Visible-light photoredox catalysis: direct synthesis of fused β-carbolines through an oxidation/[3 + 2] cycloaddition/oxidative aromatization reaction cascade in batch and flow microreactors

Abstract

Fused β-carbolines were synthesized via a visible light photoredox catalyzed oxidation/[3 + 2] cycloaddition/oxidative aromatization reaction cascade in batch and flow microreactors. Several structurally diverse heterocyclic scaffolds were obtained in good yields by coupling of tetrahydro-β-carbolines with a variety of dipolarophiles under photoredox multiple C–C bond forming events. The photoredox coupling of tetrahydro-β-carboline with 1,4-benzoquinone was significantly faster in continuous flow microreactors and the desired products were obtained in higher yields compared to batch reactors.

---

Introduction

Structurally novel and multifarious heterocycles are very important in drug discovery programs for screening new hits against biological targets. Development of efficient synthetic transformations that allow the construction of complex molecular frameworks from relatively simple and easily accessible starting materials in atom economical and multiple bond forming events involving one-pot operations is very challenging. β-Carbolines are amongst the most important biologically valuable scaffolds found in a plethora of synthetic and natural products of medicinal significance.¹ Many marine organisms, mammalian tissues and body fluids, plants, and insects contain numerous alkaloids or hormones having a β-carboline core unit (Fig. 1).^1,2 β-Carboline containing molecules possess numerous biological activities such as antineoplastic,² antimalarial,^3a antimicrobial,^3b antithrombotic,^3c hypnotic and anxiolytic,^3d,e anticonvulsive,^3f and anti-inflammatory.^3g Therefore, constructing structurally novel libraries of fused β-carboline derivatives through efficient synthetic strategies has become an important task.⁴ In recent years, considerable attention has been focused on the development of clean and sustainable energy mediated synthetic strategies due to the exhaustion and non-renewability of fossil fuels. In these perspectives, visible light photoredox catalysis⁵ has been found to be a promising alternative approach. Despite significant advances in this field, the full spectrum of the synthetic utility of visible light photoredox catalysis is yet to be explored.

Fig. 1 A few examples of natural products containing β-carboline.

A careful survey of the literature revealed that most of the photoredox catalysis deals with the functionalization of the relatively unreactive C–H bonds adjacent to N-atoms and a single C–C bond is formed in the overall process. Examples of photoredox catalysis, where multiple C–C bonds are formed, are only a few.⁶ As part of our research program towards the development of newer heterocyclic libraries of medicinal importance,⁷ herein we report the construction of fused β-carbolines via a photoredox catalyzed oxidation/[3 + 2] cycloaddition/oxidative aromatization reaction cascade in batch and flow microreactors (Scheme 1). Tetrahydro-β-carbolines were functionalized in multiple C–C bond forming events that proceeded via photoredox generation of azomethine ylides and the subsequent [3 + 2] dipolar cycloaddition reaction. It is noteworthy that the synthetic strategy described herein does not require any additional step or reagent to yield aromatized products. Thus, an efficient, atom economical, and high yielding methodology involving oxidation, 1,3-dipolar cycloaddition, and aerobic oxidative aromatization for fused β-carbolines was developed.

Scheme 1 Visible light photoredox catalyzed oxidation/[3 + 2] cycloaddition/oxidative aromatization reaction cascade for the synthesis of fused β-carboline derivatives.

Results and discussion

At the onset, we commenced our investigations by exploring the coupling of methyl 2-(1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)acetate 1a with 1,4-benzoquinone 2a. The substrate 1a was obtained by N-alkylation of tryptoline with methyl α-bromoacetate. Preliminary results revealed that in the presence of catalytic amount of the photoredox catalyst [Ru(bpy)₃Cl₂]·6H₂O and visible light (white LED) the aromatized cycloadduct 3a could be obtained in good yields (Table 1).

