Reaction Scope of Methyl 1,2,3-Triazine-5-carboxylate with Amidines and Impact of C4/C6 Substitution

Abstract

A comprehensive study of the reaction scope of methyl 1,2,3-triazine-5-carboxylate (3a) with alkyl and aryl amidines is disclosed, reacting at room temperature at remarkable rates (<5 min, 0.1 M in CH₃CN) nearly 10,000-fold faster than unsubstituted 1,2,3-triazine and providing the product pyrimidines in high yield. C4 methyl substitution of the 1,2,3-triazine (3b) had little effect on the rate of the reaction, whereas C4/C6 dimethyl substitution (3c) slowed the room temperature reaction (<24 h, 0.25 M) but displayed an unaltered scope, providing the product pyrimidines in similarly high yields. Measured second order rate constants of the reaction of 3a–c, the corresponding nitriles 3e–f, and 1,2,3-triazine itself (3d) with benzamidine and substituted derivatives quantitated the remarkable reactivity of 3a and 3e, verified the inverse electron demand nature of the reaction (Hammett ρ = −1.50 for substituted amidines, ρ = +7.9 for 5-substituted 1,2,3-triazine), and provide a quantitative measure of the impact of 4-methyl and 4,6-dimethyl substitution on the reactivity of the methyl 1,2,3-triazine-5-carboxylate and 5-cyano-1,2,3-triazine core heterocycles.

Graphical Abstract

INTRODUCTION

The inverse electron demand Diels–Alder reaction of heterocyclic azadienes constitutes powerful methodology for the preparation of complex heterocyclic structures of interest.¹ In past studies, we have systematically explored the cycloaddition reactions and applications of 1,2,4,5-tetrazines,² 1,2,4-triazines,³ 1,3,5-triazines,⁴ 1,3,4-oxadiazoles,⁵ 1,2-diazines,⁶ and recently the first monocyclic 1,2,3,5-tetrazine.⁷ The power of the cycloadditions has enabled the rapid construction of highly substituted and densely functionalized heterocyclic cores found in an extensive number of natural products.^1c Recently the field has also exploited the unusually rapid cycloaddition reactions of 1,2,4,5-tetrazines in bioorthogonal reactions, providing a foundation for novel bioconjugation techniques, the tetrazine ligation, and click chemistry for probing complex biological systems.⁸

In recent studies, we examined and extended the use of 1,2,3-triazine cycloadditions, an underexplored heterocyclic azadiene class. We systematically explored their synthesis, incorporated a wide variety of substitution patterns, defined their Diels–Alder reaction with traditional electron-rich dienophiles, and introduced a remarkably fast and efficient 1,2,3-triazine/amidine cycloaddition.⁹ It is possible, even likely, that the latter newly discovered reaction of amidines with 1,2,3-triazines represents a stepwise addition–cyclization reaction proceeding through polar intermediates. However, we also described mechanistic studies (amidine ¹⁵N label and no intermediate or byproduct observation) with results also consistent with a concerted [4+2] cycloaddition across C4/N1 (Scheme 1).^9d Although our development of the 1,2,3-triazines has been and continues to be driven by their projected use in the total syntheses of natural products that to date include dihydrolysergic acid, pyrimidoblamic acid, P-3A, and methoxatin, the 1,2,3-triazine/amidine reaction pair also constitutes a new potential powerful bioorthogonal reaction.¹⁰

Scheme 1.

Reaction of 1,2,3-triazines with amidines.

Consonant C5 substitution of 1,2,3-triazine with electron-withdrawing groups predictably increases the inverse electron demand cycloaddition reactivity. Correspondingly, methyl 1,2,3-triazine-5-carboxylate (3a) emerged as an extraordinarily reactive compound, expanding the breadth of reactions accessible with this heterocyclic azadiene class. In these studies, three examples of the newly discovered 1,2,3-triazine/amidine cycloaddition proved to be unusually rapid with 3a,^9b achieving quantitative yields instantaneously at room temperature and highlighting the potential of this reaction and class of heterocyclic azadienes.

Detailed herein is a comprehensive study of the scope of the cycloaddition reaction of 3a with a suite of amidines 4a–w that was conducted alongside 3c. This not only provided a detailed assessment of the scope and remarkable reactivity of 3a with amidines, but also enabled a direct comparison of the impact of the additional 4,6-dimethyl substitution found in 3c. The results with 3c defined this substitution impact on the cycloaddition reactivity, which also occurs at room temperature, and provided conditions where the reaction proceeds efficiently without impacting the typically high yield of the substituted pyrimidine products. Comparison rate constants for the reaction of 3a–c with benzamidine are disclosed alongside those measured for 1,2,3-triazine (3d) and the corresponding nitriles 3e–f, providing a quantitative measure of the reactivity of 3a and the impact of 4-methyl and 4,6-dimethyl substitution on the methyl 1,2,3-triazine-5-carboxylate core.

RESULTS AND DISCUSSION

The synthesis of 3a–c was accomplished by using Okitani’s method,¹² the oxidative ring expansion of N-aminopyrazoles effected by NaIO₄ in a biphasic reaction solution (Figure 1). The route proceeds from the corresponding pyrazoles 1a–c, available from commercial vendors or in single transformation from commercial materials. N-Amination was achieved by using a strong base (KO^tBu, NaH also compatible) to deprotonate the pyrazole, followed by addition of ca. 0.15 M ethereal monochloroamine to afford a mixture of N-aminopyrazoles 2a–c that contained contaminant starting material. This mixture is often difficult to separate, especially in the case of N-amination regioisomers (e.g., 2b) and was carried through the next step, forgoing purification. The subsequent NaIO₄ oxidative ring expansion generated the desired 1,2,3-triazines, which were purified by standard column chromatography. We previously reported the preparation of 3a^9b and both 3b and 3c have been synthesized previously through a similar oxidative ring expansion¹³ although no studies on the cycloaddition reactivity of these two compounds have been disclosed. 1,2,3-Triazines 3a and 3c were further characterized by X-ray (Figure 1, see also Supporting Information Tables S1–S2 and Figures S1–S2) and the significance of the X-ray of 3c is discussed later alongside rate studies quantitating the reactivities of 3a–c and related compounds.¹¹

Figure 1.

(top) Synthesis of 1,2,3-triazines. (bottom) X-ray crystal structures of 3a (left, CCDC 2069831) and 3c (right, CCDC 2069830).¹¹

With 3a–c in hand, their respective 1,2,3-triazine/amidine cycloaddition reaction were optimized, selecting benzamidine (4a) as the reacting partner and conducting the reactions on a 0.3 mmol scale with quantitation by pure product isolation. A defining characteristic of 3a is its extraordinary reactivity. Attempts to control the reaction at traditional reaction concentrations (entries 1–2) even at room temperature afforded inconsistent yields (Figure 2). This improved as more dilute reaction concentrations were employed and found to be especially effective at 0.10 M (entries 3–5). The use of lower reaction temperatures and extended reaction times did not further impact the yield (entry 7). Ultimately, the use of 1.50 equiv of 3a added as a solution in CH₃CN to a stirred solution of 4a (0.1 M final concentration) in CH₃CN at room temperature proved to be the most effective manner to achieve consistently high yields (entry 6) even with reaction times as short as 5 min. Under these conditions and even at the lower concentration of 10 mM (entry 8), the reaction of 3a with benzamidine proceeded rapidly at room temperature, providing 5a in high yield (81%, 2.5 h). Finally, despite concerns over the reactivity of 3a with nucleophiles, its reaction with benzamidine was just as effective in 30% H₂O/CH₃CN (94%, entry 9, 23 °C, minimal reaction time not established).

Figure 2.

Optimization of reaction of methyl 1,2,3-triazine-5-carboxylate (3a) with benzamidine.

