C–C Bond Formation via Direct Functionalization of Indolizines with a Bichromophoric Ruthenium Photocatalyst
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C–C Bond Formation via Direct Functionalization of Indolizines with a Bichromophoric Ruthenium Photocatalyst
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ACS Organic & Inorganic Au

Cite this: ACS Org. Inorg. Au 2026, 6, 2, 225–236
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https://doi.org/10.1021/acsorginorgau.5c00110
Published February 7, 2026

Copyright © 2026 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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An unprecedented photocatalyzed radical C(sp2)–C(sp3) alkylation protocol to prepare a range of substituted 3-alkylated indolizine derivatives, mediated by 2-mercaptothiazolidinium salts as radical sources and a new dyad-like Ruthenium complex as a photoredox catalyst, under green light irradiation, resulted in yields of up to 99%. The mild, robust, and chemoselective procedure employs inexpensive, air-insensitive, and readily accessible reagents, enabling convenient synthesis of the substituted indolizines. Moreover, different N-heteroarenes, such as 1H-indoles and 2H-indazoles, were successfully alkylated under the optimized conditions. The resulting alkylated products are scaffolds with significance for drug design in medicinal chemistry.

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Introduction

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Indolizines are valuable nitrogen-containing heterocycles that own important biologically relevant properties, being indole bioisosteres. (1−3) Over the last decades, various groups have been working on indolizine synthesis and also on their late-stage functionalization. The latter has been enabled by the advent of novel technologies and the introduction of milder synthetic protocols. (4−8) However, because their biological potential is still largely unexplored, (9) efforts need to be made to further investigate their pharmacological activities and develop more versatile methods to expand their applications in medicinal chemistry and materials science.
The formation of carbon–carbon (C–C) bonds has gained increasing importance in organic synthesis, as it allows the editing and building of the carbon backbone of every organic compound. (10) Over the last decades, well-established methods such as cross-coupling reactions have been extensively employed, being considered one of the most straightforward approaches to gaining molecular complexity from simple building blocks. Specifically, preactivated electrophiles such as aryl-, vinyl-, or alkyl (pseudo)halides are coupled with organometallic nucleophiles in an elegant and economical way. The direct C–H bond functionalization strategy offers notable advantages, such as shortening a synthetic route and reducing wasteful byproducts, compared to more traditional methods. Beyond simple academic curiosity, their practical potential is increasingly recognized for industrial applications. However, one of the main drawbacks is the need for substrate prefunctionalization, which often adds additional steps to a synthetic route. (11) Therefore, the discovery of novel protocols for the direct coupling of nonfunctionalized starting materials such as heterocycles or arenes is of high importance. (12)
With the introduction of photoredox catalysis, it became possible to overcome that limit, and a door to further developments was opened. (13−16) Under very mild conditions, photoredox catalysts enable different regioselectivities, and improve functional group tolerance, and expand the scope and versatility of C(sp2)–H functionalization strategies. Within the past few years, chemists have investigated alkyl radical precursors for C–C bond formation (Figure 1). Despite their broad applicability, some of them are associated with certain issues. For instance, Katritzky salts (17) are prepared from expensive and moisture-sensitive 2,4,6-triphenylpyrylium tetrafluoroborate, while alkyl-substituted dihydropyridines (DHPs) (18) must be synthesized from expensive alkyl aldehydes, often resulting in unsatisfying yields. Conversely, 2-mercaptoimidazolium (19) or thiazolidinium (20,21) salts have recently emerged as inexpensive and bench-stable alternatives for the generation of alkyl radicals under mild photoredox conditions.

Figure 1

Figure 1. Selected known carbon-centered radical precursors for photoredox SET processes.

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Pioneering work was conducted by Zemtsov et al. (22) in 2019, in which silyl enol ethers were efficiently alkylated by employing 2-mercaptothiazolidinium salts and an iridium photocatalyst (Scheme 1a). Yields of the desired products were generally satisfactory, although in some cases 20 mol % of [Ir(dtbbpy)(ppy)2]PF6 was required, and a basic scavenger was needed to trap the silyl protecting group and generate the alkylated ketone. More recently, Tian et al. (23) in 2024 and Zhu et al. (24) in 2025 explored the reactivity of 2-mercaptothiazolidinium salts toward the synthesis of alkylated isoquinolines and indolo[2,1-a]isoquinolines, respectively (Scheme 1b–c). In both cases, the carbon-centered radicals formed in the process were coupled with electron-poor sp2 systems in a Minisci-or Giese-type fashion. The protocols were general, and no further additives were needed to achieve good yields; however, Ir-photocatalysis was still required, and a powerful blue LED setup (30 W) was employed.

