Abstract
Photo-mediated radical dearomatization involving 5-exo-trig cyclizations has proven to be an important route to accessing spirocyclic compounds, whereas 6-exo-trig spirocyclization has been much less explored. In this work, a dearomative annulation cascade is realized through photoredox-mediated C–O bond activation of aromatic carboxylic acids to produce two kinds of spirocyclic frameworks. Mechanistically, the acyl radical is formed through oxidation of triphenylphosphine and subsequent C–O bond cleavage, followed by a 6-exo-trig cyclization/SET/protonation sequence to generate the spiro-chromanone products in an intramolecular manner. Furthermore, the protocol was extended to more challenging intermolecular tandem sequences consisting of C–O bond cleavage, radical addition to an alkene substrate, and 5-exo-trig cyclization to yield complex spirocyclic lactams.
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Introduction
Over the past decades, diversity-oriented synthesis (DOS) has evolved to yield a number of strategies for increasing the diversity and complexity of pharmaceutically relevant molecules1,2,3,4,5. Among these, increasing the content of quaternary carbon centers is regarded as a prime tool for increasing the three-dimensionality of potential drug candidates. An attractive strategy for creating three-dimensionality is through introduction of spiro centers, which are ring systems that have two rings linked together by one common atom6,7,8. Several commercially available drugs, including grisefulvin, buspirone, and spironolactone, contain such spirocyclic motifs (Fig. 1a)9,10,11. A number of synthetic protocols have been established for efficient construction of spirocyclic compounds12,13, among which dearomative spirocyclization offers a particularly straightforward route to spiro-compounds with a minimal number of synthetic steps14,15. Although ipso-annulation towards spirocycles has mainly focused on transition metal-catalyzed, electrophilic or nucleophilic dearomatization reactions15, radical pathways have gained increased attention16, promoted by the recent developments in radical chemistry17.
a Examples of spiro-containing pharmaceuticals. b Different strategies for light-mediated dearomative radical spirocyclization. c This work: spirocyclization via C–O bond activation of carboxylic acids.
Visible light-promoted photocatalysis is a sustainable and versatile synthetic tool18,19,20, which has recently revitalized the radical-mediated dearomatization manifolds aiming at accessing spirocyclic compounds16,21,22. The related synthetic strategies presented to date can be divided into direct strategies proceeding through radical ipso-cyclization23,24,25,26,27,28,29,30,31,32,33 and cascade strategies, where radical ipso-cyclization is preceded by radical addition reactions (Fig. 1b)34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49. Examples of the first category include photocatalytic manifolds developed by Wang and co-workers25,26,27, which allow accessing spiro γ-lactam indoline derivates through sequential radical dearomatization/hydroxylation, followed by either oxidation or nucleophilic substitution. In several related systems disclosed by Samec29, Cho30, and Cariou groups31, photooxygenation provides access to spirolactone, spiroazalactam and spirolactam cyclohexadienone products with molecular oxygen as the terminal oxidant. These reactions proceed via 5-exo-trig cyclization of carboxylate, iminyl, and N-amide radicals. Additionally, Jui and coworkers reported hydroarylation32 and hydroalkylation33 of arenes to construct spirocyclohexadiene skeletons through a reductive radical-polar crossover mechanism, in which aryl or alkyl radicals derived from aryl- and alkyl halides trigger regioselective 5-exo-trig radical spirocyclization. The second class of spirocyclization reactions involves visible light-promoted cascade radical addition and sequential radical ipso-cyclization reactions, which provide access to a range of spirocyclohexadienones34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49. In these sequential radical additions between diverse radicals, including alkyl34,35,36,37,38,39,40,41,42,43, acyl44, aryl radicals45, selenium-46,47, and sulfur-centered radicals36,48,49, as well as carbon-carbon double or triple bonds, the spirocyclohexadienones are formed via 5-exo-trig cyclization and hydroxylation/oxidation. Most of these photo-mediated radical dearomatization manifolds involve 5-exo-trig cyclizations, while 6-exo-trig cyclization manifolds are less explored, and the target products are mostly spirocyclohexadienones rather than spirocyclohexadienes. These limitations are mainly due to the challenges in controlling the generation of radicals and the subsequent selective cyclization16, and therefore, it is essential to develop new visible light-promoted routes to spirocyclic compounds, especially via 6-exo-trig spirocyclization.
