Morita–Baylis–Hillman reaction of 3-formyl-9H-pyrido[3,4-b]indoles and fluorescence studies of the products

  1. Nisha Devi1ORCID Logo and
  2. Virender Singh2

1Department of Chemistry, DAV University, Jalandhar-Pathankot National Highway (NH 44), Jalandhar, 144012, Punjab, India
2Department of Chemistry, Central University of Punjab, Bathinda, India

  1. Corresponding author email

Associate Editor: T. J. J. Müller
Beilstein J. Org. Chem. 2022, 18, 926–934. https://doi.org/10.3762/bjoc.18.92
Received 26 Apr 2022, Accepted 01 Jul 2022, Published 26 Jul 2022

Abstract

β-Carboline is a privileged class of the alkaloid family and is associated with a broad spectrum of biological properties. 3-Formyl-9H-pyrido[3,4-b]indole is a such potent precursor belonging to this family which can be tailored for installing diversity at various positions of β-carboline to generate unique molecular hybrids of biological importance. The present work is a step towards this and assimilates the results related to the exploration of 3-formyl-9H-β-carbolines for the synthesis of β-carboline C-3 substituted MBH adducts followed by evaluation of their fluorescent characteristic. The effect of contact time, solvent system, concentration and substituents was also studied during investigation of fluorescence properties of these derivatives.

Keywords: β-carboline; DABCO; fluorescence; MBH reaction; Michael addition; structure–fluorescence activity relationship

Introduction

Among the polycyclic alkaloids based on indole, the tricyclic structure β-carboline represents a promising class of pyridoindole alkaloids with a variety of biological activities which make them interesting synthetic targets [1-8]. Alkaloids containing the β-carboline nucleus in their molecular architecture are present ubiquitously in nature and a large number of natural products are reported representing this scaffold [9-16]. The key precursor used in the biosynthesis of β-carboline is ʟ-tryptophan which forms the basis of great abundance of β-carboline-containing natural products [17]. A broad spectrum of biological activities is displayed by this pharmacologically rich nucleus which includes antibacterial, antifungal, anticancer, anxiolytic, antimalarial, antiviral, anti-HIV, anti-Alzheimer, and anticonvulsant activities etc. [18-26]. Potent anticancer activities are shown by the majority of β-carboline-containing compounds [27-30]. Figure 1 summarizes some examples of β-carboline-based drugs and bioactive natural products some of which have even been commercialized successfully showing the importance of this nucleus [31-33]. This pharmacological richness and colossal medicinal importance is the reason that the synthesis of β-carboline-containing derivatives has been an exciting area for researchers [34-40].

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Figure 1: Few examples of β-carboline-based drugs and bioactive natural products.

The Morita–Baylis–Hillman (MBH) reaction is an astonishing C–C bond forming reaction between a carbonyl electrophile and an activated alkene leading to the formation of allylic alcohol; a highly functionalized product [41-44]. The chemistry of the MBH reaction is decorated with several unique features viz. atom economy, complexity generation and generation of a chiral center from a pro-chiral electrophile. The chemistry of the MBH reaction has gained considerable attention from the past two decades as these MBH adducts are highly functionalized and offer various points of diversity. Due to these amazing features, these MBH adducts act as starting material on which various organic transformations can be performed leading to the synthesis of various natural and synthetic products. MBH adducts itself display diverse biological activities like antifungal, antibacterial, herbicide, antiparasitic and antitumor as reviewed by Lima-Junior et al. (2012) [45].

It was envisaged that in comparison to the traditional methods like Pictet–Spengler (P-S) or Bischler–Napieralski (B-N) cyclisation, introduction of a formyl group at C-1 or C-3 position of the β-carboline frameworks may provide a new route for generating unlimited diversity at C-1 as well as at the C-3 position of β-carbolines. As depicted in Figure 2, 1-formyl-β-carbolines and 3-formyl-β-carbolines are decorated with different sites for diversification which make these synthons a promising template for the construction of β-carboline-fused frameworks via C-1 N-9, C-1 N-2 and C-3 N-2 cyclisation. Similarly, β-carboline-substituted molecular frameworks can be generated at C-3 position.