Similar optimization of the reaction of 3c with 4a began with a concentration study, conducting the reactions on a 0.3 mmol scale with quantitation by pure product isolation (Figure 3). Unlike the near instantaneous reaction of 3a, the 4,6-dimethyl substitution in 3c lowered the reactivity, allowing reactions to be conducted at higher concentrations without impacting yields (entries 1–5) and still effective at room temperature. An increase in reaction temperature (entries 6–7 vs 4) simply drove the reaction to completion more quickly as judged by TLC without impacting yield. Spectroscopic analysis of a reaction allowed to continue for an extended time (entry 8) revealed incomplete consumption of 3c and conversion to pyrimidine product. This was rectified by increasing the amount of amidine and provided optimized conditions (entry 9). Notably, and despite the 4,6-dimethyl substitution, the reaction proceeds effectively at room temperature at the modest reaction concentration of 0.25 M 3c, providing 7a in 86% yield. A small solvent screen (entries 9–13) reinforced the choice of CH₃CN but demonstrates the compatibility of the reaction with other solvents as necessary.

Figure 3.

Optimization of reaction of methyl 4,6-dimethyl-1,2,3-triazine-5-carboxylate (3c) with benzamidine.

Summarized in Figure 4 are the results of a comprehensive study of the reaction of 3a with the suite of amidines 4a–v conducted on a 0.3 mmol scale. In most cases, the reaction proceeds instantaneously at room temperature with observable evolution of nitrogen and a color change indicative of cycloaddition. Generation of the pyrimidine products can be followed by TLC and were isolated by standard silica gel chromatography in excellent yields, highlighting the ease with which substituted pyrimidines can be prepared by this method. The substrates examined include both aryl and aliphatic amidines and tolerate aryl o-substitution without noticeable impact (entries 2 and 17). Aryl amidines with halogen substituents (entries 5–7), a full range of electron-donating groups including a potentially reactive aniline amine (entries 2–4, 10–11), nearly any electron-withdrawing substituent (entries 8–9 and 12), electron-deficient heterocycles (entries 13–15), and aliphatic amidines with varying degrees of branching, including those with imposing steric features (entries 18–22), are well tolerated. Except for 5I, bearing a p-nitro group that requires a longer reaction time or more amidine for effective conversion (entry 12), the yields of pyrimidine are excellent, and the reactions were complete in <5 min at room temperature.

Figure 4.

Reaction of methyl 1,2,3-triazine-5-carboxylate (3a) with amidines.

An analogous comprehensive study of the reaction of 3c with amidines 4a–v was conducted on a 0.3 mmol scale (Figure 5). Although the reaction conditions are different from those of 3a with respect to the reaction time (12–24 h vs 5 min), 3c proved to be an excellent participant in the reaction with little difference in yield of pyrimidine product produced. In some cases, the product generated in the reaction precipitated from solution due to its limited solubility. Though normally inconsequential, inhibition of solution stirring was observed at times and negatively impacted yields, requiring elevated temperatures (60 °C) to maintain a homogeneous reaction mixture and maximize product yields (entries 5–7, 9, 12, 14, 17). Notably, this use of 60 °C (vs 23 °C) was necessary due solely to solubility and was not a result of the reactivity of 3c. Like 3a, 3c effectively reacted with both aryl and aliphatic amidines, tolerates aryl o-substituted amidines, proved effective even with sterically demanding amidines and accommodated the full range of aryl substituents observed effective with 3a, including those bearing less reactive electron-withdrawing groups and electron-deficient heterocyclic amidines.

Figure 5.

Reaction of methyl 4,6-dimethyl-1,2,3-triazine-5-carboxylate (3c) with amidines.

Because of the unusually rapid cycloadditions of 3a, the rate of reaction of 3a with benzamidine was established to quantitate this remarkable reactivity (Figure 6). The impact of mono- and dimethyl substitution on the reaction rate was also quantitated with 3b and 3c also using benzamidine (4a, 2 equiv) as the substrate. The reactions between 3a–c and 4a were conducted in acetonitrile-d₃ at room temperature (298 K) and monitored by ¹H NMR with clean conversion from reactant to product with no observable reaction intermediates or byproducts. Notably, the reactions of 3a and 3b with 4a were conducted at more dilute concentrations [0.68 mM, 3a; 0.43 mM, 3b vs 250 mM, 3c] than the preparative reactions to sufficiently slow the reaction to obtain easily quantifiable measurements.

Figure 6.

Second order rate constants.

The second order rate constant for the reaction of 3a with benzamidine (1.50 ± 0.04 M⁻¹s⁻¹) reflects the extraordinarily fast reaction, being nearly 10,000-fold faster than unsubstituted 1,2,3-triazine (3d). It proved to be roughly 10-fold lower than the reported second order rate constant for its reaction with acetamidine (13.4 ± 0.15 M⁻¹s⁻¹).¹⁴ In addition to the preparative utility of this 1,2,3-triazine, its reactivity is well within the range required of biorthogonal conjugation and labeling studies,¹⁵ and is capable of effective use at highly dilute conditions at room temperature.

The second order rate constant for the reaction of 3b with benzamidine (0.25 ± 0.004 M⁻¹s⁻¹) was found to be only 6-fold lower than 3a. The minimal impact observed with monomethyl substitution is noteworthy, as its anticipated reduced reactivity with nucleophiles provided by the C4 methyl substituent may prove useful in employing 1,2,3-triazines in bioorthogonal chemistry.

The second order rate constant for the reaction of 3c proved to be much smaller [(5.05 ± 0.03) × 10⁻⁴ M⁻¹s⁻¹, 3000-fold slower] than for the reaction of 3a. This diminished rate can be attributed to a combination of: (1) the steric effect of substitution at either center (C4/C6) engageable in the cycloaddition reaction and (2) the loss of effective 1,2,3-triazine conjugation with the electron-withdrawing methyl ester, which adopts a conformation perpendicular to the aromatic ring because of the o,o’-disubstitution (see X-ray structure in Figure 1). Nonetheless, it remains 3-fold more reactive than the unsubstituted 1,2,3-triazine (3d), which itself also participates in the reaction with amidines very effectively.⁹ The combined disruption of the C5 methyl ester conjugation and activation by the sterically imposed perpendicular conformation and the relatively lack of impact on the rate observed with monomethyl substitution (3b) suggests that the 4,6-dimethyl substitution likely has a smaller direct steric impact on the rate of reaction of 3c. Thus, the large overall impact of the dimethyl substitution with 3c appears to be more pronounced because of the added indirect steric effect of disrupting the dominant electronic activation of the C5 methyl ester.

To quantify these effects more accurately, 5-cyano-1,2,3-triazine (3e) and the corresponding 5-cyano-4,6-dimethyl-1,2,3-triazine (3f), which does not suffer a disrupted aryl conjugation of the nitrile derived from the o,o’-dimethyl substitution, were prepared and the kinetics of their reactions with benzamidine established. First, 3f was found to react with a second order rate constant of (6.3 ± 0.1) × 10⁻² M⁻¹s⁻¹ with a t_1/2 of 25 min at 4 mM (concentration used for kinetics), being >100-fold faster than 3c, a stunning 350-fold faster than the parent unsubstituted 1,2,3-triazine (3d), and only 4-fold and 25-fold slower than 3b and 3a, respectively. 5-Cyano-1,2,3-triazine (3e) proved extraordinarily reactive exhibiting a second order rate constant of 24.4 ± 0.8 M⁻¹s⁻¹ with a t_1/2 of 8 min at 36 μM (concentration required for measurable kinetics), being a little more than 15-fold faster than 3a, nearly 400-fold more reactive than 3f, and a stunning 140,000-fold faster than the parent unsubstituted 1,2,3-triazine (3d). As such, 5-cyano-1,2,3-triazine (3e) exhibits a reactivity well within the range required of effective, rapid bioconjugation studies conducted at dilute concentrations. Extrapolation of the 3e versus 3f results (400-fold difference in rates) to the 3a/3c comparison where there is a more substantial 3000-fold difference in rates, indicates that the dimethyl substitution of 3a slows the rate of reaction through both a direct and a significant indirect steric effect.

