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REACTIONS OF β-ALKOXYVINYL TRIFLUOROMETHYLKETONES. THE SYNTHESIS OF N-[1-ARYL-3-OXO-4,4,4-TRIFLUORO-1-BUTEN-1-YL]-o-PHENYLENEDIAMINES AND4-ARYL-2-TRIFLUOROMETHYL-3H-1,5-BENZODIAZEPINESHelio Gauze Bonacorso a , Livete Magali Leão Marques a , Nilo Zanatta a & Marcos AntonioPinto Martins aa Nucleo de Química de Heterociclos (NUQUIMHE) , Departamento de Química , UniversidadeFederal de Santa Maria , Santa Maria, RS, 97.105-900, BrazilPublished online: 16 Aug 2006.

To cite this article: Helio Gauze Bonacorso , Livete Magali Leão Marques , Nilo Zanatta & Marcos Antonio Pinto Martins(2002) REACTIONS OF β-ALKOXYVINYL TRIFLUOROMETHYL KETONES. THE SYNTHESIS OF N-[1-ARYL-3-OXO-4,4,4-TRIFLUORO-1-BUTEN-1-YL]-o-PHENYLENEDIAMINES AND 4-ARYL-2-TRIFLUOROMETHYL-3H-1,5-BENZODIAZEPINES, Synthetic Communications:An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:20, 3225-3232, DOI: 10.1081/SCC-120013748

To link to this article: http://dx.doi.org/10.1081/SCC-120013748

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REACTIONS OF b-ALKOXYVINYLTRIFLUOROMETHYL KETONES. THE

SYNTHESIS OF N-[1-ARYL-3-OXO-4,4,4-TRIFLUORO-1-BUTEN-1-YL]-o-

PHENYLENEDIAMINES AND 4-ARYL-2-

TRIFLUOROMETHYL-3H-1,5-BENZODIAZEPINES

Helio Gauze Bonacorso,* Livete Magali Leao Marques,Nilo Zanatta, and Marcos Antonio Pinto Martins

Nucleo de Quımica de Heterociclos (NUQUIMHE),Departamento de Quımica, Universidade Federal deSanta Maria, 97.105-900 Santa Maria, RS, Brazil

ABSTRACT

A series of five N-[1-aryl-3-oxo-4,4,4-trifluoro-1-buten-1-yl]-o-phenylenediamines 2 [CF3COCH¼C(R)NH-o-PhNH2],where R¼Ph, 4-MePh, 4-BrPh, 4-ClPh, 4-OMePh from thereaction of b-aryl-b-methoxyvinyl trifluoromethyl ketones1 with o-phenylenediamine was prepared and isolated ingood yield (59–71%). Another series of five 4-aryl-2-trifluoro-methyl-3H-1,5-benzodiazepines 3, where aryl¼Ph, 4-MePh,

SYNTHETIC COMMUNICATIONSVol. 32, No. 20, pp. 3225–3232, 2002

3225

DOI: 10.1081/SCC-120013748 0039-7911 (Print); 1532-2432 (Online)Copyright & 2002 by Marcel Dekker, Inc. www.dekker.com

*Corresponding author. E-mail: heliogb@base.ufsm.br

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4-BrPh, 4-ClPh, 4-OMePh was also obtained in an one-stepreaction from ketones 1 by an intramolecular cyclization reac-tion with o-phenylenediamine under mild acid conditions ingood yields (60–77%).

Acetylated enol ethers and acetophenone acetals[1–11] with functiona-lized acyl groups of the type CF3C(O), CCl3C(O) and CHCl2C(O) are ofgeneral interest as precursors for a variety of substituted five-, six- andseven-membered halomethylated heterocyclic compounds, e.g., isoxazolesand dihydroisoxazoles, pyrazoles and pyrazolines,[7,12–17] pyrimidines, thio-pyrimidines and pyrimidinones[18–22] and benzodiazepines.[23,24] Morespecifically, the introduction of a trifluoromethyl group into many bioactivemolecules sometimes has resulted in significant enhancement of theirpotency and duration of action because of the increased lipophilicity.[25]

