Studies on Pyrrolidinones: Chemistry of Dimethoxytriazines

Abstract

The synthesis of dimethoxytriazine-containing N-aryl substituted pyrrolidinones is realized for the first time. Three new modes of reactivity for these substrates possessing a 4,6-dimethoxy-1,3,5-triazine unit are discussed. Their treatment with acid leads to complete O-demethylation of the methoxy groups, while similar reaction in a basic medium leads to partial O-demethylation. In contrast, heating in the presence of dimethyl sulfate as the catalyst induces migration of the methyl groups from the oxygen atoms to the triazine nitrogens (Hilbert–Johnson transposition). These new scaffolds may demonstrate biological potential.

The s-triazine (1,3,5-triazine) moiety is a widespread heterocyclic system, which can be utilized as a synthetic pharmacophore with considerable therapeutic potential.[1] While less studied than pyrimidines, the biological importance of triazines has made them attractive synthetic targets. Many derivatives of this class of compounds have been synthesized, mainly for their antifungal[2] and herbicidal[3] properties. We have previously reported that several N-benzylpyrrolidinones, such as 1 [4] and 2,[5] exhibit antifungal activities, and have investigated the synthesis of heterocyclic compounds 3 containing an N-benzylpyrrolidinone group linked to a 4,6-dimethoxy-1,3,5-triazine moiety, with potential biostatic properties[6] (Figure [1]). In continuation of this research, we were interested by the possibility of attaching 1,3,5-triazinone and 1,3,5-triazine­dione cores to pyrrolidinones (at C-5). Herein, we report the synthesis of novel triazines 3 and 4, the total or partial hydrolysis of their methoxy groups, and the Hilbert–Johnson­ transposition of these compounds.

Important methods described thus far for the synthesis of dimethoxytriazines involve the Grignard or palladium-catalyzed coupling of 2-chloro-4,6-dimethoxytriazine,[7] or the reaction of a very large excess of an activated carboxylic acid with zinc dimethyl imidodicarbonimidate (5).[8] We previously reported that performing this reaction in the presence of pyridine and 4 Å molecular sieves allowed the use of only a stoichiometric amount of acid chloride, affording the known dimethoxytriazines 3a and 3b.[6] The same reaction applied to the condensation of acid chlorides 6c,[9] 7a and 7b furnished moderate to good yields of the novel dimethoxytriazines 3c, 4a and 4b (Scheme [1]). Acid chlorides 7a and 7b were obtained via the copper-catalyzed N-arylation of methyl dl-pyroglutamate (8),[10] [11] saponification of the intermediate esters 9a [10] and 9b thus obtained, and then treatment of the acids 10a and 10b with thionyl chloride (Scheme [1]).

There are no reports on the synthesis of 2-alkyltriazine-4,6-diones in the literature. In the field of dialkoxytriazines substituted at C-2 by an amino[12] or a propargyloxy[13] group, reflux of the substrate in dilute hydrochloric acid or heating at 180 °C led to the formation of the corresponding di- (or tri)-carbonyl compound. In the dimethoxypyrimidine series, many different reagents have been utilized to realize such total hydrolysis (Me₃SiX[14] in the presence of NaI,[15] CH₃COX[16] which is considered to be better,[15b] or heating in aqueous HCl,[17] which is described[18] as the superior method). Nevertheless, with dimethoxypyridine[19] or pyrimidine,[20] partial hydrolysis can occur, sometimes accompanied by migration of one of the methyl groups from oxygen to nitrogen. We studied the hydrolysis of dimethoxytriazine 3a in 20% aqueous hydrochloric acid (4 equiv, reflux, 3 h), which resulted in complete decomposition of the substrate. However, heating the same compound at reflux temperature in aqueous hydrochloric acid (1.8%) for five hours furnished a 71% yield of triazinedione 11a after recrystallization from water. Thus, hydrolysis of compounds 3b, 3c, 4a and 4b was realized under these conditions to afford products 11b, 11c, 12a and 12b in moderate to good yields (Scheme [2]). Interestingly, during these reactions with hydrochloric acid, partial hydrolysis or migration of a methyl group were not detected.

As with the total hydrolysis of alkoxytriazines, the literature proved to be very scarce concerning partial reactions. To the best of our knowledge, the only reports concerned heating 2,4,6-tripropargyloxy-1,3,5-triazines (50 °C, 1 h) in aqueous sodium hydroxide (5%), which led to hydrolysis of one of the three ether groups,[13b] and the analogous reaction in the 2,4-dimethoxy-1,3-pyrimidine series required heating the substrate at reflux temperature in aqueous sodium hydroxide (5 M) for 48 hours to give moderate yields of methoxypyrimidone, accompanied by the completely hydrolyzed product.[20] Modification of these conditions led us to heat dimethoxytriazines 3a–c and 4b at reflux temperature in the presence of potassium hydroxide (1–2 equiv) in methanol for 20–28 hours to give 62–87% yields of 2-methoxy-1,3,5-triazin-6-ones 13a–c and 14b (Scheme [3]); no by-products were isolated from these reactions.

1,3-Dimethyl-1,3,5-triazine-2,4-diones represent other potential biocides; these interesting compounds can be obtained by Hilbert–Johnson oxygen to nitrogen migration of dimethoxytriazines. The mechanism of the reaction was proved, in the pyrimidine series, to occur via a sequence of alkylation–dealkylation steps,[21] at 160–190 °C in the presence of p-toluenesulfonic acid (PTSA) derivatives,[22] or at lower temperatures by using alkylating agents,[23] or sodium iodide in N,N-dimethylformamide.[24] Again, very few reports have appeared concerning the triazine series: 2,3-dimethoxy-1,3,5-triazine[25] and 1-amino-3,5-dialkoxytriazines,[22b] were transposed at high temperature (160–250 °C), the reaction being favored by the action of p-toluenesulfonic acid. In addition, the reaction of 2-chloro-3,5-dimethoxytriazine with sodium diethoxy dithiophosphonate led to the product of oxygen to nitrogen migration.[26] Taking the above into account, dimethoxytriazines 3a and 3c were heated at reflux temperature in toluene in the presence of dimethyl sulfate for 24–48 hours to give 1,3-dimethyl-1,3,5-triazines 15a and 15c (Scheme [4]); again, no by-products were isolated from these reactions.

Products 3b, 11a,c and 13b,c were selected by the National Cancer Institute (NCI) for biological screening on a 60-cell line panel. They were tested initially at a single dose (10 μM), but did not satisfy the predetermined threshold inhibition criteria, and did not progress to the five-dose screen in order to determine their GI₅₀ (concentration that causes 50% growth inhibition) values. However, at this concentration (10 μM), chlorotriazines 3b and 13b showed modest cellular growth inhibition of leukemia cell lines (3b: 38.9% inhibition of SR; 13b: 33.4% inhibition of K562), of ovarian cancer cell lines (3b: 42.7% inhibition of IGROV1 and 43.8% inhibition of OVCAR-8), and of a renal cancer cell line (13b: 35.3% inhibition of CAKI-1). All the other tested compounds were devoid of biological activity on tumor cell lines.

In conclusion, the 2-alkyl-3,5-dimethoxy-1,3,5-triazine system represents a rarely encountered heterocyclic scaffold. We have demonstrated that partial or total hydrolysis of the methoxy groups, and a Hilbert–Johnson oxygen to nitrogen migration of the methyl groups can be realized easily by using dilute potassium hydroxide or hydrochloric acid, or by catalysis with dimethyl sulfate. These reactions allowed the preparation of a variety of potential biocides, formed from pyrrolidinones substituted at the 5-position with a triazine scaffold. The antifungal properties of these compounds will be reported in due course.