Finally, the rates of reaction of 3a with a series of p-substituted benzamidines were established to determine the substituent electronic impact. As expected, electron-donating substituents accelerate the reaction whereas electron-withdrawing groups slow the reaction consistent with the inverse electron demand nature of the reaction. A Hammett plot of the data proved linear with a slope of −1.50 (ρ = −1.50), indicating the electronic effect is large as is the substituent effect on the reaction rate (Figure 7).

Figure 7.

Hammett plot of data for 3a presented in Figure 6.

CONCLUSIONS

Herein, a comprehensive study of the scope of the cycloaddition reaction of methyl 1,2,3-triazine-5-carboxylate (3a) and methyl 4,6-dimethyl-1,2,3-triazine-5-carboxylate (3c) with amidines is described. Both provided the product pyrimidines in high yields at room temperature (< 5 min for 3a, < 24 h for 3c), react with a comprehensive set of aryl and aliphatic amidines, and proceed with clean conversion to product with no observable reaction intermediates or byproducts. Measured second order rate constants of the reaction of 3a–f with benzamidine and substituted derivatives quantitated the remarkable reactivity of 3a and 3e, verified the inverse electron demand nature of the reaction (Hammett ρ = −1.50 for substituted amidines, a huge ρ = +7.9 for 5-substituted 1,2,3-triazine), and provide a quantitative measure of the impact of 4-methyl and 4,6-dimethyl substitution on the reactivity of the methyl 1,2,3-triazine-5-carboxylate and 5-cyano-1,2,3-triazine core heterocycles.

EXPERIMENTAL SECTION

General methods.

All reagents and solvents were used as supplied without further purification unless otherwise noted. All reactions were performed in solvents dried over 4 Å molecular sieves unless otherwise noted. Amidines were purchased as their hydrochloride salts and free based by treatment with 2 M KOH (aq) and extracted with CH₂Cl₂. Preparative TLC (PTLC) and column chromatography were conducted using Millipore SiO₂ 60 F₂₅₄ PTLC (0.5 mm) and Zeochem ZEOprep 60 ECO SiO₂ (40–63 μm), respectively. Analytical TLC was conducted using Millipore SiO₂ 60 F₂₅₄ TLC (0.250 mm) plates. ¹H and ¹³C NMR spectra were obtained using a Bruker Avance III HD 600 MHz spectrometer equipped with either a 5 mm QCI or 5 mm CPDCH probe or a Bruker Avance III 500 MHz spectrometer equipped with a 5 mm BBFO probe. IR spectra were obtained using a Thermo Nicolet 380 FT-IR with a SmartOrbit Diamond ATR accessory. Mass spectrometry analysis was performed by direct sample injection on an Agilent G1969A ESI-TOF mass spectrometer. The single crystal X-ray diffraction studies were carried out on a Bruker Kappa APEX-II CCD diffractometer equipped with Mo Kα radiation (λ = 0.71073).

Synthesis of 1,2,3-triazines 3a–3c.

N-Amination of pyrazoles 1a–1c.

A flame-dried 500 mL round-bottom flask was backfilled with nitrogen and charged with pyrazole 1a (3 g, 23.8 mmol), 1b (1 g, 7.14 mmol) or 1c (3 g, 19.5 mmol), followed by addition of DMF to result in a 1 M solution. KO^tBu (1.10 equiv) was added, and the reaction mixture was stirred for 15 min at room temperature. A ~0.15 M solution of ethereal monochloramine¹⁶ (1.50 equiv) was added to the reaction mixture via cannula transfer using positive pressure from a gentle stream of nitrogen (ca. 10 min). Following completion of addition, the mixture was stirred for 1 h. The reaction was quenched with the addition of 200 mL of saturated aqueous Na₂S₂O₃ and transferred to a separatory funnel. The organic layer was separated, and the aqueous layer was extracted with CHCl₃ (3 × 100 mL). The organic layers were combined, dried over Na₂SO₄, and concentrated in vacuo. Residual DMF was removed overnight under a stream of nitrogen to afford a mixture of pyrazole/aminopyrazole that is carried through the next step without further purification.

Oxidative ring expansion of N-aminopyrazoles 2a–2c.

Material from the previous step was dissolved in CH₂Cl₂ (resulting in a 0.1 M solution) and added to a 1 L Morton flask. NaIO₄ (2.0 equiv, calculated based on 100% yield from previous step) in an equal volume of H₂O (as CH₂Cl₂) was added to the flask and the mixture was allowed to stir vigorously for 1 h. Consumption of N-aminopyrazole can be followed by TLC or MS. The reaction mixture was transferred to a 1 L separatory funnel. The organic layer was separated, the aqueous layer was extracted with CH₂Cl₂ (3 × 200 mL), and the combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. Column chromatography (SiO₂, 50–100% Et₂O/hexanes) afforded the 1,2,3-triazines 3a–c. 1,2,3-Triazines 3a–c are stable for extended periods of time if stored under a nitrogen atmosphere at 0 °C, which is especially important for 3a.

Note: 1,2,3-triazine 3c may be isolated as a liquid. This can be solidified by cooling although refrigeration temperatures may not be sufficient. The compound then remains solid at room temperature. Similarly, 1,2,3-Triazine 3b is isolated as a liquid but does not solidify under similar conditions, remaining a liquid.

Methyl 1,2,3-triazine-5-carboxylate (3a).^9b

White solid, mp 39–40 °C; 1.34 g, 40% yield over two steps. ¹H NMR (600 MHz, CDCl₃) δ 9.48 (s, 2H), 4.07 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 162.9, 148.1 (s, 2C), 119.3, 53.9; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1737, 1296, 1092, 889, 634 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₅H₅N₃O₂ + H⁺ 140.0454; Found 140.1454.¹¹

Methyl 4-methyl-1,2,3-triazine-5-carboxylate (3b).

Purple liquid (lit.¹³ oil); 540 mg, 49% yield over two steps. ¹H NMR (600 MHz, CDCl₃) δ 9.26 (s, 1H), 4.03 (s, 3H), 3.01 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 163.9, 159.3, 147.9, 119.1, 53.5, 21.6; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1734, 1538, 1437, 1300, 1257, 1135, 104, 874, 784 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₆H₇N₃O₂ + H⁺ 154.0617; Found 154.0616.

Methyl 4,6-dimethyl-1,2,3-triazine-5-carboxylate (3c).

Purple solid, mp 30 °C (lit.¹³ mp 38 °C);1.77 g, 54% yield over two steps. ¹H NMR (600 MHz, CDCl₃) δ 4.02 (s, 3H), 2.72 (s, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 165.4, 155.8 (s, 2C), 122.7, 53.4, 20.5 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1735, 1540, 1438, 1299, 1203, 1090 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₇H₉N₃O₂ + H⁺ 168.0773; Found 168.0771.¹¹

1,2,3,-Triazine (3d).

Compound 3d was prepared as previously reported^9a and is also now commercially available.

5-Cyano-1,2,3-triazine (3e).

1H-Pyrazole-4-carbonitrile (1 g, 10.7 mmol, 1.0 equiv) was dissolved in aqueous NaOH (3.7 M, 21.5 mL), added to a 100 mL round-bottom flask, and cooled to 0 °C. Hydroxylamine-O-sulfonic acid (2.43 g, 21.5 mmol, 2.0 equiv) was slowly added portionwise while maintaining a reaction temperature <60 °C. The reaction mixture was stirred for 1 h at room temperature, added to a separatory funnel, and extracted with CH₂Cl₂(3 × 50 mL). The aqueous layer was separated and subjected to the reaction conditions once more. The organic extracts were combined, dried over Na₂SO₄, and concentrated in vacuo to afford a white solid (332 mg, 57%, unoptimized) and carried through to the next step without purification. 1-Amino-1H-pyrazole-4-carbonitrile (108 mg, 1.0 mmol, 1.0 equiv) was dissolved in 25 mL of CH₂Cl₂ and added to a 100 mL round-bottom flask. NaIO₄ (428 mg, 2.0 mmol, 2.0 equiv) in 25 mL of H₂O was added and the mixture was allowed to stir vigorously for 20 min. Consumption of the N-aminopyrazole can be followed by TLC or MS. The reaction mixture was transferred to a 125 mL separatory funnel. The organic layer was separated and the aqueous layer was extracted with CH₂Cl₂ (3 × 25 mL). The organic layers were combined, dried over Na₂SO₄, and concentrated in vacuo. Column chromatography (SiO₂, 100% Et2O) followed by recrystallization (Et₂O/hexanes) afforded 3e. Orange solid, mp 72–74 °C; 10.6 mg (unoptimized). ¹H NMR (600 MHz, CD₃CN) δ 9.37 (s, 2H); ¹³C{¹H} NMR (150 MHz, CD₃CN) δ 151.2 (s, 2C), 113.8, 108.5; IR (film) ${\tilde{v}}_{\mathit{max}}$ 3097, 2243, 1508, 1343, 1226, 1030, 926, 759, 670 cm⁻¹; GCMS m/z: [M⁺] Calcd for C₄H₂N₄⁺ 106.0; Found 105.9. The title compound does not ionize at normal ESI-TOF HRMS conditions and a low-resolution GC-MS data is provided for this compound.

