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A new series of 3,6-disubstituted 2-(methylthio)-4-(trifluoromethyl)-3,4-dihydropyrimidin-4-ols displaying methyl, phenyl, aryl, and heteroaryl groups at the 6-position; and methyl, ethyl, allyl, and phenyl groups at the 3-position of the dihydropyrimidine ring, were synthesized and evaluated in vitro for acetylcholinesterase (AChE) inhibitory activity. Seven compounds showed activity with IC50 values in the lower micromolar range. The compound 4-trifluoromethyl-6-(4-fluorophenyl)-3-methyl-2-methylthio-3,4-dihydropyrimidin-4-ol (6e) had the best inhibitory activity (IC50 2.2±0.9 μM) and this inhibition was characterized as competitive. The molecular docking study showed that the AChE enzyme accommodates compound 6e in its catalytic site. The enantiomers of compound 6e, present similar interactions: π–π stacking interactions between the aromatic ring of the ligand's 4-fluorophenyl moiety and the aromatic rings of the electron-rich Trp84; and H-bonds between the hydroxyl group of Tyr121 and the hydroxyl moiety from 6e. The antioxidant effect of the dihydropyrimidin-4-ols was also investigated. This article is protected by copyright. All rights reserved.

5-Bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one was used as an efficient precursor for the synthesis of a new series of (1,2,3-triazol-1-yl)methyl-pyrimidine biheterocycles. For this stepwise synthesis, the 5-bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one was first converted into 5-azido-1,1,1-trifluoro-4-methoxypent-3-en-2-one through a nucleophilic substitution of the bromine by an azide group. This was then followed by an azide–alkyne cycloaddition reaction (click chemistry) to give the key intermediate 5-[4-alkyl(aryl)-1H-1,2,3-triazol-1-yl]-1,1,1-trifluoro-4-methoxypent-3-en-2-ones. These were cyclocondensed with 2-methylisothiourea sulfate to give a series of 2-(methylthio)-4-(1,2,3-triazol-1-yl)methyl-6-(trifluoromethyl)pyrimidines. Additionally, the 2-methylthiopyrimidine products were used to prepare a new series of 2-amino-4-(1,2,3-triazol-1-yl)methyl-6-(trifluoromethyl)pyrimidines.

This study reports a simple, fast, and efficient method for the synthesis of a new series of 1-arylethyl-2-arylethylamino-5-trifluoroacetyl-1,2,3,4-tetrahydropyridines and related compounds from the reaction of 2-alkoxy-5-trifluoroacetyl-3,4-dihydro-2H-pyrans with 2-arylethanamines and related 2-ethanamines. The desired tetrahydropyridines were obtained in excellent yields (90–98%), through a reaction that can be described as an AAB′ three-component reaction protocol following an ANRORC-type mechanism.

This paper reports a facile and convenient access by a conventional thermal procedure in ethanol as solvent to a new examples of (E)-6-[2-ferrocenylalkylidenehydrazino]nicotinic hydrazides (3) (53–72%) from the quimioselective reactions of 6-hydrazinonicotinc hydrazide (1) with acylferrocenes (2), where acyl = formyl and acetyl. Subsequently, cyclocondensation reactions of ferrocenylalkylidene hydrazones (3) with 4-R1-4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones (4), where R1 = Me, Ph, 2-Furyl, to obtain new six heterocyclic derivatives as (E)-pyrazolyl-pyridinohydrazones (5) (58–63%), are also presented. The structures of these new heterocyclic compounds 5 containing an organometallic unit were characterized and studied by NMR, ESI–MS/MS techniques. DFT calculations were also employed to assign the E configuration for compounds 3 and 5.