Table 1 The effect of light, catalyst, and solvent over the coupling of 1a and 2a to yield 3a^a

Entry	Light^b	Photo-catalyst	Loading (mol%)	Time (h)	Yield of 3a^c (%)
a Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), photo-catalyst, MeCN (5 mL), air. b 11 W white LED bulb kept at a distance of 10 cm (approx.) from the reaction vessel. c Yields of the isolated products after column chromatography. d The reaction was performed under an oxygen atmosphere. e The reaction was performed under a nitrogen atmosphere. f t-BuOOH (10 eq.) was added to the reaction mixture. ND = the desired product was not detected on TLC. NI = not isolated.
1	√	—	—	48	ND
2	X	—	—	48	ND
3	√	[Ru(bpy)3Cl2]·6H2O	1.0	12	68
4	X	[Ru(bpy)3Cl2]·6H2O	1.0	48	ND
5	√	[Ru(bpy)3Cl2]·6H2O	0.5	12	69
6	√	[Ru(bpy)3Cl2]·6H2O	0.25	24	61
7	√	Ru(bpy)3(PF6)2	0.5	12	69
8	√	Rose bengal	0.5	48	NI
9	√	Rose bengal	5	48	33
10	√	Rose bengal	10	48	30
11	√	Eosin Y	5	48	ND
12	√	Rhodamine B	5	48	ND
13^d	√	[Ru(bpy)3Cl2]·6H2O	0.5	12	69
14^e	√	[Ru(bpy)3Cl2]·6H2O	0.5	12	ND
15^e^,^f	√	[Ru(bpy)3Cl2]·6H2O	0.5	24	65

---

It was found that 0.5 mol% of [Ru(bpy)₃Cl₂]·6H₂O was sufficient to give high yields of 3a in a reasonable reaction time (Table 1, entries 3, 5 and 6). [Ru(bpy)₃Cl₂]·6H₂O and Ru(bpy)₃(PF₆)₂ were equally effective for the reaction whereas the organic dyes (rose bengal, eosin Y, rhodamine B) were less effective (Table 1, entries 5, 7, 8, 11 and 12). Among the organic dyes screened, rose bengal was somewhat effective but at higher loadings (Table 1, entries 8–10). Performing the reaction under an oxygen atmosphere did not improve the product yield whereas no product was obtained when the reaction was performed under a nitrogen atmosphere (Table 1, entries 13 and 14). However, even under a nitrogen atmosphere, a good yield of the desired product 3a was obtained using t-BuOOH as an oxidant for the reaction (Table 1, entry 15).

Having the optimal reaction conditions in hand, the generality of the reaction was investigated (Table 2). The scope of tetrahydro-β-carboline was studied by taking methyl, ethyl, benzyl, p-NO₂-benzyl esters of 2-(1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)acetate (1a–d) and ketones (1e–f). The scope of the dipolarophile was studied by taking 1,4-benzoquinone (2a), 1,4-naphthoquinone (2b), 2-[4-(1,1-dimethylethyl)phenyl]-2,5-cyclohexadiene-1,4-dione (2c), N-methylmaleimide (2d), N-ethylmaleimide (2e), and N-benzylmaleimide (2f). The reaction was found to work well with a variety of β-carbolines and dipolarophiles. In most of the cases, the reaction gave good yields of the fused β-carbolines (3a–n). As expected, the reaction of tetrahydro-β-carboline 1b with 2-[4-(1,1-dimethylethyl)phenyl]-2,5-cyclohexadiene-1,4-dione 2c gave two products in nearly 1 : 1 ratio whose structures were tentatively assigned as 3d (28%) and 3d′ (30%). In both the products (3d/3d′), the less substituted double bond of the quinone dipolarophile underwent cycloaddition with the azomethine ylide. Using diethylacetylene dicarboxylate 2g as a dipolarophile, the reaction yielded a partly oxidised product 3n under standard conditions (Table 2, entry 14). Structural elucidation and relative stereochemical assignments of 3n were carried out by 2D DQFCOSY, NOESY and HSQC experiments. However, when the reaction of diethylacetylene dicarboxylate was conducted under an oxygen atmosphere, it gave very good yield of desired aromatized product 3o (Table 2, entry 15). The product 3o was also obtained in fairly good yield under the standard reaction conditions (under air) for an extended period of time (Table 2, entry 16). β-Nitrostyrenes and ethyl acrylate were not found as good dipolarophiles for the reaction as they gave complex reaction mixtures under our standard conditions.