In addition, we have observed in the literature that the condensationof o-phenylenediamine with 1,3-dicarbonyl compounds has been the mostwidely used method and the conventional procedure for the synthesis of3H-1,5-benzodiazepines.[26,27] Recently, Venkataratnamand co-workers[28,29]

obtained trifluoromethylated 3H-1,5-benzodiazepines derived from 1,1,1-trifluoromethyl-3-(isobutoxymethylene)-2-propanones in good yield, usingmicrowave irradiation. The conventional condensation of these propa-nones, which have no aryl substituents at carbon-4, with o-arylenediaminesin refluxing xylene led to a complex mixture of products unsuitable for apreparative method. This situation prompted us to investigate the poss-ibility of the synthesis of trifluoromethylated 3H-1,5-benzodiazepines fromb-alkoxyvinyl trifluoromethyl ketones with the isolation of the acyclicintermediates. These intermediates are very important and cannot beisolated from conventional reactions between 1,3-dicarbonyl compoundsand o-phenylenediamine or using microwave irradiation. As an example,the trichloromethylated intermediate N-[1-phenyl-3-oxo-4,4,4-trichloro-1-buten-1-yl]-o-phenylenediamine, synthesized previously,[24] was submittedto the National Cancer Institute for evaluation in vitro in 3-cell line anti-cancer screen (NCS 715846). This compound showed a discreet anticanceractivity against lung, breast and CNS culture tumor cells.[31]

With continuing interest in new di- and trihalomethylated precursors,intermediates and heterocyclic structures, the aim of the present work is toreport the results of reactions of 4 aryl-4-methoxyvinyl trifluoromethylketones (1a–e) with o-phenylenediamine to isolate the intermediatesmolecules (2a–e) and the application of these vinyl ketones (1a–e) to obtain4-aryl-2-trifluoromethyl-3H-1,5-benzodiazepines (3a–e) by intramolecularcyclo-condensation reaction with o-phenylenediamine in an one-step reactionand without microwave procedures.

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The b-aryl-b-methoxyvinyl trifluoromethyl ketones (1a–e) weresynthesised from the respective acetophenone dimethyl acetals with trifluoro-acetic anhydride.[8] When b-aryl-b-methoxyvinyl trifluoromethyl ketones(1a–e) were treated with o-phenylenediamine in dichloromethane for 2 h atroom temperature, the new N-[1-aryl-3-oxo-4,4,4-trifluoro-1-buten-1-yl]-o-phenylenediamines (2a–e) were formed with 59–71% yield. Subsequently,we have found that b-aryl-b-methoxyvinyl trifluoromethyl ketones (1a–e)when treated with o-phenylenediamine in ethanol/acetic acid (4 : 1) for 2–3 h,but at 60–65�C, form 4-aryl-2-trifluoromethyl-3H-1,5-benzodiazepines(3a–e) in one-step with 60–77% yields. The compounds 2a–e could be read-ily converted into 3a–e by refluxing in dichloromethane for 1.5 h with yieldshigher than 90% (Sch. 1). All compounds 2a–e are yellow solid and stablefor many days at room temperature or for months without deterioration, ifstored in the refrigerator. All new compounds 2a–e were fully characterisedby NMR and GC/MS spectral data, the purity of compounds 2a–e and 3a–ewas assigned on the basis of elemental analysis. Selected physical and NMRspectral data are shown in Tables 1 and 2. Elemental analysis data areshown in Table 3.

Our experiments show an efficient method for the synthesis of a seriesof new N-[1-aryl-3-oxo-4,4,4-trifluoro-1-buten-1-yl]-o-phenylenediamines 2

Scheme 1.

b-ALKOXYVINYL TRIFLUOROMETHYL KETONES 3227

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and 4-aryl-2-trifluoromethyl-3H-1,5-benzodiazepines 3 from b-trifluoro-acetylated acetophenone acetals 1, which have been prepared previouslyin analytically pure form and in moderate to good yields.