All starting materials were commercially available. Thin-layer chromatography (TLC) was performed on Macherey Nagel silica gel plates containing a fluorescent indicator, and were made visual under a UV lamp at 254 nm and 366 nm. Column chromatography was accomplished on silica gel (40–60 μm; Macherey Nagel). Melting points were measured on an MPA 100 OptiMelt apparatus and are uncorrected. IR spectra were recorded on a Varian 640-IR FT-IR spectrometer. NMR spectra were acquired at 200 MHz (¹H NMR) on a Varian Gemini 2000 spectrometer, or at 400 MHz (¹H NMR) and 100 MHz (¹³C NMR) on a Varian 400 MHz Premium Shielded spectrometer. Chemical shifts (δ) are expressed in parts per million relative to TMS as the internal standard. LC–MS was accomplished using an HPLC combined with a Surveyor MSQ (Thermo Electron) equipped with an APCI source. Elemental analysis of new compounds were recorded by ‘Pôle Chimie Moléculaire’, Faculté de Sciences Mirande, Université de Bourgogne, Dijon, France. Many of the products obtained during this study were difficult to obtain in perfectly anhydrous form; similar problems have been reported previously with triazine compounds.[27]

Methyl N-Arylpyroglutamates 9a,b; General Procedure

To a suspension of methyl dl-pyroglutamate (1 equiv), CuI (0.5 equiv), Cs₂CO₃ (2 equiv), and the appropriate aryl halide (1.0–1.5 equiv) in 1,4-dioxane under an N₂ atmosphere was added dropwise the coupling ligand, N,N′-dimethylethylenediamine (DMEDA) (1 equiv) via a syringe. The mixture was then stirred at 50 °C or 60 °C for 12 or 20 h, turning blue very quickly.[10] After cooling to r.t., the mixture was filtered to remove insoluble salts and the filter cake was washed with CH₂Cl₂. The filtrate was concentrated in vacuo and the residue was partitioned between H₂O and CH₂Cl₂. The organic layer was dried over MgSO₄ and evaporated to dryness. The residue was purified by column chromatography on silica gel (EtOAc­–n-heptane) to afford pure compound 9a or 9b.

Methyl N-(Benzo[1,3]dioxol-5-yl)pyroglutamate (9a)

The general procedure was followed using methyl dl-pyroglutamate (2.0 g, 14 mmol), 5-bromo-1,3-benzodioxole (2.5 mL, 21 mmol), Cs₂CO₃ (9.1 g, 28 mmol), CuI (1.3 g, 7 mmol) and DMEDA (1.5 mL, 14 mmol) in 1,4-dioxane (40 mL). The mixture was stirred at 60 °C for 12 h. The residue was separated by chromatography on silica gel (EtOAc–n-heptane, 3:2) to afford pure product 9a as a white powder (3.13 g, 85%). The physicochemical properties were identical to those reported in the literature.[10]

Methyl N-(4-Acetylphenyl)pyroglutamate (9b)

The general procedure was followed using methyl dl-pyroglutamate (2.91 g, 20.32 mmol), 1-(4-iodophenyl)ethanone (5.00 g, 20.32 mmol), Cs₂CO₃ (13.24 g, 40.64 mmol), CuI (1.96 g, 10.16 mmol) and DMEDA (2.18 mL, 20.32 mmol) in 1,4-dioxane (50 mL). The mixture was stirred at 50 °C for 20 h. The residue was separated by chromatography on silica gel (EtOAc–n-heptane, 1:1) to afford pure product 9b.

Yield: 3.45 g (65%); white solid; mp (EtOAc) 96–99 °C; R_f  = 0.23 (EtOAc–n-heptane, 1:1).

IR (neat): 1738, 1712, 1669, 1599, 1377, 1346, 1261, 1197, 1177, 840 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 2.20–2.29 (m, 1 H, CH₂CH ₂CH), 2.48–2.56 (m, 1 H, CH ₂CH₂CH), 2.58 (s, 3H, COCH ₃), 2.59–2.64 (m, 1 H, CH ₂CH₂CH), 2.72–2.84 (m, 1 H, CH₂CH ₂CH), 3.76 (s, 3 H, COOCH ₃), 4.82 (m, 1 H, CH₂CH₂CH), 7.63 (d, J = 8.8 Hz, 2 H, ArH), 7.96 (d, J = 8.8 Hz, 2 H, ArH).

¹³C NMR (100 MHz, CDCl₃): δ = 23.1 (CH₂), 26.5 (CH₃), 31.0 (CH₂), 52.9 (CH₃), 61.0 (CH), 119.8 and 119.9 (2 rotamers, 2 CH), 129.4 and 129.5 (2 rotamers, 2 CH), 133.5 (C), 142.4 (C), 171.9 (C), 174.4 (C), 196.9 (C).

Anal. Calcd for C₁₄H₁₅NO₄·0.2H₂O: C, 63.48; H, 5.86; N, 5.29. Found: C, 63.76; H, 6.16; N, 5.53.

Pyroglutamic Acids 10a,b; General Procedure

A mixture of ester 9a or 9b (1 equiv) and aq NaOH (2 M, 2 equiv) was stirred at 80 °C for 1 or 10 h (until the starting ester had dissolved completely, which was equivalent to sodium carboxylate formation). After cooling to r.t., the stirred soln was acidified to pH 5–6 by slow addition of concd HCl. The solid obtained by filtration was washed with distilled H₂O and dried to give pure acid 10a or 10b.

N-(Benzo[1,3]dioxol-5-yl)pyroglutamic Acid (10a)

The general procedure was followed using ester 9a (0.80 g, 2.59 mmol) and aq NaOH [0.17 g, 4.25 mmol in H₂O (2.2 mL), 2 M]. The mixture was stirred at 80 °C for 10 h. The solid obtained by filtration was washed with H₂O and dried to give acid 10a.

Yield: 0.75 g (99%); white solid; mp (H₂O) 156–158 °C; R_f  = 0.24 (CH₂Cl₂).

¹H NMR (200 MHz, CDCl₃): δ = 2.15–2.30 (m, 1 H, CH₂CH ₂CH), 2.44–2.81 (m, 3 H, CH ₂CH ₂CH), 4.63 (dd, J = 8.9, 3.1 Hz, 1 H, CH₂CH₂CH), 5.81 (br s, 1 H, COOH), 5.96 (s, 2 H, OCH ₂O), 6.767 (d, J = 2.7 Hz, 1 H, ArH), 6.771 (s, 1 H, ArH), 7.06 (dd, J = 1.8, 0.9 Hz, 1 H, ArH).

¹³C NMR (100 MHz, CDCl₃–DMSO-d ₆): δ = 23.2 (CH₂), 30.6 (CH₂), 62.4 (CH), 101.2 (CH₂), 105.0 (CH), 107.9 (CH), 115.6 (CH), 132.3 (C), 145.3 (C), 147.7 (C), 173.4 (C), 174.4 (C).

Anal. Calcd for C₁₂H₁₁O₅N: C, 57.83; H, 4.45; N, 5.62. Found: C, 57.57; H, 4.31; N, 5.93.

N-(4-Acetylphenyl)pyroglutamic Acid (10b)

The general procedure was followed using ester 9b (2.40 g, 9.19 mmol) and aq NaOH [0.73 g, 18.35 mmol in H₂O (9.2 mL), 2 M]. The mixture was stirred at 80 °C for 1 h. The solid obtained by filtration was washed with H₂O and dried to give acid 10b.

Yield: 1.57 g (69%); white solid; mp (H₂O) 207–210 °C.

IR (neat): 3349, 1707, 1668, 1598, 1581, 1442, 1385, 1328, 1287, 1213, 1186, 1108, 901, 823 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 1.70–1.82 (m, 1 H, CH₂CH ₂CH), 1.83–1.97 (m, 1 H, CH ₂CH₂CH), 2.17–2.32 (m, 2 H, CH ₂CH ₂CH), 2.24 (s, 3 H, COCH₃), 6.43 (d, J = 8.8 Hz, 2 H, ArH), 6.59–6.64 (m, 1 H, CH₂CH₂CH), 7.56 (d, J = 8.8 Hz, 2 H, ArH), 12.32 (s, 1 H, COOH).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 26.9 (CH₃), 27.5 (CH₂), 30.5 (CH₂), 54.9 (CH), 111.7 (C), 126.0 (2 CH), 130.8 (2 CH), 152.6 (C), 174.2 (C), 174.6 (C), 195.6 (C).

Anal. Calcd for C₁₃H₁₃NO₄: C, 63.15; H, 5.30; N, 5.66. Found: C, 62.97; H, 5.12; N, 5.60.

