8, 7.2 Hz, 2H), 7.40 (t, J = 7.3 Hz, 1H), 4.89 (q, J = 6.6 Hz, 1H), 3.33 (s, 3H), 1.61 (d, J = 6.9 Hz, 3H); ¹³C{1H} NMR (125 MHz; CDCl₃) δ 143.8, 130.1, 128.7, 128.5, 128.3, 126.7, 71.1, 56.1, 20.0; IR (NaCl, thin film, cm⁻¹) 3413, 3161, 2986, 2932, 2823, 1449, 1116, 1097; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₁H₁₃N₃NaO⁺ 226.0951, found 226.0957.

5-(4-Fluorophenyl)-4-(1-methoxyethyl)-1H-1,2,3-triazole (4d).

Following the procedure above for compound 4a using azide 3d, the product (48 mg, 99%) was isolated as a colorless oil: ¹H NMR (500 MHz; CDCl₃) δ 10.64 (br, 1H), 7.77 (dd, J = 8.6, 5.6 Hz, 2H), 7.13 (apparent t, J = 8.6 Hz, 2H), 4.84 (q, J = 6.8 Hz, 1H), 3.32 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); ¹³C{1H} NMR (125 MHz; CDCl₃) δ 162.9 (d, J_C−F = 246.6 Hz), 130.1 (d, J_C−F = 8.9 Hz), 128.5 (d, J_C−F = 8.5 Hz), 126.3 (d, J_C−F = 2.6 Hz), 115.7 (d, J_C−F = 21.6 Hz), 115.3 (d, J_C−F = 21.1 Hz), 71.1, 56.0, 19.8; ¹⁹F{1H} NMR (376 MHz; CDCl₃) δ −112.9; IR (NaCl, thin film, cm⁻¹) 3428, 3162, 2987, 2936, 2826, 1508, 1227, 1115, 1092; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₁H₁₂FN₃NaO⁺ 244.0857, found 244.0856.

5-(4-Chlorophenyl)-4-(1-methoxyethyl)-1H-1,2,3-triazole (4e).

Following the procedure above for compound 4a using azide 3e, the product (65 mg, 93%) was isolated as a pale yellow solid: ¹H NMR (500 MHz; CDCl₃) δ 11.28 (br, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 4.85 (q, J = 6.7 Hz, 1H), 3.34 (s, 3H), 1.59 (d, J = 6.7 Hz, 3H); ¹³C{1H} NMR (125 MHz; CDCl₃) δ 143.4, 143.2, 134.7, 129.5, 129.0, 128.6, 71.1, 56.1, 19.7; IR (NaCl, thin film, cm⁻¹) 3165, 2984, 2933, 2823, 1466, 1116, 1094, 835; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₁H₁₂³⁵ClN₃ONa⁺ 260.0561, found 260.0570, [M + Na]⁺ calcd for C₁₁H₁₂³⁷ClN₃NaO⁺ 262.0532, found 262.0533.

5-(4-Ethynylphenyl)-4-(1-methoxyethyl)-1H-1,2,3-triazole (4f).

Following the procedure above for compound 4a using azide 3f, the product (48 mg, 99%) was isolated as a pale yellow solid: ¹H NMR (500 MHz; CDCl₃) δ 13.1 (br, 1H), 7.80 (d, J = 7.1 Hz, 2H), 7.60 (d, J = 7.8 Hz, 2H), 4.87 (q, J = 6.6 Hz, 1H), 3.35 (s, 3H), 3.17 (s, 1H), 1.59 (d, J = 6.6 Hz, 3H); ¹³C{1H} NMR (125 MHz; CDCl₃) δ 143.5, 143.3, 132.5, 130.6, 128.1, 122.2, 83.3, 78.3, 71.2, 56.2, 19.8; IR (NaCl, thin film, cm⁻¹) 3285, 2936, 1450, 1376, 1118; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₃H₁₃N₃NaO⁺ 250.0951, found 250.0949.

4-(1-Methoxyethyl)-5-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazole (4g).