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Figure 2: 1/3-Formyl-9H-β-carboline: new synthons for the synthesis of β-carboline-fused and substituted frameworks.

Our group has previously explored 1-formyl-β-carbolines and 3-formyl-β-carbolines for the generation of β-carboline-imidazo[1,2-a]azine conjugates at C-1 as well as C-3 position by the application of the Groebke–Blackburn–Bienaymé (GBB) multicomponent approach [46,47]. Our research group has also investigated the scope of 1-formyl-β-carbolines for generating unique molecular hybrids by application of the Morita–Baylis–Hillman reaction [48-50]. It was also revealed from a detailed literature survey that only limited reports have been documented toward exploration of 3-formyl-9H-β-carbolines for generating diversity at the β-carboline skeleton as outlined in Figure 3 [51-56].

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Figure 3: A summary of previous reports toward exploration of 3-formyl-9H-β-carbolines.

Therefore, we herein report the synthesis of C-3-substituted pyrido[3,4-b]indole MBH adducts from substituted 3-formyl-9H-β-carbolines by the application of the MBH reaction followed by evaluation of their fluorescence properties.

Results and Discussion

The current study began with the synthesis of substituted 3-formyl-9H-β-carbolines (6ae), which was accomplished by modifying the previously disclosed process as presented in Scheme 1 [46,47,57]. Pictet–Spengler (P-S) condensation of ʟ-tryptophan (1) with different aldehydes (ae) in dry DCM at room temperature yielded tetrahydro-β-carboline derivatives 2ae, which were then oxidized with KMnO4 in anhydrous DMF for 45 minutes to yield β-carboline derivatives 3ae. It was encouraging to observe that the P-S condensation with ʟ-tryptophan (1) was much faster than with the tryptophan ester, taking only 45 minutes to complete. Interestingly, KMnO4 oxidation was selective, with no decarboxylation seen. Within 15 minutes, further treatment of 3ae with methyl iodide in the presence of K2CO3 provided the corresponding methyl ester 4ae in high yield (83–87%) and ester functionality reduction with LiAlH4 in dry THF yielded the alcohols 5ae in excellent yield (90–98%). The required 3-formyl-9H-β-carbolines 6ae were obtained in 73–88% yield by oxidizing the alcohol derivatives 5ae with MnO2 in dry DCM. The present methodology is decorated with several advantages like scalability and selectivity. Additionally, no column chromatographic purification was required at any stage and each step was high yielding.

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Scheme 1: Synthesis of 3-formyl-9H-pyrido[3,4-b]indole derivatives.

After the synthesis of starting materials, the Morita–Baylis–Hillman reaction was explored for C-3 functionalization of the β-carboline framework. Accordingly, 3-formyl-9H-β-carbolines 6ae were subjected to MBH reaction with acrylonitrile A and various acrylates BE under neat conditions in the presence of DABCO as depicted in Scheme 2. All the products were furnished smoothly in 27–72% yield. During this study, it was observed that the MBH reaction of 6b with acrylonitrile A resulted in the formation of product 8bA which evidenced that 6b underwent Morita–Baylis–Hillman reaction at the electrophilic carbonyl center as well as Michael addition reaction at the nucleophilic nitrogen center (N-9). Similar results were obtained when 6e was subjected to MBH reaction with acrylonitrile A and methylacrylate B and products 8eA and 8eB were generated as outlined in Scheme 2.

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Scheme 2: Synthesis of C-3 substituted pyrido[3,4-b]indole MBH derivatives (7 and 8).

The effect of a substituent at N-9 position on the reactivity of 3-formyl-9H-pyrido[3,4-b]indole was also investigated during this study. For this purpose, the N-ethyl derivative 9e of 6e was prepared and subjected to MBH reaction with acrylonitrile A and methylacrylate B under neat conditions to generate the corresponding MBH adducts (10eA and 10eB) (Scheme 3). Interestingly, 9e showed more affinity towards this C–C bond forming transformation than 6e. It is noteworthy here that all the products were purified by column chromatography.