This paper describes an efficient approach for the synthesis of a new series of 6-[3-alkyl(aryl/heteroaryl)-5-trifluoromethyl-1H-pyrazol-1-yl]nicotinic acids (where alkyl = CH3; aryl = Ph, 4-OCH3Ph, 4,4′-BiPh; and heteroaryl = 2-Furyl) from the hydrolysis reaction of alkyl(aryl/heteroaryl)substituted 2-(5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-5-(5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-1-carbonylpyrazol-1-yl)pyridines, under basic conditions and at 70–95% yields. In a subsequent step, the esterification reaction of pyrazolyl-nicotinic acids done in thionyl chloride and methanol led to the isolation of a series of methyl 6-[alkyl(aryl/heteroaryl)-5-trifluoromethyl-1H-pyrazol-1-yl] nicotinates as stable hydrochloride salts at 64–84% yields, which could be easily converted to hydrazides to give new oxadiazolyl-pyrazolyl-pyridine tricyclic scaffolds at good yields from a [4 + 1] cyclocondensation reaction with 1,1,1-triethoxyethane and 1-(triethoxymethyl)benzene as the reagent/solvent.

A simple procedure for the synthesis and characterization of new 3-alkoxy-3-(1H-tetrazol-5-yl)propionic acids and 2-(1H-tetrazol-5-yl)tetrahydrofuran- and -(1H-tetrazol-5-yl)-2H-pyran-3-carboxylic acids from the [2 + 3] cycloaddition reactions between the nitrile group of β-cyanocarboxylic acids with sodium azide in the presence of zinc chloride is described. The tetrazolic acids were isolated in moderate to good yields and are structurally analogous to succinic acid.

This article reports a convenient and general method for the regioselective synthesis of a new series of 2-alkyl(aryl)-8-methyl-4-trifluoromethyl-7-aminoquinolines in 86–93% yields, from cycloaromatization reactions of N-(oxotrifluoroalkenyl)-2,6-diaminotoluenes in a strongly acidic medium polyphosphoric acid and absence of solvent. The enaminoketone intermediates were easily isolated from the reaction of 4-alkoxy-4-alkyl(aryl)-1,1,1-trifluoroalk-3-en-2-ones [CF3C(O)CH═C(R)OR1, where R = H, Me, Ph, 4-FPh, 4-BrPh, 4-MePh, and R1 = Me, Et] with 2,6-diaminotoluene (2,6-DAT) in methanol under mild conditions, in 46–70% yields. Another synthetic route also allowed the regioselective synthesis of 2-aryl(heteroaryl)-4-methyl-4-trifluoromethyl-7-aminoquinolines from direct cyclocondensation reactions of 4-alkoxy-4-aryl(heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones with 2,6-diaminotoluene in methanol under mild conditions, in 21–36% yields.

5-Bromo[5,5-dibromo]-1,1,1-trihalo-4-methoxy-3-penten[hexen]-2-ones are explored as precursors to the synthesis of 3-ethoxymethyl-5-trifluoromethyl-1H-pyrazoles from a cyclocondensation reaction with hydrazine monohydrate in ethanol. 3-Ethoxymethyl-carboxyethyl ester pyrazoles were formed as a result of a substitution reaction of bromine and chlorine by ethanol. The dibrominated precursor furnished 3-acetal-pyrazole that was easily hydrolyzed to formyl group. In addition, brominated precursors were used in a nucleophilic substitution reaction with sodium azide to synthesize the 3-azidomethyl-5-ethoxycarbonyl-1H-pyrazole from the reaction with hydrazine monohydrate. These products were submitted to a cycloaddition reaction with phenyl acetylene furnishing the 3-[4(5)-phenyl-1,2,3-triazolyl]5- ethoxycarbonyl-1H-pyrazoles and to reduction conditions resulting in 3-aminomethyl-1H-pyrazole-5-carboxyethyl ester. The products were obtained by a simple methodology and in moderate to good yields.

A simple procedure to obtain 4-acyl-1-substituted-1,2,3-triazoles, using a deep eutectic solvent (DES), ChCl and ethylene glycol at a 1 : 2 ratio, as the reaction medium is described. The products were obtained in high selectivity and good yields (70–84%). The advantages of the method include easy work-up, metal-free conditions, inexpensiveness, and the ability to be used four times without a loss in yield.