Following the procedure above for compound 4a using azide 3g, the product (62 mg, 98%) was isolated as a colorless solid: ¹H NMR (500 MHz; CDCl₃) δ 11.37 (s, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 4.89 (q, J = 6.6 Hz, 1H), 3.37 (s, 3H), 1.61 (d, J = 6.6 Hz, 3H); ¹³C{1H} NMR (125 MHz; CDCl₃) δ 143.7, 143.4, 133.7 (q, J_C−F = 1.6 Hz),, 130.5 (q, J_C−F = 32.6 Hz), 128.5, 125.7 (q, J_C−F = 3.8 Hz), 124.0 (q, J_C−F = 272.4 Hz), 71.2, 56.2, 19.7 ¹⁹F{1H} NMR (376 MHz; CDCl₃) δ −62.7; IR (NaCl, thin film, cm⁻¹) 3163, 2988, 2934, 1622, 1326, 1120, 1070; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₂H₁₂F₃N₃NaO⁺ 294.0825, found 294.0827.

Methyl 4-(4-(1-methoxyethyl)-1H-1,2,3-triazol-5-yl)benzoate (4h).

Following the procedure above for compound 4a using azide 3h, the product (65 mg, 99%) was isolated as a colorless solid: ¹H NMR (500 MHz; CDCl₃) δ 13.4 (br, 1H), 8.13 (d, J = 7.8 Hz, 2H), 7.91 (d, J = 7.8 Hz, 2H), 4.89 (q, J = 6.7 Hz, 1H), 3.96 (s, 3H), 3.34 (s, 3H), 1.59 (d, J = 6.1 Hz, 3H); ¹³C{1H} NMR (125 MHz; CDCl₃) δ 167.0, 143.5, 143.3, 134.9, 130.0, 129.8, 128.1, 71.2, 56.2, 52.3, 19.8; IR (NaCl, thin film, cm⁻¹) 3193, 2934, 1717, 1614, 1281, 1113; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₃H₁₅N₃NaO₃⁺ 284.1006, found 284.1002.

4-(4-(1-Methoxyethyl)-1H-1,2,3-triazol-5-yl)benzonitrile (4i).

Following the procedure above for compound 4a using azide 3i, the product (23 mg, 99%) was isolated as a colorless solid: ¹H NMR (500 MHz; CDCl₃) δ 10.26 (br, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 4.88 (q, J = 6.7 Hz, 1H), 3.36 (s, 3H), 1.59 (d, J = 6.7 Hz, 3H); ¹³C{1H} NMR (125 MHz; CDCl₃) δ 135.0, 132.5, 132.0, 129.6, 128.7, 118.7, 112.0, 71.2, 56.2, 19.6; IR (NaCl, thin film, cm⁻¹) 3172, 2985, 2933, 2826, 2228, 1613, 1115, 1092, 846; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₂H₁₂N₄NaO⁺ 251.0903, found 251.0908.

4-(1-Methoxyethyl-1,2,2,2-d₄)-5-(4-(trifluoromethyl)phenyl)-1H- 1,2,3-triazole (4j).

Following the procedure above for compound 4a using azide 3j, the product (44.0 mg, quant.) was isolated as a colorless solid:¹H NMR (500 MHz; CDCl₃) δ 13.03 (br, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 3.36 (s, 3H); ¹³C{1H} NMR (125 MHz; CDCl₃) δ 143.5, 133.9, 130.4 (q, J_C−F = 32.8 Hz), 128.4, 125.7 (q, J_C−F = 3.72 Hz), 124.0 (q, J_C−F = 273.0 Hz), 56.1. (Note that no attempt was made to detect multiplets featuring a J_C−D coupling, which were too broad to readily identify); ²H NMR (77 MHz; CDCl₃) δ 4.89 (s, 1D), 1.58 (s, 3D); ¹⁹F{1H} NMR (470 MHz, CDCl₃) δ −62.7; IR (NaCl, thin film, cm⁻¹) 3165, 3008, 2933, 2825, 2360, 2343, 1623, 1411, 1327, 1166, 1125, 1075, 1001, 849; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₂H₈D₄F₃N₃NaO⁺ 298.1076, found 298.1093.