Design plan
Acyl radicals generated from the corresponding aldehydes, acyl chlorides, and other precursors are important building blocks for the construction of carbonyl compounds50 and have been applied widely in the visible-light photocatalysis51,52. However, the direct generation of acyl radicals from readily available benzoic acids is largely unexploited due to the limitation of convenient catalytic systems53,54,55,56,57,58,59. In our reaction design, we aimed at utilizing the acyl radical as the key radical intermediate, generated from aromatic carboxylic acids, to form two different spirocyclohexadienes via both direct and indirect routes (Fig. 1c). As shown in the reaction design (Fig. 2), triphenylphosphine is oxidized by the excited iridium photocatalyst to the triphenylphosphine cation-radical via single-electron transfer. The triphenylphosphine cation-radical reacts with the deprotonated aromatic acid 1 to form the adduct 2, which undergoes β-selective C(acyl)–O bond cleavage, forming the acyl radical 3 concomitant with the loss of triphenylphosphine oxide. The acyl radical undergoes 6-exo-trig spirocyclization via dearomatization of the aromatic ring, leading to the cyclohexadienyl radical 4a. Finally, one-electron reduction yields the cyclohexadienyl anion, which is further protonated to give the chromanone-based spiro compound 5a (Path A, Fig. 2). An alternative approach to access spiro compounds via the acyl radical is to trap the acyl radical by a somophile leading to a new α-carbonyl radical that can undergo dearomative spirocyclization. In our alternative reaction design, the acyl radical 3, derived from benzoic acid 1, participates in radical addition to N-benzyl-N-(tert-butyl)acrylamide 6a to afford α-carbonyl radical intermediate 7a. This radical undergoes 5-exo-trig cyclization to yield a new cyclohexadienyl radical 8a that upon one-electron reduction and protonation provides the desired spirolactam 9a (Path B, Fig. 2).
Proposed photocatalytic cycle for intramolecular (Path A) and intermolecular (Path B) construction of spiro-compounds.
Results and discussion
Optimization of the reaction conditions
In order to investigate the feasibility of the envisioned transformation, the spirocyclization reaction was first attempted with 2-(benzyloxy)benzoic acid 1a and triphenylphosphine. After an extensive screening of the reaction conditions (Table 1 and Supplementary Tables 1–4), we were delighted to find that the desired spirocyclic product 5a was furnished in 66% yield under visible light irradiation (440 nm LEDs) in the presence of an iridium-based photocatalyst (Table 1, entry 1). The use of aqueous acetonitrile (CH3CN/H2O, 85:15 vol%) as the solvent was found to be pivotal for achieving the desired transformation (Supplementary Tables 1 and 2). In the absence of water or with an increased content of water (up to 50 vol%) a significant decrease in yield was observed (Table 1, entries 2 and 3, respectively). The use of alternative Ir-based or organic photocatalysts, including 4DPAIPN and 3DPAFIPN (Table 1, entries 4 and 5, respectively, and Supplementary Table 1), led to deteriorated yields of the desired product.
The screening of various inorganic and organic bases identified tribasic potassium phosphate as the optimal base for the reaction (Table 1, entries 6–8 and Supplementary Table 2). Furthermore, the use of an excess of triphenylphosphine (1.5 equiv.) was shown to increase the yield of the desired product (Table 1, entry 9 and Supplementary Table 3). In the absence of either light irradiation or photocatalyst, no conversion of the starting material was observed (Table 1, entry 10).
Investigation of the substrate scope
Using the optimized reaction conditions (Table 1), we explored the generality of the developed photochemical transformation. As illustrated in Fig. 3., a range of substituted 2-(aryloxy)benzoic acids were shown to engage in the radical-mediated dearomative spirocyclization to provide the corresponding spiro-chromanones. The reaction proved efficient for 2-(benzyloxy)benzoic acids that bear electron-neutral or electron-rich substituents at the carboxylate-functionalized aromatic ring. Accordingly, the substrates equipped with methoxy (5b, 5f, 5g), methyl (5c), phenyl (5d) and acetamide (5e) groups provided the expected products in generally good yields (5b–5g, 65–75%), except for the substrate with a methoxy-group at the ortho-position (5h, 15%). The substrates featuring electron-withdrawing substituents at the carboxylate-functionalized aromatic ring, including chloro (5i), bromo (5k) and acyl groups (5j), provided the corresponding products in consistently lower yields (5i–5k, 23–31%). Next, substrates with various substituents at the benzyloxy functionality were investigated. Halogenated substates featuring fluoro (5l, 5m) and chloro groups (5n) were well-tolerated and provided the expected spirocyclic products for both ortho- (5l, 45%) and meta-substituted (5m, 5n, 63–73%) substrates. Here, competitive dehalogenation was not observed, providing products with handles for further functionalization of vinylic motifs. Introducing methyl (5p) or methoxy groups (5q) at the meta-position of the benzyloxy ring was also well-tolerated (5p, 5q, 70–74%), while a CF3-functionalized substrate provided the desired product in lower yield (5o, 30%). The related disubstituted substrates bearing methyl (5r) and methoxy groups (5s), as well as a naphthalene functionality (5t) furnished the desired products in good yields (5r–5t, 58–78%). Unfortunately, para-substituted substrates, including 4-fluoro, 4-methyl, and 4-pyridinyl substrates (see Supplementary Table 6) did not provide the desired products. Furthermore, a Boc-protected aniline-derived substrate provided the corresponding N-heterocyclic spiro product, albeit in low yield (5u, 23%), while other linkers (aliphatic, thioether, amide, amino, see Supplementary Table 6) showed poor or no reactivity. In reactions with lower yields, e.g., with benzoic acids 1j and 1i, the reaction mixture after 36 h consisted of unreacted starting material (30% and 27%, respectively) together with trace amount of the aldehyde side product as determined by 1H NMR spectroscopy. The radical-mediated dearomative spirocyclization protocol was also successfully applied to pharmaceutically relevant molecules. The substrate derived from diflunisal60—a salicylic acid derivative with analgesic and anti-inflammatory properties—engaged in the spirocyclization reaction to provide the corresponding product in 56% yield (5v).
