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Synthesis of new 3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-diones via the tandem intramolecular Pinner/Dimroth rearrangement

  • Nasrin Karimi , Abolghasem Davoodnia EMAIL logo and Mehdi Pordel
Published/Copyright: January 19, 2018
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 24 Issue 1

Abstract

The reaction of 2-amino-4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles with excess aliphatic carboxylic acids in the presence of phosphoryl chloride (POCl3) afforded new 2-alkyl-5-aryl-8,8-dimethyl-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-diones in high yields. The suggested mechanism involves a tandem intramolecular Pinner/Dimroth rearrangement. The synthesized compounds were characterized by infrared (IR), proton nuclear magnetic resonance (1H NMR), carbon-13 nuclear magnetic resonance (13C NMR) and elemental analysis.

Keywords: carboxylic acids; chromeno[2,3-d]pyrimidines; Pinner/Dimroth rearrangement; POCl3

Introduction

Certain chromenes possess important biological properties such as anticancer [1], [2], antimicrobial [3], [4], antiproliferative [5], anticonvulsant [6], antimalarial [7], antibacterial [8], anti-influenza [9] and anti-rhinovirus [10], [11] activities. Other compounds with a chromene moiety are potential inhibitors of aldose reductase [12], tumor necrosis fact (TNF)-α [13], PTP1B [14], DPP-IV [14], α-glucosidase [14], [15], h-MAO-B [16], PI3Kβ [17], PI3Kδ [17] and Src kinase [18]. On the other hand, the pyrimidine moiety is found in a range of compounds exhibiting a broad spectrum of biological activities such as antitumor [19], antiproliferative [20], antileishmanial [21], antibacterial [22], antifungal [23] and antioxidant [24] properties.

Chromeno[2,3-d]pyrimidines have received much attention because of their interesting biological properties such as anticancer [25], antimicrobial [26], [27], antitubercular [27], antibacterial [28], antiproliferative [29] and antioxidant [30] activities. In conjunction with our interest in the synthesis of heterocyclic compounds [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], in this paper we report the synthesis of new chromeno[2,3-d]pyrimidine-4,6(5H,7H)-diones 3a–h by the reaction of substituted 5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles 1a–d with excess aliphatic carboxylic acids 2a, b in the presence of phosphoryl chloride (POCl3) (Scheme 1).

Scheme 1  
Scheme 1

 

Results and discussion

The starting materials 1a–d were prepared according to methods cited in the literature [41], [42], [43], [44], [45], [46]. In a model reaction, 2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (1a) was allowed to react with excess acetic acid (2a) under reflux without any solvent and catalyst. After a prolonged reaction time, only a low yield of the product was observed and a large amount of the starting material was recovered. Next, the reaction was investigated in excess acetic acid (2a) in the presence of POCl3 as the chlorinating agent. After stirring at room temperature for 300 min the mixture showed only little conversion. However, after reflux for 150 min, no starting material was observed on monitoring of the reaction by thin-layer chromatography (TLC), and a single spot for the formation of a product was seen. The product was identified as 2,8,8-trimethyl-5-phenyl-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (3a). Decreasing the reaction temperature to 100°C decreased the yield of the product from 90% to 78% under otherwise identical conditions. For comparison, synthesis of the model compound 3a was also carried out using thionyl chloride (SOCl2) under reflux conditions. Under these conditions, the product 3a was obtained in 82% yield after 180 min. Consequently, all subsequent reactions for the synthesis of compounds 3b–h were carried out in the presence of POCl3 at reflux temperature.

The structures of the newly synthesized compounds 3a–h were confirmed by analysis of spectral data and elemental analysis. For example, the proton nuclear magnetic resonance (1H NMR) spectrum of compound 3a in dimethyl sulfoxide-d6 (DMSO-d6) contains a broad singlet at δ 12.55 for the NH group and a singlet at δ 2.27 for new methyl group. These new signals along with other signals including two singlets at δ 0.97 and 1.07 for diastereotopic methyl groups and a singlet at δ 4.70 for aliphatic methine group are fully consistent with the formation of compound 3a. The infrared (IR) spectrum is devoid of the CN absorption band at 2199 cm−1 of the precursor but instead shows the NH absorption band at 3434 cm−1, which indicates the involvement of the nitrile group in the cyclization process.

On the basis of a related transformation [40], [41], a plausible mechanism for the formation of compounds 3a–hvia the tandem intramolecular Pinner/Dimroth rearrangement is presented in Scheme 2. First, chlorination of carboxylic acid 2a or 2b with POCl3 affords acyl chloride I which undergoes a reaction with the starting material 1a–d to give the intermediate product II. This compound undergoes an intramolecular Pinner reaction followed by the Dimroth rearrangement to give the final product 3a–hvia the oxazine intermediate III. Unfortunately, attempts to isolate the proposed intermediate products failed even with careful monitoring of the reaction.