EXPERIMENTAL

1H- and 13C-NMR spectra, at 200.13 and 50.32MHz respectively,were recorded on a Bruker DPX-200 in a 5-mm probe in chloroform-D

Table 1. Selected Physical and 1H/13CNMR Spectral Dataa of Compounds 2a–e

Compd.Yield(%)b M.P. (�C)c

1HNMR, � (ppm)/13CNMR,� (ppm), JC-F (Hz)

2a 64 106–108 12.2 (s, 1H, N-H), 7.5–6.4 (m, 9H, aromatic-H),

5.8 (s, 1H, H2), 3.9 (s, 2H, NH2).177.8 (q, J¼ 33.8,C¼O), 166.4 (C1), 137.0–114.1(12C, aromatic-C), 117.3 (q, J¼ 288.7, CF3),

92.9 (C2).

2b 60 131–132 12.8 (s, 1H, N-H), 7.5–6.4 (m, 8H, aromatic-H),5.8 (s, 1H, H2), 3.7 (s, 2H, NH2), 2.4 (s, 3H, CH3).

177.5 (q, J¼ 35.2, C¼O), 166.2 (C1), 137.1–116.2(12C, aromatic-C), 117.1 (q, J¼ 288.0, CF3), 92.9(C2), 21.3 ( p-CH3).

2c 71 165–166 12.1 (s, 1H, N-H), 7.4–6.5 (m, 8H, aromatic-H),

5.7 (s, 1H, H2), 3.6 (s, 2H, NH2).177.7 (q, J¼ 33.6, C¼O), 167.7 (C1), 141.4–116.2(12C, aromatic-C), 117.2 (q, J¼ 288.4, CF3),

92.1 (C2).

2d 62 139–140 12.1 (s, 1H, N-H), 7.3–6.4 (m, 8H, aromatic-H),5.8 (s, 1H, H2), 3.7 (s, 2H, NH2).178.2 (q, J¼ 34.1, C¼O), 165.2 (C1), 137.4–114.2

(12C, aromatic-C), 117.0 (q, J¼ 288.7, CF3),93.7 (C2).

2e 59 142–143 12.1 (s, 1H, N-H), 7.3–6.5 (m, 8H, aromatic-H), 5.7

(s, 1H, H2), 3.9 (s, 3H, p-OCH3), 3.8 (s, 2H, NH2).177.8 (q, J¼ 33.6, C¼O), 166.4 (C1), 132.8–114.1(12C, aromatic-C), 117.3 (q, J¼ 288.7, CF3),92.9 (C2), 55.3 ( p-OCH3).

aThe NMR spectra were recorded on a Bruker DPX-200 (1H at 200.13MHz and 13Cat 50.32MHz) in CDCl3/TMS; bYields of isolated compounds; cThe melting points

are uncorrected.

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with TMS as the internal reference. The melting points were taken on aReichert-Thermovar melting point microscope and are uncorrected. Theelemental analyses were performed on a CHN-Elementar AnalysensystemeVario EL.

Synthesis of N-[1-Aryl-2-alkyl-3-oxo-4,4,4-trifluoro-1-buten-1-yl]-o-phenylenediamines (2a–e)

General procedure: To a stirred solution of o-phenylenediamine(20mmol) in 80mL of dry dichloromethane, a solution of the 4-methoxy-4-aryl-1,1,1-trifluoro-3-buten-2-one (1a–e) (20mmol) in dry dichloromethane

Table 2. Selected Physical and 1H/13CNMR Spectral Dataa of Compounds 3a–e

Compd.Yield(%)b M.P. (�C)c

1HNMR, � (ppm)/13CNMR,� (ppm), JC-F (Hz)

3a 64 82–84 8.1–7.4 (2m, 9H, aromatic-H), 3.6 (s, 2H, H3).

81d 153.4 (C4), 144.4 (q, J¼ 35.7, C2), 141.2–125.8(10s, 12C, aromatic-C), 119.0 (q, J¼ 277.2,CF3), 31.9 (C3).