A simple and regioselectively controlled method for the preparation of both 1,4- and 1,6-regioisomers of 1-substituted 4(6)-trifluoromethyl-pyrimidin-2(1H)-ones is described. Both regioisomers were synthesized from the cyclocondensation reaction of 4-substituted 1,1,1-trifluoro-4-methoxybut-3-en-2-ones: with nonsymmetric ureas for the 1-substituted 4-(trifluoromethyl)pyrimidin-2(1H)-ones (1,4-isomer) and with nonsymmetric 1-substituted 2-methylisothiourea sulfates for the synthesis of 1-substituted 6-(trifluoromethyl)pyrimidin-2(1H)-ones (1,6-isomer). Each method furnished only the respective isomer in very good yields. The structure of the products was assigned based on the 1H and 13C NMR as well as 2D HMBC spectral analysis.

A mild and efficient protocol for the assembly of tetra-substituted 5-trifluoromethylpyrazoles is presented, involving halogenation at the 4-position of readily prepared tri-substituted 5-trifluoromethylpyrazoles to give 4-halo-1-phenyl-5-trifluoromethyl pyrazoles, and subsequent palladium-catalyzed Negishi or Buchwald–Hartwig cross-couplings to install carbon or nitrogen-based 4-substituents. Key to the success of these challenging cross-couplings is the use of XPhos and JosiPhos CyPF-tBu ligands, respectively.

The title pyrimidinones are highly regioselectively obtained by cyclocondensation of trichloro-alkenones with non-symmetric substituted isothiourea sulfates under mild basic conditions.

A concise method to synthesize 1-substituted 4-amino-2-(trifluoromethyl)-1H-pyrroles from the heterocyclization reaction of 5-bromo-4-methoxy-1,1,1-trifluoropent-3-en-2-ones with amines is described. This method has the following advantages: it uses a wide range of primary amines, starting materials are easily available, it is simple to perform, the reaction conditions are mild, it is environmentally friendly, and it furnishes yields of up to 98%.

This Letter reports the first series of seven examples of novel 7-amine-spiro[chromeno[4,3-b]quinoline- 6,1′-cycloalkanes], where cycloalkane is cyclopentane, cyclohexane, cycloheptane, 2-methyl-, 3-methyl-, 4-methyl-, and 4-t-butyl-cyclohexane. These new compounds were synthesized at yields of 30–65% by a one-pot cyclocondensation reaction of 2-aminobenzonitrile and seven examples of spiro[chroman-2,1′-cycloalkan]-4-ones, using AlCl3 as the catalyst, without solvent and under conventional thermal heating. Subsequently, these spirochromeno-quinolines were subjected to AChE and cytotoxicity activity, and molecular docking studies. Both results for these new tacrine analogues were correlated with the structural features and showed the best results for the tacrine hybrid that possesses the spirocyclopentane moiety.

Metal-free electrophilic fluorination, promoted by Selectfluor, of pyrazoles with methylene groups (CH2X), in which X = OH, OMe, F, N3, and NHMe at the C-4 position furnished the 4-fluoro-pyrazole products from unexpected C–C bond cleavage, at moderate to good yields. Otherwise, under the same reaction conditions, when X = NEt2 or SPr, the oxidation product 4-formyl-pyrazole was obtained.

A new one-pot method, for the synthesis of polysubstituted pyrrolo[3,4- d ]pyridazinones, is presented. The protocol consists in cascade reactions performed in the same media: (i) the thermal in situ pyrrole formation by the reaction of vinyl azides with 1,3-dicarbonyl compounds, via the 1,2-addition of 1,3-dicarbonyl compounds to 2 H -azirine intermediates; (ii) the nucleophilic addition of hydrazines to the ketone group present in the pyrroles previously formed, followed by intramolecular cyclization with the bordering ester, which furnishes the respective pyrrolo[3,4- d ]pyridazinones, substituted at the pyrrole and/or pyridazinone rings. All transformations occur in a two-step one-pot methodology, and a series of ten new compounds were obtained at yields of 42–87%.

