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DOI: 10.1039/D4OB01405G (Communication) Org. Biomol. Chem., 2024, Advance Article

Visible light-mediated radical addition cascade cyclization of aryl isocyanides with tricarbonyls: rapid access to substituted phenanthridines and isoquinolines†

Sabyasachi Manna, Rahul Halanuru Sreedhara and Kandikere Ramaiah Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India. E-mail: prabhu@iisc.ac.in

Received 10th June 2024 , Accepted 29th August 2024

First published on 29th August 2024

Abstract

A visible light-mediated synthesis of substituted phenanthridines and isoquinolines from ortho-substituted aryl isocyanides and tricarbonyl compounds is unveiled via the radical addition cascade cyclization (RACC) strategy. This acid/base-free method involves an oxidant (a persulphate salt) and a Ru-photocatalyst. This protocol avoids the use of halogenated compounds as pre-functionalized carbonyl precursors. The products can be easily post-modified to other important small molecules. The functional group tolerance of the reaction and the yields of the products are good without any scalability issues. The mechanistic investigation suggested the presence of a radical pathway during the reaction.

Isocyanides are privileged motifs that are of immense importance for synthesizing a variety of classes of small nitrogen-containing organic molecules over the decades.1 The diverse reactivity of isocyanides makes them attractive synthons in synthetic organic chemistry. However, unwanted side reactions limit the utility of isocyanides in organic syntheses.2 Nevertheless, their wide use in multicomponent insertion reactions3 and in various radical reactions has gained interest in recent years.4 One of the classes of radical reactions with isocyanides is radical addition cascade cyclization (RACC) under thermal and photochemical conditions via the generation of imidoyl radicals.5a The seminal report under thermal conditions originated from the Chatani group in 2012, in which boronic acids were used to access 6-alkylated phenanthridines (Scheme 1a).5b Among the photochemical methods, the pioneering report from the Yu group in 2013 employed ortho-aryl isocyanides with a suitable alkyl bromide to synthesize 6-alkylated phenanthridines (Scheme 1b).6 Following these, several reports appeared using ortho-aryl isocyanides in radical-mediated reactions for synthesizing various substituted phenanthridines.7
image file: d4ob01405g-s1.tif
Scheme 1 Previous works and the current work.

The formation of C–C bonds at the α-position of a carbonyl group is highly desirable in synthetic organic chemistry due to their wide occurrence in natural products and easy post-modification to access various classes of organic small molecules.8 The formation of C–C bonds at the α-position of a carbonyl group by the generation of a carbon-centered radical is well explored via thermal and electrochemical methods, but similar functionalization using photocatalysis is scarce.9 In photocatalysis, usually, the use of carbonyl compounds in C–C bond formation has been achieved by employing a pre-functionalized carbonyl compound such as α-halo carbonyl.10 However, a better atom-economical approach would be to use non-functionalized carbonyl compounds to generate radicals at the α-position. Thus, the Yamaguchi group, in 2013, used non-pre functionalized carbonyl compounds in Mn-catalyzed intermolecular C–H/C–H coupling reactions with heteroarenes under thermal conditions.11 In 2017, the Itoh group used them to substitute heteroarenes under visible light conditions.12 The Loh group, in 2019, used them in a divergent C–H oxidative radical functionalization of olefins.13 In 2020, we reported the photocatalytic method for synthesizing spiro-[4,5] trieneones from aryl alkynoate and electron-poor non-prefunctionalized 1,3,3′-tricarbonyl in a radical addition cascade cyclization reaction (Scheme 1c).14a We questioned whether such an electron-poor 1,3,3′-tricarbonyl radical can be added or not to a radical acceptor such as ortho-aryl isocyanide, followed by cyclization to generate nitrogen-containing heterocycles.15 In continuation of our efforts in photocatalysis and particularly alkylation of various organic small molecules,14 herein, we report the synthesis of phenanthridines and isoquinolines from ortho-aryl isocyanide and 1,3,3′-tricarbonyl compounds under visible light-mediated conditions. To the best of our knowledge, this is the first report on the synthesis of phenanthridines and isoquinolines starting from unfunctionalized carbonyls.

We started the investigation with 2-isocyano-5-methyl-1,1′-biphenyl 1a as an ortho-aryl isocyanide and triethyl methanetricarboxylate 2a as a source of a tertiary alkyl radical under visible light (CFL) irradiation conditions. We were delighted to find the formation of the desired phenanthridine 3aa in 65% NMR yield (entry 1, Table 1) using Ru(bpy)3(PF6)2 (2 mol%) as a photocatalyst and K2S2O8 as an oxidant (2 equiv.) in CH3CN[thin space (1/6-em)]:[thin space (1/6-em)]H2O (1[thin space (1/6-em)]:[thin space (1/6-em)]1, 2 mL). The reaction furnished a slightly lower yield by changing the counter anion of the photocatalyst from fluorophosphate to chloride (62%, entry 2). Water was necessary for the reaction as the reaction did not furnish the desired product 3aa in CH3CN (entry 3). Other photocatalysts such as eosin Y and (Ir[df(CF3)ppy]2(dtbpy))PF6 failed to furnish 3aa (entries 4 and 5). When the reaction mixture was degassed with argon, the yield surged to 71% (entry 6). The undesired excited state energy transfer might have caused a lower yield in the presence of oxygen. The reaction was more facile under a blue LED (78%, entry 7). Lowering the amount of both the tricarbonyl and oxidant from 2 equiv. to 1.5 equiv. did not reduce the yield of the phenanthridine (entries 8 and 9). Decreasing the amount of tricarbonyl to 1.2 equiv. reduced the product yield to 57% (entry 10). The reaction with other oxidants resulted in either no reaction or the formation of 3aa in low yields (see the ESI for more information†). It is important to note that a photocatalyst, light, and an oxidant are necessary for the reaction to proceed (entries 11–13).

