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Synthesis 2022; 54(20): 4509-4512
DOI: 10.1055/a-1878-8448
paper

A Novel and Practical Synthesis of Tryptanthrin

Yong He
a   School of Chemistry and Chemical Engineering, Hefei University of Technology,Hefei 230009, P. R. of China
b   Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Hefei 230012, P. R. of China
,
Shiyun Chen
c   Analytical &Testing Center, Hefei University, Hefei230601
,
Yonghao Gao
a   School of Chemistry and Chemical Engineering, Hefei University of Technology,Hefei 230009, P. R. of China
,
Shuangying Gui
b   Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Hefei 230012, P. R. of China
d   Department of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, P. R. of China
,
Yisi Feng∗
a   School of Chemistry and Chemical Engineering, Hefei University of Technology,Hefei 230009, P. R. of China
› Author Affiliations

The Key project of Anhui Provincial Department of Education, China (NO. KJ2020A672) and The Open Fund Project of Anhui Key Laboratory of Pharmaceutical Preparation Technology and Application (NO. 2021KFKT01 and 2021KFKT08).
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Abstract

Tryptanthrin was synthesized through a two-step reaction of oxidation and condensation in a one-pot method, with isatin and sodium hypochlorite as starting materials. The influence of sodium hypochlorite, acetonitrile dosage, oxidation reaction temperature, and reaction time on the yield of the target product during the reaction was investigated. The following optimal reaction conditions were obtained: the ratio of n (isatin) to n (sodium hypochlorite) was 2:1, and the reaction time was 6–8 hours at room temperature. The structure of tryptanthrin was confirmed by matching the IR, NMR, and mass data with the literature report. The study shows that the chemical reaction route designed in this report is short, with high yield and purity of the target product. Its low production cost and simple operation method are expected to be applicable to industrial production.


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Key words

isatin - sodium hypochlorite - Baeyer–Villiger oxidation rearrangement - tryptanthrin

Tryptanthrin is an important quinazolinone alkaloid,[1] with the chemical name indolo[2,1-b]quinazoline-6,12-dione, which occurs in Chinese herbal medicines such as Qingdai­ and Daqingye. Tryptanthrin is one of the active ingredients present in medicinal plants Strobilanthes cusia, Polygonum tinctorum Lour, and Isatis einetorial used in Traditional Chinese Medicines, among other active ingredients in these blue-producing plants. The content of tryptanthrin is very small, and due to the existing complex chemical composition system it is difficult to separate and purify. Tryptanthrin has a wide range of biological and pharmaceutical activities[2] [3] [4] and occupies a very important position in antitumor, anti-inflammatory, antibacterial, antiprotozoal, and other pharmaceutical and pesticide fields, and has always been a research hotspot in the field of organic synthesis.

There are many methods of synthesizing tryptanthrin (Scheme [1]).[5] [6] [7] [8] [9] Initially, through the Bergman method, with isatin (2) and isatoic anhydride (3) in pyridine, and with N,N-diisopropylcarbodiimide (DIC) as the condensing agent and N-methylpiperidine as a catalyst, tryptanthrin is produced under reflux condition. However, pyridine has an unpleasant odor and the dehydrating agent DIC is highly toxic. Moreover, the separation of the by-product, that is, N-substituted of urea is difficult, and it is only suitable for small-scale preparation. In recent years, many advances have been made in the research towards the synthesis of tryptanthrin. Abe[10] used indole-3-carbaldehyde and isatoic anhydride as raw materials and toluene as solvent in the presence of 5 times the amount of urea peroxide and reacted the mixture at 75 °C for 16 hours to prepare tryptanthrin and its derivatives (Scheme [1]). The reaction was carried out by the amide condensation reaction of indole-3-formaldehyde and isatoic anhydride compounds, or using indole-3-acetaldehyde and urea hydrogen peroxide (UHP) through Dakin oxidation, followed by intramolecular cyclization, to obtain tryptanthrin. Amara[11] used isatin as starting material and DMF as a solvent, and under the conditions of iodine and potassium hydroxide, with stirring at room temperature for 4 days, obtained tryptanthrin in 73% yield, using iodine as the reagent (Scheme [1]). However, the reaction time is long, which is not suitable for industrial production.