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Scheme 3: Synthesis of C-3 substituted pyrido[3,4-b]indole MBH derivatives 10.

A small library of C-3-substituted pyrido[3,4-b]indole derivatives was designed and synthesized which is presented in Figure 4. All the products were characterized using NMR, FTIR and mass spectrometry.

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Figure 4: Library of C-3-substituted pyrido[3,4-b]indole MBH derivatives 7, 8 and 10.

Fluorescence studies

Fluorescence studies of these C-3-substituted pyrido[3,4-b]indole derivatives were examined and various parameters (contact time, concentration and solvent) were optimized for obtaining the best results using 7dA as a model substrate. Fluorescence emission spectra for optimizing the contact time were recorded in chloroform at different intervals of time (5 min, 15 min, 1 h and 24 h) at 1 × 10−6 M concentration. 7dA displayed the highest fluorescence intensity after 15 minutes and its fluorescence activity lasted even after 24 h with a slight decrease in fluorescence intensity. Further, the fluorescence emission profile of 7dA was recorded in chloroform at different concentrations viz. 1 × 10−6 M, 2 × 10−6 M, 3 × 10−6 M, 4 × 10−6 M and 5 × 10−6 M which indicated that fluorescence intensity was found to increase with increase in concentration and fluorescence spectra above this concentration showed a fluorescence intensity >1000 a.u. After optimizing the time and concentration parameters, dilutions of 7dA in different organic solvents such as dichloromethane, DMF and ethyl acetate were prepared for optimizing the solvent for obtaining the best fluorescence results. Fluorescence spectra were recorded after 15 minutes of sample preparation in 5 × 10−6 M concentration and fluorescence intensity was observed to be in the following order: CHCl3 > EtOAc > CH2Cl2 > DMF. The results of the optimization studies are presented in Figure 5 and it was concluded from the studies that C-3-substituted pyrido[3,4-b]indole derivative 7dA displayed the maximum fluorescence intensity in chloroform at a concentration of 5 × 10−6 M after 15 minutes of sample preparation.

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Figure 5: Results of optimization for fluorescence studies: a) contact time; b) concentration; c) solvent.

Accordingly, fluorescence studies of all the other derivatives were conducted following these optimized parameters, i.e., time: 15 min; concentration: 5 × 10−6 M; solvent: CHCl3. The results of the fluorescence studies of all the C-3 substituted pyrido[3,4-b]indole derivatives are presented in Table 1.

Table 1: Results of fluorescence studies of C-3-substituted pyrido[3,4-b]indole derivatives 78 and 10.

sample compound R1 R2 λEx (nm) λEm (nm) flourescence intensity (a.u.)
1 7aA CH(OMe)2 CN 266 384 669.99
2 7aB CH(OMe)2 CO2Me 260 369 624.79
3 7aC CH(OMe)2 CO2Et 374 407 223.68
4 7aD CH(OMe)2 CO2n-Bu 258 378 486.49
5 7aE CH(OMe)2 CO2t-Bu 278 388 669.30
6 8bA Ph CN 278 391 592.48
7 7bB Ph CO2Me 278 384 768.75
8 7bC Ph CO2Et 278 383 766.89
9 7cB 2-Br-C6H4 CO2Me 278 375 >1000
10 7cE 2-Br-C6H4 CO2t-Bu 278 383 834.06
11 7dA 4-Br-C6H4 CN 278 386 609.70
12 7dB 4-Br-C6H4 CO2Me 294 386 768.78
13 8eA 4-Cl-C6H4 CN 270 395 385.38
14 8eB 4-Cl-C6H4 CO2Me 270 401 353.34
15 7eD 4-Cl-C6H4 CO2n-Bu 292 385 829.04
16 10eA 4-Cl-C6H4 CN 278 403 556.46
17 10eB 4-Cl-C6H4 CO2Me 270 428 415.32