Scheme 2  
Scheme 2

 

Conclusion

Synthesis of new 2-alkyl-5-aryl-8,8-dimethyl-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione derivatives 3a–h by the reaction of 2-amino-4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles 1a–d with excess aliphatic carboxylic acid 2a or 2b in the presence of POCl3 is reported. An intramolecular Pinner/Dimroth rearrangement was suggested for the formation of the products.

Experimental

All chemicals were purchased from Merck and Aldrich and used without additional purification. IR spectra were obtained as KBr pellets using a Tensor 27 Bruker spectrophotometer. The 1H NMR (300 MHz) and carbon-13 nuclear magnetic resonance (13C NMR) (75 MHz) spectra were recorded on a Bruker 300 FT spectrometer in DMSO-d6 using tetramethylsilane (TMS) as the internal standard. Elemental analyses were performed on a Thermo Finnigan Flash EA microanalyzer. Melting points were recorded on a Stuart SMP3 melting point apparatus and are not corrected. The starting materials 1a–d were prepared according to the methods cited in the literature [41], [42], [43], [44], [45], [46].

General procedure for synthesis of compounds 3a–h

A mixture of 2-amino-4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H- chromene-3-carbonitrile 1a–d (1 mmol) and excess acetic acid (2a, 2 mL) or propionic acid (2b, 2 mL) in POCl3 (1 mL) was heated under reflux for 60–150 min. Upon completion, as monitored using TLC plates, the mixture was poured into cold water (40 mL). The crude product 3a–h was collected, washed with water and crystallized from ethyl acetate.

2,8,8-Trimethyl-5-phenyl-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (3a)

White powder; yield 90%; mp 318–320°C; IR: ν 3434 (NH), 1676 cm−1 (C=O); 1H NMR: δ 0.97 (s, 3H, CH3), 1.07 (s, 3H, CH3), 2.13 (d, 1H, J=16.1 Hz, one proton of diastereotopic protons in CH2), 2.22–2.35 (m, 4H, a doublet for one proton of diastereotopic protons in CH2 overlapped with a singlet for CH3), 2.62 (s, 2H, CH2), 4.70 (s, 1H, CH), 7.10–7.30 (m, 5H, HAr), 12.55 (s br., 1H, NH); 13C NMR: δ 21.4, 27.2, 29.0, 32.4, 32.9, 50.5, 102.2, 114.2, 126.8, 128.4, 128.5, 144.3, 159.1, 160.5, 162.5, 164.2, 196.3. Anal. Calcd for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found: C, 71.16; H, 6.17; N, 8.54.

2-Ethyl-8,8-dimethyl-5-phenyl-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (3b)

Creamy powder; yield 85%; mp 315–317°C; IR: ν 3432 (NH), 1674 cm−1 (C=O); 1H NMR: δ 0.98 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.17 (t, 3H, J=7.5 Hz, CH3), 2.22 (ABq, 2H, Δν=49.4 Hz, JAB=16.1 Hz, CH2), 2.45–2.60 (m, 2H, CH2 overlapped with solvent), 2.63 (s, 2H, CH2), 4.70 (s, 1H, CH), 7.10–7.30 (m, 5H, HAr), 12.51 (s br., 1H, NH); 13C NMR: δ 11.3, 27.2, 27.6, 29.0, 32.4, 33.0, 50.5, 102.4, 114.1, 126.8, 128.4, 128.6, 144.3, 160.6, 162.6, 163.0, 164.3, 196.4. Anal. Calcd for C21H22N2O3: C, 71.98; H, 6.33; N, 7.99. Found: C, 72.27; H, 6.14; N, 8.23.

2,8,8-Trimethyl-5-(3-nitrophenyl)-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (3c)

Creamy powder; yield 82%; mp 320–322°C; IR: ν 3437 (NH), 1669 cm−1 (C=O); 1H NMR: δ 0.98 (s, 3H, CH3), 1.08 (s, 3H, CH3), 2.15 (d, 1H, J=16.1 Hz, one proton of diastereotopic protons in CH2), 2.28 (s, 3H, CH3), 2.32 (d, 1H, J=16.1 Hz, one proton of diastereotopic protons in CH2), 2.66 (s, 2H, CH2), 4.82 (s, 1H, CH), 7.54–7.61 (m, 1H, HAr), 7.69–7.73 (m, 1H, HAr), 8.02–8.07 (m, 2H, HAr), 12.58 (br s, 1H, NH); 13C NMR: δ 21.5, 27.1, 28.9, 32.4, 33.4, 50.4, 101.1, 113.1, 122.1, 123.1, 130.0, 135.4, 146.3, 147.9, 159.8, 160.5, 162.5, 164.9, 196.5. Anal. Calcd for C20H19N3O5: C, 62.99; H, 5.02; N, 11.02. Found: C, 63.30; H, 5.24; N, 10.78.

