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Lactic acid-catalyzed fusion of ninhydrin and enamines for the solvent-free synthesis of hexahydroindeno[1,2-b]indole-9,10-diones

  • Xuwen Chen and Yunyun Liu EMAIL logo
Published/Copyright: May 25, 2016
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 22 Issue 3

Abstract

The lactic acid-catalyzed reactions of ninhydrin and secondary enaminones were conducted by solvent-free grinding at room temperature to yield polycyclic 4b,9b-dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-diones.

Keywords: enaminone; grinding; ninhydrin; polycyclic product; solvent-free

Introduction

The synthesis of polycyclic organic molecules with fused heterocycles is of significant importance because of their structural resemblance with natural products [1, 2]. 4b,9b-Dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-diones (3 in Scheme 1) are a class of heterocyclic molecules with fused indeno[1,2-b]indole polycyclic structure which are known to possess various biological activities [3–7]. Therefore, synthesis of such fused heterocyclic scaffolds has received significant attention in recent years. Currently, the synthesis of compounds 3 is predominantly accessed by the reaction of ninhydrin with amine derivatives of 1,3-dicarbonyl compounds [8] alkyl propiolates [9] dialkyl acetylenedicarboxylates [10] or 1,1-bis(methylthio)-2-nitroethene compounds [11]. Since a common feature of all these methods is the in situ generation of an enaminone (or enamino ester) intermediate product, the direct application of enaminones as the reaction partners of ninhydrin has also been developed [12]. Upon on our longstanding interest in developing environmentally benign synthesis and enaminone chemistry [13–15] we report herein a solvent-free protocol for the facile synthesis of products 3 by employing nontoxic and bio-available lactic acid (LA) as catalyst.

Scheme 1 Synthesis of indeno[1,2-b]indole derivatives 3a–j.
Scheme 1

Synthesis of indeno[1,2-b]indole derivatives 3a–j.

Results and discussion

To start the exploration, the reaction of ninhydrin (1) and secondary enaminone 2a was selected. An attempted reaction of 1 and 2a in the absence of any catalyst did not produce the desired product 3a. On the other hand, compound 3a was produced in a 41% yield in the presence of a catalytic amount of acetic acid and the yield was increased to 46% in the presence of a catalytic amount of lactic acid. Under optimized condition the amount of lactic acid was 50 mol% and this treatment furnished compound 3a in an 87% yield. After the optimization of the reaction conditions, this solvent-free catalytic approach was then employed for the efficient synthesis of a variety of other ring-fused products 3b–j (Scheme 1) (See also Supplemental Material).

Conclusions

A solvent-free method for the synthesis of hexahydroindeno[1,2-b]indole derivatives 3 via the reactions of ninhydrin and secondary enaminones was developed. The environmentally benign feature of the method makes it useful in the sustainable synthesis of these important polycyclic scaffolds.

Experimental

Secondary enaminones 2 were synthesized following the literature procedure [1] and other chemicals were obtained from commercial sources and used directly without purification. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded in DMSO-d6. Melting points are not corrected.

General procedure for the synthesis of indeno[1,2-b]indoles 3a–j

A mixture of ninhydrin 1 (0.3 mmol), enaminone 2 (0.3 mmol) and lactic acid (0.15 mmol) was thoroughly grounded using a pestle and mortar at room temperature for 10 min. Then the mixture was washed with saturated NaHCO3 solution and water, filtered, and the crude product was crystallized from ethanol.

4b,9b-Dihydroxy-7,7-dimethyl-5-phenyl-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-dione (3a)

White solid; yield 87%; mp 210–212°C (lit. [11] mp 211–212°C); 1H NMR: δ 7.73 (d, 1 H, J = 6.8 Hz), 7.58–7.45 (m, 5 H), 7.30 (d, 2 H, J = 6.8 Hz), 7.26 (s, 1 H), 6.63 (d, 1 H, J = 6.4 Hz), 6.00 (brs, 1 H), 2.40 (d, 1 H, J = 17.2 Hz), 2.15 (d, 1 H, J = 15.6 Hz), 1.92 (d, 1 H, J = 15.6 Hz), 1.81 (d, 1 H, J = 17.2 Hz), 0.96 (s, 3 H), 0.89 (s, 3 H).