Table 1 Optimization studiesa

image file: d4ob01405g-u1.tif
Entry 2a (Equiv.) Photo-catalyst 3aab (%)
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), oxidant (0.4 mmol), PC (2 mol%), CH3CN[thin space (1/6-em)]:[thin space (1/6-em)]H2O (1[thin space (1/6-em)]:[thin space (1/6-em)]1, 2 mL) under a blue LED for 12 h.b NMR yield (using 1,3,5-trimethoxybenzene as an internal standard).c CH3CN was used instead of CH3CN[thin space (1/6-em)]:[thin space (1/6-em)]H2O.d Under a blue LED.e Reaction mixture was degassed with Ar for 15 min.f K2S2O8 (1.5 equiv.).g Reaction was performed in the dark.h Without K2S2O8.i Without a photocatalyst.
1 2 Ru(bpy)3(PF6)2 65
2 2 Ru(bpy)3Cl2 62
3 2 Ru(bpy)3Cl2 n.d.c
4 2 Eosin Y n.d.
5 2 (Ir[df(CF3)ppy]2(dtbpy))PF6 n.d.
6 2 Ru(bpy)3(PF6)2 71d
7 2 Ru(bpy)3(PF6)2 78d,e
8 2 Ru(bpy)3Cl2 76d,e,f
9 1.5 Ru(bpy)3(PF6)2 79d,e,f
10 1.2 Ru(bpy)3(PF6)2 57 f
11 2 Ru(bpy)3(PF6)2 Traceg
12 2 None n.d.h
13 2 Ru(bpy)3(PF6)2 n.d.i

With the optimized reaction conditions in hand, we next turned our attention to exploring the substrate scope of the reaction (Scheme 2). A suite of various ortho-isocyanobiaryl compounds, prepared readily from parent anilines, was subjected to the optimal reaction conditions, which furnished the respective phenanthridines in good to excellent yields. Both electron-donating (methyl) and electron-withdrawing (cyano, phenyl, and nitro) substituents in the aryl ring (Ar1) directly attached to the isocyanide moiety were well tolerated and afforded the corresponding phenanthridines in good yields (3ba–3ea). Substituents at the aryl ring Ar2, attached to aryl isocyanides, were also realized well, furnishing the corresponding phenanthridines in good yields (3fa–3na). The reaction worked well in the case of electron-donating (methyl and methoxy) and electron-withdrawing substituents (trifluoromethyl, cyano, and acetyl). The halides were also sustained without difficulty. The structure of 3fa was confirmed unambiguously through single crystal X-ray crystallography (CCDC 2344514†). Isocyanide, derived from 1-naphthylamine, was also well tolerated under the optimized reaction conditions to produce benzo[c]phenanthridine derivative 3oa in 55% yield. Isocyanides containing substituents in the aryl rings Ar1 and Ar2 were also tested under the optimal reaction conditions, which furnished the desired phenanthridines (3pa–3ra) in good to excellent yields. We were delighted that the isocyanide derived from menthol was well tolerated, affording the desired phenanthridine 3sa in excellent yield. Other tricarbonyls containing various esters under the optimal reaction conditions furnished the desired phenanthridines (3ta–3ua) in good yields. Unfortunately, diethyl 2-acetylmalonate and triethyl orthoformate failed to form the desired phenanthridines under the optimized reaction conditions. Also, unsubstituted dicarbonyls and alkyl-substituted dicarbonyls were unsuccessful in forming the desired phenanthridines.


image file: d4ob01405g-s2.tif
Scheme 2 Substrate scope for phenanthridines. Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), K2S2O8 (0.3 mmol), Ru(bpy)3(PF6)2 (2 mol%, 0.004 mmol), and CH3CN[thin space (1/6-em)]:[thin space (1/6-em)]H2O (2 mL, 1[thin space (1/6-em)]:[thin space (1/6-em)]1) under a blue LED for 12–16 h. Isolated yields.