Acid Chlorides 6a–c and 7a,b; General Procedure

A mixture of carboxylic acid 10a or 10b (1 equiv) and SOCl₂ (2 equiv) in CH₂Cl₂ was heated at reflux temperature under an inert atm for 2–24 h. The resulting pale yellow soln was concentrated in vacuo to give the crude acid chloride 6a–c, 7a or 7b as a pale yellow solid in quant. yield, which was used without further purification in the subsequent step.

The physicochemical properties of acid chlorides 6a–c were identical to those reported in the literature.[6]

1-(1,3-Benzodioxol-5-yl)-5-oxoprolyl Chloride (7a)

¹H NMR (400 MHz, CDCl₃): δ = 2.35–2.44 (m, 1 H, CH₂CH ₂CH), 2.56–2.80 (m, 3 H, CH ₂CH ₂CH), 4.90–4.97 (m, J = 4.7, 2.9, 1.9 Hz, 1 H, CH₂CH₂CH), 5.99 (s, 2 H, OCH ₂O), 6.72 (dd, J = 8.4, 2.0 Hz, 1 H, ArH), 6.81 (d, J = 8.2 Hz, 1 H, ArH), 7.05 (d, J = 2.0 Hz, 1 H, ArH).

1-(4-Acetylphenyl)-5-oxoprolyl Chloride (7b)

¹H NMR (400 MHz, CDCl₃): δ = 2.22–2.40 (m, 1 H, CH₂CH ₂CH), 2.43–2.81 (m, 3 H, CH ₂CH ₂CH), 2.59 (s, 3 H, COCH ₃), 4.80 (m, 1 H, CH₂CH₂CH), 7.66 (d, J = 8.6 Hz, 2 H, ArH), 8.00 (d, J = 8.6 Hz, 2 H, ArH).

Dimethoxytriazines 3a–c and 4a,b; General Procedure

Under an inert atm, a soln of acid chloride 6a–c, 7a or 7b (1 equiv) in anhyd CH₂Cl₂ was added dropwise over 30 min to a stirred mixture of zinc dimethyl imidodicarbonimidate (5) (0.5–0.75 equiv) and powdered 4 Å MS in distilled py (15 mL). After the addition was complete, the mixture was stirred at r.t. for 24 h. The mixture was filtered, the solid washed with CH₂Cl₂ and the filtrate concentrated in vacuo. The residue was co-evaporated with toluene (3 × 5 mL) in order to remove py. The remaining slurry was dissolved in CH₂Cl₂ (10 mL), washed with HCl (1 M, 3 × 10 mL), and then aq sat. NaHCO₃ soln (10 mL). Following evaporation, the obtained residue was crystallized or purified by column chromatography, then recrystallized from an appropriate solvent to give pure di­methoxytriazine 3a–c, 4a or 4b.

The physicochemical properties of triazines 3a–c were identical to those reported in the literature.[6]

1-Benzo[1,3]dioxol-5-yl-5-(4,6-dimethoxy[1,3,5]triazin-2-yl)pyrrolidine-2-one (4a)

The general procedure was followed using acid chloride 7a (0.54 g, 2.02 mmol), zinc derivative 5 (0.50 g, 1.54 mmol), py (20 mL) and CH₂Cl₂ (3 mL) in the presence of powdered 4 Å MS (2.00 g). The residue obtained upon evaporation was purified by column chromatography (EtOAc–n-heptane, 7:3) to provide pure triazine 4a.

Yield: 0.5 g (67%); white solid; mp (EtOAc–n-heptane) 114–116 °C; R_f  = 0.26 (EtOAc–n-heptane, 7:3).

¹H NMR (200 MHz, CDCl₃): δ = 2.04–2.20 (m, 1 H, CH₂CH ₂CH), 2.52–2.96 (m, 3 H, CH ₂CH ₂CH), 4.01 (s, 6 H, 2 OCH ₃), 5.05–5.12 (m, 1 H, CH₂CH₂CH), 5.92 (s, 2 H, OCH ₂O), 6.72 (dd, J = 12.7, 8.5 Hz, 2 H, ArH), 7.12 (d, J = 1.8 Hz, 1 H, ArH).

¹³C NMR (100 MHz, CDCl₃): δ = 25.1 (CH₂), 30.7 (CH₂), 55.5 (2 CH₃), 65.3 (CH), 101.3 (CH₂), 105.2 (CH), 107.9 (CH), 115.9 (CH), 132.3 (C), 145.2 (C), 147.7 (C), 172.9 (2 C), 174.8 (C), 181.9 (C).

Anal. Calcd for C₁₆H₁₆N₄O₅: C, 55.81; H, 4.68; N, 16.27. Found: C, 56.11; H, 4.51; N, 15.90.

1-(4-Acetylphenyl)-5-(4,6-dimethoxy-1,3,5-triazin-2-yl)pyrrolidin-2-one (4b)

The general procedure was followed using acid chloride 7b (1.64 g, 6.19 mmol), zinc derivative 5 (1.01 g, 3.09 mmol), py (20 mL) and CH₂Cl₂ (3 mL) in the presence of powdered 4 Å MS (3.00 g). The residue obtained upon evaporation was purified by column chromatography on silica gel (EtOAc–n-heptane, 7:3) to afford pure compound 4b.

Yield: 738 mg (35%); white solid; mp (EtOAc) 137–139 °C; R_f  = 0.13 (EtOAc–n-heptane, 1:1).

IR (neat): 1695, 1678, 1549, 1502, 1457, 1366, 1272, 1257, 1108, 1072, 1025, 932, 831 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 2.14–2.22 (m, 1 H, CH₂CH ₂CH), 2.17 (s, 3 H, COCH₃), 2.61–2.72 (m, 2 H, CH ₂CH₂CH), 2.82–2.95 (m, 1 H, CH₂CH ₂CH), 3.99 (s, 6 H, 2 OCH ₃), 5.23–5.30 (m, 1 H, CH₂CH₂CH), 7.67 (d, J = 8.4 Hz, 2 H, ArH), 7.89 (d, J = 8.4 Hz, 2 H, ArH).

¹³C NMR (100 MHz, CDCl₃): δ = 24.9 (CH₂), 26.1 (CH₃), 31.2 (CH₂), 55.5 (2 CH₃), 63.1 (CH), 120.0 (2 CH), 129.3 (2 CH), 133.1 (C), 142.7 (C), 172.9 (C), 175.1 (2 C), 181.5 (C), 196.9 (C).

Anal. Calcd for C₁₇H₁₈N₄O₄·0.5H₂O: C, 58.11; H, 5.45; N, 15.95. Found: C, 58.11; H, 5.49; N, 15.81.

O-Demethylated Derivatives 11a–c and 12a,b; General Procedure

A suspension of dimethoxytriazine 3a–c, 4a or 4b (1 equiv) in aq HCl (1.8%, 2 equiv) was heated at reflux temperature for 5 h. After cooling to r.t., the precipitate formed was filtered and washed with H₂O to afford pure triazinedione 11a–c, 12a or 12b.

6-[1-(2-Methylbenzyl)-5-oxopyrrolidin-2-yl]-1,3,5-triazine-2,4(1H,3H)-dione (11a)

The general procedure was followed using dimethoxytriazine 3a (1.00 g, 3.05 mmol) and HCl (1.8%, 10.5 mL). Pure compound 11a was obtained after filtration.

Yield: 650 mg (71%); white solid; mp (H₂O) 136–137 °C.

IR (neat): 3500, 3386, 1727, 1686, 1662, 1611, 1433, 1413, 1244, 1156, 953, 905, 795, 540 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 1.98–2.07 (m, 1 H, CH₂CH ₂CH), 2.20 (s, 3 H, ArCH ₃), 2.25–2.45 (m, 3 H, CH ₂CH ₂CH), 3.89 (d, J = 15.2 Hz, 1 H, ArCH ₂N), 4.10 (dd, J = 8.7, 2.6 Hz, 1 H, CH₂CH₂CH), 4.72 (d, J = 15.2 Hz, 1 H, ArCH ₂N), 7.07 (d, J = 7.2 Hz, 1 H, ArH), 7.10–7.18 (m, 3 H, ArH), 11.25 (s, 1 H, CONHCN), 12.09 (s, 1 H, CONHCO).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 19.1 (CH₃), 23.9 (CH₂), 29.2 (CH₂), 43.2 (CH₂), 58.5 (CH), 126.3 (CH), 128.0 (CH), 128.9 (CH), 130.7 (CH), 134.4 (2 C), 137.0 (C), 168.9 (2 C), 175.0 (C).