5-Cyano-4,6-dimethyl-1,2,3-triazine (3f).

3,5-Dimethyl-1H-pyrazole-4-carbonitrile (121 mg, 1.0 mmol) was dissolved in a mixture EtOH (15 mL) and 3 M aqueous NaOH (5 mL). Hydroxylamine-O-sulfonic acid (339 mg, 3.0 mmol, 3.0 equiv) was added portionwise with temperature control (<60 °C), and the reaction mixture was stirred for 1 h at room temperature. EtOH was removed under reduced pressure, and water (20 mL) was added to the residue. The mixture was extracted with CH₂Cl₂ (3 × 40 mL). The organic phases were combined, dried over Na₂SO₄, concentrated in vacuo, and carried through the next step. 1-Amino-3,5-dimethyl-1H-pyrazole-4-carbonitrile from the previous step was dissolved in 25 mL of CH₂Cl₂ and added to a 100 mL round-bottom flask. NaIO₄ (428 mg, 2.0 mmol, 2.0 equiv, calculated based on 100% yield from previous step) in 25 mL of H₂O was added to the flask and the mixture was allowed to stir vigorously for 1 h. Consumption of the N-aminopyrazole can be followed by TLC or MS. The reaction mixture was transferred to a 125 mL separatory funnel. The organic layer was separated, and the aqueous layer was extracted with CH₂Cl₂ (3 × 25 mL). The organic layers were combined, dried over Na₂SO₄, and concentrated in vacuo. Column chromatography (SiO₂, 33% hexanes/Et₂O) afforded 5-cyano-4,6-dimethyl-1,2,3-triazine (3f). White solid, mp 132 °C (decomp.); 42.0 mg, 31% over two steps. ¹H NMR (600 MHz, CDCl₃) δ 2.91 (s, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 160.0 (s, 2C), 112.5, 107.3, 21.3 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 2933, 2232, 1540, 1394, 1266, 1241, 1026, 948, 738 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₆H₆N₄ + H⁺ 135.0665; Found 135.0665 .

Reaction of methyl 1,2,3-triazine-5-carboxylate (3a) with amidines 4a–v.

A 10 mL double-necked round-bottom flask was flame dried and backfilled with nitrogen. Amidine (0.300 mmol) was added to the reaction vessel, followed by 1.5 mL of CH₃CN (resulting in a 0.2 M solution) under a nitrogen atmosphere and stirring was initiated. A solution of 1,2,3-triazine 3a (0.450 mmol, 1.50 equiv) in 1.5 mL of CH₃CN was added dropwise to the reaction mixture (final concentration 0.1 M for 4). The mixture was stirred for 5 min, then concentrated in vacuo with SiO₂, and purified by column chromatography (50% Et₂O/hexanes unless specified otherwise) to afford the desired pyrimidine product 5.

Methyl 2-phenylpyrimidine-5-carboxylate (5a).^9b,17,18

White solid, mp 146–148 °C (lit. mp 159–161 °C^9b and 161–163 °C¹⁸); 59.5 mg, 93%. ¹H NMR (600 MHz, CDCl₃) δ 9.31 (s, 2H), 8.54–8.49 (m, 2H), 7.55–7.48 (m, 3H), 3.98 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 167.4, 164.6, 158.6 (s, 2C), 136.7, 132.0, 129.1 (s, 2C), 128.9 (s, 2C), 121.6, 52.7; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1723, 1585, 1541, 1426, 1386, 1597, 1133, 759, 694 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₂H₁₀N₂O₂ + H⁺ 215.0821; Found 215.0824.

Larger Scale: Benzamidine (4a, 1.25 mmol) was added to a flame-dried 25 mL round-bottom flask, followed by 6.25 mL of CH₃CN under a nitrogen atmosphere and stirring was initiated. A solution of 1,2,3-triazine 3a (1.87 mmol, 1.50 equiv) in 6.25 mL of CH₃CN was added dropwise to the reaction mixture (final concentration of 4a is 0.1 M). The mixture was stirred for 5 min, concentrated in vacuo with SiO₂, and purified by column chromatography (50% Et₂O/hexanes) to provide pyrimidine product 5a (white solid, 266.8 mg, 99%).

Methyl 2-(o-tolyl)pyrimidine-5-carboxylate (5b).

White solid, mp 76 °C; 62.8 mg, 92%. ¹H NMR (600 MHz, CDCl₃) δ 9.35 (dd, J = 2.3, 1.2 Hz, 2H), 7.94 (dd, J = 7.7, 1.6 Hz, 1H), 7.38 (td, J = 7.5, 1.8 Hz, 1H), 7.35–7.28 (m, 2H), 4.01–3.97 (m, 3H), 2.59 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 170.4, 164.6, 158.0 (s, 2C), 138.2, 137.1, 131.7, 131.1, 130.5, 126.1, 121.0, 52.7, 21.5; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1717, 1585, 1539, 1384, 1420, 1287, 1197, 1135, 761, 648 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₃H₁₂N₂O₂ + H⁺ 229.0977; Found 229.0982.

Methyl 2-(m-tolyl)pyrimidine-5-carboxylate (5c).

White solid, mp 110 °C; 66.0 mg, 97%. ¹H NMR (600 MHz, CDCl₃) δ 9.28 (s, 2H), 8.33–8.27 (m, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.33 (ddd, J = 8.0, 1.8, 1.0 Hz, 1H), 3.96 (s, 3H), 2.44 (d, J = 1.8 Hz, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 167.4, 164.5, 158.5 (s, 2C), 138.5, 136.6, 132.8, 129.6, 128.8, 126.3, 121.5, 52.6, 21.5; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1716, 1583, 1541, 1420, 1682, 1292, 1131, 776, 691 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₃H₁₂N₂O₂ + H⁺ 229.0977; Found 229.0982.

Methyl 2-(p-tolyl)pyrimidine-5-carboxylate (5d).

White solid, mp 165–167 °C; 63.1 mg, 92%. ¹H NMR (600 MHz, CDCl₃) δ 9.29 (dd, J = 3.2, 2.0 Hz, 2H), 8.34–8.28 (m, 2H), 7.40 (td, J = 7.6, 2.5 Hz, 1H), 7.36–7.33 (m, 1H), 3.98 (dd, J = 3.0, 1.8 Hz, 3H), 2.45 (d, J = 2.1 Hz, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 167.5, 164.6, 158.5 (s, 2C), 138.6, 136.6, 132.8, 129.6, 128.8, 126.3, 121.5, 52.7, 21.6; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1718, 1584, 1537, 1423, 1385, 1290, 1132, 789 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₃H₁₂N₂O₂ + H⁺ 229.0977; Found 229.0982.

Methyl 2-(4-fluorophenyl)pyrimidine-5-carboxylate (5e).