Table 2 Evaluation of the substrate scope^a

Entry	Tetrahydro-β-carboline 1	Dipolarophile 2	Product 3; Rxn. time; yield^b (%)
a Reaction conditions: tetrahydro-β-carboline 1 (0.1 mmol), dipolarophile 2 (0.1 mmol), [Ru(bpy)3Cl2]·6H2O (0.5 mol%), MeCN (5 mL), 11 W white LED bulb, air. b Yields of the isolated products after column chromatography. c Combined yield for 3d (28%) and 3d′(30%). d The reaction was performed under an oxygen atmosphere.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15^d
16

---

All the reactions gave several spots on TLC at the beginning but after a longer reaction run a clean spot (corresponding to our desired product) appeared on TLC and by-products were minimized. Although moderate to good yields (58–80%) of the desired products were obtained, no other by-product could be isolated using column chromatography and characterized. In other similar photoredox [3 + 2] cycloadditions, an external oxidant (other than O₂) is required to obtain aromatized products.⁶ However, it is noteworthy that most of the reactions we performed yielded aromatized products using air as the green oxidant. It is also noticeable that the reaction is compatible with tetrahydro-β-carbolines containing a free amine (NH) group, therefore all the products can be derivatized easily through N-alkylation/acylation.

In the past decade, continuous flow microreactors have received considerable attention for performing organic transformation in safer and efficient ways.⁸ Due to their small dimensions, microreactors are associated with high heat and mass transfer efficiency, very high surface to volume ratio and enhanced illumination homogeneity. These features make microreactors a very good tool for photochemistry.⁹ Considering these aspects, a continuous flow protocol for the photoredox catalyzed coupling of tetrahydro-β-carbolines with dipolarophile was developed. Handling gaseous reagents (oxygen), and precisely controlling their flow rates in segmented flow microfluidic conditions are somewhat tricky. Therefore, in order to have an operationally simple microfluidic set-up, we preferred t-BuOOH as an oxidant over gaseous oxygen. The reagents, photo-catalyst and oxidant were introduced through two syringe pumps into visible light transparent capillary microreactors (PFA tubing, id = 500 μm, length = 5 m, volume = 0.98 mL) which were wrapped over a visible light source (11 W white LED). Schematic illustration of the photochemical reaction in flow microreactors is depicted in Fig. 2. The results of this study are given in Table 3. The short length scale and high illumination homogeneity in the microreactor provide increased photon flux. It resulted in an acceleration of the coupling reaction; full conversion was observed in a residence time of 8 minutes (Table 3, entry 3). Moreover the yields were slightly better in microreactors (75%) than in batch conditions (69%). Decreasing the stoichiometry of oxidant (t-BuOOH) from 10 eq. to 5 eq. resulted in low yields of the desired product (Table 3, entry 5). The daily outcome of the flow reactor was calculated to be 2.16 mmol of the product per day which shows that the microreactor has the potential for scale up production.

Fig. 2 (a) Schematic illustration of the photoredox coupling in flow microreactors. (b) Picture of the capillary microreactor wrapped over a visible light source (LED).