Reaction conditions: carboxylic acid (0.3 mmol, 1 equiv.), triphenylphosphine (1.5 equiv.), K3PO4 (1 equiv.), [Ir(dF(CF3)ppy)2(dtbbpy)](PF6), (1 mol%) CH3CN/H2O (85:15 vol%, 6 mL), N2, blue LEDs (440 nm), 36 h, fan cooling (35–40 °C). Further derivatization of products 5a and 5s were performed under the following conditions: (i) NaBH4, MeOH, 0 °C, 2 h; (ii) MeMgBr, THF, 0 °C, 16 h; (iii) H2, Pd/C, MeOH, 12 h; (iv) H2, Pd/C, MeOH, 60 h; (v) TFA, CH2Cl2, 16 h.
Similarly, the substrate functionalized with (R)-(+)-1-phenylethanol was converted to the corresponding spiro-chromanone in 47% yield with the stereogenic center being intact (5w, see Supplementary Figs. 93, 94). The synthetic utility of the developed protocol was demonstrated by upscaling two of the model reactions and subsequent conversion of the resulting products into a range of spirocyclic derivatives (Fig. 3, bottom). To our delight, increasing the scale of the reaction (from 0.3 mmol to 4 or 5 mmol) provided the expected products 5a and 5s in 63% and 75% yields, respectively, that is with nearly identical efficiency compared to the smaller-scale reactions. The carbonyl group in spiro-chromanone 5a was efficiently reduced to the corresponding secondary alcohol with NaBH4 (5aa, 91%) or converted to the corresponding methyl alcohol with MeMgBr (5ab, 82%), while preserving the 1,4-diene functionality. In contrast, hydrogenation of compound 5a with hydrogen over Pd/C resulted in facile reduction of the 1,4-diene moiety. In this reaction, concomitant selective hydrogenation of the carbonyl group to the secondary alcohol was observed at shorter reaction times (5ac, 70%), while at longer reaction times the initially formed alcohol functionality undergoes reductive deoxygenation to yield a completely saturated product (5ad, 69%). In addition, the trimethoxy-substituted spiro-chromanone (5s) was readily converted to cyclohexenone derivative 5sa in 93% yield upon treatment with trifluoroacetic acid.
The key mechanistic aspects of the developed transformation were elucidated by a series of experiments (Fig. 4). First, efficient quenching of Ir-based photocatalyst by triphenylphosphine was confirmed through fluorescence quenching studies (Fig. 4a, KSV = 965 M–1), while no appreciable quenching was observed for the starting material (1a and deprotonated 1a, KSV = 11 and 13 M–1, respectively). A slightly increased quenching was observed for the product 5a and the triphenylphosphine oxide (KSV = 50 and 42 M–1, respectively).
a Fluorescence quenching of [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (15 µM) by PPh3 and other reaction components (1a, deprotonated 1a, 5a, and Ph3PO) in MeCN/H2O (85:15 vol%). b Control experiments with substrate 1a with radical traps (TEMPO and 1,1-diphenylethylene) and different deuterated solvents.
Addition of an excess of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) to the reaction mixture under standard conditions completely inhibited formation of the spirocyclic product (Fig. 4b), supporting the free-radical nature of the developed transformation. Furthermore, formation of the proposed acyl radical intermediate was confirmed by a trapping experiment with an excess of 1,1-diphenylethylene. As evident from the distribution of cyclic and linear products in this reaction (4:1 cyclic/linear), intermolecular trapping of the acyl radical by 1,1-diphenylethylene easily outcompetes the intramolecular spirocyclization step under the employed reaction conditions. Finally, deuterium labeling experiments with CD3CN/H2O or CH3CN/D2O as the solvents firmly support that the terminal step of the developed reaction proceeds through one-electron reduction of the spirocyclic C-radical intermediate, followed by protonation of the formed carbanion.
