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Synthesis of novel trifluoromethyl-containing heterocycle-fused troponoid compounds

  • Wentao Gao EMAIL logo , Rui Liu and Yang Li
Published/Copyright: October 16, 2012
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 18 Issue 4

Abstract:

A facile synthesis of novel trifluoromethyl-containing pyrano-, pyrazolo- and isoxazolo-fused tropone compounds 4a,b, 5a,b, and 6a,b, respectively, by cyclizations of (E)-3-[3-(trifluoromethylphenyl)acryloyl]tropolones 3a,b is described. The substrates 3a,b were prepared by Claisen-Schmidt condensation reaction of 3-acetyltropolone (1) with 3- or 4-(trifluoromethyl)benzaldehydes 2a,b.

Keywords: aromatic hydrazine; Claisen-Schmidt condensation; cyclization; hydroxylamine hydrochloride; trifluoromethyl; tropone

Introduction

It is well known that the introduction of a trifluoromethyl group into bioactive organic molecules strongly affects their unique features such as polarity and lipid solubility (Asahina et al., 2005; Liu et al., 2008; Chowdhury et al., 2009; Feng et al., 2010). A large volume of synthetic work on this subject has been published (Donohue et al., 2002; Sloop et al., 2002; Loska et al., 2007; Shaaban 2008).

By contrast, troponoid-based compounds, especially heterocycle-fused troponoids, exhibit potent biological and pharmacological activities such as antiviral (Nakazawa et al., 2012), antifungal (Angawi et al., 2003) and antimalarial (Seephonkai et al., 2001) activities. In particular, a new heterocycle-fused troponoid, namely cordytropolone, discovered in the culture broth of Cordyceps sp. BCC 1681, shows promise to be developed into a new antimalarial drug (Seephonkai et al., 2001). The troponoid moiety is an important structural part of other biologically important molecules in the area of drug discovery (Cavazza et al., 2000; Isakovic et al., 2001; Nair et al., 2006). Therefore, the interesting and remarkable bioactivity surrounding the troponoid moiety continues to be a vector in the development of novel and interesting types of new drug candidates (Baldwin et al., 2003; Mori et al., 2003; Wahlström et al., 2004). In recent years, our group has synthesized a number of novel substituted or fused troponoid compounds (Gao et al., 1989, 2009, 2010a,b, 2012; Gao and Zheng, 2000; Li and Gao, 2010; Li et al., 2009, 2012a,b). Building upon this evolving expertise and diversifying our work on the synthesis of new troponoid compounds, we would like to report, herein, the synthesis of a series of novel trifluoromethyl-containing bicyclic heterocycle-fused troponoid compounds.

Results and discussion

The Claisen-Schmidt condensation of 3-acetyltropolone (1) with 3- or 4-(trifluoromethyl)benzaldehyde according to our previously published methodology (Li et al., 2009; Chang et al., 2010) furnished the respective (E)-3-(3-(trifluoromethylphenyl)acryloyl)tropone 3a,b in high yield (Scheme 1). These compounds served as precursors for the construction of the desired trifluoromethyl-containing bicyclic heterocycle-fused troponoid skeleton.

Scheme 1
Scheme 1

Our recent work has shown that the I2/DMSO/H2SO4 system is an efficient reagent for intramolecular oxidative cyclization of 3-cinnamoyltropolones (Gao et al., 2009; Li et al., 2009). In this work, this approach was extended on the oxidative cyclization of trifluoromethyl-substituted tropolones 3a and 3b (Scheme 2). After usual workup followed by purification of crude products by crystallization from 1,4-dioxane, the desired flavone-like products 4a and 4b were obtained in yields of 66% and 68%, respectively. In this reaction, to ensure precipitation of the product directly from the reaction mixture, a minimal amount of DMSO was used. Oxidative cyclization was also attempted using the DMSO-I2 reagent system in the absence of concentrated H2SO4, according to the literature method by Lokhande et al. (2005). This reaction produced products 4a,b in low yields.

Scheme 2
Scheme 2

Isoxazoles and pyrazoles are important classes of biologically active heterocycles, being readily applied to drug design, and have a rich chemistry because of their easy reductive cleavage and susceptibility to ring transformations (Nakamura et al., 2003; Penning et al., 2006). In this work, the synthesis of trifluoromethyl-substituted isoxazolo- and pyrazolo-fused troponoids was accomplished by cyclization of 3a,b with bifunctional agents (Scheme 3). The methodology has been used by us previously for the synthesis of related compounds (Gao et al., 1989, 2010a, 2012; Li and Gao 2010; Li et al., 2012a,b). Thus, the treatment of tropolones 3a,b with phenylhydrazine hydrochloride or hydroxylamine hydrochloride in refluxing ethanol under reflux conditions furnished the respective products 5a,b and 6a,b in acceptable yields of 54–62%.

Scheme 3
Scheme 3

Conclusion

The construction of a series of novel trifluoromethyl-containing pyrano-, pyrazolo- and isoxazolo-fused bicyclic tropones compounds was achieved.

