Novel 2H-[1,2,4]thiadiazolo[2,3-a]pyrimidine derivatives bearing chiral S(−)-2-(4-chlorophenyl)-3-methylbutyric acid moiety: Design, synthesis and herbicidal activity

2.1 Material and reagents

All the reagents and solvents were of the commercial quality and were used without purification. Elemental analysis was performed on a PE-2400 elemental analyze, the C, H and N analysis were repeated twice. ¹H NMR spectra were obtained with a Bruker AM-400 spectrometer with chemical shifts reported as ppm (in DMSO-d₆, TMS as internal standard). Mass spectra were recorded on a HP-5988A mass spectrometer at 70 ev. Melting points were determined by an X-6 micro-melting point apparatus and were uncorrected.

2.2 General procedure for the preparation of 2H-[1,2,4]thiadiazolo[2,3-a]pyrimidine derivatives(5a–f)

The synthetic routes of the target compounds 5a–f were shown in Scheme 1. According to our reported procedure (Xue et al., 2004a,b), S(−)-2-(4-chlorophenyl)-3-methylbutyric acid 1, prepared by using the previously reported method (Zhang and Zhao, 2008), were treated with SOCl₂ and KSCN, respectively, affording the intermediates 2 with moderate yields of 75%, which were used directly without further purification. The following nucleophilic reaction of 2 with 4,6-disubstituted-2-amino-pyrimidine 3a–f, led to the key intermediates 4a–f, respectively. The subsequent oxidizing cyclization of 4a–f with Br₂ in CH₂Cl₂ afforded the target compounds 5a–f, which were recrystallized twice from DMF/EtOH/H₂O with satisfied yields of 75–80%, respectively.

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Scheme 1

The synthetic routes of the target compounds.

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All the target compounds were pale yellow solid and stable at room temperature, no hygroscopic, insoluble in water and readily soluble in DMF and DMSO.

5a: S(−)-2-(4-chlorophenyl)-N-(5,7-dimethyl-2H-[1,2,4]thiadiazolo[2,3-a]pyrimidin-2-ylidene)-3-methyl butanamide. Yield 78%, mp 254–256 °C. $[\alpha ]{\hspace{0.17em}}_{\text{D}}^{20}$ , −10.5 (c, 1.15, methanol). ¹H NMR δ ppm: 0.70 (3H,d, CH(CH₃)₂), 0.90 (3H, d, CH(CH₃)₂), 2.20–2.40 (1H, m, CH(CH₃)₂), 2.10 (3H, s, CH₃), 2.20 (3H, s, CH₃), 3.90–4.10 (1H, m, CHCH(CH₃)₂), 5.94 (1H, s, py-5′-H), 7.30-7.50 (4H, m, Ph-H). MS (EI⁺) calcd for C₁₈H₁₉ClN₄OS M⁺ 374.1, found 374.5. Element Anal. Calc. for C₁₈H₁₉ClN₄OS M⁺ 374.1: C 57.67, H 5.11, N 14.94. Found: C 57.61, H 5.15, N 14.92%.

5b: S(−)-2-(4-chlorophenyl)-N-(5,7-dimethoxy-2H-[1,2,4]thiadiazolo[2,3-a]pyrimidin-2-ylidene)-3-methyl butanamide. Yield 80%, mp 252–255 °C. $[\alpha ]{\hspace{0.17em}}_{\text{D}}^{20}$ , −19.2 (c, 0.90, methanol). ¹H NMR δ ppm: 0.80 (3H, d, CH(CH₃)₂), 1.00 (3H, d, CH(CH₃)₂), 2.10–2.30 (1H, m, CH(CH₃)₂), 3.80–4.00 (1H, m, CHCH(CH₃)₂), 4.41 (3H, s, CH₃), 4.60 (3H, s, CH₃), 5.91 (1H, s, py-5′-H), 7.20–7.40 (4H, m, Ph-H). MS (EI⁺) calcd for C₁₈H₁₉ClN₄O₃S. M⁺ 406.1, found 406.3. Element Anal. Calc. for C₁₈H₁₉ClN₄O₃S: C 53.13, H 4.71, N 13.77. Found: C 53.10, H 4.76, N 13.72%.