Table 3 The effect of flow rate/reaction time over the coupling of tetrahydro-β-carboline 1a with 1,4-benzoquinone 2a in flow microreactors

Entry	Flow rate (μL min^−1)			Rxn. time (m)	Yield of 3a^a (%)
	β-Carboline 1a & 1,4-benzoquinone 2a	Photocatalyst	t-BuOOH
a Yields of the isolated products after column chromatography.
1	200	200	80	2	25
2	100	100	40	4	60
3	50	50	20	8	75
4	25	25	10	16	75
5	50	50	10	9	55

---

The formation of fused heterocycles through the photoredox coupling of tetrahydro-β-carbolines with dipolarophiles can be explained by a plausible mechanism depicted in Scheme 2. [Ru(bpy)₃Cl₂]·6H₂O gets activated by visible light and accepts an electron from β-carboline 1 to give a cation radical 4. Next the intermediate 4 loses a proton to yield iminium ion 5 which further loses another proton to yield an azomethine ylide 6. The azomethine ylide 6 undergoes an 1,3-dipolar cycloaddition reaction with dipolarophile 2 to yield a cycloadduct 7 which readily aromatizes to final product 3.

Scheme 2 A plausible mechanism for the visible light photoredox catalyzed oxidation/[3 + 2] cycloaddition/oxidative aromatization reaction cascade for the synthesis of fused β-carbolines.

Conclusions

In conclusion, we have developed an efficient photoredox catalyzed oxidation/[3 + 2] cycloaddition/oxidative aromatization reaction cascade to yield structurally diverse heterocyclic frameworks. Multiple new C–C bonds were formed during the photoredox catalysis via generation of azomethine ylides from tetrahydro-β-carbolines followed by the [3 + 2] cycloaddition reaction with a variety of dipolarophiles. The synthetic strategy we developed allows the formation of fused β-carboline derivatives in a manner that is atom economical, green and sustainable. The reaction efficiency was studied in batch and continuous flow microreactors. The use of continuous flow microreactors led to an improved irradiation over the reaction mixture, and offered considerably shorter reaction time and better yields of products compared to batch reactors.

Acknowledgements

R.A.M. is thankful to the Department of Science & Technology, India for financial support (GAP 0378 & GAP 0470). Financial support in part from 12^th Five Year Plan Project “Affordable Cancer Therapeutics (ACT-CSC-0301)” is also acknowledged. J. S. K. and G. S. S. are thankful to NIPER Hyderabad, and S. B. is thankful to UGC India for his fellowship.