Experimental

All reagents were obtained from Fluka and used without purification. Melting points were determined by using WRS-1B melting points apparatus and are uncorrected. 1H NMR spectra were recorded on a Bruker Avance 400 NMR spectrometer at 400 MHz. Electrospray ionization (ESI) mass spectra were determined using an MSD VL ESI1 spectrometer. Elemental analysis was performed using an Elementar Vario EL-III element analyzer. The progress of reactions was monitored by thin-layer chromatography (TLC) on silica gel GF254 using ethyl acetate/petroleum ether (1:4) as eluent.

Preparation of 3-(3-(trifluoromethylphenyl)acryloyl)tropolones 3a,b

An aqueous solution of 5% KOH (5 mL) was added dropwise to a stirred solution of 3-acetyltropolone (1, 1 mmol, 164 mg) and 1.5 equimolar amount of 3- or 4-(trifluoromethyl)benzaldehyde (2a,b, 1.5 mmol, 261 mg) in 50% aqueous methanol (5 mL). The mixture was stirred at room temperature for 24 h and then quenched by addition of water (5 mL) and acidified with 1 M HCl. The resultant precipitate of 3a,b was collected by filtration, washed with water, dried and crystallized from methanol.

3-(3-(3-(Trifluoromethyl)phenyl)acryloyl)tropolone (3a)

This compound was obtained as bright yellow crystals from 2a (3-(trifluoromethyl)benzaldehyde); yield 83%; mp 188–189°C; 1H NMR (CDCl3): δ 7.02–7.05 (m, 2H), 7.41 (d, 1H, J = 16 Hz), 7.45 (d, 1H, J = 8 Hz), 7.63 (d, 1H, J = 11 Hz), 7.81 (d, 1H, J = 8 Hz), 7.86–7.90 (m, 2H), 8.43 (d, 1H, J = 16 Hz), 8.45 (d, 1H, J = 11 Hz), 10.42 (s, 1H); MS: m/z 321.1 [M+H]+. Anal. Calcd for C17H11F3O3: C, 63.75; H, 3.46. Found: C, 63.53; H, 3.31.

3-(3-(4-(Trifluoromethyl)phenyl)acryloyl)tropolone (3b)

This compound was obtained as bright yellow crystals from 2b (4-(trifluoromethyl)benzaldehyde); yield 87%; mp 209–210°C; 1H NMR (CDCl3): δ 7.14–7.19 (m, 1H), 7.34 (d, 1H, J = 16 Hz), 7.36–7.42 (m, 1H), 7.57 (d, 1H, J = 11 Hz), 7.63–7.66 (m, 2H), 8.19 (d, 1H, J = 16 Hz), 7.97–8.07 (m, 2H), 8.38 (d, 1H, J = 11 Hz), 10.39 (1H, s); MS: m/z 321.0 [M+H]+. Anal. Calcd for C17H11F3O3: C, 63.75; H, 3.46. Found: C, 63.47; H, 3.51.

Preparation of 2-[3- or 4-(trifluoromethyl)phenyl]cyclohepta[b]pyran-4,9-diones (4a,b)

A mixture of compound 3a,b (1 mmol, 320 mg), DMSO (8 mL) and 2–4 drops of concentrated H2SO4 was stirred at 110°C for 15 min and then treated with I2 (0.1 mmol, 25.4 mg) and stirred for an additional 12 h. After completion of the reaction as monitored by TLC, the mixture was cooled to room temperature. The resulting precipitate of 4a,b was collected by filtration and crystallized from 1,4-dioxane.

2-[3-(Trifluoromethyl)phenyl]cyclohepta[b]pyran-4,9-dione (4a)

This compound was obtained as a yellowish-brown solid from 3a (3-(3-(3-(trifluoromethyl)phenyl)acryloyl)tropolone); yield 66%; mp 203–205°C; 1H NMR (DMSO-d6): δ 7.53 (s, 1H), 7.67 (d, 1H, J = 11 Hz), 7.82–7.86 (m, 2H), 7.97 (s, 1H), 8.07 (d, 1H, J = 8 Hz), 8.32–8.40 (m, 3H); MS: m/z 318.9 [M+H]+. Anal. Calcd for C17H9F3O3: C, 64.16; H, 2.85. Found: C, 63.89; H, 3.01.

2-[4-(Trifluoromethyl)phenyl]cyclohepta[b]pyran-4,9-dione (4b)

This compound was obtained as a yellowish-brown solid from 3b (3-(3-(4-(trifluoromethyl)phenyl)acryloyl)tropolone); yield 68%; mp 216–218°C; 1H NMR (CF3COOD): δ 7.56 (s, 1H), 7.63–7.67 (m, 2H), 7.81 (d, 1H, J = 12 Hz), 7.92 (d, 2H, J = 7 Hz), 8.26 (d, 2H, J = 7 Hz), 8.53 (d, 1H, J = 11 Hz); MS: m/z 319.1 [M+H]+. Anal. Calcd for C17H9F3O3: C, 64.16; H, 2.85. Found: C, 64.43; H, 2.66.