Scheme 1

Scheme 1. 2-Mercaptothiazolidinium Salts as Alkyl Radical Sources
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As part of our continuous effort to develop effective photocatalysts (25−28) and methods for the direct functionalization of heterocycles, (29−31) we wanted to apply such a system for the direct alkylation of electron-rich heteroaromatic compounds, such as indolizines. Herein, we present a photocatalyzed radical C(sp2)–C(sp3) alkylation protocol to prepare a range of substituted 3-alkylated indolizine derivatives 2, mediated by 2-mercaptothiazolidinium salts as radical sources in N,N-dimethylacetamide (DMA) and a new dyad-like complex [Ru(dpp)2(dMeODPAT-Tz-bpy)](PF6)2 (PC2) as the photoredox catalyst, under green light irradiation, with up to 90% yield (Scheme 1d).

Results and Discussion

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2-Phenylindolizine-1-carbonitrile 1a was chosen as the model substrate for the optimization studies. Unlike our previous works, we found that for the presented reaction, a green LED excites the photocatalyst sufficiently. In general, a longer wavelength is always desirable, since side reactions and subsequent reactions are less likely to be promoted. Upon exploring our established photocatalyst PC1 under these conditions, we were pleased to observe the formation of the desired alkylated product 2a with 67% yield. Additionally, a secondary product, the 3,5-dialkylated indolizine 2a′ was formed in 18% yield (entry 1, Table 1). Interested by this outcome, we synthesized a series of related photocatalysts based on PC1, in which the triarylamine unit was diversely substituted (entries 2–4, Table 1). Among these, the best result was obtained by using PC2, which provided an improved yield of 2a and a higher selectivity compared to the byproduct 2a′ (entry 2, Table 1). Sterically hindered and electron-rich triarylamines, as in the case of PC3 and PC4, led to a slight switch in the selectivity in favor of the byproduct 2a′ (entries 3–4, Table 1). Common ruthenium-based photocatalysts (e.g., [Ru(bpy)3](PF6)2 and [Ru(phen)3](PF6)2) were not able to efficiently convert substrate 1a (entries 5–6, Table 1). Only [Ru(dpp)3](PF6)2 was able to fully convert the starting indolizine to product 2a, albeit in a lower yield compared to PC2 (entry 7, Table 1). Analogously, strongly reducing Ir(ppy)3 was not efficient in converting indolizine 1a, as the byproduct 2a′ was produced with 23% yield (entry 8, Table 1). 4-CzIPN, an organic photocatalyst, was not suitable for the reaction, yielding only 30% of the desired product (entry 9, Table 1). In conclusion, the designed PC2 outperformed commercially available photocatalysts listed in Table 1. No product formation was observed in the control experiment without a photocatalyst, highlighting the importance of the latter for the developed protocol (entry 10, Table 1). Ultimately, PC2 was used at 0.5 mol %, which was found to be the optimal catalyst loading. The photocatalyst was still visible after the reaction via TLC, but due to the low amount of applied photocatalyst, the latter was not isolated. Optimal radical source loading was kept at 1.5 equiv, as lower loadings did not lead to full conversion of the starting indolizine 1a (entries 11–12, Table 1). Reducing the reaction time was beneficial, as within 2 h it was possible to achieve full conversion and limited formation of 2a′, hence resembling the optimized conditions (entry 14, Table 1). By employing a weaker photocatalytic setup (i.e., 3 W vs 15 W), only 19% of the desired product 2a was isolated over 16 h of reaction time (entry 15, Table 1). This outcome highlights how the reaction kinetics are affected by the intensity of the LEDs used.
Table 1. Optimization Studies for the Synthesis of Indolizine 2ab
EntryPhotoredox CatalystRadical Source eqTimeLEDsYielda (2a: 2a′: 1a)
1PC11.53 hgreen (15 W, 515 nm)67%: 18%: 0%
2PC21.53 hgreen (15 W, 515 nm)70%: 16%: 0%
3PC31.53 hgreen (15 W, 515 nm)68%: 17%: 0%
4PC41.53 hgreen (15 W, 515 nm)60%: 20%: 0%
5[Ru(bpy)3](PF6)21.53 hgreen (15 W, 515 nm)47%: 0%: 50%
6[Ru(phen)3](PF6)21.53 hgreen (15 W, 515 nm)43%: 0%: 57%
7[Ru(dpp)3](PF6)21.53 hgreen (15 W, 515 nm)52%: 19%: 0%
8Ir(ppy)31.53 hgreen (15 W, 515 nm)59%: 23%: 0%
94-CzIPN1.53 hgreen (15 W, 515 nm)30%: 0%: 70%
10–1.53 hgreen (15 W, 515 nm)0%: 0%: 100%
11PC21.13 hgreen (15 W, 515 nm)69%: 8%: 13%
12PC21.253 hgreen (15 W, 515 nm)70%: 9%: 5%
13PC21.51 hgreen (15 W, 515 nm)67%: 9%: 9%
14PC21.52 hgreen (15 W, 515 nm)70%: 12%: 0% (isolated)
15PC21.516 hgreen (3 W, 515 nm)19%: 0%: 81%
a