5c: S(−)-2-(4-chlorophenyl)-N-(5,7-dichloro-2H-[1,2,4]thiadiazolo[2,3-a]pyrimidin-2-ylidene)-3-methyl-butanamide. Yield 76%, mp 245–247 °C. $[\alpha ]{\hspace{0.17em}}_{\text{D}}^{20}$ , −19.0 (c, 1.00, methanol). ¹H NMR δ ppm: 1.00 (3H, d, CH(CH₃)₂), 1.20 (3H, d, CH(CH₃)₂), 2.45–2.55 (1H, m, CH(CH₃)₂), 3.90–4.00 (1H, m, CHCH(CH₃)₂), 6.92 (1H, s, py-5′-H), 7.30–7.40 (4H, m, Ph-H). MS (EI⁺) calcd for C₁₆H₁₃Cl₃N₄OS M⁺ 415.7, found 416.0. Element Anal. Calc. for C₁₆H₁₃Cl₃N₄OS: C 46.23, H 3.15, N 13.48. Found: C 46.29, H 3.08, N 13.40%.

5d: S(−)-N-(7-chloro-5-methoxy-2H-[1,2,4]thiadiazolo[2,3-a]pyrimidin-2-ylidene)-2-(4-chlorophenyl)-3-methylbutanamide. Yield 75%, mp 251–253 °C. $[\alpha ]{\hspace{0.17em}}_{\text{D}}^{20}$ , −10.9 (c, 1.80, methanol). ¹H NMR δ ppm: 1.00 (3H, d, CH(CH₃)₂), 1.10 (3H, d, CH(CH₃)₂), 2.30–2.40 (1H, m, CH(CH₃)₂), 3.90–4.00 (1H, m, CHCH(CH₃)₂), 4.15 (3H, s, OCH₃), 5.74 (1H, s, py-5^′-H), 7.50–7.60 (4H, m, Ph-H). MS (EI⁺) calcd for C₁₇H₁₆Cl₂N₄O₂S M⁺ 410.0, found 410.2. Element Anal. Calc. for C₁₇H₁₆Cl₂N₄O₂S: C 49.64, H 3.92, N 13.62. Found: C 49.72, H 3.85, N 13.59%.

5e: S(−)-2-(4-chlorophenyl)-N-(5-hydroxy-7-methyl-2H-[1,2,4]thiadiazolo[2,3-a]pyrimidin-2-ylidene)-3-methylbutanamide. Yield 80%, mp >300 °C. $[\alpha ]{\hspace{0.17em}}_{\text{D}}^{20}$ , −12.1 (c, 0.50, methanol). ¹H NMR δ ppm: 0.90 (3H, d, CH(CH₃)₂), 1.10 (3H, d, CH(CH₃)₂), 2.40-2.55 (1H, m, CH(CH₃)₂), 2.49 (3H, s, CH₃), 3.90–4.05 (1H,m, CHCH(CH₃)₂), 6.87 (1H, s, py-5^′-H), 7.30–7.50 (4H, m, Ph-H). MS (EI⁺) calcd for C₁₇H₁₇ClN₄O₂S M⁺ 376.1, found 376.1. Element Anal. Calc. for C₁₇H₁₇ClN₄O₂S: C 54.18, H 4.55, N 14.87. Found: C 54.24, H 4.51, N 14.82%.

5f: S(−)-N-(7-chloro-5-methyl-2H-[1,2,4]thiadiazolo[2,3-a]pyrimidin-2-ylidene)-2-(4-chlorophenyl)-3-methylbutanamide. Yield 80%, mp 235–237 °C. $[\alpha ]{\hspace{0.17em}}_{\text{D}}^{20}$ , −14.3 (c, 0.80, methanol). ¹H NMR δ ppm: 1.00 (3H, d, CH(CH₃)₂), 1.10 (3H, d, CH(CH₃)₂), 2.11 (3H, s, CH₃), 2.30–2.40 (1H, m, CH(CH₃)₂), 3.90–4.00 (1H, m, CHCH(CH₃)₂), 5.74 (1H, s, py-5^′-H), 7.50–7.60 (4H, m, Ph-H). MS (EI⁺) calcd for C₁₇H₁₆Cl₂N₄OS M⁺ 394.0, found 394.2. Element Anal. Calc. for C₁₇H₁₆Cl₂N₄OS: C 51.65, H 4.08, N 14.17. Found: C 51.72, H 3.99, N 14.10%.