Subsequently, we investigated the feasibility of the developed protocol for synthesis of spiro-lactams through a related intermolecular mechanism. This reaction was envisioned to proceed through intermolecular addition of the photochemically-generated acyl radical to a N-benzyl-N-(tert-butyl)acrylamide somophile, followed by intramolecular spirocyclization of the formed C-radical intermediate. It has previously been shown that the tert-butyl group is beneficial to achieve spirocyclizations on the benzyl ring33, but the tert-butyl group can easily be removed under mild conditions using copper(II) triflate61. This transformation was expected to pose a significant challenge, as the high-energy acyl radical must undergo addition to a somophile in an intermolecular fashion, while outcompeting deleterious HAT and SET processes, that are less pronounced in the complementary intramolecular reaction. To our delight, the optimized conditions were readily applicable for the proposed intermolecular spirocyclization reaction (Tables S4 and S5), and its scope was evaluated on a range of benzoic acid and acrylamide derivatives (Fig. 5). Benzoic acids featuring substituents at the para-position, including methyl (9b), methoxy (9c) and fluoro substituents (9d), readily engaged in the reaction to deliver the corresponding spirocyclic lactams in reasonable yields (9a–9d, 61–68%). For benzoic acids having a more electron-withdrawing substituent, such as 4-chlorobenzoic acid, the target product was obtained in lower yield (9e, 46%). Trisubstituted benzoic acids equipped with methoxy (9f) and methyl groups (9g) were efficiently converted to the corresponding spirocyclic products (9f, 9g, 65–68%). The heterocycle-containing 2-furoic acid was also tolerated, albeit providing the desired product in relatively low yield (9h, 35%). With respect to acrylamide acceptors with 4-methoxybenzoic acid as the acyl radical donor, the more sterically encumbered 2,6-dimethyl substituted somophile displayed poor reactivity (9i, 27%), while the electron-rich 3,5-dimethoxy substituted somophile provided the desired product in high yield (9j, 81%). Adapalene (9k), a third-generation topical retinoid primarily used in the treatment of acne, psoriasis, and photoaging62, delivered the expected spirocyclic product in reasonable yield (9k, 48%), highlighting the applicability of the disclosed protocol for late-stage modification of complex biologically relevant compounds.
Reaction conditions: carboxylic acid (0.2 mmol, 1 equiv.), acrylamide acceptor (2 equiv.), triphenylphosphine (2 equiv.) K3PO4 (1 equiv.), [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (1 mol%), CH3CN/H2O (85:15 vol%, 4 mL), N2, blue LEDs (440 nm), 48 h, fan cooling (35–40 °C). acarboxylic acid (2 equiv.), acrylamide acceptor (0.2 mmol, 1 equiv.).
Furthermore, the mechanism of the developed transformations was investigated using density functional theory (DFT) calculations at the B3LYP/6-311+G(d,p)-D363,64,65,66 level of theory in combination with the Polarizable Continuum Model (CPCM, UFF, acetonitrile)67,68 as implemented in Gaussian 16 (Revision B.01)69. The photocatalytic generation of triphenylphosphinyl cation-radical was previously investigated by Xie, Zhu, and coworkers70. In their calculations, photoexcitation of [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) was found endergonic by 58.0 kcal mol–1, while the following SET between the excited-state photocatalyst and Ph3P is exergonic by 0.8 kcal mol–1 with nearly null energy barrier (0.01 kcal mol–1). According to our calculations, deprotonation of carboxylic acid 1a by K3PO4 to yield the potassium carboxylate 1a-K was found highly exergonic, while the following replacement of the potassium cation by the triphenylphosphinyl cation-radical leads to the ionic complex 1a-PPh3 of similar free energy (lowered by 0.1 kcal mol–1, Fig. 6). For this complex, the spin density of the cation-radical is localized almost exclusively on the phosphorus atom. In the following step of the reaction, formation of a covalent P–O bond between the phosphinyl radical cation and the carboxylate is accompanied by a spin density shift from the phosphorous center to the aromatic ring of the formed radical intermediate Int-2, which is less stable compared to the ionic intermediate 1a-PPh3 by 8.5 kcal mol–1. Subsequently, intermediate Int-2 undergoes homolytic C–O bond cleavage via TS1 with an overall Gibbs free energy of activation of approximately 11 kcal mol–1 to form acyl radical complex Int-3i (Fig. 6)
DFT-investigation of the dearomatization mechanism at the B3LYP/6-311+G(d,p)–D3–CPCM(acetonitrile, UFF) level of theory.
