Synthesis and antimicrobial activity of 4-(5-ARYL-2-FUROYL)morpholines and 4-[(5-ARYL-2-FURYL)carbonothioyl] morpholines

Yuliia  Matiichuk; Yuri  Gorak; Roman Martyak; Taras Chaban; Volodymyr  Ogurtsov; Igor Chaban; Vasyl  Matiychuk

doi:10.3897/pharmacia.68.e46942

Abstract

By the reaction of furan-2-carboxylic acids and furfural with diazonium salts 1a-j the arylfuran-2-carboxylic acids 4a-e and 5-arylfuran-2-carbaldehydes 5a-f were synthesized. Acids 4a-e were transformed into appropriated acylchlorides 6a-e and were used for preparation of 4-(5-aryl-2-furoyl)morpholines 7a-e. 4-[(5-Aryl-2-furyl)carbonothioyl]morpholines 8a-f were prepared from aldehydes 5a-f by using Willgerodt-Kindler reaction. The structures of the obtained compounds were confirmed by ¹H NMR spectroscopy and elemental analysis. All these new compounds gave spectroscopic data in accordance with the proposed structures. The antimicrobial activities of synthesized compounds 7a-e and 8a-f were investigated and the compounds with high activity against C. neoformans ATCC 208821 were identified.

Keywords

antimicrobial activity, 4-(5-aryl-2-furoyl)morpholines, 4-[(5-aryl-2-furyl)carbonothioyl]morpholines

Introduction

The development of methods of combinatorial synthesis of heterocyclic compounds and their biological evaluation are important points in organic and medical chemistry. In our previous work we have developed methods of synthesis of furan (Obushak et al. 2008; Gorak et al. 2009), pyrazole (Matiichuk et al. 2008), thiazole (Tsyalkovsky et al. 2005; Zimenkovskii et al. 2006; Ostapiuk et al. 2012; Chaban et al. 2019a) and triazole (Pokhodylo et al. 2009a) derivatives based on using of diazonium salt as starting reagents. Some condensed molecules were also prepared (Pokhodylo et al. 2009b; Zubkov et al. 2010; Klenina et al. 2013, 2017; Chaban et al. 2014, 2016, 2017, 2018, 2019b, c; Zelisko et al. 2015). Arendiazonium salts are obtained from available aromatic amines.

In this article we described the synthesis and antimicrobial evaluation of morfolides and thiomorfolides of 5-arylfuran-2-carboxylic acids. It should be noticed that 5-aryl-2-furamides possessing various types of biological and pharmacological activities such as anticancer (Cui et al. 2010), anti-inflammatory (Kort et al. 2008) and antihyperalgesic (Yogeeswari et al. 2011). These compounds were investigated as agents for treatment of infectious diseases that are caused by microorganisms like Mycobacterium tuberculosis (Jeankumar et al. 2012) and Trypanosoma brucei (Urich et al. 2014; Manda et al. 2014) parasites, having additionally in mind the lack of information on the biological properties of 5-phenylfuran-2-carbothioamide.

Experimental part

Materials and methods

All chemicals were of analytical grade and commercially available. All reagents and solvents were used without further purification and drying. All the melting points were determined in an open capillary and are uncorrected. ¹H- spectra were recorded on a Varian Mercury 400 (400 MHz for ¹H) instrument with TMS or deuterated solvent as an internal reference. Satisfactory elemental analyses were obtained for new compounds (C±0.17, H±0.21, N±0.19).

Chemistry

General procedure of preparation 4-(5-aryl-2-furoyl)morpholines (7a-e). A solution of acyl chlorides 0.005 mol in 20 mL dioxane and morfoline (0.001 mol) were stirred at room temperature for 1 hour. Next the mixture was poured in 50ml of water. The resulting solid was filtered, washed with water, dried, and crystallized with ethanol-DMFA.

4-[5-(4-Fluorophenyl)-2-furoyl]morpholine (7a). Yield 85%; m.p. = 116–117 °C.¹H NMR (400 MHz, DMSO-d6) d 7.87–7.77 (m, 2H, ArH), 7.32 (t, J 8.8 Hz, 2H, ArH), 7.13 (d, J 3.6 Hz, 1H, 3-Н_Fur), 7.09 (d, J 3.6 Hz, 1H, 4-Н_Fur), 3.73 (brs, 4H, (CH₂)₂N), 3.66 (brs, 4H, (CH₂)₂O). Anal. Calculated for C₁₅H₁₄FNO₃: C, 65.45; H, 5.13; N, 5.09.Found: C, 65.58; H, 5.17; N, 5.14.