Notes and references

1. (a) T. A. Mansoor, C. Ramalhete, J. Molnar, S. Mulhovo, M. J. U. Ferreira and A.-C. Tabernines, J. Nat. Prod., 2009, 72, 1147; (b) R. Cao, W. Peng, Z. Wang and A. Xu, Curr. Med. Chem., 2007, 14, 479; (c) K. Higuchi and T. Kawasaki, Nat. Prod. Rep., 2007, 24, 843; (d) T. Kawasaki and K. Higuchi, Nat. Prod. Rep., 2005, 22, 761; (e) G. M. Carbrera and A. M. Seldes, J. Nat. Prod., 1999, 62, 759; (f) M. M. Airaksinen and I. Kari, Med. Biol., 1981, 59, 190.
2. (a) J. R. Allen and B. R. Holmstedt, Phytochemistry, 1979, 19, 1573; (b) V. Bazika, T.-W. Lang, S. Pappelbaum and E. Corday, Am. J. Cardiol., 1966, 17, 227; (c) Y. Boursereau and I. Coldham, Bioorg. Med. Chem. Lett., 2004, 14, 5841; (d) M. R. Uskokovic and G. Grethe, The Alkaloids, ed. R. H. F. Manske, Academic Press, New York, 1973, vol. 14, p. 181; (e) S. Schwikkard and R. V. Heerden, Nat. Prod. Rep., 2002, 19, 675; (f) J. C. P. Steele, N. C. Veitch, G. C. Kite, M. S. J. Simmonds and D. C. Warhurst, J. Nat. Prod., 2002, 65, 85.
3. (a) T. B. Beghyn, J. Charton, F. Leroux, G. Laconde, A. Bourin, P. Cos, L. Maes and B. Deprez, J. Med. Chem., 2011, 54, 3222; (b) P. Molina, P. M. Fresnda, S. Gareia-Zafra and P. Almendros, Tetrahedron Lett., 1994, 35, 8851; (c) M. Zhao, L. Bi, W. Bi, C. Wang, Z. Yang, J. Ju and S. Peng, Bioorg. Med. Chem., 2006, 14, 4761; (d) M. Ozawa, Y. Nakada, K. Sugimachi, F. Yabuuchi, T. Akai, E. Mizuta, S. Kuno and M. Yamaguchi, Jpn. J. Pharmacol., 1994, 64, 179–187; (e) G. Biggio, A. Concas, S. Mele and M. G. Corda, Brain Res. Bull., 1987, 19, 301; (f) G. Dorey, G. Poissonnet, M. C. Potier, L. P. D. Carvalho, P. Venault, G. Chapouthier, J. Rossier, P. Potier and R. H. Dodd, J. Med. Chem., 1989, 32, 1799; (g) A. M. Deveau, M. A. Labroli and C. M. Dieckhaus, Bioorg. Med. Chem. Lett., 2001, 11, 1251.
4. (a) N. Srinivasan and A. Ganesan, Chem. Commun., 2003, 916; (b) C. Liu and R. A. Widenhoefer, J. Am. Chem. Soc., 2004, 126, 10250; (c) A. S. Karpov, T. Oeser and T. J. J. Müller, Chem. Commun., 2004, 1502; (d) S. Shirakawa, K. Liu, H. Ito and K. Maruoka, Chem. Commun., 2011, 47, 1515; (e) S. Zhao, X. Liao and J. M. Cook, Org. Lett., 2002, 4, 687; (f) G. Varchi, A. Battaglia, C. Samori, E. Baldelli, B. Danieli, G. Fontana, A. Guerrini and E. Bombardelli, J. Nat. Prod., 2005, 68, 1629; (g) D. Sawant, R. Kumar, P. R. Maulik and B. Kundu, Org. Lett., 2006, 8, 1525.
5. (a) R. Brimioulle, D. Lenhart, M. M. Maturi and T. Bach, Angew. Chem., Int. Ed., 2015, 54, 3872; (b) D. P. Hari and B. Konig, Chem. Commun., 2014, 50, 6688; (c) C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev., 2013, 113, 5322; (d) D. Ravelli, M. Fagnoni and A. Albini, Chem. Soc. Rev., 2013, 42, 97; (e) H. Jiang, C. Huang, J. Guo, C. Zeng, Y. Zhang and S. Yu, Chem. – Eur. J., 2012, 18, 15158; (f) L. Shi and W. Xia, Chem. Soc. Rev., 2012, 41, 7687; (g) J. Xuan and W.-J. Xiao, Angew. Chem., Int. Ed., 2012, 51, 6828; (h) J. M. R. Narayanam and C. R. J. Stephenson, Chem. Soc. Rev., 2011, 40, 102.