Yields were determined by 1H NMR using dibromomethane as the internal standard, unless otherwise stated.

b

Values for the excited-state redox potentials in V Vs SCE were obtained according to the literature. (32)

With the optimized conditions in hand, the scope and limitations of the reaction protocol were investigated (Scheme 2). Different radical sources of T were evaluated on various substituted 2-phenylindolizines 1. Radical sources bearing an ester group, such as T1–T3, were initially applied. Consistent yields were obtained when both 2-(phenyl)indolizine-1-carbonitrile 1a and 2-phenylindolizine 1b were employed (i.e., 64–72%). In contrast, a decrease in yields was observed with indolizine-1-carboxylates 1c and 1d, with the ethyl analogue producing the lowest amount of the desired product among them. In the case of radical source T3, a secondary radical was generated: due to steric and electronic factors, only indolizine 2b-3 was recovered in 51% yield. The presence of an electron-withdrawing group on the indolizine core was found to be unfavorable, as indolizine 2a-3 was isolated with a significantly lower yield of 14%.

Scheme 2

Scheme 2. Radical Sources Substrate Scope for the Direct Radical Alkylation
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Various 1-(indolizin-3-yl)ketones were prepared by employing radical sources T4–T8. Simple acetone derivatives such as 2a-3 and 2b-3 were prepared in good yields (53% and 69%, respectively). Replacing the methyl group with a more electron-donating isopropyl group, as in T5, resulted in decreased yields of the desired product. This highlights the significant influence of electronic effects on the coupling efficiency between the radical source and the indolizine scaffold. Excellent results were achieved with acetophenone derivatives, where the substituent at the 4-position of the phenyl ring notably modulates the final product yields. Electron-withdrawing groups (e.g., CF3 in T8) enhance the formation of the alkylated indolizines, regardless of the substituent at position 1. Conversely, electron-rich phenyl rings (e.g., 4-MeOC6H4 in T7) generally diminish yields, with only indolizine 1b being able to generate product 2b-7 in a consistent yield of 62%. In this context, indolizine-1-carboxylates 1c and 1d afforded slightly lower yields compared to 1a and 1b. However, in contrast to the previous analogues, indolizine 1d outperformed the methyl derivative overall.
N,N-Dimethylacetamide derivatives were successfully isolated in good yields, starting from radical source T9. These compounds serve as promising precursors for the synthesis of potentially interesting and novel entactogens. (33,34)
Thereafter, different electron-withdrawing groups, other than a simple carbonyl on radical source T, were applied. In the case of T10, 1-(indolizin-3-yl)acetonitriles 2a-d-10 were successfully isolated in good yields, ranging from 34 to 67%. Conversely to previous results, indolizine-1-carboxylates 1c and 1d demonstrated superior yields compared to indolizine 1a. This shows how the slightly less electron-deficient 1c and 1d can be more easily coupled with a methylene radical that bears a strong electron-withdrawing group, and vice versa, according to Hammett parameters. (35)
If no electron-withdrawing group is capable of exerting a mesomeric effect (e.g., CF3 in T11) in the formed methylene radical, a decrease in yield is observed. Furthermore, for indolizine 1a, a loss of selectivity is noted, resulting in the isolation of an inseparable mixture of regioisomeric products.
As a control experiment, radical source T12 was applied under the optimized conditions. In this case, a secondary radical bearing a two-electron-donating group was generated, which successfully reacted only with substrate 1a. However, product 2a-12 was isolated in only 12% yield, indicating the need for an electron-withdrawing group on the generated methylene radical.
Successively, we proceeded to evaluate the indolizine scope under the optimized reaction conditions (Scheme 3). Unsubstituted 1H-indolizines were investigated first: yields of the desired products 2e–2i were consistent (64–77%), regardless of the substituent at position 4 of the phenyl substituent. A slightly reduced yield (59%) was observed for indolizine 2k. This decrease may be attributed to steric hindrance caused by the methoxy group at the 2-position of the phenyl ring, which likely prevents the addition of the generated radical. The protocol proved to be respectful of OH functionalities, as product 2j was isolated with 47% yield. Indolizine 1l, a bioisostere of the gastroprotective drug Zolimidine, (36) was efficiently coupled with the alkyl radical, forming product 2l in 77% yield. Heteroaromatics (e.g., thiophene) were also tolerated, as shown by the successful synthesis of product 2m, isolated in 63% yield. In contrast, further substitution of the 6-position of the indolizine core led to diminished yields, regardless of the electronic nature of the substituent on the 2-position. This trend is demonstrated by indolizine 2n isolated in 49% yield. Conversely, an improved outcome was obtained when the substituent on the 6-position was modestly electron-withdrawing (e.g., Br vs Me), as for indolizine 2o, which was obtained in 57% yield. Simple 2-methylindolizine 1p was also evaluated, resulting in the successful isolation of product 2p in a yield of 51%.