The latter liberates triphenylphosphine oxide to provide the free acyl radical species Int-3ii in an exergonic process. The key spiro-cyclization step takes place from acyl radical Int-3iii via TS2 to form the chromanone radical species in a slightly exergonic process. In the final stage of the reaction, SET from the reduced Ir(II) photocatalyst to the delocalized C-centered radical Int-4 concludes the photocatalytic cycle in a slightly endergonic process (0.4 kcal mol–1). Finally, the thereby formed carbanion Int-4i is protonated by K2HPO4 to yield the final product 5a in an exergonic process. The potential energy surface was also investigated for the tandem intermolecular radical addition/spirocyclization reaction (see Supplementary Table 8 and Supplementary Fig. 6). The reaction follows the same mechanistic pathway as the intramolecular spirocyclization through initial C–O bond cleavage (TS3’), and the activation barrier for the formation of the acyl radical from benzaldehyde is slightly lower (7.2 kcal mol–1) than for 1a (see Supplementary Table 8 and Supplementary Fig. 6). In the presence of the acrylamide-based somophile, the acyl radical first undergoes radical addition to the somophile via TS4’ (2.1 kcal mol–1), generating a stable α-carbonyl radical (–19.8 kcal mol–1). The α-carbonyl radical attacks at the ipso-carbon of the benzyl moiety in a 5-exo-trig fashion via TS5’, which leads to the delocalized radical to ultimately deliver the final product upon an overall exergonic SET/protonation sequence.
In summary, we have developed an effective, modular, and regioselective methodology to access two kinds of spirocyclic frameworks through visible light-mediated radical dearomatization. Originating from readily available benzoic acids in the presence of triphenylphosphine by photocatalysis, acyl radicals can either engage in the direct intramolecular 6-exo-trig cyclization to provide complex spiro-chromanones or be trapped by alkene-based somophiles, followed by a 5-exo-trig cyclization to furnish valuable spirocyclic lactams in an intermolecular tandem manner. The protocols show great substrate scopes and functional group compatibilities, emphasizing the synthetic viability and applicability in late-stage modification. This provides an efficient and versatile radical-based framework for constructing spiro-compounds, exhibiting promising practical applications in both academic and industrial settings.
Methods
Materials and procedures for synthesis of substrates and catalysts
Optimization of reaction conditions and general procedures, fluorescence quenching studies, and computational studies
See Supplementary Results and discussion, Supplementary Figs. 1–6 and Supplementary Tables 1–8.
Characterization data
See Supplementary Note 1.
NMR spectra and HPLC chromatograms of substrates and products
Data availability
Supplementary data are available in the online version of the paper. The supplementary data contains experimental procedures, 1H, 13C, 19F NMR spectra, XYZ coordinates for all optimized structures, figures of fluorescence quenching. Correspondence and reasonable requests for materials should be addressed to P.D.
References
Arya, P., Joseph, R., Gan, Z. & Rakic, B. Exploring new chemical space by stereocontrolled diversity-oriented synthesis. Chem. Biol. 12, 163–180 (2005).
Morton, D., Leach, S., Cordier, C., Warriner, S. & Nelson, A. Synthesis of natural-product-like molecules with over eighty distinct scaffolds. Angew. Chem. Int. Ed. 48, 104–109 (2009).
Burke, M. D. & Schreiber, S. L. A planning strategy for diversity-oriented synthesis. Angew. Chem. Int. Ed. 43, 46–58 (2004).
Schreiber, S. L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287, 1964 (2000).
Tan, D. S. Diversity-oriented synthesis: Exploring the intersections between chemistry and biology. Nat. Chem. Biol. 1, 74–84 (2005).
Zheng, Y., Tice, C. M. & Singh, S. B. The use of spirocyclic scaffolds in drug discovery. Bioorg. Med. Chem. Lett. 24, 3673–3682 (2014).
Chupakhin, E., Babich, O., Prosekov, A., Asyakina, L. & Krasavin, M. Spirocyclic Motifs in natural products. Molecules 24, 4165 (2019).
Hiesinger, K., Dar’in, D., Proschak, E. & Krasavin, M. Spirocyclic scaffolds in medicinal chemistry. J. Med. Chem. 64, 150–183 (2021).
Harris, C. M., Roberson, J. S. & Harris, T. M. Biosynthesis of griseofulvin. J. Am. Chem. Soc. 98, 5380–5386 (1976).
Petersen, A. B., Rønnest, M. H., Larsen, T. O. & Clausen, M. H. The chemistry of griseofulvin. Chem. Rev. 114, 12088–12107 (2014).
Garthwaite, S. M. & McMahon, E. G. The evolution of aldosterone antagonists. Mol. Cell. Endocrinol. 217, 27–31 (2004).