4-[5-(4-Nitrophenyl)-2-furoyl]morpholine (7b). Yield 82%; m.p. = 191–192 °C. ¹H NMR (400 MHz, DMSO-d6) d 8.31 (d, J 7.6 Hz, 2H, ArH), 8.02 (d, J 7.6 Hz, 2H, ArH), 7.44 (d, J 3.2 Hz, 1H, 3-Н_Fur), 7.21 (d, J 3.2 Hz, 1H, 4-Н_Fur), 3.74 (brs, 4H, (CH₂)₂N), 3.67 (br s, 4H, (CH₂)₂O). Anal. Calculated for C₁₅H₁₄N₂O₅: C, 59.60; H, 4.67; N, 9.27. Found: C, 59.51; H, 4.63; N, 9.33.

4-[5-(2,5-Dichlorophenyl)-2-furoyl]morpholine (7c). Yield 91%; m.p.= 105–106 °C.¹H NMR (400 MHz, DMSO-d6) d 7.83 (d, J 2.0 Hz, 1H, 6-HArH), 7.63 (d, J 8.8 Hz, 1H, 3-HArH), 7.48 (dd, J 8.6, 2.4 Hz, 1H, 4-HArH), 7.30 (d, J 3.6 Hz, 1H, 3-Н_Fur), 7.18 (d, J 3.6 Hz, 1H, 4-Н_Fur), 3.72 (brs, 4H, (CH₂)₂N), 3.66 (brs, 4H, (CH₂)₂O). Anal. Calculated for C₁₅H₁₃Cl₂NO₃: C, 55.24; H, 4.02; N, 4.29. Found: C, 55.12; H, 3.97; N, 4.32.

4-[5-(2,6-Dichlorophenyl)-2-furoyl]morpholine (7d). Yield 87%; m.p. = 103–104 °C. ¹H NMR (400 MHz, DMSO-d6) d 7.83 (d, J 2.3 Hz, 1H), 7.62 (d, J 8.6 Hz, 1H), 7.48 (dd, J 8.6, 2.4 Hz, 1H), 7.30 (d, J 3.6 Hz, 1H, 3-Н_Fur), 7.17 (d, J 3.6 Hz, 1H, 4-Н_Fur), 3.72 (brs, 4H, (CH₂)₂N), 3.66 (brs, 4H, (CH₂)₂O). Anal. Calculated for C₁₅H₁₃Cl₂NO₃: C, 55.24; H, 4.02; N, 4.29. Found: C, 55.11; H, 3.96; N, 4.21.

4-[5-(4-Chloro-2-nitrophenyl)-2-furoyl]morpholine (7e). Yield 93%; m.p. = 135–136 °C. ¹H NMR (400 MHz, DMSO-d6) d 8.18 (s, 1H, 3-HArH), 7.96 (d, J 8.8 Hz, 1H, 5-HArH), 7.87 (d, J 8.4 Hz, 1H, 6-Н ArH), 7.19 (d, J 3.2 Hz, 1H, 3-Н_Fur), 7.17 (d, J 3.2 Hz, 1H, 4-Н_Fur), 3.63 (br s, 8H, 4´CH₂). Anal. Calculated for C₁₅H₁₃ClN₂O₅: C, 53.50; H, 3.89; N, 8.32. Found: C, 53.39; H, 3.84; N, 8.37.

General procedure of preparation 4-[(5-aryl-2-furyl)carbonothioyl]-morpholines (8a-f). A mixture of 0.01 mol of arylfurfurals 6, 0.013 mol of morfoline, and 0.32 g (0.01 mol) of fine powder of sulfurin 20 ml of DMF was stirred at 100 °C for 6 hours. The cooled reaction mixture was diluted with water (100 ml) and the precipitate which was separated was filtered off and recrystallized with ethanol-DMFA.