2-Ethyl-8,8-dimethyl-5-(3-nitrophenyl)-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (3d)

Creamy powder; yield 80%; mp 301–303°C; IR: ν 3426 (NH), 1673 cm−1 (C=O); 1H NMR: δ 0.99 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.17 (t, 3H, J=7.4 Hz, CH3), 2.24 (ABq, 2H, Δν=49.4 Hz, JAB=16.0 Hz, CH2), 2.45–2.62 (m, 2H, CH2 overlapped with solvent), 2.67 (s, 2H, CH2), 4.82 (s, 1H, CH), 7.57 (t, 1H, J=7.7 Hz, HAr), 7.71 (t, 1H, J=7.6 Hz, HAr), 8.01–8.10 (m, 2H, HAr), 12.49 (br., 1H, NH); 13C NMR: δ 11.2, 19.0, 27.2, 27.8, 28.9, 32.4, 33.5, 50.4, 101.2, 113.1, 122.0, 123.2, 130.0, 135.4, 146.4, 147.9, 160.6, 162.8, 163.8, 165.0, 196.5. Anal. Calcd for C21H21N3O5: C, 63.79; H, 5.35; N, 10.63. Found: C, 63.50; H, 5.54; N, 10.85.

5-(4-Chlorophenyl)-2,8,8-trimethyl-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (3e)

White powder; yield 87%; mp 316–318°C; IR: ν 3423 (NH), 1663 cm−1 (C=O); 1H NMR: δ 0.97 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.90–2.40 (m, 5H, CH2 overlapped with CH3), 2.61 (s, 2H, CH2), 4.68 (s, 1H, CH), 7.15–7.45 (m, 4H, HAr), 12.60 (s br., 1H, NH); 13C NMR: δ 21.4, 27.2, 28.9, 31.2, 32.4, 32.7, 50.4, 101.7, 113.7, 128.4, 130.4, 131.4, 143.2, 159.3, 160.4, 162.5, 164.4, 196.4. Anal. Calcd for C20H19ClN2O3: C, 64.78; H, 5.16; N, 7.55. Found: C, 64.59; H, 5.01; N, 7.73.

5-(4-Chlorophenyl)-2-ethyl-8,8-dimethyl-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (3f)

Yellow powder; yield 86%; mp 260–262°C; IR: ν 3441 (NH), 1673 cm−1 (C=O); 1H NMR: δ 0.98 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.17 (t, 3H, J=7.5 Hz, CH3), 2.22 (ABq, 2H, Δν=47.5 Hz, JAB=16.1 Hz, CH2), 2.50–2.60 (m, 2H, CH2 overlapped with solvent), 2.63 (s, 2H, CH2), 4.68 (s, 1H, CH), 7.24 (d, 2H, J=8.6 Hz, HAr), 7.31 (d, 2H, J=8.6 Hz, HAr), 12.57 (br., 1H, NH); 13C NMR: δ 11.2, 27.3, 27.7, 28.9, 32.4, 32.8, 50.5, 101.9, 113.7, 128.4, 130.5, 131.4, 143.2, 160.6, 162.5, 163.3, 164.4, 196.4. Anal. Calcd for C21H21ClN2O3: C, 65.54; H, 5.50; N, 7.28. Found: C, 65.77; H, 5.31; N, 7.49.

2,8,8-Trimethyl-5-(4-methylphenyl)-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (3g)

Yellow powder; yield 88%; mp 262–265°C; IR: ν 3446 (NH), 1672 cm−1 (C=O); 1H NMR: δ 0.97 (s, 3H, CH3), 1.07 (s, 3H, CH3), 2.12 (d, 1H, J=16.1 Hz, one proton of diastereotopic protons in CH2), 2.22 (s, 3H, CH3), 2.24–2.34 (m, 4H, a doublet for one proton of diastereotopic protons in CH2 overlapped with a singlet for CH3), 2.60 (s, 2H, CH2), 4.65 (s, 1H, CH), 7.03 (d, 2H, J=8.0 Hz, HAr), 7.10 (d, 2H, J=8.0 Hz, HAr), 12.54 (s br., 1H, NH); 13C NMR: δ 14.6, 21.0, 21.4, 27.1, 29.0, 32.4, 32.5, 50.5, 102.3, 114.3, 128.4, 129.0, 135.9, 141.4, 158.9, 160.4, 162.5, 164.0, 196.3. Anal. Calcd for C21H22N2O3: C, 71.98; H, 6.33; N, 7.99. Found: C, 71.70; H, 6.17; N, 8.19.