Triazole Synthesis via Prototropic Shift.

Due to the observed break in mechanism, a mixture of both prototropic and sigmatropic triazole products (4 and 5) were observed in some cases. This has been noted below where possible. These NH triazoles also demonstrated dynamic behavior by ¹H NMR and ¹³C NMR. In most cases, the ¹³C resonances for the triazole carbons were not readily detected (very broad and weak signal). For triazole 5e and 5i, a ¹³C NMR is provided in the Supporting Information that was collected at rt in CDCl₃ and a second ¹³C NMR is provided that was collected at 60 °C in C₆D₆, where the remaining carbons are detectable.

4-((4-Chlorophenyl)(methoxy)methyl)-5-methyl-1H-1,2,3-tria- zole (5e).

A solution of azide 3e (70 mg, 0.34 mmol) and NaOMe (0.77 mL, 25 wt % in MeOH, 3.40 mmol) in MeOH (2.5 mL) was heated to 60 °C in a sealed 4 mL vial. After 24 h, the solution was cooled to room temperature, acidified with AcOH (4 mL, 1 M in H₂O, 4 mmol) and extracted with EtOAc (5 × 5 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Purification by flash chromatography (gradient elution 40–100% EtOAc in hexanes) afforded the product 5e (15 mg, 18%) as a colorless oil. Triazole 4e (53 mg, 70%) was also isolated as a colorless oil: ¹H NMR (500 MHz; CDCl₃) δ 12.26 (br, 1H), 7.33 (m, 4H), 5.51 (s, 1H), 3.39 (s, 3H), 2.21 (s, 3H); ¹³C{1H} NMR (125 MHz; CDCl₃) 138.0, 133.6, 128.9, 128.6, 128.2, 128.0, 77.1, 56.9, 10.0; ¹³C{1H} NMR (125 MHz; C₆D₆, 60 °C) 144.9, 140.6, 139.2, 133.8, 128.8, 128.4, 77.8, 56.5, 10.0; IR (NaCl, thin film, cm⁻¹) 3155, 2928, 1595, 1408, 1194, 1089, 1014, 970, 835; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₁H₁₂ClN₃ONa⁺ 260.0561, found 260.0555.

4-((4-Ethynylphenyl)(methoxy)methyl)-5-methyl-1H-1,2,3-tria- zole (5f).

Following the procedure above for compound 5e using azide 3f, triazole 4f (33 mg, 50%) and triazole 5f (17 mg, 26%, colorless oil) were isolated: ¹H NMR (500 MHz; CDCl₃) δ 7.49 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 5.54 (s, 1H), 3.40 (s, 3H), 3.07 (s, 1H), 2.19 (s, 3H); ¹³C{1H} NMR (125 MHz; CDCl₃) 140.2, 132.2, 126.5, 121.6, 83.3, 77.4, 77.4, 57.0, 10.0; IR (NaCl, thin film, cm⁻¹) 3287, 2934, 1591, 1501, 1192, 1090, 1018, 969, 847; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₃H₁₃N₃ONa⁺ 250.0951, found 250.0948.

4-(Methoxy(4-(trifluoromethyl)phenyl)methyl)-5-methyl-1H- 1,2,3-triazole (5g).

Following the procedure above for compound 5e using azide 3g, triazole 4g (11 mg, 14%) and triazole 5g (57 mg, 71%, colorless oil) were isolated: ¹H NMR (500 MHz; CDCl₃) δ 13.17 (br. s, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 5.61 (s, 1H), 3.41 (s, 3H), 2.21 (s, 3H); ¹³C{1H} NMR (125 MHz; CDCl₃) δ 143.6, 133.3 (J_C−F = 1.6 Hz), 130.6, 129.9 (J_C−F = 32.5 Hz), 126.8, 125.3 (J_C−F = 3.6 Hz), 124.0 (J_C−F = 273.5 Hz), 77.2, 57.0, 9.8; ¹⁹F{1H} NMR (470 MHz, CDCl₃) δ −62.6; IR (NaCl, thin film, cm⁻¹) 3141, 2937, 1620, 1415, 1326, 1163, 1126, 1067, 1018, 971; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₂H₁₂F₃N₃ONa⁺ 294.0825, found 294.0825.