A study is presented for the synthesis of a series of 1-tert-butyl-3(5)-(trifluoromethyl)-1H-pyrazoles from the reaction of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [CF3C(O)CH=C(R1)(OR), where R = Et and R1 = H or R = Me and R1 = Me, Ph, 4-Me-C6H4, 4-MeO-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-I-C6H4, fur-2-yl, thien-2-yl, or naphth-2-yl] with tert-butylhydrazine hydrochloride. When [BMIM][BF4] (1-butyl-3-methylimidazolium tetrafluoroborate) and pyridine were used as the reaction media, we obtained a mixture of 1-tert-butyl-3(5)-trifluoromethylpyrazoles. The formation of 5-trifluoromethyl-1-tert-butyl-1H-pyrazoles with high regioselectivity occurred when the reaction was carried out with NaOH in EtOH. The formation of 1-tert-butyl-3-trifluoromethyl-1H-pyrazoles occurred, after hydrolysis of the 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones in H2O and H2SO4, followed by cyclization in [BMIM][BF4] and pyridine.

The regioselective synthesis and characterization of a new series of 3-aryl-7-trifluoromethyl[1,2,4]triazolo[4,3–a]pyrimidines from the oxidative heterocyclization of 2-(N′-benzylidenehydrazino)-4-trifluoromethylpyrimidines with copper dichloride is described. J. Heterocyclic Chem., (2011).

The facile and convenient access by a conventional procedure in ethanol as solvent to a new series of succinyl-spaced pyrazoles including 1,4-bis[5-(trichloromethyl)-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl]butane-1,4-diones (64–82%) and the respective dehydrated derivatives as 1,4-bis[5-(trichloromethyl)-1H-pyrazol-1-yl]butane-1,4-diones in 57–82% yields, from the regioselective cyclocondensation reactions of 4-substituted 4-methoxy-1,1,1-trichloroalk-3-en-2-ones with succinic acid dihydrazide, where the 4-substituents are Me, Ph, 4-FC6H4, 4-ClC6H4, 4-NO2C6H4, 2-furyl, and 2-thienyl, is reported. J. Heterocyclic Chem., 2011.

Reactions of trihalomethylated enones with dimethylisothiourea sulfate furnish chemoselectivity 2-methylthiotetrahydropyrimidine or -dihydropyrimidine derivatives depending on the reaction conditions and electronic effects of the substituents on the enones.

A simple, convenient and regioselective one-pot condensation reaction is used for the preparation of the title pyrazoles, e.g. (III).

The antioxidant capacity of a series of six novel synthetic pyrazoline derivatives (i) 5-hydroxy-3-methyl-5- trifluoromethyl-4,5-dihydro-1 H -carbaldehyde-pyrazole, (ii) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1 H -1-acetyl-pyrazole, (iii) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1 H -carboxyamide-pyrazole, (iv) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5- dihydro-1 H -1-benzoyl-pyrazole, (v) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1 H -1-(2-hydroxybenzoyl)-pyrazole and (vi) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1 H -1-(4-methoxybenzoyl)-pyrazole was evaluated as the capacity of compounds to transfer a hydrogen atom (protection against brain lipid peroxidation and glutathione oxidation) and their capacity to transfer a single electron (ferric-reducing antioxidant power (FRAP) and 1,1-diphenyl-2-picrylhydrazyl radical scavenging (DPPH) assays). Compound 5 had the highest free radical scavenging capacity in the DPPH assay, while compound 2 had the highest FRAP value (P < 0.05). Only compounds 1, 4 and 5 protected against lipid peroxidation in rat brain homogenate. However, compound 5 was the most effective to prevent basal and iron-, sodium nitroprusside- and H 2 O 2 -stimulated lipid peroxidation (IC 50 < 15 μ M) and the only one effective to block glutathione oxidation-mediated by H 2 O 2 (at 150 μ M). Our results indicate that compound 5 has the greatest potential to prevent oxidative damage in brain homogenates.