Rios, R. Enantioselective methodologies for the synthesis of spiro compounds. Chem. Soc. Rev. 41, 1060–1074 (2012).
Pawlowski, R., Skorka, P. & Stodulski, M. Radical-mediated non-dearomative strategies in construction of spiro compounds. Adv. Synth. Catal. 362, 4462–4486 (2020).
James, M. J., O’Brien, P., Taylor, R. J. K. & Unsworth, W. P. Synthesis of spirocyclic indolenines. Chem. Eur. J. 22, 2856–2881 (2016).
Reddy, C. R., Prajapti, S. K., Warudikar, K., Ranjan, R. & Rao, B. B. ipso-Cyclization: An emerging tool for multifunctional spirocyclohexadienones. Org. Biomol. Chem. 15, 3130–3151 (2017).
Yang, W.-C., Zhang, M.-M. & Feng, J.-G. Recent advances in the construction of spiro compounds via radical dearomatization. Adv. Synth. Catal. 362, 4446–4461 (2020).
Li, W., Xu, W., Xie, J., Yu, S. & Zhu, C. Distal radical migration strategy: An emerging synthetic means. Chem. Soc. Rev. 47, 654–667 (2018).
Prier, C. K., Rankic, D. A. & MacMillan, D. W. Visible light photoredox catalysis with transition metal complexes: Applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).
Romero, N. A. & Nicewicz, D. A. Organic photoredox catalysis. Chem. Rev. 116, 10075–10166 (2016).
Yu, X.-Y., Chen, J.-R. & Xiao, W.-J. Visible light-driven radical-mediated C–C bond cleavage/functionalization in organic synthesis. Chem. Rev. 121, 506–561 (2021).
Okumura, M. & Sarlah, D. Visible-light-induced dearomatizations. Eur. J. Org. Chem. 2020, 1259–1273 (2020).
Cheng, Y.-Z., Feng, Z., Zhang, X. & You, S.-L. Visible-light induced dearomatization reactions. Chem. Soc. Rev. 51, 2145–2170 (2022).
Kachkovskyi, G., Faderl, C. & Reiser, O. Visible light-mediated synthesis of (Spiro)anellated furans. Adv. Synth. Catal. 355, 2240–2248 (2013).
Hu, B. et al. Visible light-induced intramolecular dearomative cyclization of α-bromo-N-benzyl-alkylamides: Efficient construction of 2-azaspiro[4.5]decanes. Chem. Commun. 52, 3709–3712 (2016).
Wang, Q. et al. Synthesis of gem-difluorinated spiro-γ-lactam oxindoles by visible-light-induced consecutive difluoromethylative dearomatization, hydroxylation, and oxidation. Chem. Eur. J. 24, 11283–11287 (2018).
Wang, Q. et al. Visible-light-mediated dearomatization/cyanation cascade reaction of indoles: Access to highly functionalized spiro-γ-lactam indolines with two contiguous sterically congested quaternary carbon stereocenters. Adv. Synth. Catal. 360, 2879–2884 (2018).
Wang, Q., Qu, Y., Liu, Y., Song, H. & Wang, Q. Synthesis of functionalized spirocyclic indolines by visible light-induced one-pot sequential difluoromethylative dearomatization, hydroxylation, and substitution reactions. Adv. Synth. Catal. 361, 4739–4747 (2019).
Wu, L., Hao, Y., Liu, Y., Song, H. & Wang, Q. Visible-light-induced dearomative oxamination of indole derivatives and dearomative amidation of phenol derivatives. Chem. Commun. 56, 8436–8439 (2020).
Li, H., Subbotina, E., Bunrit, A., Wang, F. & Samec, J. S. M. Functionalized spirolactones by photoinduced dearomatization of biaryl compounds. Chem. Sci. 10, 3681–3686 (2019).
Soni, V. K. et al. Generation of N-centered radicals via a photocatalytic energy transfer: Remote double functionalization of arenes facilitated by singlet oxygen. J. Am. Chem. Soc. 141, 10538–10545 (2019).
Habert, L. & Cariou, K. Photoinduced aerobic iodoarene-catalyzed spirocyclization of N-Oxy-amides to N-fused spirolactams. Angew. Chem. Int. Ed. 60, 171–175 (2021).
Flynn, A. R., McDaniel, K. A., Hughes, M. E., Vogt, D. B. & Jui, N. T. Hydroarylation of arenes via reductive radical-polar crossover. J. Am. Chem. Soc. 142, 9163–9168 (2020).
McDaniel, K. A., Blood, A. R., Smith, G. C. & Jui, N. T. Dearomatization of unactivated arenes via catalytic hydroalkylation. ACS Catal. 11, 4968–4972 (2021).