Anal. Calcd for C₁₅H₁₆N₄O₃·H₂O: C, 56.60; H, 5.70; N, 17.60. Found: C, 56.19; H, 5.79; N, 17.93.

6-[1-(4-Chlorobenzyl)-5-oxopyrrolidin-2-yl]-1,3,5-triazine-2,4(1H,3H)-dione (11b)

The general procedure was followed using dimethoxytriazine 3b (1.00 g, 2.87 mmol) and HCl (1.8%, 8.5 mL). Pure compound 11b was obtained after filtration.

Yield: 763 mg (83%); white solid; mp (H₂O) 167–169 °C.

IR (neat): 3364, 2945, 1759, 1665, 1611, 1491, 1458, 1394, 1360, 1248, 997, 791 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 2.03–2.09 (m, 1 H, CH₂CH ₂CH), 2.32–2.39 (m, 3 H, CH ₂CH ₂CH), 4.00 (d, J = 15.2 Hz, 1 H, ArCH ₂N), 4.26 (dd, J = 9.2, 3.6 Hz, 1 H, CH₂CH₂CH), 4.77 (d, J = 15.6 Hz, 1 H, ArCH ₂N), 7.28 (d, J = 8.8 Hz, 2 H, ArH), 7.42 (d, J = 8.8 Hz, 2 H, ArH), 11.32 (s, 1 H, CONHCN), 12.22 (s, 1 H, CONHCO).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 23.7 (CH₂), 29.1 (CH₂), 44.1 (CH₂), 58.6 (CH), 128.9 (2 CH), 130.3 (2 CH), 132.4 (C), 136.1 (2 C), 168.9 (2 C), 175.3 (C).

Anal. Calcd for C₁₄H₁₃ClN₄O₃·1.5H₂O: C, 48.35; H, 4.64; N, 16.11. Found: C, 48.31; H, 4.25; N, 16.12.

6-[1-(1,3-Benzodioxol-5-ylmethyl)-5-oxopyrrolidin-2-yl]-1,3,5-triazine-2,4(1H,3H)-dione (11c)

The general procedure was followed using dimethoxytriazine 3c (0.71 g, 1.95 mmol) and HCl (1.8%, 7.5 mL). Pure compound 11c was obtained after filtration.

Yield: 548 mg (85%); white solid; mp (H₂O) 219–221 °C.

IR (neat): 3080, 2929, 2760, 1754, 1687, 1658, 1604, 1498, 1455, 1245, 1029, 915, 793, 665, 631, 530 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 1.95–2.05 (m, 1 H, CH₂CH ₂CH), 2.19–2.43 (m, 3 H, CH ₂CH ₂CH), 3.83 (d, J = 14.9 Hz, 1 H, ArCH ₂N), 4.15 (dd, J = 8.5, 2.9 Hz, 1 H, CH₂CH₂CH), 4.65 (d, J = 14.9 Hz, 1 H, ArCH ₂N), 5.97 (dd, J = 3.1, 0.8 Hz, 2 H, OCH ₂O), 6.67 (dd, J = 7.8, 1.6 Hz, 1 H, ArH), 6.77 (d, J = 1.6 Hz, 1 H, ArH), 6.83 (d, J = 7.8 Hz, 1 H, ArH), 11.27 (s, 1 H, CONHCN), 12.14 (s, 1 H, CONHCO).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 23.7 (CH₂), 29.3 (CH₂), 44.5 (CH₂), 58.5 (CH), 101.4 (CH₂), 101.6 (CH), 109.0 (CH), 121.9 (CH), 130.7 (C), 147.0 (C), 148.8 (2 C), 169.0 (C), 175.1 (2 C).

Anal. Calcd for C₁₅H₁₄N₄O₅: C, 54.55; H, 4.27; N, 16.96. Found: C, 54.79; H, 4.44; N, 16.99.

6-[1-(Benzo[1,3]dioxol-5-yl)-5-oxopyrrolidin-2-yl]-1,3,5-triazine-2,4(1H,3H)-dione (12a)

The general procedure was followed using dimethoxytriazine 4a (0.15 g, 0.44 mmol) and HCl (1.8%, 6 mL). Pure compound 12a was obtained after filtration.

Yield: 113 mg (81%); white solid.

¹H NMR (400 MHz, DMSO-d ₆): δ = 2.25–2.36 (m, 1 H, CH₂CH ₂CH), 2.40–2.63 (m, 3 H, CH ₂CH ₂CH), 5.00–5.03 (m, 1 H, CH₂CH₂CH), 6.28 (s, 2 H, OCH ₂O), 7.08 (dd, J = 8.4, 1.9 Hz, 1 H, ArH), 7.17 (d, J = 8.4 Hz, 1 H, ArH), 7.45 (d, J = 1.9 Hz, 1 H, ArH), 10.15 (s, 1 H, NH), 11.61 (s, 1 H, NH).

Anal. Calcd for C₁₄H₁₂N₄O₅: C, 53.17; H, 3.82; N, 17.71. Found: C, 53.43; H, 4.05; N, 17.40.

6-[1-(4-Acetylphenyl)-5-oxopyrrolidin-2-yl]-1,3,5-triazine-2,4(1H,3H)-dione (12b)

The general procedure was followed using dimethoxytriazine 4b (0.26 g, 0.75 mmol) and HCl (1.8%, 10 mL). Pure compound 12b was obtained after filtration.

Yield: 112 mg (47%); white solid; mp (H₂O) 170–173 °C.

IR (neat): 3547, 3476, 1717, 1677, 1616, 1599, 1421, 1356, 1267, 1222, 1039, 848, 772, 620, 547 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 2.33–2.40 (m, 1 H, CH₂CH ₂CH), 2.58–2.69 (m, 1 H, CH₂CH ₂CH), 2.67 (s, 3 H, COCH ₃), 2.72–2.80 (m, 2 H, CH ₂CH₂CH), 5.24 (dd, J = 8.4, 2.8 Hz, 1 H, CH₂CH₂CH), 7.79 (d, J = 8.4 Hz, 2 H, ArH), 8.09 (d, J = 8.4 Hz, 2 H, ArH), 11.49 (s, 1 H, CONHCN), 12.66 (s, 1 H, CONHCO).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 23.8 (CH₂), 27.0 (CH₃), 31.0 (CH₂), 60.4 (CH), 119.7 (2 CH), 129.6 (2 CH), 132.9 (C), 142.8 (2 C), 168.6 (C), 175.2 (C), 197.1 (C).

Anal. Calcd for C₁₅H₁₄N₄O₄·MeOH·H₂O: C, 52.74; H, 5.53; N, 15.3. Found: C, 52.79; H, 5.12; N, 15.18.

Mono O-Demethylated Derivatives 13a–c and 14b; General Procedure

Dimethoxytriazine 3a–c or 4b (1 equiv) was added to a soln of KOH (1–2 equiv) in MeOH and the resulting mixture heated at reflux temperature for 19–28 h. After cooling to r.t., the solvent was evaporated in vacuo and the residue dissolved in CH₂Cl₂. All insoluble salts were removed by filtration and the filtrate was concentrated in vacuo. Et₂O was then added to the crude residue and the obtained precipitate was collected by filtration to give pure product 13a–c or 14b.

6-Methoxy-4-[1-(2-methylbenzyl)-5-oxopyrrolidin-2-yl]-1,3,5-triazin-2(1H)-one (13a)

The general procedure was followed using dimethoxytriazine 3a (0.50 g, 1.52 mmol) and KOH (0.085 g, 1.52 mmol) in MeOH (10 mL). The reaction mixture was heated at reflux temperature for 24 h. The obtained white solid was filtered and dried to provide mono O-demethylated product 13a.