Pain is the most common complaint in the medical field and the identification of compounds that can effectively treat painful states without induction of side-effects remains a major challenge in biomedical research. The aim of the present study was to investigate the antinociceptive effect of a novel compound, 3-(4-fluorophenyl)-5-trifluoromethyl-1H-1-tosylpyrazole (compound A) in several models of pain in mice and compare with those produced by the known trifluoromethyl-containing pyrazole compound celecoxib. Compound A or celecoxib were administrated by oral (78–780 µmol/kg), intrathecal (9–22.5 nmol/site) or intracerebroventricular (9–22.5 nmol/site) routes. Oral administration of either compound A or celecoxib abolished the mechanical allodynia, but not the oedema caused by intraplantar injection of carrageenan. Similarly, compound A reduced the overt nociception, but not the oedema, produced by bradykinin or capsaicin. However, compound A (500 µmol/kg, orally) did not alter nociception nor oedema caused by intraplantar injection of prostaglandin E2 or glutamate, whereas celecoxib reduced only the nociception induced by the former. Moreover, oral and intrathecal administration of compound A or celecoxib also reduced the nociception induced by acetic acid. However, only celecoxib reduced the acetic acid-induced nociception when it was injected by the intracerebroventricular route. Finally, neither compound A nor celecoxib was able to produce antinociceptive effect in the tail-flick test or to alter the motor performance and the body temperature. Besides, compound A or celecoxib did not induce gastric lesion. Thus, compound A seems to be an interesting prototype for the development of novel analgesic drugs.

This paper reports a comparative study of the chemoselectivity and yields of the synthesis of N-alkyl-4-(trihalomethyl)-1H-pyrimidin-2-ones carried out by the cyclocondensation of 4-alkoxy-1,1,1-trihalo-3-alken-2-ones (enones) with methyl- and allylureas with the N-alkylation of 4-(trihalomethyl)-1H-pyrimidin-2-ones with methyl iodide and allyl bromide. To determine the chemoselectivity of the products obtained, all compounds were fully analyzed by 1H and 13C NMR and 2D HMBC spectroscopy. This study has demonstrated that the cyclocondensation reactions give better yields and furnish either N1- or N3-alkylated products depending on both the reaction conditions and the substituents on the enones, whereas the alkylation of pyrimidin-2-ones gives lower overall yields and either an N1-alkylated product or a mixture of N1- and O-alkylated products.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

The regioselective synthesis of 3- and 5-substituted-isoxazoles from the reaction of β-dimethyl-aminovinyl ketones [R-C(O)CHCH-NMe2, where R Ph, MeO-4-C6H4, F-4-C6H4, Cl-4-C6H4, Br-4-C6H4, O2N-4-C6H4, fur-2-yl, thien-2-yl, pyrrol-2-yl, Et and CCl3] and hydroxylamine hydrochloride varying only the reaction conditions (with and without the addition of pyridine) is reported.

This paper describes the synthesis and characterization of a new series of 4-substituted-3-ethoxycarbonyl-6-trifluoromethyl-(1,2,3)-oxathiazinane-S-oxides and 3-(4,6-diphenyl-pyrimidin-2-yl)-6-trifluoromethyl-(1,2,3)oxathiazinane-S-oxides from the cyclization reaction of 4,4,4-trifluoro-3-hydroxybutylcarbamates and 4-(4,6-diphenyl-pyrimidin-2-ylamino)-1,1,1-trifluoro-butan-2-ols with thionyl chloride. The analysis of the NMR data allowed us to define important features of the molecular structure. Significant chemical and structural differences were observed between the trifluoromethylated oxathiazinanes obtained in this work from other analogue compounds reported in the literature.

The one-pot synthesis of a novel series of amino-protected 6-alkyl-, 6-aryl-, 6-heteroaryl- and 5,6-fused-cycloalkane 4-trifluoromethyl-2-acetylaminopyrimidines, where alkyl = Me; aryl = Ph, 4-CH3Ph, 4-FPh, 4-ClPh, 4-BrPh, 4-OCH3Ph, 4-NO2Ph, 4,4′-biphenyl, 1-naphthyl; heteroaryl = 2-thienyl, 2-furyl and cycloalkyl = c-C6H4, c-C7H5 from the reaction of substituted 4-methoxy-1,1,1-trifluoroalk-3-en-2-ones with 1-acetylguanidine in acetonitrile or propan-2-ol as solvent, is reported. The acetylamino group of 2-acetylaminopyrimidines was hydrolyzed under three different conditions to afford the corresponding free 2-aminopyrimidines.