Methyl 4-(methoxy(5-methyl-1H-1,2,3-triazol-4-yl)methyl)- benzoate (5h).

Following the procedure above for compound 5e using azide 3h, triazole 5h (18 mg, 35%) was isolated as a colorless oil: ¹H NMR (500 MHz; CDCl₃) δ 12.12 (brs, 1H), 8.05–7.99 (m, 2H), 7.47 (d, J = 8.1 Hz, 2H), 5.60 (s, 1H), 3.92 (s, 3H), 3.41 (s, 3H), 2.18 (s, 3H); ¹³C{1H} NMR (125 MHz; CDCl₃) 166.9, 144.7, 130.0, 129.7, 129.6, 126.5, 77.4, 57.1, 52.1, 10.0; IR (NaCl, thin film, cm⁻¹) 3147, 2931, 2359, 1723, 1611, 1436, 1283, 1193, 1096, 1019, 967 752; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₃H₁₅N₃O₃Na⁺ 284.1006, found 284.0999.

4-(Methoxy(5-methyl-1H-1,2,3-triazol-4-yl)methyl)benzonitrile (5i).

Following the procedure above for compound 5e using azide 3i, triazole 5i (67 mg, 76%) was isolated as a colorless oil: ¹H NMR (500 MHz; CDCl₃) δ 12.56 (brs, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 5.60 (s, 1H), 3.41 (s, 3H), 2.20 (s, 3H); ¹³C{1H} NMR (125 MHz; CDCl₃) 145.0, 132.2, 127.1, 118.6, 111.5, 77.0, 57.1, 9.9; ¹H NMR (500 MHz, C₆D₆) δ 7.14–7.10 (m, 2H), 7.06–7.02 (m, 2H), 5.33 (s, 1H), 3.03 (s, 3H), 2.00 (s, 3H); ¹³C{1H} NMR (126 MHz, C₆D₆, 60 °C) δ 145.3, 144.3, 140.4, 132.2, 127.3, 118.7, 112.2, 77.6, 56.7, 9.9; IR (NaCl, thin film, cm⁻¹) 3143, 2933, 2359, 2229, 1608, 1503, 1444, 1280, 1190, 1092, 971, 798; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₂H₁₂N₄ONa⁺ 251.0903, found 251.0906.

4-(Methoxy(4-(trifluoromethyl)phenyl)methyl)-5-(methyl-d₃)-1H- 1,2,3-triazole (5j).

Following the procedure above for compound 5e using azide 3j, triazole 5j (49 mg, 71%) was isolated as a yellow oil: ¹H NMR (500 MHz; CDCl₃) δ 13.14 (br, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 5.62 (s, 0.5H, ~50%H and ~50%D), 3.41 (s, 3H); ¹³C{1H} NMR (125 MHz, CDCl₃) δ 143.9, 143.6 (apparent d assigned 1 C for 5j-d₄ and 1 C for 5j-d₃), 139.6, 129.9 (q, J_C−F = 31.8 Hz), 126.8, 125.4, (q, J_C−F = 3.7 Hz), 124.1 (q, J_C−F = 271.7 Hz), 77.3, 57.0 (apparent d assigned 1 C for 5j-d₄ and 1 C for 5j-d₃); ²H NMR (77 MHz; CDCl₃) δ 5.61 (s, 0.5D, ~50%H and ~50%D), 2.17 (s, 3D); ¹⁹F{1H} NMR (470 MHz, CDCl₃) δ −62.6; IR (NaCl, thin film, cm⁻¹) 3136, 3027, 2936, 2828, 1660, 1619, 1588, 1412, 1327, 1166, 1125, 1068, 1018, 821; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₂H₈D₄F₃N₃NaO⁺ 298.1076, found 298.1076, [M + Na]⁺ calcd for C₁₂H₉D₃F₃N₃NaO⁺ 297.1013, found 297.1020.