3b 65 118–120 7.9–7.2 (2d/m, 8H, aromatic-H), 3.4 (s, 2H,H3),2.4 (s, 3H, p-CH3).153.5 (C4), 144.6 (q, J¼ 35.5, C2), 142.0–125.8

(10s, 12C, aromatic-C), 119.2 (q, J¼ 277.0,CF3), 32.0 (C3), 21.5 ( p-CH3).

3c 77 116–118 7.9–7.2 (d/m, 8H, aromatic-H), 3.4 (s, 2H, H3).152.8 (C4), 144.3 (q, J¼ 34.8 , C2), 141.1–125.7

(10s, 12C, aromatic-C), 118.8 (q, J¼ 277.1,CF3), 31.8 (C3).

3d 63 98–100 8.0–7.2 (d/m, 8H, aromatic-H), 3.4 (s, 2H, H3).

151.9 (C4), 143.7 (q, J¼ 35.6, C2), 140.9–126.7(10s, 12C, aromatic-C), 118.9 (q, J¼ 277.0,CF3), 31.7 (C3).

3e 60 78–80 8.1–7.0 (2d/m, 8H, aromatic-H), 3.8 (s, 3H,p-OCH3), 3.6 (s, 2H, H3).153.0 (C4), 144.3 (q, J¼ 35.5, C2), 141.5–125.5

(10s, 12C, aromatic-C), 118.9 (q, J¼ 277.2,CF3), 55.4 ( p-OCH3), 31.7 (C3).

aThe NMR spectra were recorded on a Bruker DPX-200 (1H at 200.13MHz and13C at 50.32MHz) in CDCl3/TMS; bYields of isolated compounds; cThe meltingpoints are uncorrected; dSee Ref. [30].

b-ALKOXYVINYL TRIFLUOROMETHYL KETONES 3229

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was added for 1 h at 20–25�C. The mixture was stirred for 1 h at 20–25�C.The solvent was evaporated and the solid or crude oily products 2a–e wererecrystallized from diethylether (yields 59–71%, Table 1).

Synthesis of 4-Aryl-2-trifluoromethyl-3H-1,5-benzodiazepines (3a–e)

General procedure: To a stirred solution o-phenylenediamine (6mmol)in 4mL of dry ethanol and 1mL acetic acid, 4-alkoxy-4-aryl(alkyl)-1,1,1-trifluoro-3-buten-2-ones (1a–e) (6mmol) was added in small portions at60�C. The mixture was stirred for 2–3 h at 60�C. The solvent was removedand the crude solid products 3a–e were recrystallized from methanol (yields60–77%, Table 2).

ACKNOWLEDGMENTS

The authors thank the financial support from the Conselho Nacionalde Desenvolvimento Cientıfico de Tecnologico (CNPq/PADCT III-Proj.62.0228/97-0-QEQ).

Table 3. Elemental Analysis Data of Compounds 2a–e and 3a–e

CompoundMolecular FormulaWeight (g/mol)

Elemental Analysis (%)

Calculated Found

C H N C H N

2a C16H13F3N2O (306.28) 62.74 4.28 9.16 62.45 4.23 9.102b C17H15F3N2O (320.31) 63.75 4.72 8.75 63.60 4.39 8.50

2c C16H12BrF3N2O (385.18) 49.89 3.14 7.27 49.70 3.09 7.182d C16H12ClF3N2O (340.73) 56.40 3.55 8.22 56.20 3.30 8.172e C17H15F3N2O2 (336.31) 60.71 4.50 8.33 60.61 4.22 8.293a C16H11F3N2 (288.27) 66.66 3.85 9.72 66.66 4.06 9.71

3b C17H13F3N2 (302.29) 67.54 4.33 9.27 67.58 4.55 9.293c C16H10BrF3N2 (367.16) 52.34 2.75 7.03 52.21 2.81 7.063d C16H10ClF3N2 (322.71) 59.55 3.12 8.68 59.50 3.26 8.72

3e C17H13F3N2 (318.29) 64.15 4.12 8.80 64.02 4.28 8.87

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Received in the USA September 14, 2001

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