This work describes the synthesis of a novel series of 2-methylsulfanyl-tetrahydropyrimidines, from the cyclocondensation reaction of β-alkoxyvinyl trihalomethyl ketones with 2-methyl-2-thiopseudourea sulfate, in good yields. A detailed 1H- and 13C-NMR study was performed on the 2-methylsulfanyl-tetrahydropyrimidines obtained and 3D structures were proposed based on AM1 calculations supported by 1H NMR coupling constants and NOESY experiments.

The regiospecific synthesis of a series of twelve 5-trifluoromethyl-4,5-dihydropyrazoles and -pyrazoles from the cyclocondesation reaction of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [F3CC(O)CH=C(R1)OR, where R1 = Me, Et, Pr, iso-Pr, Bu, iso-Bu, Ph, H; and R = Me, Et] with phenylhydrazine in toluene by environmentally benign microwave induced techniques is reported. It is shown that under appropriated conditions, the variation of microwave irradiation power leads to 4,5-dihydropyrazole or pyrazole derivatives. This paper also includes the use of montmorillonite K-10 as a solid support for the synthesis of pyrazoles under solvent free conditions.

The simple preparation of the title compounds succeeds in moderate to good yields via cyclocondensation of 4-substituted ethyl 4-alkoxy-2-oxobut-3-eneoates with 2-methyl or 2-benzylisothiourea.

Reaction of trifluoroacetylated Kabbe adducts (IV) with phenylhydrazine or methylhydrazine proceeds with apposite regioselectivity furnishing chromenopyrazoles (VI) or (VIII), respectively.

A new, efficient and easy route for the preparation of a series of 2-alkyl(aryl) substituted 4-oxo-4H-pyrido-[1,2-a]pyrimidines, where alkyl = CH3; aryl = C6H5, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-CH3C6H4, 4-OCH3C6H4, 4-NO2C6H4 in 45–80 % yield from the reaction of β-alkoxyvinyl trichloromethyl ketones with 2-aminopyridine under mild conditions, is then reported.

A convenient method for the synthesis of a novel series of 11, specifically substituted, noncondensed 5,5-bicycles 2-[3-phenyl-5-hydroxy-5-trichloromethyl-4,5-dihydro-1H-pyrazol-1-yl]-4-aryl-5-alkylthiazoles (3a–k; 65–94% yield) from the reactions of 3-phenyl-5-hydroxy-5-trichloromethyl-4,5-dihydro-1H-1-pyrazolethiocarboxyamide (1) with substituted 2-bromo-4′-acetophenones (2a–f) and 2-bromo-4′-propiophenones (2g–k) is reported. Dehydration of compounds 3a–k with a mixture of concentrated sulfuric acid/chloroform furnished the corresponding 2-[3-phenyl-5-trichloromethyl-1H-pyrazol-1-yl]-4-aryl-5-alkylthiazoles (4a–k) in good yields (61–93%). © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:132–137, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10113

The synthesis of a novel series of twelve 4-(trihalomethyl)dipyrimidin-2-ylamines, from the cyclo-condensation reaction of 4-(trichloromethyl)-2-guanidinopyrimidine, with β-alkoxyvinyl trihalomethyl ketones, of general formula: X3C-C(O)-C(R2)=C(R1)-OR, where: X = F, Cl; R = Me, Et, -(CH2)2-, -(CH2)3-; R1 = H, Me; R2 = H, Me, -(CH2)2-, -(CH2)3-, is reported. The reactions were carried out in acetonitrile under reflux for 16 hours, leading to the dipyrimidin-2-ylamines in 65-90% yield. Depending on the substituents of the vinyl ketone, tetrahydropyrimidines or aromatic pyrimidine rings were obtained from the cyclization reaction. When X = Cl, elimination of the trichloromethyl group was observed during the cyclization step. The structure of 4-(trihalomethyl)dipyrimidin-2-ylamines was studied in detail by 1H-, 13C- and 2D-nmr spectroscopy.