Zoom Image
Scheme 1Previously reported synthesis route for tryptanthrin. References to the methods are indicated in square brackets.

Using different organic dyes of fluorescein and Rose Bengal as catalysts,[12] starting from isatin (2) with DMF as the solvent and K2CO3 (0.2 equiv) as a base, under the irradiation of 23 W fluorescent bulbs, tryptanthrin was prepared in 76% yield (Scheme [1]). This provides a transition-metal-free and environmentally friendly method for synthesizing tryptanthrin, but the high-boiling-point solvent DMF was used in the reaction, which is unfavorable for environmental protection. Liao[13] developed a new TEMPO/CoCl2-promoted aerobic oxidation of indole, providing a one-step tandem reaction to obtain tryptanthrin derivatives in moderate to good yields and with good regioselectivity, but the reaction time is long and the yield low. Reddy[14] provided a new CuI/DMSO-mediated oxidation domino reaction to synthesize tryptanthrin derivatives using 2-aminoacetophenone and isatoic anhydride as starting materials, but the high-boiling-point solvent of DMSO was used in the reaction, resulting in cumbersome post-processing and pollution of the environment (Scheme [1]).

Oxidation reactions are among the most important classes of reactions in organic synthesis, and their synthetic scope and utility have advanced significantly over the past few decades. Most efforts have been directed to the development of transition-metal-based catalysts. In contrast, much less attention has been paid to the development of non-metallic oxidation systems, largely ignoring their inherent advantages. Sodium hypochlorite is a well-established catalyst for oxidation processes and is now used extensively in industrial applications and organic synthesis as a safe, mild, and economically alternative to heavy metal reagents as highly selective oxidation catalysts for the production of pharmaceuticals. Due to the good biological activity of tryptanthrin and its derivatives[15] [16] [17] [18] [19] an efficient short synthesis of tryptanthrin is needed while the existing synthetic methods have certain defects. Based on other studies, we envisioned that the direct transformation of isatin to tryptanthrin could be achieved by sodium hypochlorite.

Herein, we report a new strategy for the synthesis of tryptanthrin from isatin using sodium hypochlorite under anaerobic conditions. Very few researchers have reported the self-condensation of isatin to generate tryptanthrin, and to the best of our knowledge,[20] this work represents the first example of the one-step synthesis of tryptanthrin via direct C–H transformation.

Investigation of Reaction Conditions for the Synthesis of Tryptanthrin

The synthesis of tryptanthrin and its halo derivatives is conducted by using the corresponding isatin derivatives and aqueous sodium hypochlorite as starting materials and is prepared by a one-pot reaction of oxidation and condensation under homogeneous or heterogeneous conditions (Scheme [2]). We screened and compared four different solvents, including acetonitrile, 1,4-dioxane, dichloromethane, and tetrahydrofuran. At room temperature, the yields of the three water-miscible organic solvents were not significantly different (Table [1], entries 2, 8, and 9). When the organic solvents were immiscible with water, the reaction was slow and the yield was low; when a certain amount of phase-transfer catalyst, tetrabutylammonium bromide, was added, the reaction rate can be appropriately increased, but the yield and compound purity are not as good as those achieved using homogeneous solvents (entries 6 and 7).

Zoom Image
Scheme 2Synthesis route for tryptanthrin (1, R = H) and its halo derivatives

Table 1 Optimization of Synthetic Conditions for Tryptanthrin (1, R = H)

Enter

Equiv

Solvent

Time (h)

Temp (°C)

Yield (%)a

3

1 (R = H)

 1

2:0.8

MeCN

6

rt

 4

64

 2

2:1

MeCN

6

rt

 5

78

 3

2:1.2

MeCN

6

rt

26

61

 4

2:1.4

MeCN

6

rt

63

31

 5

1:1

MeCN

6

rt

81

 3

 6

2:1

DCMb

6

rt

14

 6

 7

2:1

DCMb

6

rt

11

53

 8

2:1

THF

6

rt

 6

73

 9

2:1

1,4-dioxane

6

rt

 7

69

10

2:1

MeCN

6

0–10

12

45

11

2:1

MeCN

6

40–50

 0

34

12

2:1

MeCN

4

rt

10

68

13

2:1

MeCN

8

rt

 1

84

a Reaction optimization scale at gram level.

b Addition of 0.1% tetrabutylammonium bromide (mass ratio of isatin).