Gao, F., Yang, C., Gao, G.-L., Zheng, L. & Xia, W. Visible-light induced trifluoromethylation of N-arylcinnamamides for the synthesis of CF3-containing 3,4-disubstituted dihydroquinolinones and 1-Azaspiro[4.5]decanes. Org. Lett. 17, 3478–3481 (2015).
Gu, Z., Zhang, H., Xu, P., Cheng, Y. & Zhu, C. Visible-light-induced radical tandem aryldifluoroacetylation of cinnamamides: Access to difluoroacetylated quinolone-2-ones And 1-Azaspiro[4.5]decanes. Adv. Synth. Catal. 357, 3057–3063 (2015).
Zhang, Z., Tang, X.-J. & Dolbier, W. R. Photoredox-catalyzed intramolecular difluoromethylation of N-benzylacrylamides coupled with a dearomatizing spirocyclization: Access to CF2H-containing 2-azaspiro[4.5]deca-6,9-diene-3,8-diones. Org. Lett. 18, 1048–1051 (2016).
Tang, S. et al. Visible-light-induced dearomative spirocyclization of N-benzylacrylamides toward perfluorinated azaspirocyclic cyclohexadienones. Tetrahedron Lett. 58, 2127–2130 (2017).
Dong, W. et al. Visible-light-induced intermolecular dearomative cyclization of 2-bromo-1,3-dicarbonyl compounds and alkynes: Synthesis of spiro[4.5]deca-1,6,9-trien-8-ones. Org. Lett. 20, 5762–5765 (2018).
Dong, W. et al. Photocatalytic radical ortho-dearomative cyclization: Access to spiro[4.5]deca-1,7,9-trien-6-ones. J. Org. Chem. 86, 3697–3705 (2021).
Zhu, M., Zhou, K., Zhang, X. & You, S.-L. Visible-light-promoted cascade alkene trifluoromethylation and dearomatization of indole derivatives via intermolecular charge transfer. Org. Lett. 20, 4379–4383 (2018).
Dong, W., Yuan, Y., Xie, X. & Zhang, Z. Visible-light-driven dearomatization reaction toward the formation of spiro[4.5]deca-1,6,9-trien-8-ones. Org. Lett. 22, 528–532 (2020).
Gao, X., Yuan, Y., Xie, X. & Zhang, Z. Visible-light-induced cascade dearomatization cyclization between alkynes and indole-derived bromides: A facile strategy to synthesize spiroindolenines. Chem. Commun. 56, 14047–14050 (2020).
Manna, S., Someswara Ashwathappa, P. K. & Prabhu, K. R. Visible light-mediated ipso-annulation of activated alkynes: Access to 3-alkylated spiro[4,5]-trienones, thiaspiro[4,5]-trienones and azaspiro[4,5]-trienones. Chem. Commun. 56, 13165–13168 (2020).
Liu, Y. et al. Visible-light-mediated Ipso-carboacylation of alkynes: Synthesis of 3-acylspiro[4,5]trienones from N-(p-methoxyaryl)propiolamides and acyl chlorides. J. Org. Chem. 83, 2210–2218 (2018).
Yuan, L. et al. Photocatalyzed cascade Meerwein addition/cyclization of N-benzylacrylamides toward azaspirocycles. Org. Biomol. Chem. 16, 2406–2410 (2018).
Sahoo, S. R., Das, B., Sarkar, D., Henkel, F. & Reuter, H. Visible light assisted selenylative intramolecular dearomative carbo-spirocyclisation (IDCS) of homologated-Ynones. Chem. Eur. J. 2020, 891–896 (2020).
Zhou, X.-J. et al. Visible-light-promoted selenylative spirocyclization of Indolyl-ynones toward the formation of 3-selenospiroindolenine anticancer agents. Chem. Asian J. 15, 1536–1539 (2020).
Wei, W. et al. Visible-light-enabled spirocyclization of alkynes leading to 3-sulfonyl and 3-sulfenyl azaspiro[4,5]trienones. Green. Chem. 19, 5608–5613 (2017).
Ho, H. E. et al. Visible-light-induced intramolecular charge transfer in the radical spirocyclisation of indole-tethered ynones. Chem. Sci. 11, 1353–1360 (2020).
Chatgilialoglu, C., Crich, D., Komatsu, M. & Ryu, I. Chemistry of acyl radicals. Chem. Rev. 99, 1991–2070 (1999).
Raviola, C., Protti, S., Ravelli, D. & Fagnoni, M. Photogenerated acyl/alkoxycarbonyl/carbamoyl radicals for sustainable synthesis. Green. Chem. 21, 748–764 (2019).
Banerjee, A., Lei, Z. & Ngai, M.-Y. Acyl radical chemistry via visible-light photoredox catalysis. Synthesis 51, 303–333 (2019).
