Photoactivation of an electron donor–acceptor encounter complex in an organic solvent cage, a phenomenon that has been described in Mulliken theory, has been known for decades, but it has not been employed as a photoactivation step in the design of photocatalysis for organic synthesis until recent years. We report herein an iododecarboxylation reaction that applies this concept for photoactivation by using a catalyst to facilitate electron transfer and to suppress back electron transfer in the photoexcited state. Under irradiation of 456 nm blue light-emitting diodes, PPh3 catalyzes the iododecarboxylation of aliphatic carboxylic acid-derived N-(acyloxy)phthalimide with lithium iodide as iodine source. The reaction delivers primary, secondary, and bridgehead tertiary alkyl iodides in acetone solvent, and the alkyl iodide products were easily used to generate C–N, C–O, C–F, and C–S bonds to allow various decarboxylative transformations without using transition-metal or organic dye-based photocatalysts. This protocol is applicable to redox-active esters derived from various natural products and pharmaceuticals.
Article
Triphenylphosphine-catalyzed Alkylative Iododecarboxylation with Lithium Iodide under Visible Light
https://doi.org/10.21203/rs.3.rs-51576/v1
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published 22 Oct, 2020
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Decarboxylative transformations1–4 that convert a carboxylate group into a functionality that is a versatile handle for various further transformations, such as the recent development of alkylative decarboxylative borylation5,6, are of great significance in organic synthesis. Alternatively, a low-cost alkylative decarboxylative iodination reaction has similarly high merits for use with aliphatic carboxylic acids in organic synthesis. The importance of decarboxylative halogenation of aliphatic carboxylates in organic synthesis is reflected in several named reactions, such as the Hunsdiecker reaction7, the Kochi reaction8, and Barton halogenative decarboxylation9 (Fig. 1A). Decarboxylative halogenation generates organohalides, which are among the most versatile building-blocks in modern organic synthesis10–12. Alkyl iodide represents the most reactive electrophile among the various alkyl halides; thus, efficient decarboxylative iodination offers a platform for a variety of decarboxylative transformations13 from easily available carboxylic acids. Decarboxylative iodination of aromatic carboxylic acids and their derivatives has been extensively reported14,15. Notably, a recent report by Larrosa and co-workers16 delineated an efficient transition-metal-free decarboxylative iodination of arene carboxylic acid using molecular iodine. However, reports on efficient decarboxylative iodination of aliphatic carboxylic acid derivatives remain relatively rare because alkyl iodides are susceptible to various metal catalysts and nucleophiles. Reported examples of decarboxylative iodination of aliphatic carboxylic acid derivatives include halogenative decarboxylation of Barton esters with iodoform17, oxidative methods using iodobenzene diacetate and molecular iodine under light18, decarboxylation of bridgehead carboxylic acid with t-BuOCl and HgI219, and a recent photoredox method using iridium photoredox catalyst and N-iodosuccinimide that proceeds with moderate yields20. The propensity of iodine cations to undergo electrophilic substitution with arenes presents another challenge in chemoselective decarboxylative iodination for complex molecules containing electron-rich arene moieties21. Decarboxylative iodination using an iodide salt under mild redox neutral conditions would thus be useful for direct functionalization of complex substrates. We posited that our recently reported strategy of photoactivation of transiently assembled chromophores composed of a redox-active ester (RAE), an iodide salt, and a triarylphosphine for alkyl radical generation, provides an expedient method for alkylative decarboxylative iodination22. The principle of radical generation is based on the photoactivation of an electron donor–acceptor (EDA) encounter complex in an organic solvent cage to generate free-radical ions after diffusion23 (Fig. 1B). Solvation and noncovalent interactions between substrates play crucial roles in determining the productive photoactivation and subsequent diffusion process24–27. This principle of photoactivation can be utilized to design a catalytic cycle for bond formation with a catalyst that facilitates electron transfer from a donor moiety to an acceptor moiety and to suppress undesired back electron transfer to induce further fragmentation of radical ion species28,29 (Fig. 1B). Herein, we implement this hypothesis to design a decarboxylative iodination of aliphatic carboxylates.
As depicted in Fig. 1C, an iodide salt, triphenylphosphine, and an RAE transiently assemble to form a chromophore as indicated by the light-yellow appearance of the solution and absorbs up to blue visible light in the UV-Vis spectrum (see Supplementary Information for details). The EDA encounter complex can be a transiently assembled species in a solvent cage that is held through weak, noncovalent interactions30–33, and hence is not isolable. Photoactivation of the EDA encounter complex results in an electron transfer process that forms an •I–PPh3 radical and a phthalimide radical anion, which triggers subsequent decarboxylation to deliver an alkyl radical. It is worth mentioning that, although similar UV-Vis absorption spectra were observed in the absence of PPh3 (see Supplementary Information for more details), the presence of PPh3 is crucial to suppress back electron transfer from the phthalimide radical anion to •I by forming thermodynamically stable •I–PPh3, and to prevent formation of I2, which was found to be detrimental. The alkyl radical reacts with •I–PPh3 to produce alkyl iodides and regenerate PPh3; hence, the reaction is catalytic in PPh3. We document herein a PPh3-catalysed photochemical alkylative decarboxylative iodination of aliphatic carboxylic acid-derived RAEs. The simplicity and low cost of this protocol, taken together with the high electrophilicity of alkyl iodides under either SN2 or metal-catalysed conditions, provide an expedient pathway for the development of a variety of decarboxylative transformations.