White solid, mp 130–135 °C; 64.0 mg, 92%. ¹H NMR (600 MHz, CDCl₃) δ 9.29 (s, 2H), 8.57–8.51 (m, 2H), 7.22–7.15 (m, 3H), 3.99 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 166.4, 165.5 (d, ¹J_C-F = 252.6 Hz), 164.6, 158.6 (s, 2C), 133.0 (d, ⁴J_C-F 2.8 Hz), 131.4 (d, ³J_C-F = 9.3 Hz, 2C), 121.6, 116.0 (d, ²J_C-F = 22.0 Hz, 2C), 52.7; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1721, 1589, 1544, 1426, 1294, 1195, 1129, 799, 651 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₂H₉FN₂O₂ + H⁺ 233.0726; Found 233.0730.

Methyl 2-(4-chlorophenyl)pyrimidine-5-carboxylate (5f).¹⁷

White solid, mp 177–179 °C (lit.¹⁷ mp 177–179 °C); 72.1 mg, 96%. ¹H NMR (600 MHz, CDCl₃) δ 9.29 (s, 2H), 8.49–8.43 (m, 2H), 7.47 (dq, J = 8.6, 2.0, 1.3 Hz, 2H), 3.99 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 166.4, 164.5, 158.6 (s, 2C), 138.4, 135.2, 130.4 (s, 2C), 129.1 (s, 2C), 121.8, 52.8, 52.7; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1722, 1582, 1426, 1296, 1130, 790, 651 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₂H₉ClN₂O₂ + H⁺ 249.0431; Found 249.0433.

Methyl 2-(4-bromophenyl)pyrimidine-5-carboxylate (5g).

White solid, mp 193–195 °C; 77.9 mg, 88%. ¹H NMR (600 MHz, CDCl₃) δ 9.30 (s, 2H), 8.42–8.37 (m, 2H), 7.67–7.62 (m, 2H), 4.00 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 166.5, 164.5, 158.6 (s, 2C), 135.7, 132.1 (s, 2C), 130.7 (s, 2C), 127.1, 121.9, 52.8; IR (film) ${\tilde{v}}_{\mathit{max}}$ 2954, 1717, 1582, 1426, 1295, 1132, 791 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₂H₉BrN₂O₂ + H⁺ 292.9926; Found 292.9927.

Methyl 2-(4-(trifluoromethyl)phenyl)pyrimidine-5-carboxylate (5h).

White solid, mp 176–179 °C; 76.7 mg, 91%. ¹H NMR (600 MHz, CDCl₃) δ 9.34 (s, 2H), 8.66–8.61 (m, 2H), 7.78–7.74 (m, 2H), 4.00 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 166.0, 164.3, 158.7 (s, 2C), 139.9 (q, ⁵J_C-F = 1.5 Hz), 133.4 (q, ²J_C-F = 32.5 Hz), 129.4 (s, 2C), 125.8 (q, ³J_C-F = 4.0 Hz, 2C), 124.1 (q, ¹J_C-F = 272.6 Hz), 122.4, 52.8; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1716, 1586, 1544, 1430, 1332, 1305, 1161, 1115, 862, 799 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₃H₉F₃N₂O₂ + H⁺ 283.069; Found 283.0697.

Methyl 2-(4-cyanophenyl)pyrimidine-5-carboxylate (5i).

White solid, mp 168–172 °C; 53.2 mg, 75%. ¹H NMR (600 MHz, CDCl₃) δ 9.35 (s, 2H), 8.67–8.62 (m, 2H), 7.83–7.78 (m, 2H), 4.01 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 165.5, 164.2, 158.7 (s, 2C), 140.6, 132.6 (s, 2C), 129.5 (s, 2C), 122.5, 118.6, 115.2, 52.9; IR (film) ${\tilde{v}}_{\mathit{max}}$ 2921, 2230, 1723, 1586, 1538, 1426, 1300, 1134, 842, 798, 734 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₃H₉N₃O₂ + H⁺ 240.0773; Found 240.0775.

Methyl 2-(4-methoxyphenyl)pyrimidine-5-carboxylate (5j).

White solid, mp 162–164 °C; 62.3 mg, 84%. ¹H NMR (600 MHz, CDCl₃) δ 9.27–9.24 (m, 2H), 8.51–8.45 (m, 2H), 7.04–6.98 (m, 2H), 4.00–3.96 (m, 3H), 3.89 (dd, J = 2.6, 1.1 Hz, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 167.1, 164.8, 163.0, 158.5 (s, 2C), 131.0 (s, 2C), 129.4, 120.8, 114.3 (s, 2C), 55.6, 52.6; IR (film) ${\tilde{v}}_{\mathit{max}}$ 2955, 1720, 1585, 1426, 1297, 1160, 1131, 1025, 848, 799 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₃H₁₂N₂O₃ + H⁺ 245.0926; Found 245.0930.

Methyl 2-(4-aminophenyl)pyrimidine-5-carboxylate (5k).

Yellow solid, mp 220 °C; 64.6 mg, 94%. Purified using 5% MeOH/CH₂Cl_2.; ¹H NMR (600 MHz, CDCl₃) δ 9.21 (d, J = 1.1 Hz, 2H), 8.37–8.33 (m, 2H), 6.78–6.73 (m, 2H), 4.08–4.04 (brs, 2H), 3.97 (d, J = 1.1 Hz, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 167.4, 165.0, 158.5 (s, 2C), 150.3, 131.1 (s, 2C), 126.9, 120.2, 114.8 (s, 2C), 52.5; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1720, 1630, 1578, 1421, 1290, 1173, 884 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₂H₁₁N₃O₂ + H⁺ 230.0930; Found 230.0928.

Methyl 2-(4-nitrophenyl)pyrimidine-5-carboxylate (5I).

Pale yellow solid, mp 233–235 °C; 41.9 mg, 54%. ¹H NMR (600 MHz, CDCl₃) δ 9.38 (s, 2H), 8.74–8.69 (m, 2H), 8.38–8.33 (m, 2H), 4.02 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 165.2, 164.2, 158.8 (s, 2C), 150.0, 142.3, 130.0 (s, 2C), 124.0 (s, 2C), 122.7, 53.0; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1722, 1546, 1523, 1427, 1346, 1300, 1134, 806 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₂H₉N₃O₄ + H⁺ 260.0671; Found 260.0672.

Methyl 2-(thien-2-yl)pyrimidine-5-carboxylate (5m).¹⁷

White solid, 187–188 °C (lit.¹⁷ mp 187–190 °C); 28.1 mg, 88%. ¹H NMR (600 MHz, CDCl₃) δ 9.20 (s, 2H), 8.12 (dd, J = 3.7, 1.2 Hz, 1H), 7.59 (dd, J = 5.0, 1.3 Hz, 1H), 7.19 (dd, J = 5.0, 3.7 Hz, 1H), 3.98 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 164.4, 164.0, 158.7 (s, 2C), 142.5, 132.2, 131.3, 128.9, 121.0, 52.7; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1721, 1589, 1541, 1435, 1300, 1259, 1131, 857, 802, 732, 641 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₀H₈N₂O₂S + H⁺ 221.0389; Found 221.0385.

Methyl 2-(pyrid-2-yl)pyrimidine-5-carboxylate (5n).^9b

White solid, mp 171 °C (lit.^9b mp 164 °C); 53.8 mg, 84%. ¹H NMR (600 MHz, CDCl₃) δ 9.41 (s, 2H), 8.89–8.85 (m, 1H), 8.59 (dt, J = 7.8, 0.9 Hz, 1H), 7.89 (td, J = 7.8, 1.8 Hz, 1H), 7.45 (ddd, J = 7.7, 4.7, 1.2 Hz, 1H), 4.00 (d, J = 0.7 Hz, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 166.0, 164.3, 158.9 (s, 2C), 153.8, 150.5, 137.3, 125.8, 124.6, 122.9, 52.8; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1716, 1629, 1574, 1420, 1281, 1171, 1129, 799 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₁H₉N₃O₂ + H⁺ 216.0773; Found 216.0770.

Methyl [2,2′-bipyrimidine]-5-carboxylate (5o).