Zhang, M., Xie, J. & Zhu, C. A general deoxygenation approach for synthesis of ketones from aromatic carboxylic acids and alkenes. Nat. Commun. 9, 3517 (2018).
Stache, E. E., Ertel, A. B., Rovis, T. & Doyle, A. G. Generation of phosphoranyl radicals via photoredox catalysis enables voltage-independent activation of strong C–O bonds. ACS Catal. 8, 11134–11139 (2018).
Zhang, M., Yuan, X.-A., Zhu, C. & Xie, J. Deoxygenative deuteration of carboxylic acids with D2O. ACS Catal. 58, 312–316 (2019).
Jiang, H. et al. Synthesis of dibenzocycloketones by acyl radical cyclization from aromatic carboxylic acids using methylene blue as a photocatalyst. Green. Chem. 21, 5368–5373 (2019).
Ruzi, R., Liu, K., Zhu, C. & Xie, J. Upgrading ketone synthesis direct from carboxylic acids and organohalides. Nat. Commun. 11, 3312 (2020).
Li, Y. et al. Highly selective synthesis of all-carbon tetrasubstituted alkenes by deoxygenative alkenylation of carboxylic acids. Nat. Commun. 13, 10 (2022).
Su, J. et al. Generation of oxyphosphonium ions by photoredox/cobaloxime catalysis for scalable amide and peptide synthesis in batch and continuous-flow. Angew. Chem. Int. Ed. 61, e202112668 (2022).
Brogden, R. N., Heel, R. C., Pakes, G. E., Speight, T. M. & Avery, G. S. Diflunisal: A review of its pharmacological properties and therapeutic use in pain and musculoskeletal strains and sprains and pain in osteoarthritis. Drugs 19, 84–106 (1980).
Evans, V., Mahon, M. F. & Webster, R. L. A mild, copper-catalysed amide deprotection strategy: Use of tert-butyl as a protecting group. Tetrahedron 70, 7593–7597 (2014).
Shroot, B. & Michel, S. Pharmacology and chemistry of adapalene. J. Am. Acad. Dermatol. 36, S96–S103 (1997).
Becke, A. D. Density‐functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 98, 5648–5652 (1993).
Lee, C., Yang, W. & Parr, R. G. Development of the Colle–Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B 37, 785–789 (1988).
Krishnan, R., Binkley, J. S., Seeger, R. & Pople, J. A. Self‐consistent molecular orbital methods. XX. A basis set for correlated wave functions. J. Chem. Phys. 72, 650–654 (1980).
Frisch, M. J., Pople, J. A. & Binkley, J. S. Self‐consistent molecular orbital methods 25. Supplementary functions for Gaussian basis sets. J. Chem. Phys. 80, 3265–3269 (1984).
Barone, V. & Cossi, M. Quantum calculation of molecular energies and energy gradients in solution by a conductor solvent model. J. Phys. Chem. A 102, 1995–2001 (1998).
Barone, V., Cossi, M. & Tomasi, J. Geometry optimization of molecular structures in solution by the polarizable continuum model. J. Comput. Chem. 19, 404–417 (1998).
Frisch, M. J. et al. Gaussian 16 Rev. C.01 (Wallingford, CT, 2016).
Ruzi, R. et al. Deoxygenative arylation of carboxylic acids by aryl migration. Chem. Eur. J. 25, 12724–12729 (2019).
Acknowledgements
Financial support from Wenner-Gren Foundation (grant no. UPD-2020-0228 and UPD2021-0145), FORMAS (grant no. 2019-01269), Swedish Research Council (grant no. 2020-04764), Olle Engkvist Foundation (204-0175), Magnus Bergvall Foundation, and KTH Royal Institute of Technology is gratefully acknowledged. The National Supercomputer Center (NSC) in Linköping are acknowledged for providing computational resources. A.Z.T. acknowledges financial support from the Ministry of Education and Science of the Russian Federation (project no. FZEN-2020-0022), and the Ecological Analytical Core Facility Center of the Kuban State University for providing the necessary equipment.
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P.D. and C.Z. devised the initial concept of the work. C.Z. and A.S. contributed to the synthesis of starting materials and products. A.S. performed fluorescence spectra. P.D. conducted DFT calculations. A.Z.T. carried out the MS analysis of all compounds. C.Z., P.D., A.S., and M.D.K. worked with the discussion of the data and wrote the manuscript.
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Zhou, C., Shatskiy, A., Temerdashev, A.Z. et al. Highly congested spiro-compounds via photoredox-mediated dearomative annulation cascade. Commun Chem 5, 92 (2022). https://doi.org/10.1038/s42004-022-00706-3
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DOI: https://doi.org/10.1038/s42004-022-00706-3
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