5-Benzyl-4b,9b-dihydroxy-7,7-dimethyl-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-dione (3b)

White solid; yield 82%; mp 186–188°C (lit. [11] mp 188–189°C); 1H NMR: δ 7.78 (d, 1 H, J = 7.6 Hz), 7.73–7.66 (m, 2 H), 7.56 (t, 1 H, J = 7.6 Hz), 7.32–7.22 (m, 5 H), 7.01 (brs, 1 H), 5.96 (brs, 1 H), 5.13 (d, 1 H, J = 16.8 Hz), 4.83 (d, 1 H, J = 16.8 Hz), 2.08–1.92 (m, 4 H), 0.84 (s, 3 H), 0.70 (s, 3 H).

4b,9b-Dihydroxy-7,7-dimethyl-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-dione (3c)

White solid; yield 77%; mp 226–228°C (lit. [11] mp 229–230°C); 1H NMR: δ 9.04 (s, 1 H), 7.79 (d, 2 H, J = 3.6 Hz), 7.65 (d, 1 H, J = 7.6 Hz), 7.55–7.52 (m, 1 H), 6.47 (s, 1 H), 5.49 (s, 1 H), 2.21 (d, 1 H, J = 17.2 Hz), 2.09 (d, 1 H, J = 17.2 Hz), 1.97–1.87 (m, 2 H), 1.01 (s, 3 H), 0.80 (s, 3 H).

4b,9b-Dihydroxy-5-phenyl-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-dione (3d)

Pale yellow solid; yield 85%; mp 209–211°C (lit. [11] mp 212°C); 1H NMR: δ 7.73 (d, 1 H, J = 6.8 Hz), 7.56–7.48 (m, 5 H), 7.33–7.28 (m, 3 H), 6.62 (d, 1 H, J = 7.2 Hz), 6.02 (s, 1 H), 2.47–2.39 (m, 1 H), 2.16–1.96 (m, 3 H), 1.81–1.77 (m, 2 H).

4b,9b-Dihydroxy-5-(p-tolyl)-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-dione (3e)

White solid; yield 84%; mp; 228–231°C; 1H NMR: δ 7.72 (d, 1 H, J = 7.2 Hz), 7.58–7.51 (m, 2 H), 7.29 (d, 2 H, J = 8.0 Hz), 7.21–7.17 (m, 3 H), 6.68 (d, 1 H, J = 7.2 Hz), 5.96 (s, 1 H), 2.38 (s, 4 H), 2.14–1.95 (m, 3 H), 1.78 (d, 2 H, J = 4.8 Hz); 13C NMR: δ 197.6, 189.7, 164.8, 147.3, 137.4, 134.79, 134.71, 133.2, 130.1, 129.4, 129.2, 124.9, 123.2, 106.4, 96.3, 83.5, 37.1, 23.6, 21.7, 20.7. ESI-HR-MS. Calcd for C22H19NNaO4 [M+Na]+: m/z 384.1206. Found: m/z 384.1210.

5-(3-Chlorophenyl)-4b,9b-dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-dione (3f)

White solid; yield 80%; mp 223–226°C; 1H NMR: δ 7.74 (d, 1 H, J = 7.2 Hz), 7.62–7.49 (m, 5 H), 7.34 (s, 1 H), 7.24 (d, 1 H, J = 6.8 Hz), 6.67 (d, 1 H, J = 7.6 Hz), 6.06 (s, 1 H), 2.46 (s, 1 H), 2.16–2.00 (m, 3 H), 1.82–1.77 (m, 2 H); 13C NMR: δ 197.9, 190.5, 164.8, 147.5, 138.1, 135.5, 135.2, 133.6, 130.9, 130.8, 129.5,128.6, 128.4, 125.2, 123.8, 107.7, 97.0, 83.9, 37.6, 24.0, 22.2. ESI-HRMS. Calcd for C21H16ClNNaO4 [M+Na]+: m/z 404.0660. Found: m/z 404.0667.

5-Benzyl-4b,9b-dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-dione (3g)

White solid; yield 86%; mp 207–208°C (lit. [11] mp 209–210°C]; 1H NMR: δ 7.82 (d, 1 H, J = 7.6 Hz), 7.73–7.68 (m, 2 H), 7.57 (t, 1 H, J = 7.2 Hz), 7.33–7.24 (m, 5 H), 6.93 (s, 1 H), 5.79 (s, 1 H), 5.13 (d, 1 H, J = 16.8 Hz), 4.82 (d, 1 H, J = 16.8 Hz), 2.22–2.14 (m, 1 H), 2.03–1.96 (m, 3 H), 1.72–1.55 (m, 2 H).