Yield: 380 mg (80%); yellow solid.

IR (neat): 3080, 2929, 2760, 1754, 1687, 1658, 1604, 1498, 1455, 1245, 1029, 915, 793, 665, 631, 530 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 1.77–1.90 (m, 1 H, CH₂CH ₂CH), 2.12–2.32 (m, 2 H, CH ₂CH₂CH), 2.16 (s, 3 H, ArCH ₃), 2.35–2.45 (m, 1 H, CH₂CH ₂CH), 3.67 (s, 3 H, OCH ₃), 3.71 (d, J = 15.2 Hz, 1 H, ArCH ₂N), 3.93 (dd, J = 8.5, 2.9 Hz, 1 H, CH₂CH₂CH), 4.84 (d, J = 15.2 Hz, 1 H, ArCH ₂N), 6.99 (d, J = 7.2 Hz, 1 H, ArH), 7.08–7.18 (m, 3 H, ArH).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 19.1 (CH₃), 24.6 (CH₂), 29.9 (CH₂), 42.6 (CH₂), 53.2 (CH), 61.8 (CH₃), 126.3 (CH), 127.7 (CH), 128.7 (CH), 130.6 (CH), 135.0 (C), 136.6 (C), 172.2 (C), 175.0 (2 C), 177.8 (C).

LC–MS (APCI⁺): m/z 315.1 [M + H]⁺.

4-[1-(4-Chlorobenzyl)-5-oxopyrrolidin-2-yl]-6-methoxy-1,3,5-triazin-2(1H)-one (13b)

The general procedure was followed using dimethoxytriazine 3b (0.25 g, 0.72 mmol) and KOH (0.040 g, 0.72 mmol) in MeOH (8 mL). The reaction mixture was heated at reflux temperature for 24 h. The obtained white solid was filtered and dried to provide mono O-demethylated product 13b.

Yield: 209 mg (87%); yellow solid.

IR (neat): 3043, 2756, 1755, 1667, 1489, 1423, 1212, 1088, 915, 799, 672 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 2.02–2.10 (m, 1 H, CH₂CH ₂CH), 2.32–2.45 (m, 2 H, CH ₂CH₂CH), 2.61–2.76 (m, 1 H, CH₂CH ₂CH), 3.84 (d, J = 15.1 Hz, 1 H, ArCH ₂N), 3.86 (s, 3 H, OCH ₃), 4.21 (m, 1 H, CH₂CH₂CH), 4.95 (d, J = 15.1 Hz, 1 H, ArCH ₂N), 7.12 (d, J = 8.2 Hz, 2 H, ArH), 7.26 (d, J = 8.2 Hz, 2 H, ArH).

Anal. Calcd for C₁₅H₁₅ClN₄O₃: C, 53.82; H, 4.52; N, 16.74. Found: C, 54.12; H, 4.80; N, 17.01.

4-[1-(1,3-Benzodioxol-5-ylmethyl)-5-oxopyrrolidin-2-yl]-6-methoxy­-1,3,5-triazin-2(1H)-one (13c)

The general procedure was followed using dimethoxytriazine 3c (0.50 g, 1.40 mmol) and KOH (0.156 g, 2.79 mmol) in MeOH (10 mL). The reaction mixture was heated at reflux temperature for 28 h. The obtained white solid was filtered and dried to provide mono O-demethylated product 13c.

Yield: 350 mg (73%); yellow solid; mp (Et₂O) 230–232 °C.

IR (neat): 2955, 1663, 1560, 1489, 1444, 1363, 1242, 1203, 1099, 1035, 835, 772, 650 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 1.79–1.90 (m, 1 H, CH₂CH ₂CH), 2.13–2.29 (m, 2 H, CH ₂CH₂CH), 2.31–2.42 (m, 1 H, CH₂CH ₂CH), 3.58 (d, J = 14.9 Hz, 1 H, ArCH ₂N), 3.56 (s, 3 H, OCH ₃), 3.99 (dd, J = 8.6, 3.2 Hz, 1 H, CH₂CH₂CH), 4.73 (d, J = 14.9 Hz, 1 H, ArCH ₂N), 5.97 (s, 2 H, OCH ₂O), 6.60 (dd, J = 7.8, 1.5 Hz, 1 H, ArH), 6.70 (d, J = 1.5 Hz, 1 H, ArH), 6.81 (d, J = 7.8 Hz, 1 H, ArH).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 24.4 (CH₂), 30.0 (CH₂), 44.4 (CH₂), 53.2 (CH), 61.8 (CH₃), 101.3 (CH₂), 108.6 (CH), 108.7 (CH), 121.5 (CH), 131.2 (C), 146.8 (C), 147.8 (C), 172.1 (C), 175.1 (2C), 177.4 (C).

LC–MS (APCI⁺): m/z 345.1 [M + H]⁺.

4-[1-(4-Acetylphenyl)-5-oxopyrrolidin-2-yl]-6-methoxy-1,3,5-triazin-2(1H)-one (14b)

The general procedure was followed using dimethoxytriazine 4b (0.35 g, 1.02 mmol) and KOH (0.114 g, 2.04 mmol) in MeOH (10 mL). The reaction mixture was heated at reflux temperature for 19 h. The obtained white solid was filtered and dried to provide mono O-demethylated product 14b.

Yield: 208 mg (62%); yellow solid.

¹H NMR (400 MHz, DMSO-d ₆): δ = 2.18–2.24 (m, 1 H, CH₂CH ₂CH), 2.45–2.68 (m, 3 H, CH ₂CH ₂CH), 3.43 (s, 3 H, COCH ₃), 3.58 (s, 3 H, OCH₃), 4.97–5.02 (m, 1 H, CH₂CH₂CH), 7.70 (d, J = 8.2 Hz, 2 H, ArH), 7.91 (d, J = 8.2 Hz, 2 H, ArH).

LC–MS (APCI⁺): m/z 329.1 [M + H]⁺.

Hilbert–Johnson Transposition; General Procedure

A soln of dimethoxytriazine 3a or 3c (1 equiv) and Me₂SO₄ (1 equiv) in toluene was heated at reflux temperature for 23 or 48 h. After cooling to r.t., the mixture was concentrated in vacuo and the crude residue was treated with Et₃N (1 equiv) and H₂O. The organic compounds were extracted into CH₂Cl₂. After evaporation of the solvent, the resulting solid was recrystallized from absolute EtOH to afford the pure product 15a or 15c.

1,3-Dimethyl-6-[1-(2-methylbenzyl)-5-oxopyrrolidin-2-yl]-1,3,5-triazine-2,4(1H,3H)-dione (15a)

The general procedure was followed using dimethoxytriazine 3a (0.72 g, 2.20 mmol) and Me₂SO₄ (0.28 g, 2.20 mmol) in toluene (15 mL). The mixture was heated at reflux temperature for 23 h. After recrystallization, the obtained white precipitate was filtered to provide pure product 15a.

Yield: 374 mg (52%); yellow solid; mp (EtOH) 113–116 °C.

IR (neat): 1727, 1655, 1591, 1453, 1417, 1365, 1287, 1238, 1160, 986, 788, 752 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 1.92–2.01 (m, 1 H, CH₂CH ₂CH), 2.27 (s, 3 H, ArCH ₃), 2.36–2.58 (m, 2 H, CH ₂CH₂CH), 2.64–2.68 (m, 1 H, CH₂CH ₂CH), 3.10 (s, 3 H, NCH ₃), 3.36 (s, 3 H, NCH ₃), 4.15 (d, J = 14.4 Hz, 1 H, ArCH ₂N), 4.28 (dd, J = 9.0, 3.1 Hz, 1 H, CH₂CH₂CH), 4.99 (d, J = 14.8 Hz, 1 H, ArCH ₂N), 6.96 (d, J = 7.2 Hz, 1 H, ArH), 7.09–7.12 (m, 1 H, ArH), 7.15–7.22 (m, 2 H, ArH).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 19.1 (CH₃), 22.9 (CH₂), 28.9 (CH₃), 29.0 (CH₂), 31.0 (CH₃), 43.3 (CH₂), 57.5 (CH), 126.2 (CH), 127.8 (CH), 128.6 (CH), 130.6 (CH), 134.7 (C), 136.9 (C), 151.7 (C), 154.7 (C), 166.5 (C), 175.1 (C).