White solid, mp 156 °C; 55.3 mg, 85%. ¹H NMR (600 MHz, CDCl₃) δ 9.43 (s, 2H), 8.97 (d, J = 4.9 Hz, 2H), 7.40 (t, J = 4.8 Hz, 1H), 3.94 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 164.5, 163.8, 161.7, 159.2 (s, 2C), 158.2 (s, 2C), 123.9, 122.0, 52.9; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1722, 1580, 1540, 1407, 1379, 1295, 1141, 773, 647; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₀H₈N₄O₂ + H⁺ 217.0726; Found 217.0728.

Methyl 2-benzylpyrimidine-5-carboxylate (5p).

White solid, mp 92 °C; 60.7 mg, 88%. ¹H NMR (600 MHz, CDCl₃) δ 9.20 (s, 2H), 7.35 (d, J = 7.3 Hz, 2H), 7.30 (td, J = 7.7, 1.6 Hz, 2H), 7.23 (td, J = 7.2, 1.4 Hz, 1H), 4.36 (s, 2H), 3.95 (d, J = 1.8 Hz, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 173.5, 164.4, 158.5 (s, 2C), 137.5, 129.3 (s, 2C), 128.7 (s, 2C), 127.0, 121.6, 52.7, 46.2; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1717, 1586, 1428, 1296, 1270, 1126, 1033, 700 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₃H₁₂N₂O₂ + H⁺ 229.0977; Found 229.0984.

Methyl 2-(2,6-dichlorobenzyl)pyrimidine-5-carboxylate (5q).

White solid, mp 100 °C; 82.3 mg, 92%. ¹H NMR (600 MHz, CDCl₃) δ 9.17 (d, J = 1.6 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.18 (t, J = 8.1 Hz, 1H), 4.75 (s, 2H), 3.94 (d, J = 1.4 Hz, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 171.6, 164.4, 158.5 (s, 2C), 136.5, 133.9, 128.9 (s, 2C), 128.2 (s, 2C), 121.7, 52.7, 41.2; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1728, 1586, 1429, 1293, 1127, 1038, 774, 628 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₃H₁₀Cl₂N₂O₂ + H⁺ 297.0198; Found 297.0201.

Methyl 2-methylpyrimidine-5-carboxylate (5r).^9b,14,17

White solid, mp 63 °C (lit.^9b mp 54–56 °C); 31.6 mg, 69%. ¹H NMR (600 MHz, CDCl₃) δ 9.16 (d, J = 4.3 Hz, 2H), 3.95 (d, J = 3.9 Hz, 3H), 2.80 (d, J = 4.5 Hz, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 172.1, 164.5, 158.2 (s, 2C), 121.3, 52.7, 26.5; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1724, 1593, 1555, 1437, 1308, 1258, 1130, 765 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₇H₈N₂O₂ + H⁺ 153.0664; Found 153.0664.

Methyl 2-isopropylpyrimidine-5-carboxylate (5s).^17,19

White solid, mp 24–25 °C (lit.¹⁷ mp 26–28 °C); 53.0 mg, 98%. ¹H NMR (600 MHz, CDCl₃) δ 9.18 (d, J = 1.0 Hz, 2H), 3.95 (d, J = 1.4 Hz, 3H), 3.27 (heptd, J = 6.8, 0.9 Hz, 1H), 1.35 (dd, J = 7.1, 1.3 Hz, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 179.3, 164.6, 158.3 (s, 2C), 121.4, 52.6, 38.1, 21.6 (2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 2969, 1731, 1588, 1429, 1292, 1128, 1037, 815, 757 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₉H₁₂N₂O₂ + H⁺ 181.0973; Found 181.0977.

Methyl 2-(tert-butyl)pyrimidine-5-carboxylate (5t).¹⁷

White solid, mp 51 °C (lit.¹⁷ mp 60–62 °C); 48.5 mg, 83%. ¹H NMR (600 MHz, CDCl₃) δ 9.20 (d, J = 1.0 Hz, 2H), 3.96 (d, J = 1.0 Hz, 3H), 1.44–1.41 (m, 9H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 181.2, 164.7, 157.8 (s, 2C), 121.0, 52.6, 40.1, 29.6 (s, 3C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 2960, 1724, 1588, 1285, 1166, 1125, 1034, 756 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₀H₁₄N₂O₂ + H⁺ 195.1134; Found 195.1136.

Methyl 2-cyclopropylpyrimidine-5-carboxylate (5u).

White solid, mp 45 °C; 49.1 mg, 92%. ¹H NMR (600 MHz, CDCl₃) δ 9.04 (d, J = 1.5 Hz, 2H), 3.91 (d, J = 1.9 Hz, 3H), 2.29 (tt, J = 8.6, 4.0 Hz, 1H), 1.23–1.17 (m, 2H), 1.17–1.11 (m, 2H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 176.2, 164.7, 158.0 (s, 2C), 120.8, 52.5, 19.0, 12.4 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1730, 1588, 1457, 1293, 1092, 889, 626 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₉H₁₀N₂O₂ + H⁺ 179.0821; Found 179.0822.

Methyl 2-cyclohexylpyrimidine-5-carboxylate (5v).

White solid, mp 43 °C; 60.3 mg, 91%. ¹H NMR (600 MHz, CDCl₃) δ 9.18 (t, J = 1.3 Hz, 2H), 3.97–3.93 (m, 3H), 2.95 (ttd, J = 11.9, 3.6, 1.6 Hz, 1H), 2.04–1.97 (m, 2H), 1.89–1.82 (m, 2H), 1.78–1.71 (m, 1H), 1.68–1.58 (m, 2H), 1.41 (ddt, J = 12.9, 10.0, 7.0 Hz, 2H), 1.35–1.22 (m, 1H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 178.4, 164.7, 158.2 (s, 2C), 121.4, 52.6, 47.9, 31.9 (s, 2C), 26.2 (s, 2C), 26.0; IR (film) ${\tilde{v}}_{\mathit{max}}$ 2927, 2850, 1725, 1587, 1545, 1430, 1287, 1126, 893, 807, 757 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₂H₁₆N₂O₂ + H⁺ 221.1290; Found 221.1293.

Reaction of methyl 4,6-dimethyl-1,2,3-triazine-5-carboxylate (3c) with amidines 4a–v.

A 2-dram vial was charged with 0.300 mmol of 3c, followed by 1.2 mL of CH₃CN, resulting in a 0.25 M solution. Amidine (2.0 equiv) was added as a solid in a single portion to the reaction mixture. If necessary, the reaction mixture was warmed to 60 °C in an oil bath to maintain homogeneity. The reaction mixture was stirred for 24 h, concentrated in vacuo with SiO₂, and purified by column chromatography (50% Et₂O/hexanes unless specified otherwise) to afford the desired pyrimidine products 7.

Methyl 4,6-dimethyl-2-phenylpyrimidine-5-carboxylate (7a).

White solid, mp 49 °C; 67.4 mg, 91%. ¹H NMR (600 MHz, CDCl₃) δ 8.48–8.45 (m, 2H), 7.50–7.47 (m, 3H), 3.97 (s, 3H), 2.61 (s, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 168.5, 165.0 (s, 2C), 163.9, 137.3, 131.1, 128.7 (s, 2C), 128.7 (s, 2C), 123.9, 52.6, 23.4 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1725, 1545, 1431, 1395, 1263, 1085, 897, 748, 694 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₄H₁₄N₂O₂ + H⁺ 243.1134; Found 243.1136.

Methyl 4,6-dimethyl-2-(o-tolyl)pyrimidine-5-carboxylate (7b).

Clear oil; 65.4 mg, 85%. ¹H NMR (600 MHz, CDCl₃) δ 7.77 (dd, J = 7.5, 1.6 Hz, 1H), 7.35–7.24 (m, 3H), 3.97 (d, J = 2.0 Hz, 3H), 2.60 (d, J = 2.2 Hz, 6H), 2.52 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 168.4, 167.0, 164.5 (s, 2C), 137.9, 137.4, 131.4, 130.9, 129.7, 126.1, 123.4, 52.7, 23.2 (s, 2C), 21.03; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1726, 1546, 1433, 1261, 1149, 1084, 900, 753 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₅H₁₆N₂O₂ + H⁺ 257.1290; Found 257.1295.