Scheme 3

Scheme 3. Indolizines Substrate Scope for the Direct Radical Alkylation
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Compared to 1H-indolizines, indolizine-1-carbonitriles showed a dependence on the electronic nature of the substituent at the 2-position. The presence of strong electron-donating methoxy substituents, regardless of the position on the phenyl ring, significantly enhanced the reaction efficiency, converting substrates 1r and 1w into the desired indolizines in 86% and 90% yields, respectively. On the other side, electron-withdrawing substituents (e.g., halogens or CF3 group) inhibit the desired pathway, affording products 2s, 2t, and 2u in 53%, 67%, and 50% yields, respectively. Simple p-tolyl or 2-thienyl substituents did not affect the reaction outcome, resulting in the formation of both products 2q and 2x in 72% yield, similar to indolizine 2a-1. An OH group was well tolerated, as shown for product 2v, which was isolated with a higher yield compared to its 1H-indolizine analogue 2j (i.e., 68% vs 47% yield). Conversely, attaching an ethyl ester group at the 2-position of the indolizine core improved the yield of the desired product, with compound 2y isolated in 45% yield, albeit this was lower than in previous examples of 2-phenylindolizine-1-carbonitriles. In the case of indolizine-1-carbonitrile 1z, the absence of any substituent on the 2-position led to a decreased yield and a loss in selectivity. Product 2z was isolated in 30% yield as an inseparable 1:2 mixture of the desired 3-alkylated and 5-alkylated products.
Indolizine-1-carboxylates were further investigated under the optimized conditions. Generally, as previously stated, methyl indolizine-1-carboxylates were higher yielding compared to their ethyl analogues, as shown for products 2aa and 2ag, isolated with 58% and 43% yields, respectively. In contrast to these findings, the introduction of a CF3 group at the 4-position of the phenyl ring─with respect to indolizine 1c─resulted in no significant change in the overall yield. Specifically, indolizine 2ab was obtained in 46% yield, comparable to 47% for 2c-1. The presence of a 2-thienyl substituent on the 2-position proved to be beneficial for the yields, compared to the phenyl derivatives 2c-1 and 2d-1, as products 2ac and 2ah were isolated in 75% and 69% yield, respectively. Similarly, the absence of an aromatic substituent at the 2-position led to only a slight reduction in yield, with methyl 2-methylindolizine-1-carboxylate 1ad affording the desired product in 53% yield. For indolizine-1,2-carboxylates, a clear trend was observed: higher yields were obtained with increasing numbers of methyl ester groups on the indolizine core. Specifically, desired products 2ae and 2af were isolated in yields of 42% and 37%, respectively. Ethyl indolizine-1-carboxylate 1ai was also coupled with the radical source T1. Remarkably, similar to product 2z, no selectivity was noted between the 3- and 5-positions on the indolizine core, resulting in an inseparable mixture of regioisomers that was isolated in 28% yield.
1-Sulfonylindolizines proved to be challenging substrates under the optimized conditions. Regardless of the substituents present at both the 1- and 2-positions, the reactions consistently yielded comparable results, with product yields ranging from 40% to 44% for compounds 2aj–2am. The desired products were invariably obtained as a mixture with their corresponding 5-alkylated regioisomers, indicating limited regioselectivity under the current conditions. Notably, indolizine 1an was the only case exhibiting reversed regioselectivity, with the 5-alkylated indolizine emerging as the major product. This outcome can be attributed to steric effects, as the isopropyl group at the 2-position hinders radical insertion at the 3-position, directing the reaction toward the 5-position. Further functionalization of the indolizine core at the 7-position with a methoxy group significantly enhanced both yield and regioselectivity. Thus, products 2ao and 2ap were obtained with improved yields (48% and 63%, respectively) as single regioisomers, in contrast to previous examples.