Anal. Calcd for C₁₇H₂₀N₄O₃·H₂O: C, 58.95; H, 6.40; N, 16.17. Found: C, 58.92; H, 6.41; N, 15.76.

6-[1-(1,3-Benzodioxol-5-ylmethyl)-5-oxopyrrolidin-2-yl]-1,3-dimethyl-1,3,5-triazine-2,4(1H,3H)-dione (15c)

The general procedure was followed using dimethoxytriazine 3c (0.69 g, 1.90 mmol) and Me₂SO₄ (0.24 g, 1.90 mmol) in toluene (15 mL). The reaction mixture was heated at reflux temperature for 48 h. After recrystallization, the obtained white precipitate was filtered to provide pure product 15c.

Yield: 212 mg (46%); yellow solid; mp (EtOH) 167–169 °C.

IR (neat): 1730, 1658, 1593, 1489, 1441, 1366, 1282, 1246, 1162, 1031, 919, 789 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 1.98–2.15 (m, 1 H, CH₂CH ₂CH), 2.22–2.34 (m, 2 H, CH ₂CH₂CH), 2.35–2.40 (m, 1 H, CH₂CH ₂CH), 3.16 (s, 3 H, NCH ₃), 3.23 (s, 3 H, NCH ₃), 3.77 (d, J = 14.8 Hz, 1 H, ArCH ₂N), 4.67 (d, J = 14.4 Hz, 1 H, ArCH ₂N), 4.67 (d, J = 9.6 Hz, 1 H, CH₂CH₂CH), 5.96 (s, 2 H, OCH ₂O), 6.72–6.74 (m, 1 H, ArH), 6.81–6.84 (m, 2 H, ArH).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 22.3 (CH₂), 28.9 (CH₃), 29.0 (CH₂), 31.1 (CH₃), 44.7 (CH₂), 57.5 (CH), 101.4 (CH₂), 108.6 (CH), 109.0 (CH), 121.9 (CH), 131.2 (C), 146.9 (C), 147.8 (C), 151.8 (C), 154.8 (C), 166.6 (C), 175.2 (C).

Anal. Calcd for C₁₇H₁₈N₄O₅·1.5H₂O: C, 52.57; H, 5.54; N, 14.43. Found: C, 52.59; H, 5.10; N, 14.18.

Acknowledgment

The authors gratefully acknowledge the ‘Ministerul Educaţ�iei, Cercetării, Tineretului ş�i Sportului’ (Romania) for a scholarship (L. L.), and the NCI (National Cancer Institute) (USA) for biological evaluation of several compounds on their 60-cell panel.