2-Ethyl-8,8-dimethyl-5-(4-methylphenyl)-8,9-dihydro-3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione (3h)

White powder; yield 87%; mp 318–320°C; IR: ν 3433 (NH), 1672 cm−1 (C=O); 1H NMR: δ 0.97 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.16 (t, 3H, J=7.5 Hz, CH3), 2.12 (d, 1H, J=16.1 Hz, one proton of diastereotopic protons in CH2), 2.22 (s, 3H, CH3), 2.29 (d, 1H, J=16.1 Hz, one proton of diastereotopic protons in CH2), 2.50–2.60 (m, 2H, CH2 overlapped with solvent), 2.62 (s, 2H, CH2), 4.66 (s, 1H, CH), 7.03 (d, 2H, J=7.9 Hz, HAr), 7.10 (d, 2H, J=7.9 Hz, HAr), 12.51 (s br., 1H, NH); 13C NMR: δ 11.3, 21.0, 27.2, 27.6, 29.0, 32.4, 32.6, 50.5, 102.5, 114.2, 128.4, 129.0, 135.9, 141.4, 160.5, 162.5, 162.9, 164.1, 196.3. Anal. Calcd for C22H24N2O3: C, 72.50; H, 6.64; N, 7.69. Found: C, 72.73; H, 6.46; N, 7.88.

Acknowledgments

This work was supported by the Islamic Azad University, Mashhad Branch, Iran.

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Received: 2017-10-31
Accepted: 2017-12-10
Published Online: 2018-01-19
Published in Print: 2018-02-23

©2018 Walter de Gruyter GmbH, 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.

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Research progress in quinazoline derivatives as multi-target tyrosine kinase inhibitors
  4. Research Articles
  5. A bio-inspired approach to proline-derived 2,4-disubstituted oxazoles
  6. Solvent-free preparation of 3-aryl-2-[(aryl)(arylamino)]methyl-4H-furo[3,2-c]chromen-4-one derivatives using ZnO-ZnAl2O4 nanocomposite as a heterogeneous catalyst
  7. Synthesis of 4-arylethyl-6-arylpyrimidine-2-thiols through aza-Michael addition/nucleophilic addition/aromatization tandem reactions
  8. 3-Carboxy-1-sulfopyridin-1-ium chloride ([CPySO3H]+Cl−): an efficient catalyst for one-pot synthesis of hexahydroquinoline-3-carboxamides
  9. Synthesis of new 3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-diones via the tandem intramolecular Pinner/Dimroth rearrangement
  10. A new synthesis of pyrrolo[3,2-d]pyrimidine derivatives by a one-pot, three-component reaction in the presence of L-proline as an organocatalyst
  11. Diversity-oriented synthesis of amide derivatives of tricyclic thieno[2,3-d]pyrimidin-4(3H)-ones and evaluation of their influence on melanin synthesis in murine B16 cells
  12. Synthesis, crystal structure, molecular docking studies and bio-evaluation of some N4-benzyl-substituted isatin- 3-thiosemicarbazones as urease and glycation inhibitors
  13. Ultrasound-assisted synthesis and antimicrobial activity of tetrazole-based pyrazole and pyrimidine derivatives
https://doi.org/10.1515/hc-2017-0228
Keywords for this article
carboxylic acids; chromeno[2,3-d]pyrimidines; Pinner/Dimroth rearrangement; POCl3
Creative Commons
BY-NC-ND 3.0

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Research progress in quinazoline derivatives as multi-target tyrosine kinase inhibitors
  4. Research Articles
  5. A bio-inspired approach to proline-derived 2,4-disubstituted oxazoles
  6. Solvent-free preparation of 3-aryl-2-[(aryl)(arylamino)]methyl-4H-furo[3,2-c]chromen-4-one derivatives using ZnO-ZnAl2O4 nanocomposite as a heterogeneous catalyst
  7. Synthesis of 4-arylethyl-6-arylpyrimidine-2-thiols through aza-Michael addition/nucleophilic addition/aromatization tandem reactions
  8. 3-Carboxy-1-sulfopyridin-1-ium chloride ([CPySO3H]+Cl−): an efficient catalyst for one-pot synthesis of hexahydroquinoline-3-carboxamides
  9. Synthesis of new 3H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-diones via the tandem intramolecular Pinner/Dimroth rearrangement
  10. A new synthesis of pyrrolo[3,2-d]pyrimidine derivatives by a one-pot, three-component reaction in the presence of L-proline as an organocatalyst
  11. Diversity-oriented synthesis of amide derivatives of tricyclic thieno[2,3-d]pyrimidin-4(3H)-ones and evaluation of their influence on melanin synthesis in murine B16 cells
  12. Synthesis, crystal structure, molecular docking studies and bio-evaluation of some N4-benzyl-substituted isatin- 3-thiosemicarbazones as urease and glycation inhibitors
  13. Ultrasound-assisted synthesis and antimicrobial activity of tetrazole-based pyrazole and pyrimidine derivatives
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