As a key motif for the synthesis of novel organic fluorophores, (37) indolizino[1,2-c]quinolin-6(5H)-one 1aq was also investigated under the optimized conditions. The targeted compound 2aq was successfully isolated in a satisfactory yield of 62%. 1-Phenyl-2-(trimethylsilyl)indolizine 1ar yielded an interesting outcome: although the isolated yield of 2ar was modest (i.e., 21%), no TMS group was detected on the indolizine core after the reaction. The latter suggests a potential limitation in the protocol’s tolerance for certain functional groups. Another limitation was highlighted with the reaction of simple indolizine 1as, as the desired product was obtained with a scarce 6% yield. This outcome points out the fact that substitution at either the 1- or 2-position is necessary for the reaction to occur efficiently.
To summarize, electronic factors mainly govern the addition of the generated electrophilic radicals to the indolizine core. The 3-position is the primary site of alkylation in indolizines featuring a higher electron density on the five-membered ring. The presence of strong electron-withdrawing substituents at positions 1 or 2, or the absence of a substituent at position 2, diminishes the selectivity by promoting the formation of 5-alkylated products. This shift occurs due to a redistribution of electron density toward the six-membered ring and the inability to stabilize a carbocation intermediate (as shown for INT-III in Scheme 10). Therefore, careful selection between the generated radical and indolizine electronic properties is crucial for optimizing reaction outcomes.
To assess the generality of our designed protocol, different N-heteroarenes were subjected to the optimized reaction conditions (Scheme 4). Like indolizines, indazoles are important nitrogen-containing aromatic compounds that play a crucial role in the field of pharmaceutical chemistry because of their wide range of biological activities. (38) 2-(4-Methoxyphenyl)-2H-indazole 1at was successfully coupled with radical source T1, yielding compound 2at in 44% yield. A higher yield was obtained when the N-heteroarene substrate was a protected tryptophan 1au: chemoselective C2 functionalization was achieved in a 71% yield. Because of its intrinsic simplicity and excellent functional group tolerance, our protocol is well-suited for the selective late-stage functionalization of more complex peptides. (39)

Scheme 4

Scheme 4. Substrate Scope of N-Heteroarenes
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The versatility of the developed protocol was demonstrated through a 2.0 mmol-scale experiment, yielding indolizine 2a in 69% under optimized conditions (Scheme 5). Notably, the reaction time required extension from 2 to 6 h, as only 27% of product 2a was isolated after the initial 2-h period.

Scheme 5

Scheme 5. Reaction Scale-Up
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Zolpidem was the first imidazo[1,2-a]pyridine drug to enter the market in 1992 and is used to treat insomnia. (40) Despite its interesting pharmacological profile, its preparation requires multiple synthetic steps and the use of toxic reagents, such as SOCl2 to install the amide functional group. (41) Indolizines are recognized as bioisosteres of imidazo[1,2-a]pyridines. (42) Given their relevance in medicinal chemistry, (1) we efficiently synthesized compound 2av-9 within a one-step procedure, achieving a synthetically useful yield of 53% (Scheme 6).