6. (a) Y.-Q. Zou, L.-Q. Lu, L. Fu, N.-J. Chang, J. Rong, J.-R. Chen and W.-J. Xiao, Angew. Chem., Int. Ed., 2011, 50, 7171; (b) M. Rueping, D. Leonori and T. Poisson, Chem. Commun., 2011, 47, 9615; (c) C. Vila, J. Lau and M. Rueping, Beilstein J. Org. Chem., 2014, 10, 1233; (d) L. Huang and J. Zhao, Chem. Commun., 2013, 49, 3751; (e) S. Guo, H. Zhang, L. Huang, Z. Guo, G. Xiong and J. Zhao, Chem. Commun., 2013, 49, 8689; (f) H. Hou, S. Zhu, F. Pan and M. Rueping, Org. Lett., 2014, 16, 2872; (g) Q.-H. Deng, Y.-Q. Zou, L.-Q. Lu, Z.-L. Tang, J.-R. Chen and W.-J. Xiao, Chem. – Asian J., 2014, 9, 2432; (h) J. Xie, Q. Xue, H. Jin, H. Li, Y. Cheng and C. Zhu, Chem. Sci., 2013, 4, 1281; (i) X. Ju, D. Li, W. Li, W. Yu and F. Bian, Adv. Synth. Catal., 2012, 354, 3561; (j) D. Lenhart and T. Bach, Beilstein J. Org. Chem., 2014, 10, 890; (k) S. Zhu, A. Das, L. Bui, H. Zhou, D. P. Curran and M. Rueping, J. Am. Chem. Soc., 2013, 135, 1823.
7. (a) A. Kamal, C. N. Reddy, M. Satyaveni, D. Chandrasekhar, J. B. Nanubolu, K. K. Singarapu and R. A. Maurya, Chem. Commun., 2015, 51, 10475; (b) A. Kamal, K. N. V. Sastry, D. Chandrasekhar, G. S. Mani, P. R. Adiyala, J. B. Nanubolu, K. K. Singarapu and R. A. Maurya, J. Org. Chem., 2015, 80, 4325; (c) R. A. Maurya, P. R. Adiyala, D. Chandrasekhar, C. N. Reddy, J. S. Kapure and A. Kamal, ACS Comb. Sci., 2014, 16, 466.
8. For selected recent articles and reviews over flow microreactors, see: (a) T. Lebleu, J. Maddaluno and J. Legros, Org. Chem. Front., 2015, 2, 324; (b) A. Xolin, A. Stévenin, M. Pucheault, S. Norsikian, F.-D. Boyer and J.-M. Beau, Org. Chem. Front., 2014, 1, 992; (c) B. Gutmann, D. Cantillo and C. O. Kappe, Angew. Chem., Int. Ed., 2015, 54, 6688; (d) R. A. Maurya, C. P. Park, J. H. Lee and D.-P. Kim, Angew. Chem., Int. Ed., 2011, 50, 5952; (e) S. Sharma, R. A. Maurya, K.-I. Min, G.-Y. Jeong and D.-P. Kim, Angew. Chem., Int. Ed., 2013, 52, 7564; (f) K. C. Basavaraju, S. Sharma, R. A. Maurya and D.-P. Kim, Angew. Chem., Int. Ed., 2013, 52, 6735; (g) S. T. R. Mueller and T. Wirth, ChemSusChem, 2015, 8, 245; (h) C. Wiles and P. Watts, Green Chem., 2014, 16, 55.
9. For selected recent articles and reviews over photochemical reactions in flow microreactors, see: (a) Y. Su, N. J. W. Straathof, V. Hessel and T. Noel, Chem. – Eur. J., 2014, 20, 10562; (b) C. P. Park, R. A. Maurya, J. H. Lee and D.-P. Kim, Lab Chip, 2011, 11, 1941; (c) X. Wang, G. D. Cuny and T. Noel, Angew. Chem., Int. Ed., 2013, 52, 7860; (d) K. Asano, Y. Uesugi and J.-i. Yoshida, Org. Lett., 2013, 15, 2398; (e) M. Neumann and K. Zeitler, Org. Lett., 2012, 14, 2658; (f) R. A. Maurya, C. P. Park and D. P. Kim, Beilstein J. Org. Chem., 2011, 7, 1158; (g) J. W. Tucker, Y. Zhang, T. F. Jamison and C. R. J. Stephenson, Angew. Chem., Int. Ed., 2012, 51, 4144; (h) E. K. Lumley, C. E. Dyer, N. Pamme and R. W. Boyle, Org. Lett., 2012, 14, 5724; (i) D. Cantillo, O. de Frutos, J. A. Rincón, C. Mateos and C. O. Kappe, J. Org. Chem., 2014, 79, 8486; (j) J. W. Beatty and C. R. J. Stephenson, J. Am. Chem. Soc., 2014, 136, 10270; (k) D. Cantillo, O. de Frutos, J. A. Rincón, C. Mateos and C. O. Kappe, Org. Lett., 2014, 16, 896.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5qo00207a

---