Methyl 4,6-dimethyl-2-(m-tolyl)pyrimidine-5-carboxylate (7c).

White solid, mp 78 °C; 69.5 mg, 91 %. ¹H NMR (600 MHz, CDCl₃) δ 8.28 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1H), 3.96 (d, J = 1.9 Hz, 3H), 2.61 (d, J = 1.8 Hz, 6H), 2.45 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 168.5, 164.9 (s, 2C), 164.0, 138.3, 137.2, 131.9, 129.2, 128.6, 125.9, 123.8, 52.6, 23.4 (s, 2C), 21.6; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1730, 1544, 1428, 1254, 1208, 1084, 832, 874, 699 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₅H₁₆N₂O₂ + H⁺ 257.1290; Found 257.1292.

Methyl 4,6-dimethyl-2-(p-tolyl)pyrimidine-5-carboxylate (7d).

White solid, mp 59 °C; 60.8 mg, 79%. ¹H NMR (600 MHz, CDCl₃) δ 8.36 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 3.95 (d, J = 2.2 Hz, 3H), 2.60 (d, J = 2.3 Hz, 6H), 2.41 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 168.5, 164.9 (s, 2C), 163.8, 141.4, 134.6, 129.4 (s, 2C), 128.6 (s, 2C), 123.5, 52.5, 23.4 (s, 2C), 21.6; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1721, 1543, 1395, 1267, 1178, 1085, 790 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₅H₁₆N₂O₂ + H⁺ 257.1290; Found 257.1293.

Methyl 4,6-dimethyl-2-(4-fluorophenyl)pyrimidine-5-carboxylate (7e).

White solid, mp 119 °C; 65.4 mg, 84%. ¹H NMR (600 MHz, CDCl₃) δ 8.53–8.45 (m, 2H), 7.20–7.13 (m, 2H), 3.97 (s, 3H), 2.60 (s, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 168.4, 165.1 (s, 2C), 165.0 (d, ¹J_C-F = 250.9 Hz), 162.9, 133.5 (d, ⁴J_C-F = 3.3 Hz), 130.9 (d, ³J_C-F = 8.8 Hz, 2C), 123.8, 115.6 (d, ²J_C-F = 22.0 Hz, 2C), 52.6, 23.4 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1730, 1546, 1429, 1258, 1160, 1085, 852, 796 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₄H₁₃FN₂O₂ + H⁺ 261.1039; Found 261.1045.

Methyl 2-(4-chlorophenyl)-4,6-dimethylpyrimidine-5-carboxylate (7f).

White solid, mp 121 °C; 70.6 mg, 85%. ¹H NMR (600 MHz, CDCl₃) δ 8.45–8.40 (m, 2H), 7.47–7.42 (m, 2H), 3.97 (s, 3H), 2.60 (s, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 168.4, 165.1 (s, 2C), 162.8, 137.4, 135.8, 130.1 (s, 2C), 128.9 (s, 2C), 124.1, 52.7, 23.4; IR (film) ${\tilde{v}}_{\mathit{max}}$ 1718, 1544, 1429, 1262, 1084, 791, 653 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₄H₁₃ClN₂O₂ + H⁺ 277.0744; Found 277.1746.

Methyl 2-(4-bromophenyl)-4,6-dimethylpyrimidine-5-carboxylate (7g).

White solid, mp 101 °C; 86.1 mg, 90%. ¹H NMR (600 MHz, CDCl₃) δ 8.34 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 3.96 (s, 3H), 2.59 (s, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 168.3, 165.1 (s, 2C), 162.8, 136.2, 131.8 (s, 2C), 130.3 (s, 2C), 125.9, 124.1, 52.6, 23.3 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1725, 1543, 1427, 1266, 1137, 1089, 1008, 791 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₄H₁₃BrN₂O₂ + H⁺ 321.0239; Found 321.0238.

Methyl 4,6-dimethyl-2-(4-(trifluoromethyl)phenyl)pyrimidine-5-carboxylate (7h).

White solid, mp 46–47 °C; 88.1 mg, 95%. ¹H NMR (600 MHz, CDCl₃) δ 8.58 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H), 3.98 (d, J = 1.6 Hz, 3H), 2.61 (d, J = 2.2 Hz, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 168.2, 165.2 (s, 2C), 162.4, 140.6, 132.6 (q, ²J_C-F = 32.6 Hz), 129.0 (s, 2C), 125.5 (q, ³J_C-F = 3.7 Hz, 2C), 124.6, 124.26 (q, ¹J_C-F = 272.4 Hz), 52.7, 23.3 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1727, 1547, 1320 ,1261, 1103, 1064, 1018, 861, 799 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₅H₁₃F₃N₂O₂ + H⁺ 311.1007; Found 311.1009.

Methyl 2-(4-cyanophenyl)-4,6-dimethylpyrimidine-5-carboxylate (7i).

White solid, mp 171 °C; 74.7 mg, 93%. ¹H NMR (600 MHz, CDCl₃) δ 8.60 (dt, J = 7.9, 1.8 Hz, 2H), 7.77 (dt, J = 8.5, 1.7 Hz, 2H), 3.98 (d, J = 0.9 Hz, 3H), 2.62 (d, J = 1.9 Hz, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 168.1, 165.3 (s, 2C), 161.9, 141.3, 132.4 (s, 2C), 129.2 (s, 2C), 124.9, 118.9, 114.4, 52.8, 23.3 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 2232, 1722, 1544, 1432, 1275, 1089, 843, 795 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₅H₁₃N₃O₂ + H⁺ 268.1086; Found 268.1090.

Methyl 4,6-dimethyl-2-(4-methoxyphenyl)pyrimidine-5-carboxylate (7j).

White solid, mp 135 °C; 69.1 mg, 85%. ¹H NMR (600 MHz, CDCl₃) δ 8.46–8.40 (m, 2H), 7.00–6.94 (m, 2H), 3.94 (d, J = 1.7 Hz, 3H), 3.86 (d, J = 2.2 Hz, 3H), 2.58 (d, J = 1.7 Hz, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 168.6, 164.9 (s, 2C), 163.5, 162.2, 130.4 (s, 2C), 130.0, 123.0, 114.0 (s, 2C), 55.4, 52.4, 23.4 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1722, 1541, 1428, 1401, 1255, 1165, 1087, 1029, 540, 795 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₅H₁₆N₂O₃ + H⁺ 273.1239; Found 273.1239.

Methyl 2-(4-aminophenyl)-4,6-dimethylpyrimidine-5-carboxylate (7k).

Yellow solid, mp 106 °C; 69.2 mg, 90%. ¹H NMR (600 MHz, CDCl₃) δ 8.34–8.29 (m, 2H), 6.76–6.71 (m, 2H), 3.95 (s, 3H), 2.58 (s, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 168.7, 164.9 (s, 2C), 163.8, 149.5, 130.5 (s, 2C), 127.4, 122.5, 114.7 (s, 2C), 52.5, 23.5 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1718, 1606, 1548, 1369, 1264, 1173, 1087, 888 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₄H₁₅N₃O₂ + H⁺ 258.1243; Found 258.1248.

Methyl 4,6-dimethyl-2-(4-nitrophenyl)pyrimidine-5-carboxylate (7I).

White solid, mp 132 °C; 22.7 mg, 26%. ¹H NMR (600 MHz, CDCl₃) δ 8.68–8.64 (m, 2H), 8.34–8.29 (m, 2H), 3.99 (s, 3H), 2.63 (s, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 168.0, 165.3 (s, 2C), 161.6, 149.6, 143.0, 129.6 (s, 2C), 125.0, 123.8 (s, 2C), 53.5, 23.3 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1726, 1554, 1518, 1346, 1274, 1092, 871, 852, 694 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₄H₁₃N₃O₄ + H⁺ 288.0984; Found 288.0986.