Scheme 6

Scheme 6. One-Step Synthesis of Zolpidem Bioisostere
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Numerous imidazo[1,2-a]pyridines have been reported to exhibit antitubercular (anti-TB) activity. (43,44) In 2022, Khetmalis et al. developed a series of new anti-TB drugs by tethering imidazo[1,2-a]pyridines to tetrahydropyridines, demonstrating promising biological activity. (45) Inspired by these findings, we developed a new approach, starting from indolizine 1o, to synthesize a functionalized bioisostere of a key anti-TB precursor. After preparing the desired intermediate 2o, its efficient Suzuki coupling with the corresponding tetrahydropyridine derivative led to compound 3 with 90% yield (Scheme 7).

Scheme 7

Scheme 7. Synthesis of a Precursor for an Anti-TB Agents Bioisostere from 2o
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To showcase the synthetic versatility of the installed 2-methoxy-2-oxoethan-1-yl (−CH2CO2Me) group, indolizine 2a was subjected to a series of further modifications. Initially, deprotonation of the activated methylene unit with a strong base, such as sodium hydride (NaH) enabled electrophilic trapping with 4-acetamidobenzenesulfonyl azide (p-ABSA), resulting in compound 4a (Scheme 8a). This intermediate can be readily transformed into the corresponding ketone or reduced to synthesize a nonnatural α-amino acid. When an electrophile such as a haloalkane─specifically 1,4-dibromobutane─is employed, compound 4b is prepared with 73% yield (Scheme 8b). Additionally, indolizine 2a can participate in a Knoevenagel-type reaction with aldehydes; for our purposes, we utilized a Fluvastatin precursor, leading to the formation of compound 4c (Scheme 8c). Indolizine 4c, given its extended π-system, showed interesting spectroscopic properties. When the same optimized conditions are applied to indolizine 2a, the formation of compound 2a′ was observed in good yield (Scheme 8d).

Scheme 8

Scheme 8. Derivatization of Indolizine 2a
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Upon selective hydrolysis of the ester functionality of indolizine 2a, compound 4d was produced in quantitative yield (Scheme 9a). The free carboxylic acid group in compound 4d can be easily coupled with a variety of nucleophiles by means of the DCC/DMAP system (Scheme 9b). When N,O-dimethylhydroxylamine was employed, Weinreb amide 5a was produced in 93% yield; these intermediates are particularly useful for the synthesis of other carbonyl compounds, such as ketones, when treated with organometallic compounds. (46) The amino group of the potent entactogen drug MDA (47,48) was also coupled with 4d, yielding compound 5b in good yield. Lastly, the coupling between the naturally occurring monoterpenoid (2S,5R)-menthol and indolizine 4d produced ester 5c in quantitative yield.

Scheme 9

Scheme 9. Derivatization of the Carboxylate Moiety
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Based on our previous work (29,30) and other literature reports, (49−51) a plausible reaction mechanism for the indolizine photocatalytic radical C(sp2)–C(sp3) alkylation can be proposed (Scheme 10). First, photoredox catalyst PC2 is excited (from Ru2+ (L1) to Ru2+ *(L1) upon green light irradiation). The interaction between Ru2+ *(L1) and the radical source T1 (Ep = −0.91 V vs SCE) can generate the alkyl radical via Single-Electron-Transfer (SET), because of the higher reducing power of PC2 (E0 [Ru2+ (L1)•+/Ru2+ *(L1)] = −1.22 V vs SCE), following C–S bond fragmentation through a β-scission process (INT-I). This latter generates a molecule of 3-methylthiazolidine-2-thione as a byproduct, alongside the desired alkyl radical. The formed radical can be intercepted by indolizine 1 to produce INT-II. The resulting radical species can then be oxidized by Ru2+ (L1)•+ to carbocation INT-III, as the reduction potential of the oxidized catalyst is sufficiently high (E0 [Ru2+ (L1)•+/Ru2+ (L1)] = +0.69 V vs SCE). This process regenerates the catalyst and closes the photoredox cycle. Ultimately, a proton is readily abstracted from INT-III, thereby restoring aromaticity and yielding the desired product 2. Additionally, a competitive radical pathway such as a radical chain process cannot be ruled out, as the initial irreversible quenching appears to be the limiting factor for the overall quantum yield. The latter is consistent with the relatively long irradiation time that implies a low overall quantum yield (i.e., well below 10%), suggesting that all photons are absorbed at the given catalyst loading, but the reaction time is relatively long with the high-power LEDs. (30)