4-{[5-(4-Isopropylphenyl)-2-furyl]carbonothioyl}morpholine (8a). Yield 65%; m.p. = 65–66 °C. ¹H NMR(400 MHz, DMSO-d6) d 7.69 (d, J 7.6 Hz, 2H, ArH), 7.34 (d, J 7.6 Hz, 2H, ArH), 7.15 (d, J 2.0 Hz, 1H, 3-Н_Fur), 7.03 (d, J 2.0 Hz, 1H, 4-Н_Fur), 4.14 (brs, 4H, (CH₂)₂N), 3.75 (brs, 4H, (CH₂)₂O), 2.92 (septet, J 6.8 Hz, 1H, CHMe₂), 1.21 (d, J 6.8 Hz, 6H, CH(CH₃)₂). Anal. Calculated for C₁₈H₂₁NO₂S: C, 68.54; H, 6.71; N, 4.44; S, 10.16. Found: C, 68.67; H, 6.79; N, 4.51; S, 10.22.

4-{[5-(2-Fluorophenyl)-2-furyl]carbonothioyl}morpholine (8b). Yield 73%; m.p. = 89–90 °C. ¹H NMR (400 MHz, DMSO-d6) d 7.82 (dt, J 8.0, 1.6 Hz, 1H, ArH), 7.42–7.34 (m, 1H, ArH), 7.33–7.20 (m, 2H, ArH), 7.14 (d, J 3.6 Hz, 1H, 3-Н_Fur), 6.91 (t, J 3.6 Hz, 1H, 4-Н_Fur), 4.17 (brs, 4H, (CH₂)₂N), 3.79 (br s, 4H, (CH₂)₂O). Anal. Calculated for C₁₅H₁₄FNO₂S: C, 61.84; H, 4.84; N, 4.81; S, 11.01. Found: C, 61.72; H, 4.78; N, 4.88; S, 10.92.

4-{[5-(4-Bromophenyl)-2-furyl]carbonothioyl}morpholine (8c). Yield 82%;m.p. =142–143 °C. ¹H NMR(400 MHz, DMSO-d6) d 7.72 (d, J 8.4 Hz, 2H, ArH), 7.66 (d, J 8.4 Hz, 2H, ArH), 7.17 (d, J 3.2 Hz, 1H, 3-Н_Fur), 7.14 (d, J 3.6 Hz, 1H, 4-Н_Fur), 4.14 (brs, 4H, (CH₂)₂N), 3.75 (brs, 4H, (CH₂)₂O). Anal. Calculated for C₁₅H₁₄BrNO₂S: C, 51.15; H, 4.01; N, 3.98; S, 9.10. Found: C, 51.02; H, 3.96; N, 4.05; S, 9.16.

4-{[5-(2,6-Dichlorophenyl)-2-furyl]carbonothioyl}morpholine (8d). Yield 69%; m.p. = 120–121 °C. ¹H NMR (400 MHz, DMSO-d6) d 7.68–7.61 (m, 2H, ArH), 7.58–7.51 (m, 1H, ArH), 7.18 (d, J 2.8 Hz, 1H, 3-Н_Fur), 6.84 (d, J 2.8 Hz, 1H, 4-Н_Fur), 4.22 (brs, 2H, CH₂N), 3.95 (brs, 2H, CH₂N), 3.72 (br s, 4H, (CH₂)₂O). Anal. Calculated for C₁₅H₁₃Cl₂NO₂S: C, 52.64; H, 3.83; N, 4.09; S, 9.37. Found: C, 52.51; H, 3.77; N, 4.14; S, 9.45.

4-{[5-(3,5-Dichlorophenyl)-2-furyl]carbonothioyl}morpholine (8e). Yield 75%; m.p.= 238–239 °C. ¹H NMR (400 MHz, DMSO-d6) d 7.80 (s, 2H, ArH), 7.59 (s, 1H, ArH), 7.35 (d, J 2.8 Hz, 1H, 3-Н_Fur), 7.13 (d, J 2.8 Hz, 1H, 4-Н_Fur), 4.23 (brs, 2H, CH₂N), 4.01 (brs, 2H, CH₂N), 3.74 (brs, 4H, (CH₂)₂O). Anal. Calculated for C₁₅H₁₃Cl₂NO₂S: C, 52.64; H, 3.83; N, 4.09; S, 9.37. Found: C, 52.69; H, 3.89; N, 4.01; S, 9.46.