• References

• 1a Baldaniya BB, Patel PK. E-J. Chem. 2009; 6: 673
  Search in Google Scholar
• 1b Almeida L, Aquila B, Chuaqui CE, Guan HP, Huang S, Ioannidis S, Lamb M, Peng B, Shi J, Su M, Su QB. WO2009016410, 2009 ; Chem. Abstr. 2010, 153, 456713.
• 1c Niyaz NM, Guenthenspberger KA, Hunter R, Brown AV, Nugent JS. US 20090093481, 2009 ; Chem. Abstr. 2009, 150, 398582.
• 1d Liu B, Lee Y, Zou JM, Petrassi HM, Joseph RW, Chao WC, Michelotti EL, Bukhtiyarova M, Springman EB, Dorsey BD. Bioorg. Med. Chem. Lett. 2010; 20: 6592
  CrossrefSearch in Google Scholar
• 1e Solankee A, Kapadia K, Ciric A, Sokovic M, Doytchinova I, Geronikaki A. Eur. J. Med. Chem. 2010; 45: 510
  CrossrefSearch in Google Scholar
• 1f Pareek PK, Mithlesh Pareek D, Chaudhary M, Pareek A, Kant R, Ojha KG. Main Group Chem. 2011; 10: 63
  Search in Google Scholar
• 1g Ojha H, Gahlot P, Tiwari AK, Pathak M, Kakkar R. Chem. Biol. Drug Des. 2011; 77: 57
  CrossrefSearch in Google Scholar
• 1h Fanelli C, Fabbri AA, Monti S, Menicagli R, Pini D, Rapaccini SM, Samaritani S, Salvadori P Presented at the 7^th International Congress of Plant Pathology, Edinburgh, Scotland, August 9–16, 1998; British Society for Plant Pathology: Birmingham (UK), 1998, Abstr. 5.6.8.
• 1i Samaritani S, Fabbri AA, Fanelli C, Menicagli R, Salvadori P. Presented at the XXV Convegno Nazionale della Divisione di Chimica Organica, Folgaria, Italy. September 8–12, 1998 Società Chimica Italiana (Divisione di Chimica Organica); Rome: 1998. Abstr. p. P124 (Vol. 1)
  Search in Google Scholar
• 1j Ricelli A, Fabbri AA, Fanelli C, Menicagli R, Samaritani S, Pini D, Rapaccini SM, Salvadori P. Restaurator 1999; 97
• 2a Singhal GH, Roebke H. DE 2115318, 1971 ; Chem. Abstr. 1972, 76, 72560.
• 2b Just M, Glase I. DD 248590, 1987 ; Chem. Abstr. 1988, 108, 131864.
• 2c Koizumi K, Yamashita O, Wakabayashi K, Tomono K, Sasayama H. WO 9720825, 1997 ; Chem. Abstr. 1997, 127, 95296.
• 2d Gajare AS, Bhawsar SB, Shinde DB, Shingare MS. Indian J. Chem., Sect B: Org. Chem. Incl. Med. Chem. 1998; 37: 510
  Search in Google Scholar
• 3a Zhao H, Liu Y, Cui Z, Beattie D, Gu Y, Wang Q. J. Agric. Food Chem. 2011; 59: 11711
  CrossrefSearch in Google Scholar
• 3b Abell LM, Schloss JV, Rendina AR. Target-site Directed Herbicide Design, ACS Symposium Series No. 524. American Chemical Society; Washington DC: 1993: 16
  Search in Google Scholar
• 3c Triazine Herbicides: Risk Assessments, ACS Symposium Series No. 524. Ballantine L, McFarland J, Hackett D. American Chemical Society; Washington DC: 1998: xi
  CrossrefSearch in Google Scholar
• 4a Rigo B, Lespagnol C, Pauly M. J. Heterocycl. Chem. 1986; 23: 183
  CrossrefSearch in Google Scholar
• 4b Laboratoires PaulyM. EP 135144, 1985 ; Chem. Abstr. 1985, 103, 123914.
• 5 Cauliez P, Couturier D. J. Heterocycl. Chem. 1993; 30: 921
  CrossrefSearch in Google Scholar
• 6 Oudir S, Rigo B, Hénichart J.-P, Gautret P. Synthesis 2006; 2845
  Thieme Connect
• 7a Menicagli R, Samaritani S, Zucchelli V. Tetrahedron 2000; 56: 9705
  CrossrefSearch in Google Scholar
• 7b Menicagli R, Samaritani S, Gori S. Tetrahedron Lett. 1999; 40: 8419
  CrossrefSearch in Google Scholar
• 7c Samaritani S, Menicagli R. Tetrahedron 2002; 58: 1381
  CrossrefSearch in Google Scholar
• 7d Menicagli R, Samaritani S, Signore G, Vaglini F, Dalla Via L. J. Med. Chem. 2004; 47: 4649
  CrossrefSearch in Google Scholar
• 7e Courme C, Gillon S, Gresh N, Vidal M, Garbay C, Florent J.-C, Bertounesque E. Tetrahedron Lett. 2008; 49: 4542
  CrossrefSearch in Google Scholar
• 8a Rembarz G, Fischer E, Roeber KCh, Ohff R, Crahmer H. J. Prakt. Chem. 1969; 311: 889
  CrossrefSearch in Google Scholar
• 8b Chiang GC. US Patent 4933450, 1990 ; Chem. Abstr. 1990, 113, 231414.
• 8c Gates PS, Jones GP, Saunders DE. WO9309099, 1993 ; Chem. Abstr. 1993, 119, 180810.
• 8d Voss O, Dudfield PJ, Bauer K, Bieringer H, Rosinger C, Ford MJ, Green D. DE 19521355, 1996 ; Chem. Abstr. 1997, 126, 144293.
• 8e Weiss S, Krommer H. US Patent 6342600, 2002 ; Chem. Abstr. 2002, 136, 134795.
• 9 The synthesis of the mixed anhydride of N-methylenedioxy-benzyl pyroglutamic acid and trifluoroacetic acid has been described previously, see: Bourry A, Akue-Gedu R, Rigo B, Hénichart J.-P, Sanz G, Couturier D. J. Heterocycl. Chem. 2003; 40: 989
  CrossrefSearch in Google Scholar
• 10 Ghinet A, Oudir S, Hénichart J.-P, Rigo B, Pommery N, Gautret P. Tetrahedron 2010; 66: 215
  CrossrefSearch in Google Scholar
• 11 Cauliez P, Rigo B, Fasseur D, Couturier D. J. Heterocycl. Chem. 1991; 28: 1143
  CrossrefSearch in Google Scholar
• 12 Thurston JT, Schaefer FC, Dudley JR, Holm-Hansen D. J. Am. Chem. Soc. 1951; 73: 2992
  CrossrefSearch in Google Scholar
• 13a Azev YA, Dülcks T, Gabel D. Tetrahedron Lett. 2003; 44: 8689
  CrossrefSearch in Google Scholar
• 13b Azev YA, Gabel D, Dulks T, Shorshnev SV, Klyuev NA. Pharm. Chem. J. 2004; 38: 197
  CrossrefSearch in Google Scholar
• 14 Pomeisi K, Holy A, Pohl R, Horska K. Tetrahedron 2009; 65: 8486
  CrossrefSearch in Google Scholar
• 15a Kraljevic TG, Kristafor S, Suman L, Kralj M, Ametamey SM, Cetina M, Raic-Malic S. Bioorg. Med. Chem. 2010; 18: 2704
  CrossrefSearch in Google Scholar
• 15b Kraljevic TG, Petrovic M, Kristafor S, Makuc D, Plavec J, Ross TL, Ametamey SM, Raic-Malic S. Molecules 2011; 16: 5113
  CrossrefSearch in Google Scholar
• 16a Prekupec S, Makuc D, Plavec J, Suman L, Kralj M, Pavelic K, Balzarini J, De Clercq E, Mintas M, Raic-Malic S. J. Med. Chem. 2007; 50: 3037
  CrossrefSearch in Google Scholar
• 16b Mitchell ML, Son JC, Guo H, Im Y.-A, Cho EJ, Wang J, Hayes J, Wang M, Paul A, Lansdon EB, Chen JM, Graupe D, Rhodes G, He G.-X, Geleziunas R, Xu L, Kim CU. Bioorg. Med. Chem. Lett. 2010; 20: 1589
  CrossrefSearch in Google Scholar
• 17a Khan MW, Kundu NG. J. Chem. Res., Synop. 1999; 20
• 17b Tang J, Maddali K, Dreis CD, Sham YY, Vince R, Pommier Y, Wang Z. Bioorg. Med. Chem. Lett. 2011; 21: 2400
  CrossrefSearch in Google Scholar
• 18 Nencka R, Votruba I, Hrebabecky H, Jansa P, Tloust’ova E, Horska K, Masojidkova M, Holy A. J. Med. Chem. 2007; 50: 6016
  CrossrefPubMedSearch in Google Scholar
• 19 Katritzky AR, Popp FD, Waring AJ. J. Chem. Soc. B 1966; 565
  Crossref
• 20 Wong JL, Fuchs DS. J. Org. Chem. 1970; 35: 3786
  CrossrefSearch in Google Scholar
• 21 Newkome GR, Nayak A, Otemaa J, Van D A, Benton WH. J. Org. Chem. 1978; 43: 3362
  CrossrefSearch in Google Scholar
• 22a Kato T, Oda N, Ito I. Chem. Pharm. Bull. 1977; 25: 215
  CrossrefSearch in Google Scholar
• 22b Schaefer FC, Dudley JR, Thurston JT. J. Am. Chem. Soc. 1951; 73: 3004
  CrossrefSearch in Google Scholar
• 23 Hilbert GE, Johnson TB. J. Am. Chem. Soc. 1930; 52: 2001
  CrossrefSearch in Google Scholar
• 24 Das P, Kundu NG. J. Chem. Res., Synop. 1996; 298
• 25 Piskala A. Tetrahedron Lett. 1964; 5: 2587
  CrossrefSearch in Google Scholar
• 26 Zimin MG, Fomakhin EV, Gol’dfarb EI, Pudovik AN. Zh. Obshch. Khim. 1986; 56: 553 ; Chem. Abstr. 1987, 106, 102397
  Search in Google Scholar
• 27a Dudley JR, Thurston JT, Schaefer FC, Holm-Hansen D, Hull CJ, Adams P. J. Am. Chem. Soc. 1951; 73: 2986
  CrossrefSearch in Google Scholar
• 27b Thurston JR, Dudley JR, Kaiser DW, Hechenbleikner I, Schaefer FC, Holm-Hansen D. J. Am. Chem. Soc. 1951; 73: 2981
  CrossrefSearch in Google Scholar