Methyl 4,6-dimethyl-2-(thien-2-yl)pyrimidine-5-carboxylate (7m).

White solid, mp 58 °C; 62.1 mg, 84%. ¹H NMR (600 MHz, CDCl₃) δ 8.05 (dd, J = 3.7, 1.2 Hz, 1H), 7.50 (dd, J = 5.0, 1.2 Hz, 1H), 7.14 (dd, J = 5.0, 3.7 Hz, 1H), 3.95 (s, 3H), 2.57 (s, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 168.2, 165.3 (s, 2C), 160.5, 143.0, 130.7, 130.0, 128.5, 123.3, 52.6, 23.3 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1724, 1531, 1436, 1262, 1126, 1084, 851, 797, 710 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₂H₁₂N₂O₂S + H⁺ 294.0698; 294.0695.

Methyl 4,6-dimethyl-2-(pyrid-2-yl)pyrimidine-5-carboxylate (7n).

Yellow solid, mp 48 °C; 62.5 mg, 86%. ¹H NMR (600 MHz, CDCl₃) δ 8.84 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.52 (dt, J = 7.9, 1.1 Hz, 1H), 7.83 (td, J = 7.7, 1.8 Hz, 1H), 7.38 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 3.96 (s, 3H), 2.65 (s, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 168.2, 165.4 (s, 2C), 162.7, 154.5, 150.3, 137.1, 125.3, 125.1, 124.2, 52.7, 23.3 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1726, 1549, 1432, 1270, 1159, 1087 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₃H₁₃N₃O₂ + H⁺ 244.1086; Found 244.1091.

Methyl 4,6-dimethyl-[2,2′-bipyrimidine]-5-carboxylate (7o).

Yellow solid, mp 79 °C; 60.2 mg, 82%. ¹H NMR (600 MHz, CDCl₃) δ 9.04 (d, J = 5.0 Hz, 2H), 7.43 (t, J = 4.9 Hz, 1H), 3.99 (s, 3H), 2.71 (d, J = 0.7 Hz, 7H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 167.8, 165.7 (s, 2C), 162.3, 161.4, 158.2 (s, 2C), 126.5, 121.5, 52.8, 23.3 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1727, 1547, 1423, 1282, 1198, 1092, 912, 810, 784 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₂H₁₂N₄O₂ + H⁺ 245.1039; Found 245.1039.

Methyl 2-benzyl-4,6-dimethylpyrimidine-5-carboxylate (7p).

Clear oil; 66.8 mg, 87%. ¹H NMR (600 MHz, CDCl₃) δ 7.39–7.34 (m, 2H), 7.28 (dd, J = 8.5, 6.9 Hz, 2H), 7.22–7.18 (m, 1H), 4.21 (s, 2H), 3.92 (d, J = 0.7 Hz, 3H), 2.50 (s, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 169.2, 168.3, 164.8 (s, 2C), 138.1, 129.2 (s, 2C), 128.5 (s, 2C), 126.6, 123.8, 52.6, 45.9, 23.0 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1727, 1551, 1433, 1254, 1090, 818, 748, 703 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₅H₁₆N₂O₂ + H⁺ 257.1290; Found 257.1295.

Methyl 2-(2,6-dichlorobenzyl)-4,6-dimethylpyrimidine-5-carboxylate (7q).

White solid, mp 64–66 °C; 96.3 mg, 99%. ¹H NMR (600 MHz, CDCl₃) δ 7.32 (dd, J = 8.0, 1.9 Hz, 2H), 7.14 (t, J = 8.0 Hz, 1H), 4.60 (s, 2H), 3.92 (d, J = 1.1 Hz, 3H), 2.44 (d, J = 1.9 Hz, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 168.4, 167.2, 164.7 (s, 2C), 136.6, 134.4, 128.4 (s, 2C), 128.0 (s, 2C), 123.8, 52.6, 40.8, 23.1 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1727, 1551, 1435, 1253, 1088, 923, 765 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₅H₁₄Cl₂N₂O₂ + H⁺ 325.0511; Found 325.0511.

Methyl 2,4,6-trimethylpyrimidine-5-carboxylate (7r).²⁰

White solid, mp 55–56 °C (lit.²⁰ mp 56–58 °C); 46.5 mg, 86%. ¹H NMR (600 MHz, CDCl₃) δ 3.92 (d, J = 1.9 Hz, 3H), 2.65 (d, J = 1.7 Hz, 3H), 2.48 (d, J = 2.2 Hz, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 168.3, 167.8, 164.6 (s, 2C), 123.4, 52.6, 26.1, 23.0 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1729, 1555, 1434, 1257, 1092 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₉H₁₂N₂O₂ + H⁺ 181.0977; Found 181.0979.

Methyl 4,6-dimethyl-2-isopropylpyrimidine-5-carboxylate (7s).

Clear oil; 49.1 mg, 79%. ¹H NMR (600 MHz, CDCl₃) δ 3.94–3.90 (m, 3H), 3.10 (pdd, J = 6.7, 3.2, 1.7 Hz, 1H), 2.51–2.46 (m, 6H), 1.29 (ddd, J = 7.1, 3.8, 1.7 Hz, 6H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 175.1, 168.6, 164.3 (s, 2C), 123.5, 52.5, 37.7, 23.1 (s, 2C), 21.7 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1729, 1552, 1434, 1253, 1098 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for 209.1291 (C₁₁H₁₆N₂O₂ + H⁺ requires 209.1290).

Methyl 2-(tert-butyl)-4,6-dimethylpyrimidine-5-carboxylate (7t).

Clear oil; 51.2 mg, 77%. ¹H NMR (600 MHz, CDCl₃) δ 3.93 (d, J = 0.9 Hz, 3H), 2.49 (d, J = 1.2 Hz, 6H), 1.36 (d, J = 1.5 Hz, 9H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 176.9, 169.0, 163.8 (s, 2C), 123.0, 52.5, 39.4, 29.6 (s, 3C), 23.2 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 2957, 1730, 1552, 1268, 1204, 1088 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₂H₁₈N₂O₂ + H⁺ 223.1447; Found 223.1448.

Methyl 2-cyclopropyl-4,6-dimethylpyrimidine-5-carboxylate (7u).

White solid, mp 38–39 °C; 44.5 mg, 72%. ¹H NMR (600 MHz, CDCl₃) δ 3.90 (d, J = 1.6 Hz, 3H), 2.44 (d, J = 1.7 Hz, 6H), 2.15 (tdd, J = 8.1, 5.5, 3.9 Hz, 1H), 1.15–1.08 (m, 2H), 1.06–0.98 (m, 2H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 171.7, 168.6, 164.4 (s, 2C), 122.9, 52.4, 23.1 (s, 2C), 18.3, 11.0 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 1726, 1552, 1435, 1250, 1100, 941, 872, 811 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₁H₁₄N₂O₂ + H⁺ 207.1134; Found 207.1136.

Methyl 2-cyclohexyl-4,6-dimethylpyrimidine-5-carboxylate (7v).

Clear oil; 82.6 mg, 84%. ¹H NMR (600 MHz, CDCl₃) δ 3.91 (d, J = 2.3 Hz, 3H), 2.78 (tdt, J = 11.8, 4.8, 2.4 Hz, 1H), 2.47 (d, J = 2.8 Hz, 6H), 1.94–1.87 (m, 2H), 1.84–1.77 (m, 2H), 1.73–1.66 (m, 1H), 1.65–1.55 (m, 3H), 1.37 (tdd, J = 13.0, 10.3, 2.4 Hz, 2H), 1.32–1.21 (m, 1H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 174.2, 168.6, 164.3 (s, 2C), 123.5, 52.5, 47.6, 31.8 (s, 2C), 26.3 (s, 2C), 26.0, 23.1 (s, 2C); IR (film) ${\tilde{v}}_{\mathit{max}}$ 2928, 2853, 1729, 1552, 1434, 1254, 1091 cm⁻¹; HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₁₄H₂₀N₂O₂ + H⁺ 249.1603; Found 249.1607.