Scheme 10

Scheme 10. Proposed Reaction Mechanism
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Conclusion

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In summary, a mild, robust, and chemoselective protocol for the radical C(sp2)–C(sp3) alkylation of indolizines has been established. The reaction employs inexpensive, air-insensitive, and readily accessible reagents, enabling the convenient synthesis of substituted indolizines, which can be further used as scaffolds for drug design in medicinal chemistry. The protocol has proven to be general and can be scaled up to gram-scale without significant loss in yields. Moreover, different N-heteroarenes, such as 1H-indoles and 2H-indazoles, have been successfully alkylated under the optimized conditions.

Experimental Section

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General Experimental

All reactions were carried out under an atmosphere of nitrogen in oven-dried glassware, unless otherwise stated. All reactions that required heating were conducted by using a steel heat-on block. All chemicals were purchased and used without further purification unless otherwise mentioned. Anhydrous solvents were dried according to standard procedures before use and stored in a glovebox. All NMR-spectra spectra were measured using either BRUKER Digital AVANCE 400 MHz FT-NMR or BRUKER Digital AVANCE III 600 MHz FT-NMR. Chemical shifts are reported in ppm, and the coupling constants in Hz. All mass spectra were measured using a Hewlett-Packard Agilent LC/MSD-System Series HP 1100 with API-ES, and the detector is TOF. All UV–vis spectra were measured using a JASCO V-650 spectrophotometer or a JASCO V-760 spectrophotometer. The reactions were traced by thin-layer chromatography with silica gel 60 (F254, MERCK KGAA). For the detection of substances, quenching was used at either 254 or 366 nm with a UV lamp. Preparative column chromatography was conducted through silica gel 60 (230–400 mesh).
All cyclic voltammetry experiments were performed in 0.1 M [Bu4N][PF6] MeCN solution with an Autolab PGSTAT204 potentiostat/galvanostat (Metrohm). A cell with a three-electrode configuration was used. The glassy carbon working electrode (d = 2 mm) was polished before each measurement with a 0.03 μm Al2O3 slurry and then rinsed thoroughly with deionized water and MeCN. A platinum sheet was used as the counter electrode, while the reference electrode was Ag/AgCl (3.0 M KCl). The measurements were performed at a temperature of 22 °C under a nitrogen atmosphere after the solutions were bubbled with the same gas for 10 min. A prebubbler was also included in the experimental setup to prevent excessive evaporation of the solvent. The IUPAC plotting convention was used to plot the voltammograms. The initial potential was set to 0.0 V, and the scan proceeded in the oxidation direction up to the potential shown in the plot.
Reactions were performed in closed vials, illuminated from below with five Avonec 3 W High Power LEDs (https://www.avonec.de/3w-high-power-led/) affixed to a cooling block, and the setup was prevented from heating through a continuous airflow, as depicted in Figure S1. No filters were used during the irradiation process. The emission spectrum of the green LEDs used is shown in Figure S2.

General Procedure for the Photoredox Experiments

General Procedure A

In a glovebox, to a vial filled with indolizine 1 (0.20 mmol, 1.00 equiv), radical source T (0.30 mmol, 1.50 equiv), and PC2 (1.6 mg, 1.0 μmol, 0.5 mol %), DMA (0.4 mL, 0.50 M) was added. The vial was sealed, and the mixture was irradiated with green LEDs (15 W, 515 nm) for 2 h at rt outside of the glovebox. The reaction mixture was partitioned between H2O and Et2O, and the organic phase was extracted. The water phase was extracted with Et2O 3 times, and the combined organic phases were washed with H2O and brine. The organic phase was dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the functionalized product 2.