4-{[5-(2-Chloro-4-nitrophenyl)-2-furyl]carbonothioyl}morpholine (8f). Yield 81%; m.p. = 142–143 °C. ¹H NMR (400 MHz, DMSO-d6) d 8.40 (s, 1H, 3-HArH), 8.28 (d, J 8.8 Hz, 1H, 5-HArH), 8.11 (d, J 8.8 Hz, 1H, 6-HArH), 7.52 (d, J 2.8 Hz, 1H, 3-Н_Fur), 7.19 (d, J 2.8 Hz, 1H, 4-Н_Fur), 4.27 (brs, 2H, CH₂N), 3.99 (brs, 2H, CH₂N), 3.75 (brs, 4H, (CH₂)₂O). Anal. Calculated for C₁₅H₁₃ClN₂O₄S: C, 51.07; H, 3.71; N, 7.94; S, 9.09. Found: C, 51.16; H, 3.79; N, 7.82; S, 9.17.

Microbiology

Antibacterial data collection to signify bacterial strains and growth conditions. Inhibition of bacterial growth was determined measuring absorbance at 600 nm (OD600), using a Tecan M1000 Pro monochromator plate reader. The percentage of growth inhibition was calculated for each of them, using the negative control (media only) and positive control (bacteria without inhibitors) at the same time as references.

Antifungal data collection. Growth inhibition of C. albicans was determined measuring absorbance at 530 nm (OD530), while the growth inhibition of C. neoformans was determined measuring the difference in absorbance between 600 and 570 nm (OD600-570), after the addition of resazurin (0.001% final concentration) and incubation at 35 °C for additional 2 h. The absorbance was measured using a Biotek Synergy HTX plate reader. The percentage of growth inhibition was calculated for each of them, using the negative control (media only) and positive control (bacteria without inhibitors) at the same time as references.

Inhibition. Percentage growth inhibition of an individual sample is based on Negative controls (media only) and positive controls (bacterial/fungal media without inhibitors). Negative inhibition values indicate that the growth rate (or OD600) is higher compared to the Negative Control (Bacteria/fungi only, set to 0% inhibition). The growth rates for all bacteria and fungi has a variation of -/+ 10%, which is within the reported normal distribution of bacterial/fungal growth (https://www.co-add.org).

Results and discussion

Chemistry

Our synthesis started from aromatic diazonium salts 1a–j and furan-2-carboxylic acids 2 or furfural 3. At first stage furan compounds undergo acylation in Meerwein reaction condition (Obushak et al. 2008) according methods described in literature (Gorak et al. 2009). As a result 5-arylfuran-2-carboxylic acids 4a-e and 5-arylfuran-2-carbaldehydes 5a-f were synthesized. To prepare target morfolides the acids 4a–e were transformed into appropriated acylchlorides 6a–e. They were used in acylation of morfoline. The reaction was performed in dioxane at the room temperature. Thiomorfolides 8a–f were prepared by using Wilgerodt-Kindler reaction according to the procedure which was described in scheme (Fedorovich et al. 2007).

Scheme.

Synthesis of 4-(5-aryl-2-furoyl)morpholines and 4-[(5-aryl-2-furyl)carbonothioyl] morpholines.

The structures of prepared compounds were confirmed by ¹H NMR spectroscopy and elemental analysis. ¹H NMR spectral data of compounds 7a-e and 8a-f revealed supporting evidence to identify their structures. The two singlet signals belonging to morfoline protons in compounds 7a-e were detected at 3.72–3.74 and 3.66–3.67 ppm respectively. But the chemical shift of the CH₂NCH₂ protons of morpholine ring in compounds 8a-f were detected in the range of 3.75–4.01 and 4.14–4.27 ppm as two singlet peaks. This means that the rotation around the C(S)-N bonds is restricted.

Biology

The antimicrobial screening was performed by CO-ADD (the Community for Antimicrobial Drug Discovery) funded by the Wellcome Trust (UK) and the University of Queensland (Australia) (https://www.co-add.org). The growth inhibition was measured against five bacterial strains (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Staphylococcus aureus) and two fungal strains (Candida albicans and Cryptococcus neoformans). The standard concentration employed for screening was 32 mg/ml in DMSO. The observed in vitro antimicrobial activities of our synthesized products 7a–e and 8a–f are tabulated in Table 1.

Table 1.

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Antimicrobial activity compounds 7a–e and 8a–f.