Structure–fluorescence activity relationships

From the results presented in Table 1, some structure–fluorescence activity relationships were concluded which are outlined in Figure 6. It was concluded from the structure–fluorescence activity relationships of C-3-substituted pyrido[3,4-b]indole derivatives that the products with o-bromophenyl substituent at R1 position (7cB and 7cE) were the most fluorescent derivatives among all. Also, substituted phenyl derivatives were more fluorescent than the dimethoxymethyl substituted derivatives 7aA7aE. Further, it was observed that an ethyl substituent at N-9 position of β-carboline decreased the fluorescence intensity in 10eA10eB than 7eD which is a N-unsubstituted derivative while the λemission was red shifted in N-ethyl-substituted derivatives as is clearly indicated from the data presented in Table 1. CO2n-Bu and CO2t-Bu substituents enhanced the fluorescence intensity more than the other substituents (7aE, 7cE and 7eD). It is noteworthy here that in the derivatives prepared from the same aldehydes, a noticeable decrease in fluorescence intensity of product 8 (Morita–Baylis–Hilman + Michael adducts 8bA, 8eA and 8eB) was observed than in case of product 7 (Morita–Baylis–Hilman adducts 7bB, 7bC and 7eD) while their λemission was red-shifted in comparison to type 7 compounds. This difference in the fluorescence intensity values of compound 7 and 8 may be attributed to the addition of a substituent at N-9 position of the β-carboline ring after Michael addition reaction (CH2CH2CN or CH2CH2CO2Me).

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Figure 6: Pictorial representation of structure–fluorescence activity relationship of C-3 substituted pyrido[3,4-b]indole derivatives 7, 8 and 10.

Conclusion

In conclusion, we have successfully explored 3-formyl-1-aryl-9H-pyrido[3,4-b]indole derivatives for the C-3 functionalization by application of the MBH reaction to generate C-3-substituted β-carboline MBH adducts. It was revealed from spectroscopic analysis that few derivatives underwent MBH reaction as well as Michael addition reaction to form type 8 compounds. Additionally, the scope of the reaction was further extended and the effect of substituents at the N-9 position on the reactivity of 3-formyl-1-aryl-9H-pyrido[3,4-b]indoles was also investigated. Furthermore, fluorescence properties of these β-carboline conjugates were also studied and they were found to exhibit excellent fluorescence characteristics. Different parameters like contact time, concentration, solvent effects and substituent effects were examined for obtaining the optimal results. It was observed that the MBH derivatives exhibited excellent fluorescence characteristics at a concentration of 5 × 10−6 M in chloroform solvent after 15 minutes of sample preparation. Derivatives 7cB and 7cE bearing an o-bromophenyl substituent at R1 position emerged as two most fluorescent compounds in the present series. Furthermore, products of type 7 (Morita–Baylis–Hilman adducts) were more fluorescent than products 8 (Morita–Baylis–Hilman + Michael adducts). Antimicrobial evaluation of the title compounds is underway and will be reported in due course.

Supporting Information

Supporting information contains detailed experimental procedure for the synthesis of compounds 69 and 10 followed by detailed characterization data and copies of 1H NMR and 13C NMR spectra of newly synthesized compounds 610.

Supporting Information File 1: Experimental procedures and characterization data.
Format: PDF Size: 3.5 MB Download

Acknowledgements

We acknowledge the Indian Institute of Technology Ropar, SAIF Division and Central Instrumental Facility, GJ University of Science and Technology, Hisar is gratefully acknowledged for recording spectroscopic data reported in this paper.

Funding

N. D. acknowledges the financial support from MHRD, New Delhi in the form of Senior Research fellowship. V. S. gratefully acknowledges the financial support in the form of research grant from DST (CS-361/2011), DST-FIST (CSI-228/2011) and CSIR (02(0202)/14/EMR-II), New Delhi (India).

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