General Procedure B

In a glovebox, to a vial filled with indolizine 1 (0.20 mmol, 1.00 equiv), radical source T (0.30 mmol, 1.50 equiv), and PC2 (1.6 mg, 1.0 μmol, 0.5 mol %), DMA (0.4 mL, 0.50 M) was added. The vial was sealed, and the mixture was irradiated with green LEDs (15 W, 515 nm) for 2 h at rt outside of the glovebox. The reaction mixture was partitioned between H2O and Et2O, and the organic phase was extracted. The water phase was extracted with Et2O 3 times, and the combined organic phases were washed with H2O and brine. The organic phase was dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the functionalized product 2, alongside the byproduct of the reaction, as an inseparable mixture. The mixture was dissolved in DCM/Et2O (0.25 M, 1:1), and an excess of methyl iodide (0.90 mmol, 3.0 equiv) was added. The resulting mixture was stirred for 3 h at 40 °C, after which the solvent was evaporated in vacuo. The residue was suspended in Et2O, the precipitated solid was filtered, washed with Et2O, and the filtrate was collected and concentrated in vacuo, yielding the desired product 2.

General Procedure C

In a glovebox, to a vial filled with indolizine 1 (0.20 mmol, 1.00 equiv), radical source T (0.22 mmol, 1.10 equiv), and PC2 (1.6 mg, 1.0 μmol, 0.5 mol %), DMA (0.4 mL, 0.50 M) was added. The vial was sealed, and the mixture was irradiated with green LEDs (15 W, 515 nm) for 2 h at rt outside of the glovebox. The reaction mixture was partitioned between H2O and Et2O, and the organic phase was extracted. The water phase was extracted with Et2O 3 times, and the combined organic phases were washed with H2O and brine. The organic phase was dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the functionalized product 2.

General Procedure D

In a glovebox, to a vial filled with indolizine 1 (0.20 mmol, 1.00 equiv), radical source T (0.22 mmol, 1.10 equiv), and PC2 (1.6 mg, 1.0 μmol, 0.5 mol %), DMA (0.4 mL, 0.50 M) was added. The vial was sealed, and the mixture was irradiated with green LEDs (15 W, 515 nm) for 2 h at rt outside of the glovebox. The reaction mixture was partitioned between H2O and Et2O, and the organic phase was extracted. The water phase was extracted with Et2O 3 times, and the combined organic phases were washed with H2O and brine. The organic phase was dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the functionalized product 2, alongside the byproduct of the reaction, as an inseparable mixture. The mixture was dissolved in DCM/Et2O (0.25 M, 1:1), and an excess of methyl iodide (0.66 mmol, 3.0 equiv) was added. The resulting mixture was stirred for 3 h at 40 °C, after which the solvent was evaporated in vacuo. The residue was suspended in Et2O, the precipitated solid was filtered, washed with Et2O, and the filtrate was collected and concentrated in vacuo, yielding the desired product 2.

Data Availability

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The data underlying this study are available in the published article and its Supporting Information.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsorginorgau.5c00110.

  • Full experimental description, spectral data of the compounds, and additional spectroscopy data (PDF)

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Author Information

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  • Corresponding Author
  • Author
  • Author Contributions

    K.K.S. performed the radical C(sp2)–C(sp3) alkylation of indolizines and synthesized and characterized the Ru(II) complexes (i.e., PC1–4). R.W. supervised each part of the project and wrote the manuscript with contributions from all the authors. All authors have given approval of the final version of the manuscript.

  • Notes
    The authors declare no competing financial interest.

References

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This article references 51 other publications.

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  • Abstract

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    Figure 1

    Figure 1. Selected known carbon-centered radical precursors for photoredox SET processes.

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    Scheme 1

    Scheme 1. 2-Mercaptothiazolidinium Salts as Alkyl Radical Sources
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    Scheme 2

    Scheme 2. Radical Sources Substrate Scope for the Direct Radical Alkylation
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    Scheme 3

    Scheme 3. Indolizines Substrate Scope for the Direct Radical Alkylation
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    Scheme 4

    Scheme 4. Substrate Scope of N-Heteroarenes
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    Scheme 5

    Scheme 5. Reaction Scale-Up
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    Scheme 6

    Scheme 6. One-Step Synthesis of Zolpidem Bioisostere
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    Scheme 7

    Scheme 7. Synthesis of a Precursor for an Anti-TB Agents Bioisostere from 2o
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    Scheme 8

    Scheme 8. Derivatization of Indolizine 2a
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    Scheme 9

    Scheme 9. Derivatization of the Carboxylate Moiety
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    Scheme 10

    Scheme 10. Proposed Reaction Mechanism
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  • References

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