Compound	S. aureus ATCC 43300	E. coli ATCC ATCC 25922	K. pneumoniae ATCC 700603	P. aeruginosa ATCC 27853	A. baumannii ATCC 19606	C. albicans ATCC 90028	C. neoformans ATCC 208821
7a	50.3; 54.9	0.0; 1.4	3.8; 9.0	-4.9; -7.7	13.1; 2.9	4.1; 5.8	-14.1; -8.7
7b	13.1; 34.9	1.5; 4.8	-0.1; 15.3	-1.1; 4.1	1.8; 3.5	3.9; 7.3	85.1; 96.2
7c	27.6; 31.6	2.1; 4.6	-4.8; 9.9	-0.9; 2.0	2.6; 5.9	1.4; 4.6	55.9; 57.5
7d	-18.5; -7.3	6.1; 9.0	-1.6; 1.4	2.8; 3.1	-13.1; 13.6	18.5; 7.2	30.7; 33.8
7e	-12.8; 2.1	-1.6; 0.4	11.9; 9.0	4.0; 6.0	-0.2; -9.3	3.2; 3.4	24.6; 26.8
8a	30.0; 30.3	0.7; 1.8	4.7; 6.3	-7.8; 0.6	-10.3; 3.6	13.7; 15.3	96.9; 98.2
8b	12.7; 9.8	0.5; 1.0	10.1; 6.2	-2.6; 2.7	10.9; 21.7	35.7; 59.0	52.0; 63.8
8c	11.6; 6.7	-4.0; -5.2	0.5; 8.0	-3.3; -5.1	4.7; 5.0	5.0; 6.7	100.7; 95.2
8d	0.8; 1.4	2.0; 2.5	11.5; 3.4	-2.0; -2.6	20.0; 9.6	-1.2; 0.9	-11.9; -4.3
8e	2.0; 8.0	2.3; 2.3	3.6; 4.3	-2.0; 2.9	10.1; 6.0	12.8; 18.5	-21.9; -31.2
8f	-10.4; -11.4	-5.4; -8.3	-6.7; -6.9	-1.8; -3.6	-11.4; -11.7	1.2; 5.4	-12.0; -12.7

In most cases the tested compounds 7a-e and 8a-g displayed a low antimicrobial activity in vitro when screened on the tested microorganisms. But compounds 7a, 7c and 8a have shown weak to medium antibacterial activity against gram-positive bacteria Staphylococcus aureus ATCC 43300 with range of GP= 27.6–54.9% and 7b, 8a and 8c high activity against fungi Cryptococcus neoformans ATCC 208821 (GP=85.1–100.7%). For compounds 7b, 8a and 8c MIC and cytotoxicity to Human embryonic kidney and Human red blood cells were also investigated. They demonstrated significant activity (MIC = 4–16ug/ml) and low cytotoxicity to Human embryonic kidney and Human red blood cells. In all cases HkСС₅₀ and HmHC₁₀ were above >32 ug/ml. The selectivity indexes were also calculated. They were above 2 for tested compounds (Table 2).

Table 2.

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Antimicrobial activity and cytotoxicity to Human embryonic kidney cells and 7b and 8a,c (ug/mL).

Compound	MIC	HkСС₅₀	HmHC₁₀	SI = HC₁₀/ MIC
7b	8; 8	>32; >32	>32; >32	>4; >4
8a	4; 4	>32; >32	>32; >32	>8; >8
8c	16; 16	>32; >32	>32; >32	>2; >2

A retrospective antimicrobial activity results analysis of the subjects 4-(5-aryl-2-furoyl)morpholines and 4-[(5-aryl-2-furyl)carbonothioyl] morpholines allowed us to distinguish the following chemical optimization vectors. Test compounds exhibit different activity, which is determined by the nature of the substituent. The resulting 4-(5-aryl-2-furoyl)morpholines (7a-e) have no high antimicrobial activity. however, compound 7b has high antifungal activity which allows us to conclude the pharmacophore properties of the nitro group in 2-furoylmorpholines moiety. 4-[(5-Aryl-2-furyl)carbonothioyl] morpholines (8a-f) exhibits relatively not very high antimicrobial activity. However, compounds 8a and 8c were found to have high antifungal activity. The results obtained demonstrate that the antimicrobial effect of the synthesized compounds is probably due to the contribution of morpholine nucleus and a number of structural fragments that are pharmacophore for the class heterocycles and the type of pharmacological activity.