2.3 Biological activity

The herbicidal activities of target compounds were evaluated by flat-utensil method according with the standard bioactivity test procedures of Shanghai Academy of Agricultural Sciences in China (Xue et al., 2005a,b). The three monocotyledon weeds and two dicotyledon weeds used to test the herbicidal activity of compounds are Echinochloa crusgallis L., Sorghum bicolort, Digitaria sanguinalis (L.) scop Chenopodium serotinum (L.) and Amaranthus retroflexus L., respectively. Seeds were planted in a 6 cm-diameter flat-utensil containing artificial mixed soil. Length of root and stalk of the above ground tissues was measured after treatment for 6 days. The inhibition ratio is used to describe the control efficiency of the compounds. Dosage (activity ingredient) for each compound is 50 ppm and 100 ppm. Purified compounds were dissolved in 100 μL N,N-dimethylformamide with the addition of 30 mL water and 1% Tween 80 to give 50 ppm and 100 ppm concentration for each sample. Then it was sprayed using a laboratory belt sprayer delivering at 3.0 mL-spray-volume. For comparison, another flat-utensil containing the mixture of the same amount of water, N,N-dimethylformamide and Tween 80 was sprayed as control. Triplicate each treatment. Activity numbers represent percent displaying herbicidal damage as compared to control. The inhibition ratio is calculated by the following equation: $$\text{Inhibition ration}=1-\frac{\text{comparison}}{\text{treatment}}\times 100\%$$

3.1 Synthesis of 2H-[1,2,4]thiadiazolo[2,3-a]pyrimidine derivatives(5a–f) and characterization

Firstly, S(−)-2-(4-chlorophenyl)-3-methylbutyric acid 1 was acylated by SOCl₂ followed by isothiocyanation and coupling reactions with 4,6-disubstituted-2-amino-pyrimidine 3a–f to give N′-(4,6-disubstituted-pyrimid-2-yl)-N-[2-(4-chlorophenyl)-3-methylbutyric)]-thiourea 4a–f in moderate yield. Then the title compounds 5a–f were successfully obtained using bromine as cyclic reagent with overall 50–60% yield. Compounds 5a–f were characterized by ¹H NMR, EI and elemental analysis. All results are in full agreement with the proposed structures. For example, the singlet signal at 6.87 ppm (pyrimidine) and the doublet signal at 0.9 and 1.1 ppm (CH(CH₃)₂) of ¹H NMR spectra suggest that compound 5e is consistent with its structure, and MS matches the calculated values to show the [M]⁺ ions as 376.1. The results of elemental analyses are in good agreement with those calculated for the suggested formula. The melting points are sharp indicating the purity of these compounds.

3.2 Biological activity of target compounds

The herbicidal activities of the target compounds were evaluated against a variety of weeds by flat-utensil method according with the standard bioactivity test procedures of Shanghai Academy of Agricultural Sciences in China. The results were summarized in Table 1.

From Table 1, we could find that most of the target compounds had moderate inhibitory activities and selectivities against root and stalk of monocotyledon and dicotyledon plants. Compounds 5a and 5f showed the highest inhibitory activities against root and stalk of Amaranthus retroflexus L. in higher concentration (1.0 × 10⁻⁴ μg/mL), while compounds 5d and 5e showed good activities against root of Echinochloa crusgallis L. and stalk of Chenopodium serotinum L., respectively. It was worth noting that the chiral target compounds showed improved herbicidal activities to some extent over their racemic counterparts (such as 5a versus (±)5a and 5b versus (±)5b) against a variety of tested weeds, which might be contributed by the introduction of chiral active unit. Further structure–herbicidal activity relationships about the designed compounds were under the way. The present work provided a novel class of chirality-based thiadiazolopyrimidine derivatives with potential herbicidal activities for further optimization.