• References

• 1a Baldaniya BB, Patel PK. E-J. Chem. 2009; 6: 673
  Search in Google Scholar
• 1b Almeida L, Aquila B, Chuaqui CE, Guan HP, Huang S, Ioannidis S, Lamb M, Peng B, Shi J, Su M, Su QB. WO2009016410, 2009 ; Chem. Abstr. 2010, 153, 456713.
• 1c Niyaz NM, Guenthenspberger KA, Hunter R, Brown AV, Nugent JS. US 20090093481, 2009 ; Chem. Abstr. 2009, 150, 398582.
• 1d Liu B, Lee Y, Zou JM, Petrassi HM, Joseph RW, Chao WC, Michelotti EL, Bukhtiyarova M, Springman EB, Dorsey BD. Bioorg. Med. Chem. Lett. 2010; 20: 6592
  CrossrefSearch in Google Scholar
• 1e Solankee A, Kapadia K, Ciric A, Sokovic M, Doytchinova I, Geronikaki A. Eur. J. Med. Chem. 2010; 45: 510
  CrossrefSearch in Google Scholar
• 1f Pareek PK, Mithlesh Pareek D, Chaudhary M, Pareek A, Kant R, Ojha KG. Main Group Chem. 2011; 10: 63
  Search in Google Scholar
• 1g Ojha H, Gahlot P, Tiwari AK, Pathak M, Kakkar R. Chem. Biol. Drug Des. 2011; 77: 57
  CrossrefSearch in Google Scholar
• 1h Fanelli C, Fabbri AA, Monti S, Menicagli R, Pini D, Rapaccini SM, Samaritani S, Salvadori P Presented at the 7^th International Congress of Plant Pathology, Edinburgh, Scotland, August 9–16, 1998; British Society for Plant Pathology: Birmingham (UK), 1998, Abstr. 5.6.8.
• 1i Samaritani S, Fabbri AA, Fanelli C, Menicagli R, Salvadori P. Presented at the XXV Convegno Nazionale della Divisione di Chimica Organica, Folgaria, Italy. September 8–12, 1998 Società Chimica Italiana (Divisione di Chimica Organica); Rome: 1998. Abstr. p. P124 (Vol. 1)
  Search in Google Scholar
• 1j Ricelli A, Fabbri AA, Fanelli C, Menicagli R, Samaritani S, Pini D, Rapaccini SM, Salvadori P. Restaurator 1999; 97
• 2a Singhal GH, Roebke H. DE 2115318, 1971 ; Chem. Abstr. 1972, 76, 72560.
• 2b Just M, Glase I. DD 248590, 1987 ; Chem. Abstr. 1988, 108, 131864.
• 2c Koizumi K, Yamashita O, Wakabayashi K, Tomono K, Sasayama H. WO 9720825, 1997 ; Chem. Abstr. 1997, 127, 95296.
• 2d Gajare AS, Bhawsar SB, Shinde DB, Shingare MS. Indian J. Chem., Sect B: Org. Chem. Incl. Med. Chem. 1998; 37: 510
  Search in Google Scholar
• 3a Zhao H, Liu Y, Cui Z, Beattie D, Gu Y, Wang Q. J. Agric. Food Chem. 2011; 59: 11711
  CrossrefSearch in Google Scholar
• 3b Abell LM, Schloss JV, Rendina AR. Target-site Directed Herbicide Design, ACS Symposium Series No. 524. American Chemical Society; Washington DC: 1993: 16
  Search in Google Scholar
• 3c Triazine Herbicides: Risk Assessments, ACS Symposium Series No. 524. Ballantine L, McFarland J, Hackett D. American Chemical Society; Washington DC: 1998: xi
  CrossrefSearch in Google Scholar
• 4a Rigo B, Lespagnol C, Pauly M. J. Heterocycl. Chem. 1986; 23: 183
  CrossrefSearch in Google Scholar
• 4b Laboratoires PaulyM. EP 135144, 1985 ; Chem. Abstr. 1985, 103, 123914.
• 5 Cauliez P, Couturier D. J. Heterocycl. Chem. 1993; 30: 921
  CrossrefSearch in Google Scholar
• 6 Oudir S, Rigo B, Hénichart J.-P, Gautret P. Synthesis 2006; 2845
  Thieme Connect
• 7a Menicagli R, Samaritani S, Zucchelli V. Tetrahedron 2000; 56: 9705
  CrossrefSearch in Google Scholar
• 7b Menicagli R, Samaritani S, Gori S. Tetrahedron Lett. 1999; 40: 8419
  CrossrefSearch in Google Scholar
• 7c Samaritani S, Menicagli R. Tetrahedron 2002; 58: 1381
  CrossrefSearch in Google Scholar
• 7d Menicagli R, Samaritani S, Signore G, Vaglini F, Dalla Via L. J. Med. Chem. 2004; 47: 4649
  CrossrefSearch in Google Scholar
• 7e Courme C, Gillon S, Gresh N, Vidal M, Garbay C, Florent J.-C, Bertounesque E. Tetrahedron Lett. 2008; 49: 4542
  CrossrefSearch in Google Scholar
• 8a Rembarz G, Fischer E, Roeber KCh, Ohff R, Crahmer H. J. Prakt. Chem. 1969; 311: 889
  CrossrefSearch in Google Scholar
• 8b Chiang GC. US Patent 4933450, 1990 ; Chem. Abstr. 1990, 113, 231414.
• 8c Gates PS, Jones GP, Saunders DE. WO9309099, 1993 ; Chem. Abstr. 1993, 119, 180810.
• 8d Voss O, Dudfield PJ, Bauer K, Bieringer H, Rosinger C, Ford MJ, Green D. DE 19521355, 1996 ; Chem. Abstr. 1997, 126, 144293.
• 8e Weiss S, Krommer H. US Patent 6342600, 2002 ; Chem. Abstr. 2002, 136, 134795.
• 9 The synthesis of the mixed anhydride of N-methylenedioxy-benzyl pyroglutamic acid and trifluoroacetic acid has been described previously, see: Bourry A, Akue-Gedu R, Rigo B, Hénichart J.-P, Sanz G, Couturier D. J. Heterocycl. Chem. 2003; 40: 989
  CrossrefSearch in Google Scholar
• 10 Ghinet A, Oudir S, Hénichart J.-P, Rigo B, Pommery N, Gautret P. Tetrahedron 2010; 66: 215
  CrossrefSearch in Google Scholar
• 11 Cauliez P, Rigo B, Fasseur D, Couturier D. J. Heterocycl. Chem. 1991; 28: 1143
  CrossrefSearch in Google Scholar
• 12 Thurston JT, Schaefer FC, Dudley JR, Holm-Hansen D. J. Am. Chem. Soc. 1951; 73: 2992
  CrossrefSearch in Google Scholar
• 13a Azev YA, Dülcks T, Gabel D. Tetrahedron Lett. 2003; 44: 8689
  CrossrefSearch in Google Scholar
• 13b Azev YA, Gabel D, Dulks T, Shorshnev SV, Klyuev NA. Pharm. Chem. J. 2004; 38: 197
  CrossrefSearch in Google Scholar
• 14 Pomeisi K, Holy A, Pohl R, Horska K. Tetrahedron 2009; 65: 8486
  CrossrefSearch in Google Scholar
• 15a Kraljevic TG, Kristafor S, Suman L, Kralj M, Ametamey SM, Cetina M, Raic-Malic S. Bioorg. Med. Chem. 2010; 18: 2704
  CrossrefSearch in Google Scholar
• 15b Kraljevic TG, Petrovic M, Kristafor S, Makuc D, Plavec J, Ross TL, Ametamey SM, Raic-Malic S. Molecules 2011; 16: 5113
  CrossrefSearch in Google Scholar
• 16a Prekupec S, Makuc D, Plavec J, Suman L, Kralj M, Pavelic K, Balzarini J, De Clercq E, Mintas M, Raic-Malic S. J. Med. Chem. 2007; 50: 3037
  CrossrefSearch in Google Scholar
• 16b Mitchell ML, Son JC, Guo H, Im Y.-A, Cho EJ, Wang J, Hayes J, Wang M, Paul A, Lansdon EB, Chen JM, Graupe D, Rhodes G, He G.-X, Geleziunas R, Xu L, Kim CU. Bioorg. Med. Chem. Lett. 2010; 20: 1589
  CrossrefSearch in Google Scholar
• 17a Khan MW, Kundu NG. J. Chem. Res., Synop. 1999; 20
• 17b Tang J, Maddali K, Dreis CD, Sham YY, Vince R, Pommier Y, Wang Z. Bioorg. Med. Chem. Lett. 2011; 21: 2400
  CrossrefSearch in Google Scholar
• 18 Nencka R, Votruba I, Hrebabecky H, Jansa P, Tloust’ova E, Horska K, Masojidkova M, Holy A. J. Med. Chem. 2007; 50: 6016
  CrossrefPubMedSearch in Google Scholar
• 19 Katritzky AR, Popp FD, Waring AJ. J. Chem. Soc. B 1966; 565
  Crossref
• 20 Wong JL, Fuchs DS. J. Org. Chem. 1970; 35: 3786
  CrossrefSearch in Google Scholar
• 21 Newkome GR, Nayak A, Otemaa J, Van D A, Benton WH. J. Org. Chem. 1978; 43: 3362
  CrossrefSearch in Google Scholar
• 22a Kato T, Oda N, Ito I. Chem. Pharm. Bull. 1977; 25: 215
  CrossrefSearch in Google Scholar
• 22b Schaefer FC, Dudley JR, Thurston JT. J. Am. Chem. Soc. 1951; 73: 3004
  CrossrefSearch in Google Scholar
• 23 Hilbert GE, Johnson TB. J. Am. Chem. Soc. 1930; 52: 2001
  CrossrefSearch in Google Scholar
• 24 Das P, Kundu NG. J. Chem. Res., Synop. 1996; 298
• 25 Piskala A. Tetrahedron Lett. 1964; 5: 2587
  CrossrefSearch in Google Scholar
• 26 Zimin MG, Fomakhin EV, Gol’dfarb EI, Pudovik AN. Zh. Obshch. Khim. 1986; 56: 553 ; Chem. Abstr. 1987, 106, 102397
  Search in Google Scholar
• 27a Dudley JR, Thurston JT, Schaefer FC, Holm-Hansen D, Hull CJ, Adams P. J. Am. Chem. Soc. 1951; 73: 2986
  CrossrefSearch in Google Scholar
• 27b Thurston JR, Dudley JR, Kaiser DW, Hechenbleikner I, Schaefer FC, Holm-Hansen D. J. Am. Chem. Soc. 1951; 73: 2981
  CrossrefSearch in Google Scholar