(E)-Methyl 3-(2-amino-4-chloro-6-morpholinopyrimidin-5-yl)acrylate

Abstract

The synthesis of methyl (E)-3-(2-amino-4-chloro-6-morpholinopyrimidin-5-yl)acrylate 3 was accomplished using a Schlosser-modified Wittig reaction. Complete ¹H and ¹³C NMR signal assignments confirm the formation of E-alkene.

1. Introduction

The biological properties of pyrimidine derivatives are well known and widely documented [1,2,3,4,5,6]; research continues to be directed toward the synthesis of these systems with substituents and functional groups that allow for the expansion of their potential applications in different biological phenotypes and structural diversities [7,8,9,10]. Synthetic approaches include variations and substrate diversity in the classic Biginelli reaction [11,12,13], and the modification of available pyrimidine derivatives. The use of halo pyrimidine carbaldehyde derivatives as precursors provides several functionalizable sites to form C–C bonds through aldol and related reaction mechanisms, and C-N bonds through S_NAr mechanisms, reactions related to ammonia derivatives [14,15,16,17], and the Wittig olefination reaction [14,18].

In this context, we continue to explore the scope and synthetic versatility of 2-Amino-4,6-dichloropyrimidine-5-carbaldehyde in Wittig olefination reactions combined with S_NAr reactions (Figure 1).

2. Results and Discussion

2-Amino-4,6-dichloropyrimidine-5-carbaldehyde can be obtained via the Vilsmeier-Haack chloroformylation reaction of 2-amino-4,6-dihydroxypyrimidine, an inexpensive and commercially available compound [19]. The compound 2-Amino-4,6-dichloropyrimidine-5-carbaldehyde can be derived and modified through its four functionalizable sites: an amino substituent, two chloro substituents, and the aldehyde functionality. Using the S_NAr mechanism, chloro has been replaced by amino groups through an efficient and stoichiometrically controlled procedure using different primary and secondary amines and anilines, thus generating C–N bonds [20,21]. In contrast, the aldehyde functionality opens up options for structural diversification via Claisen–Schmidt [21] and Knoevenagel [22] condensation reactions and Horner–Wadsworth–Emmons and Wittig olefination reactions [14,15,16].

The Wittig reaction has been widely studied, and interest remains because of the new reaction conditions, catalytic variants, and mechanistic and computational analyses. Currently, the disadvantages of the classical reaction have been overcome, and strategies are available that allow the Wittig reaction to be combined with other synthetic applications, such as the formation of heterocyclic compounds by intermolecular or intramolecular aza-Wittig reactions, Wittig olefination with photo-assisted reactions, and S_NAr–Wittig reactions. The extension of the reaction is mainly due to characteristics such as regiospecificity, stereoselectivity, mild reaction conditions, easily obtainable starting materials, and ylide and ylene tolerance to functional groups [23,24,25,26]. In this context, the Wittig olefination reaction was carried out from 2-amino-4-chloro-6-morpholinopyrimidine-5-carbaldehyde 2 and methyl (triphenylphosphoranylidene)acetate as a phosphoru-stabilized carbon nucleophilic for the preparation of methyl (E)-3-(2-amino-4-chloro-6-morpholinopyrimidin-5-yl)acrylate 3, with good yield 80% (Scheme 1).

This reaction has several advantages, such as the use of methyl (triphenylphosphoranylide-ne)acetate as triphenylphosphonium ylides, which is commercially available, inexpensive, and stable and, together with the lithium salt, favors the formation of E-alkenes. This combination is known as the Schlosser modification of the Wittig reaction and allows for methyl (E)-3-(2-amino-4-chloro-6-morpholinopyrimidin-5-yl)acrylate 3 to be obtained in good yield, which is separated by simple filtration, because the reaction is carried out in DMF, which dissolves the phosphine oxide byproduct.

2-amino-4-chloro-6-morpholinopyrimidine-5-carbaldehyde 2 was prepared as previously described [20]. The use of phosphonium ylide enables the Wittig reaction to proceed without strong bases (BuLi, NaH, and KOtBu), diverging from the conventional conditions. In our hands, conducting this transformation under base-free conditions prevented substrate 2 from undergoing competitive nucleophilic processes, delivering product 3 in a high isolated yield (80%) while preserving reaction fidelity [25,26,27].

(E)-3-(2-amino-4-chloro-6-morpholinopyrimidin-5-yl)acrylate 3 was characterized by IR, ¹H, ¹³C NMR, and HRMS (see spectra in the Supplementary Materials). Figure 2 shows the ¹H NMR spectra of compound 2 (black) and 3 (blue). Comparative analysis confirmed the formation of E-alkene 3, as indicated by the large coupling constant of its olefinic protons (J = 15.93 Hz).

The isolated and characterized (E)-3-(2-amino-4-chloro-6-morpholinopyrimidin-5-yl)acrylate 3, obtained in good yield (80%), does not rule out the partial reversibility of the oxaphosphetane intermediate, but suggests that the observed E-selectivity arises from the thermodynamically more stable trans-oxaphosphetane, which affords E-alkene upon phosphine oxide elimination.