When the reaction temperature is low, the reaction is incomplete (Table [1], entry 10); when it continues to increase to 45 ± 5 °C (entry 11), it may be that the oxidation rate of compound 2 to compound 3 is faster, and isatin cannot be condensed with compound 3 in time and degrades into anthranilic acid.[21] (After extraction and separation, the pH of the aqueous phase was adjusted to 2–3 by adding acid, a white solid was precipitated, and the color of bromocresol green was positive). The yield of the target product was low.

Reaction Mechanism

Isatin can undergo a self-dimerization reaction to obtain the natural product tryptanthrin. In this paper, a possible reaction mechanism based on the experimental results is proposed (Scheme [3]). First, isatin undergoes Baeyer–Villiger­ oxidation under the action of sodium hypochlorite to give isatoic anhydride (a), and then the nitrogen lone electron pair of isatin attacks the isatoic anhydride to form the intermediate (b), which undergoes intramolecular electron transfer to remove a molecule of CO2 to furnish the intermediate (c), and then the intermediate (c) undergoes intramolecular dehydration and ring-closure reaction to afford the target product tryptanthrin.

Zoom Image
Scheme 3 Proposed mechanism of sodium hypochlorite catalyzed reactions toward tryptanthrin

Conclusions

In common organic solvents such as acetonitrile, tetrahydrofuran, and 1,4-dioxane, the precursors can form a homogeneous solution with water, has a certain solubility for compound 2, and can accelerate the reaction rate. In addition, it can form a heterogeneous solution with water. Adding a certain amount of phase-transfer catalyst can appropriately increase the reaction rate, but both the reaction time and production cycle are long, which is not conducive to industrial production. At room temperature, when n(2)/n(NaClO) = 1:1, in acetonitrile solvent, stirring for 6 hours to obtain isatoic anhydride, the highest yield can reach 81%. When n(2)/n(NaClO) = 2:1, isatin was partially oxidized to isatoic anhydride, and, finally, isatoic anhydride was condensed with isatin to obtain tryptanthrin in one pot, and the yield could reach 84%. A small quantity of unreacted compound 3 or 2 remains, which can be washed with 0.1% aqueous sodium hydroxide solution or destroyed to o-aminobenzoic acid to remove it, without column separation, and can be recrystallized from the DCM/MeOH system to obtain tryptanthrin. This process has the advantages of simple operation, high yield, and easy availability of starting materials, which provides an experimental basis for its wider application.


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Tryptanthrin (1, R = H); Typical Procedure

MeCN (20 mL) and aq 4% NaClO (18 g, 10.0 mmol) were sequentially added to a solution of isatin (2; 2.94 g, 20 mmol), and the mixture was stirred at rt for 8 h. The color of the reaction solution gradually changed from dark red to yellow. The reaction process was monitored by TLC (EtOAc/hexane1:5). After the reaction, the reaction solution was adjusted with 5% aq Na2S2O3 to make the starch-KI test paper negative. MeCN was recovered under reduced pressure, and the residue was extracted with EtOAc (40 mL). The organic layer was washed sequentially with 0.1% aq NaOH and H2O and dried (anhyd Na2SO4). The solvent was removed under reduced pressure, and the residue was recrystallized to obtain tryptanthrin as yellow-green needle-like crystals; yield: 2.1 g (84%); mp 266.4–267.4 °C.

IR (KBr): 3066, 3029, 2925, 1725, 1684, 1593, 1459, 1354, 1313, 777, 756 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.41 (1 H, t, J = 8.0 Hz, ArH), 7.65 (1 H, t, J = 8.0 Hz, ArH), 7.76 (1 H, t, J = 8.0 Hz, ArH), 7.83 (1 H, t, J = 8.0 Hz, ArH), 7.89 (1 H, d, J = 8.0 Hz, ArH), 8.00 (1 H, d, J = 8.0 Hz, ArH), 8.40 (1 H, d, J = 8.0 Hz, ArH), 8.59 (1 H, d, J = 8.0 Hz, ArH).

13C NMR (100 MHz, CDCl3): δ = 118.0, 122.0, 123.8, 125.4, 127.3, 127.6, 130.3, 130.8, 135.2, 138.3, 144.4, 146.4, 146.7, 158.1, 182.6.