After successfully applying our developed protocol for synthesizing phenanthridines, we decided to augment the realization of this strategy for other isocyanide systems. Recent literature reports indicated that vinyl isocyanides can be good radical acceptors for the RACC process in accessing isoquinoline derivatives.7d,f,16 We were curious about the outcome of applying our method to vinyl isocyanides. Therefore, various vinyl isocyanides derived from benzophenone derivatives were employed under the optimal reaction conditions for this purpose, and to our delight, we obtained the isoquinoline derivatives with good to excellent yields (Scheme 3). Thus, the vinyl isocyanides derived from simple benzophenone underwent annulation with tricarbonyl compounds, affording the substituted isoquinolines (4aa–4ca) in good yields. The isocyanides derived from substituted benzophenones were tolerated well under the optimal reaction conditions, producing the desired isoquinolines (4da–4ea) in excellent yields.


image file: d4ob01405g-s3.tif
Scheme 3 Substrate scope for isoquinolines. Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), K2S2O8 (0.3 mmol), Ru(bpy)3(PF6)2 (2 mol%, 0.004 mmol), and CH3CN[thin space (1/6-em)]:[thin space (1/6-em)]H2O (2 mL, 1[thin space (1/6-em)]:[thin space (1/6-em)]1) under a blue LED for 12–16 h. Isolated yields.

Notably, a gram-scale synthesis of phenanthridine 3aa was successfully carried out (61% yield), demonstrating the scalability of the methodology. The synthetic utility of the protocol was realized in successfully transforming the tricarbonylated phenanthridine 3aa into dicarbonylated phenanthridine 5aa (77% yield) by performing a retro-Claisen reaction (Scheme 4). We were delighted to be able to synthesize 2,6-dimethylphenanthridine 6aa (91% yield) from the tricarbonylated phenanthridine 3aa in the presence of LiCl and H2O via decarboxylation at an elevated temperature.


image file: d4ob01405g-s4.tif
Scheme 4 Gram-scale synthesis of phenanthridine and its synthetic utility.

Next, we were interested in understanding the mechanistic aspects of the reaction. It was observed that, under the typical reaction conditions, a dimerized product of the tricarbonyl compound formed as a by-product (Scheme 5). When 2 equiv. of the radical scavenger 2,2′,6,6′-tetramethylpiperidinooxy-1-oxyl (TEMPO) were added into the model reaction, the formation of product 3aa was entirely ceased. These observations indicate that the reaction proceeds via a radical intermediate.


image file: d4ob01405g-s5.tif
Scheme 5 Control studies.

Based on the literature6,7 and our previous study,14 we present a plausible mechanism in Scheme 6. At first, the photo-irradiation of the catalyst Ru(bpy)3(PF6)2, under visible light, produces a long-lived photoexcited *Ru(bpy)3(PF6)2. The photoexcited *Ru(II) is a strong reductant (EII*/III1/2 = −0.83 vs. SCE in MeCN/H2O = 1[thin space (1/6-em)]:[thin space (1/6-em)]1),14,17 which is capable of reducing the persulfate anion (E1/2 = 1.75 V vs. SCE),18 affording an oxidized Ru(III) species, a sulfate dianion, and a sulfate radical anion. The tricarbonyl-substituted alkyl radical A is then generated through a hydrogen-atom transfer (HAT) between 2a and the sulfate radical anion. The high acidity (pKa = 10.7 in CH3CN[thin space (1/6-em)]:[thin space (1/6-em)]H2O)14a of tricarbonyl 2a facilitates this process, and deprotonation followed by SET by a sulphate radical anion cannot be ruled out as well. This electron-deficient alkyl radical A then undergoes intermolecular addition regioselectivity to the ortho-aryl isocyanide 1a, forming an imidoyl radical B. In the next crucial step, the pendant ortho-aryl group intercepts the imidoyl radical B intramolecularly to provide the cyclohexadienyl type alkyl radical C. This alkyl radical C is then finally oxidized by Ru(III) (EIII/II1/2 = 1.29 vs. SCE in MeCN/H2O = 2[thin space (1/6-em)]:[thin space (1/6-em)]1),18 resulting in the formation of carbocation D and Ru(II), thus completing the photo cycle. The carbocation D, upon deprotonation, is then rearomatized to form the desired product E, the phenanthridine.


image file: d4ob01405g-s6.tif
Scheme 6 Plausible reaction mechanism.

In conclusion, we have developed a visible light-mediated radical-addition-cascade cyclization of ortho-aryl isocyanides with tricarbonyls to access substituted phenanthridines at room temperature. Remarkably, this tertiary alkyl motif installation strategy was successfully extended to the synthesis of isoquinolines by employing vinyl isocyanides as the radical acceptor. The functional group tolerance of this method is impressive, and the yields of the desired products are good. The tricarbonyl moiety can be transformed into the dicarbonyl moiety or into a methyl group through simple post-modification, which can effectively open the possibility of accessing a myriad of important small molecules through further post-modification. We believe these new classes of phenanthridines and isoquinolines will find applications in the synthetic world of organic chemistry and pharmaceutical chemistry.

Data availability

The crystal structure of 3fa (CCDC 2344514†) has been deposited at the Cambridge Crystallographic Data Centre.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank SERB, IISc, and Dynarx Technology India Ltd, Bangalore, for their financial support. We thank Mr Kishore Kumar Sindogi (SSCU, Indian institute of Science) for the help in X-ray crystal structure analysis.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2344514. For ESI and crystallographic data in CIF or other electronic formats, see DOI: https://doi.org/10.1039/d4ob01405g
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