4b,9b-Dihydroxy-5-isopropyl-4b,5,6,7,8,9b-hexahydroindeno [1,2-b]indole-9,10-dione (3h)

White solid; yield 76%; mp 206–208°C (lit. [11] 205°C); 1H NMR: δ 7.95 (d, 1 H, J = 7.6 Hz), 7.80 (t, 1 H, J = 7.2 Hz), 7.70 (d, 1 H, J = 7.6 Hz), 7.58 (t, 1 H, J = 7.6 Hz), 6.75 (s, 1 H), 5.69 (s, 1 H), 4.63–4.56 (m, 1 H), 2.71–2.67 (m, 1 H), 2.51–2.45 (m, 1 H), 2.04 (s, 2 H), 1.83–1.74 (m, 2 H), 1.45 (d, 3 H, J = 6.4 Hz), 1.24 (d, 3 H, J = 6.4 Hz).

4b,9b-Dihydroxy-5-(2-hydroxyethyl)-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-dione (3i)

White solid; yield 77%; mp 208–209°C (lit. [11] mp 209–210°C); 1H NMR: δ 7.93 (d, 1 H, J = 7.2 Hz), 7.79 (t, 1 H, J = 7.2 Hz), 7.70 (d, 1 H, J = 7.6 Hz), 7.58 (t, 1 H, J = 7.2 Hz), 6.68 (s, 1 H), 5.64 (s, 1 H), 4.93 (s, 1 H), 3.81–3.78 (m, 1 H), 3.62 (s, 3 H), 2.61–2.35 (m, 2 H), 2.04 (s, 2 H), 1.84–1.67 (m, 2 H).

4b,9b-Dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-dione (3j)

White solid; yield 84%; mp 235–236°C (lit. [11] mp 237–238°C); 1H NMR: δ 9.16 (s, 1 H ), 7.81 (s, 1 H), 7.67 (d, 1 H, J = 7.6 Hz), 7.56 (m, 1 H), 6.53 (s, 1 H), 5.56 (s, 1 H), 2.40 (m, 1 H), 2.24–2.19 (m, 1 H), 2.02 (m, 2 H), 1.82–1.68 (m, 2 H).

Funding source: Natural and Science Foundation of Jiangxi Province

Award Identifier / Grant number: 20142BAB213007

Funding statement: This work was financially supported by the Natural and Science Foundation of Jiangxi Province (20142BAB213007).

Acknowledgments:

This work was financially supported by the Natural and Science Foundation of Jiangxi Province (20142BAB213007).

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Supplemental Material:

The online version of this article (DOI: 10.1515/hc-2016-0048) offers supplementary material, available to authorized users.

Received: 2016-4-7
Accepted: 2016-4-30
Published Online: 2016-5-25
Published in Print: 2016-6-1

©2016 by De Gruyter

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-2016-0048
Keywords for this article
enaminone; grinding; ninhydrin; polycyclic product; solvent-free
Creative Commons
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Articles in the same Issue

  1. Frontmatter
  2. Research Articles
  3. TiCl2·2H2O catalyzed one-pot synthesis of highly functionalized tetrahydropiperidines and evaluation of their antimicrobial activities
  4. 2,5-Disubstituted 1,3,4-oxadiazole derivatives of chromeno[4,3-b]pyridine: synthesis and study of antimicrobial potency
  5. Catalytic synthesis and antimicrobial activity of N-(3-chloro-2-oxo-4-phenylazetidin-1-yl)-4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamides
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  7. Synthesis and biological activity studies of some new hybrid compounds derived from antipyrine
  8. Diastereoselective synthesis of dispiro[indoline-3,1′-cyclobutane-2′,3″-indolines] via visible light catalyzed cyclodimerization of 3-phenacylideneoxindoles
  9. Synthesis of 6-alkylsulfanyl-1,4-dihydropyridines as potential multidrug resistance modulators
  10. Lactic acid-catalyzed fusion of ninhydrin and enamines for the solvent-free synthesis of hexahydroindeno[1,2-b]indole-9,10-diones
  11. Efficient synthesis of N-arylsulfonyl-1,2,3-triazoles from 1,1-dibromo-2-arylethylenes
  12. A direct synthetic route to fused tricyclic quinolones from 2,3-diaminoquinolin-4(1H)one
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