Conclusions

In our work, we presented an efﬁcient synthesis and antimicrobial activity evaluation of some 4-(5-aryl-2-furoyl)morpholines and 4-[(5-aryl-2-furyl)carbonothioyl] morpholines. First, antimicrobial activity was detected among the compounds tasted. Further optimization of the structure to improve their activities is currently in progress.

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Obushak ND, Lesyuk AI, Gorak YI, Matiichuk VS (2009) Mechanism of Meerweinarylation of furan derivatives. Russian Journal of Organic Chemistry 45(9): 1375–1381. https://doi.org/10.1134/S1070428009090103

Open-access antimicrobial screening program (2016) Open-access antimicrobial screening program. https://www.co-add.org/

Ostapiuk YV, Obushak MD, Matiychuk VS, Naskrent M, Gzella AK (2012) A convenient method for the synthesis of 2-[(5-benzyl-1,3-thiazol-2-yl) imino]-1,3-thiazolidin-4-one derivatives. Tetrahedron Letters 53(5): 543–545. https://doi.org/10.1016/j.tetlet.2011.11.093

Pokhodylo NT, Savka RD, Matiichuk VS, Obushak ND (2009a) Synthesis and selected transformations of 1-(5-methyl-1-aryl-1H-1,2,3- triazol-4-yl)ethanones and 1-[4-(4-R-5-methyl-1H-1,2,3-triazol-1-yl)phenyl] ethanones. Russian Journal of General Chemistry 79(2): 309–314. https://doi.org/10.1134/S1070363209020248

Pokhodylo NT, Matiychuk VS, Obushak ND (2009b) A convenient method for the synthesis of thiopyrano[4,3-c]quinoline, a new heterocyclic system. Chemistry of Heterocyclic Compounds 45(1): 121–122. https://doi.org/10.1007/s10593-009-0238-2

Tsyalkovsky VM, Kutsyk RV, Matiychuk VS, Obushak ND, Klyufinskaya TI (2005) Synthesis and antimicrobial activity of 5-(R1-benzyl)-2-(R 2-benzylidenehydrazono)-3-(2-furylmethyl)thiazolidin-4-ones. Pharmaceutical Chemistry Journal 39(5): 245–247. https://doi.org/10.1007/s11094-005-0126-8

Urich R, Grimaldi R, Luksch T, Frearson JA, Brenk R, Wyatt PG (2014) The Design and Synthesis of Potent and Selective Inhibitors of Trypanosomabrucei Glycogen Synthase Kinase 3 for the Treatment of Human African Trypanosomiasis. Journal of Medicinal Chemistry 57(18): 7536–7549. https://doi.org/10.1021/jm500239b

Yogeeswari P, Menon N, Semwal A, Arjun M, Sriram D (2011) Discovery of molecules for the treatment of neuropathic pain. Synthesis, antiallodynic and antihyperalgesic activities of 5-(4-nitrophenyl)furoic-2-acid hydrazones. European Journal of Medicinal Chemistry 46(7): 2964–2970. https://doi.org/10.1016/j.ejmech.2011.04.021

Zelisko N, Atamanyuk D, Ostapiuk Y, Bryhas A, Matiychuk V, Gzella A, Lesyk R (2015) Synthesis of fused thiopyrano[2,3-d][1,3]thiazoles via hetero-Diels-Alder reaction related tandem and domino processes. Tetrahedron 71(50): 9501–9508. https://doi.org/10.1016/j.tet.2015.10.019

Zimenkovskii BS, Kutsyk RV, Lesyk RB, Matyichuk VS, Obushak ND, Klyufinska TI (2006) Synthesis and antimicrobial activity of 2,4-dioxothiazolidine-5-acetic acid amides. Pharmaceutical Chemistry Journal 40(6): 303–306. https://doi.org/10.1007/s11094-006-0115-6

Zubkov FI, Ershova JD, Zaytsev VP, Obushak MD, Matiychuk VS, Sokolova EA, Khrustalev VN, Varlamov AV (2010) The first example of an intramolecular Diels-Alder furan (IMDAF) reaction of iminium salts and its application in a short and simple synthesis of the isoindolo[1, 2-a]isoquinoline core of the jamtine and hirsutine alkaloids. Tetrahedron Letters 51(52): 6822–6824. https://doi.org/10.1016/j.tetlet.2010.10.046