3. Materials and Methods

3.1. General

Methyl (triphenylphosphoranylidene)acetate, lithium iodide, and all solvents were purchased from Sigma-Aldrich (St. Louis, MO, USA; Merck, Kenilworth, NJ, USA) and used without further purification. The melting point (uncorrected) was determined using a Thermo Scientific IA 9100/Capillary melting point apparatus (Electrothermal House, Essex, UK). ¹H and ¹³C NMR spectra were recorded on a Bruker Avance 400 spectrometer (Bremen, Germany) operating at 400 and 100 MHz, respectively, using DMSO-d₆ as the solvent and tetramethylsilane (δ 0.00 ppm) as the internal standard. Chemical shifts (δ) are reported in ppm and coupling constants (J) in hertz. High-resolution mass spectra (HRMS) were obtained using an Agilent Technologies QTOF 6520B spectrometer coupled to an Agilent 1200 HPLC system equipped with an Agilent Zorbax Extend C18 column (2.1 × 50 mm, 1.8 μm; PN 727700-902) using electrospray ionization (ESI) in the positive mode (Agilent, Santa Clara, CA, USA). The HPLC method employed a flow rate of 0.4 mL/min with a gradient from acetonitrile/water (10%, containing 0.1% formic acid) to acetonitrile (containing 0.1% of formic acid).

3.2. Synthesis of Methyl (E)-3-(2-amino-4-chloro-6-morpholinopyrimidin-5-yl)acrylate 3

Equimolar amounts (1.0 mmol) of the 2-amino-4-chloro-6-morpholinopyrimidine-5-carbaldehyde 2 and methyl (triphenylphosphoranylidene)acetate were mixed in 10 mL DMF, then lithium iodide (0.268 g, 2 mmol) was editioned and the mixture was refluxed for 5 h. The mixture was then allowed to cool to room temperature, and DMF was removed under reduced pressure. Crude product 3 was further purified by recrystallization from ethanol and isolated by filtration as a brown solid. m.p. 218–220 °C. 80%. ¹H 400 MHz DMSO–d₆ RT δ: 3.32 (bb, 4H, N–CH₂), 3.64 (t, 4H, O–CH₂), 3.70 (s, 3H, OCH₃), 6.15 (d, 1H, Hα, J = 15.93 Hz), 7.21 (s, 2H, NH₂), 7.62 (d, 1H, Hβ, J = 15.93 Hz). ¹³C 100 MHz DMSO-d₆ RT δ: 48.9 (N–CH₂), 51.4 (OCH₃), 65.7 (O–CH₂), 101.3 (C–5, pyirimidine), 116.3 (Cα), 137.8 (Cβ), 160.6 (C–4, pyirimidine), 160.9 (C–6, pyirimidine), 165.9 (C–2, pyirimidine), 167.1 (C=O). IR (KBr) cm⁻¹ 3295–3186 (NH₂ st), 2968–2946 (C–H st), 1701 (C=O st) 1623 (C=C st), 1525 (C–N st), 1106 (C–O st), 1072 (C–O, st). HR-MS calc. For C₁₂H₁₅ClN₄O₃ 298.0833 found 298.0824.

3.3. Synthesis of 2-Amino-4-chloro-6-morpholinopyrimidine-5-carbaldehyde 2

A solution of 2-amino-4,6-dichloro-5-formylpyrimidine (1 mmol), morpholine (1 mmol), and triethylamine (1 mmol) in ethanol (10.0 mL) was heated under reflux for 3 h. The reaction mixture was then allowed to cool to room temperature, and the product was collected by filtration, washed with ethanol, and air-dried. Yellow solid. m.p. 172–174 °C. 81%. ¹H 400 MHz DMSO–d₆ RT: 3.46 (t, 4H, CH₂), 3.64 (t, 4H, CH₂), 7.52 (broad s, 1H, NH₂), 7.64 (broad s, 1H, NH₂), 9.85 (s, 1H, CH O). ¹³C NMR 100 MHz DMSO–d₆ RT δ: 48.9, 66.1, 103.4, 161.2, 162.8, 166.6, 183.4 (CH=O). IR (KBr) cm⁻¹ 3351–3200 (NH₂ st), 1632 (C=O st), 1579 (C=N st), 1115 (C–O, st), 1034 (C–N, st). MS m/z (abundance %): 244 (M⁺², 4), 242 (M⁺, 11), 225 (18), 129 (27), 94 (15), 69 (28), 55 (48), 43 (100). Anal. calc. for C₉H₁₁ClN₄O₂: C 44.55, H 4.57, N 23.09 found C 44.50, H 4.33, N 23.35.

4. Conclusions

Overall, the combination of a stabilized ylide under robust base-free conditions outperformed traditional basic protocols in terms of yield, functional group tolerance, and stereochemical control. Although the reaction requires a slightly longer time, its operational simplicity and enhanced selectivity make this strategy an appealing option for the synthesis of functionalized alkenes, in which stereochemical purity and substrate stability are critical.