LC-MS: m/z [M + H]+ calcd for C15H8N2O2: 249.0; found: 249.1.


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2,8-Dichlorotryptanthrin (1; R = Cl)

Yellow solid; yield: 79%; mp 286.3–288.1 °C.

IR (KBr): 3069, 1732, 1676, 1589, 1461, 1334, 1299, 846, 749 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.84 (1 H, dd, J = 8.6 2.4 Hz, ArH), 7.94 (1 H, dd, J = 8.5 2.1 Hz, ArH), 8.01 (1 H, d, J = 8.6 Hz, ArH), 8.06 (1 H, d, J = 2.0 Hz, ArH), 8.42 (1 H, d, J = 2.4 Hz, ArH), 8.55 (1 H, d, J = 8.5 Hz, ArH).

13C NMR (100 MHz, CDCl3): δ = 119.5, 121.0, 123.3, 124.7, 127.2, 128.3, 132.2, 135.7, 137.0, 140.7, 143.8, 144.6, 145.0, 156.8, 181.0.

LC-MS: m/z [M + H]+ calcd for C15H6Cl2N2O2: 317.0; found: 317.2.


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2,8-Dibromotryptanthrin (1; R = Br)

Yellow solid; yield: 71%; mp 291.3–293.8 °C.

IR (KBr): 3067, 2922, 1730, 1673, 1587, 1459, 1332, 1298, 845, 747 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.79 (1 H, dd, J = 8.6 2.2 Hz, ArH), 7.84 (1 H, dd, J = 8.6 2.4 Hz, ArH), 7.90 (1 H, d, J = 2.2 Hz, ArH), 8.01 (1 H, d, J = 8.6 Hz, ArH), 8.42 (1 H, d, J = 2.4 Hz, ArH), 8.62 (1 H, d, J = 8.6 Hz, ArH);

13C NMR (100 MHz, CDCl3): δ = 119.3, 123.1, 125.3, 127.2, 132.2, 133.6, 135.7, 137.0, 137.8, 143.9, 144.2, 145.0, 156.8, 164.3, 181.9.

LC-MS: m/z [M + H]+ calcd for C15H6Br2N2O2: 404.9; found: 405.1.


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Isatoic Anhydride (3)

In addition, according to the test operation (Table [1], entry 5), the white solid of isatoic anhydride was isolated by column separation.

IR (KBr): 3104, 3068, 2934, 1766, 1725, 1615, 1599, 1487, 1362, 1260, 765, 681 cm–1.

1H NMR (400 MHz, CD3OD): δ = 6.58 (1 H, t, J = 7.5 Hz, ArH), 6.73 (1 H, d, J = 8.1 Hz, ArH), 7.24 (1 H, t, J = 7.5 Hz, ArH), 7.81 (1 H, d, J = 8.1 Hz, ArH).

13C NMR (100 MHz, CD3OD): δ = 109.9, 110.2, 115.1, 116.3, 131.2, 133.5, 151.4, 170.1.

LC-MS: m/z [M + H]+ calcd for C8H5NO3: 164.1; found: 164.1.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors gratefully acknowledge the test service support provided by the University of Science and Technology of China. We also gratefully acknowledge Professor Wu Zonghao from Hefei Huafang Pharmaceutical Technology Co., Ltd. for his guidance and support.

H.Y. conceived the review and wrote the manuscript. C.S.Y. collected the literature work, F.Y.S. and G.S.Y. edited the manuscript. All authors read and approved the final version of the manuscript.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1878-8448.
  • Supporting Information

Corresponding Author

Yisi Feng
School of Chemistry and Chemical Engineering
Hefei University of Technology, Hefei 230009
P. R. of China   

Publication History

Received: 24 April 2022

Accepted after revision: 20 June 2022

Accepted Manuscript online:
20 June 2022

Article published online:
02 August 2022

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Zoom Image
Scheme 1Previously reported synthesis route for tryptanthrin. References to the methods are indicated in square brackets.
Zoom Image
Scheme 2Synthesis route for tryptanthrin (1, R = H) and its halo derivatives
Zoom Image
Scheme 3 Proposed mechanism of sodium hypochlorite catalyzed reactions toward tryptanthrin