Preparation of 1-phenyl-3-[3-(trifluoromethyl)styryl]cyclohepta[c]pyrazol-8(1H)-ones (5a,b)

A solution of 3a,b (1 mmol, 320 mg) in ethanol (10 mL) was stirred and treated with phenylhydrazine hydrochloride (217 mmg, 1.5 mmol). The mixture was heated under reflux for 24 h, then cooled to room temperature and quenched with water. The resulting precipitate of 5a,b was collected by filtration and crystallized from ethanol.

1-Phenyl-3-[3-(trifluoromethyl)styryl]cyclohepta[c]pyrazol-8(1H)-one (5a)

This compound was obtained as a yellowish-brown solid from 3a (3-(3-(3-(trifluoromethyl)phenyl)acryloyl)tropolone); yield 54%; mp 195–197°C; 1H NMR (DMSO-d6): δ 7.66–7.71 (m, 7H), 7.74 (d, 1H, J = 16 Hz), 7.91 (d, 1H, J = 11 Hz), 7.95 (d, 1H, J = 16 Hz), 7.98–8.01 (m, 3H), 8.41 (s, 1H), 8.87 (d, 1H, J = 8 Hz); MS: m/z 392.9 [M+H]+. Anal. Calcd for C23H15F3N2O: C, 70.40; H, 3.85; N, 7.14. Found: C, 70.26; H, 4.13; N, 6.93.

1-Phenyl-3-[4-(trifluoromethyl)styryl]cyclohepta[c]pyrazol-8(1H)-one (5b)

This compound was obtained as a yellowish-brown solid from 3b (3-(3-(4-(trifluoromethyl)phenyl)acryloyl)tropolone); yield 58%; mp 204–206°C; 1H NMR (DMSO-d6): δ 6.92 (d, 1H, J = 12 Hz), 6.99–7.03 (m, 1H), 7.42–7.50 (m, 6H), 7.65 (d, 1H, J = 16 Hz), 7.76 (d, 2H, J = 8 Hz), 7.95 (d, 1H, J = 16 Hz), 8.01 (d, 2H, J = 8 Hz), 8.17 (d, 1H, J = 11 Hz); MS: m/z 393.1 [M+H]+. Anal. Calcd for C23H15F3N2O: C, 70.40; H, 3.85; N, 7.14. Found: C, 70.22; H, 3.95; N, 7.03.

Preparation of 3-[3- or 4-(trifluoromethyl)styryl]-8H-cyclohepta[d]isoxazol-8-ones (6a,b)

A solution of tropolone 3a or 3b (1 mmol, 320 mg) in ethanol (10 mL) was stirred and treated with hydroxylamine hydrochloride (104 mmg, 1.5 mmol). The mixture was heated under reflux for 24 h, then cooled to room temperature and quenched with water. The resultant precipitate of 6a,b was collected by filtration and crystallized from ethanol.

3-[3-(Trifluoromethyl)styryl]-8H-cyclohepta[d]isoxazol-8-one (6a)

This compound was obtained as a yellowish-brown solid from 3a (3-(3-(3-(trifluoromethyl)phenyl)acryloyl)tropolone); yield 62%; mp 197–199°C; 1H NMR (DMSO-d6): δ 7.12–7.25 (m, 2H), 7.28 (d, 1H, J = 16 Hz), 7.58–7.81 (m, 4H,), 8.05 (d, 1H, J = 11 Hz), 8.12–8.27 (m, 2H); MS: m/z 318.0 [M+H]+. Anal. Calcd for C17H10F3NO2: C, 64.36; H, 3.18; N, 4.41. Found: C, 64.56; H, 3.00; N, 4.20.

3-[4-(Trifluoromethyl)styryl]-8H-cyclohepta[d]isoxazol-8-one (6b)

This compound was obtained as a yellowish-brown solid from 3b (3-(3-(4-(trifluoromethyl)phenyl)acryloyl)tropolone); yield 56%; mp 215–216°C; 1H NMR (DMSO-d6): δ 7.12–7.15 (1H, m), 7.27 (1H, d, J = 16 Hz), 7.62 (1H, d, J = 16 Hz), 7.64 (1H, d, J = 11 Hz), 7.78–7.82 (3H, m), 7.98–8.05 (3H, m); MS: m/z 318.1 [M+H]+. Anal. Calcd for C17H10F3NO2: C, 64.36; H, 3.18; N, 4.41; Found: C, 64.15; H, 3.36; N, 4.19.

Corresponding author: Wentao Gao, Institute of Superfine Chemicals, Bohai University, Keji Street, Jinzhou, 121000, P. R. China

The authors would like to thank the Natural Science Foundation of Liaoning Province for financial support (Grant No. 201202001).

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Received: 2012-8-13
Accepted: 2012-9-8
Published Online: 2012-10-16
Published in Print: 2012-10-01

©2012 Walter de Gruyter GmbH & Co. KG, Berlin/Boston

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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https://doi.org/10.1515/hc-2012-0122
Keywords for this article
aromatic hydrazine; Claisen-Schmidt condensation; cyclization; hydroxylamine hydrochloride; trifluoromethyl; tropone
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Articles in the same Issue

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