The optimized reaction conditions are shown at the top of Fig. 2. In a transparent Schlenk tube, a mixture of RAE (1) (0.2 mmol), lithium iodide (0.3 mmol), and a catalytic amount of PPh3 (10 mol%) in degassed acetone solvent (0.1 M) was irradiated under blue LEDs at room temperature for 24 h. The desired iodination product 2 was obtained in 91% yield and only a trace amount of decarboxylative protonation by-product 3 was detected by 1H NMR analysis. Key controlling parameters are shown in Fig. 2. The results of testing various alkali iodides, shown in the first row of Fig. 2, showed that as the cation radius of the alkali metal increases (from Li to Cs), the yield of 2 gradually decreases. Protonation by-product 3 was detected in significant amounts when RbI or CsI was used. The conversion of 1 dramatically decreased when CaI2 was used, resulting in a low yield (46%) of 2. The use of either ZnI2 or n-Bu4NI as iodine source was entirely ineffective. These results revealed a significant cation effect and suggest that the cations affect assembly of the chromophore in a solvent cage, and hence affect the rate of electron transfer and subsequent radical decarboxylation. Solvation heavily influences the extent to which a transiently assembled EDA encounter complex18 can affect the reaction outcome (second row of Fig. 2). Amide solvents such as DMF and DMA primarily resulted in the formation of decarboxylative protonation products. Acetonitrile (MeCN), ethyl acetate (EtOAc), dichloromethane (DCM), and trifluorotoluene (PhCF3) were all unsuitable solvents. Tetrahydrofuran (THF) was a suitable solvent, whereas the use of dioxane as solvent gave no product. A mixed THF/acetone solvent system appeared to be optimal. The remarkable and subtle solvent effect was also demonstrated by testing ketone derivatives as solvent. Acetone is an optimal solvent, and using butan-2-one gave reduced yield. In sharp contrast, the use of nonan-5-one or 3-methylbutan-2-one as the solvent resulted in no decarboxylative transformation.
The scope of the reaction is summarized in Fig. 3. A broad range of alkyl carboxylates with various functionalities was readily converted into the corresponding primary, secondary, and bridgehead tertiary alkyl iodides. Functional groups, such as ether (4, 14), imide (5), aryl bromide (6), aryl aldehyde (7), aryl pinacol boronate (8), alkene (9), ester (10, 26, 27), amide (15, 16), trifluoromethyl (12), aryl chloride (13), aryl iodide (20), ketone (24), and hydroxy (25) were compatible. Iodination of the electron-rich arene moiety (4, 6, 10) was not observed. N-Protected piperidine iodides, such as N-tert-butoxycarbonyl (16), benzyloxycarbonyl (17, 19) and benzoyl (18, 20), were obtained in good yields. Both cyclic and acyclic secondary carboxylic acid-derived RAEs reacted well (14–22). For the reaction leading to 21, the by-product of intramolecular radical cyclization on the ortho-C-H of phenyl was detected. Heteroarene moieties, such as thiophene (11) and furan (15), were tolerated without undergoing electrophilic C–H iodination. RAEs derived from bridgehead carboxylic acids gave bridgehead tertiary iodides in good to excellent yields (23–27).
The mild redox-neutral conditions of the protocol encouraged us to test synthetic modifications of a series of RAEs derived from natural products and pharmaceuticals. As shown in Fig. 4, RAEs derived from linoleic acid (28), oleic acid (29), erucic acid (30), and undecenoic acid (31) smoothly underwent decarboxylative iodination with the stereochemical integrity of the alkene moieties remaining intact. RAEs derived from medicinal compounds and complex natural products, such as pregabalin (32, 33), mycophenolic acid (34), gabapentin (35, 36), dehydrocholic acid (37), chloroambucil (38), baclofen (39), estrone (40), and lithocolic acid (41) also reacted smoothly to deliver the corresponding iodides. The relatively low yield of chloroambucil (38) could be partially explained by a competitive Finkelstein reaction. It is worth noting that the unprotected phenolic hydroxyl in mycophenolic acid (34) is compatible. For estrone analogue 40, the electron-rich phenyl ring, which is susceptible to electrophilic halogenation, remained unaffected. The alkyl iodides derived from these natural products and pharmaceuticals are suitable for introduction into bioactive structure motifs to construct complex molecules or for further diversification.
The reaction did not work well for obtaining ordinary tertiary iodide, probably because of the low bond-dissociation energy of the tertiary alkyl–I bond and because of its tendency to generate a tertiary carbon cation34. Testing RAE derived from gemfibrozil resulted in the formation of a mixture of alkene regioisomers (equation 1) with no product of decarboxylative iodination detected.
Radical cyclization experiments unequivocally proved that the reactions proceed through a process involving free alkyl radicals (Scheme 1). Reactions using 1.5 equivalent of LiCl or LiBr in the presence of 10 mol% of LiI did not produce any decarboxylative chlorination or bromination product (equation 2), suggesting that a carbon cation is not oxidatively generated with •I–PPh3.
Scheme 1 Radical cyclization experiments.
Simply treating the obtained cyclic secondary alkyl iodides with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at 60 °C in one pot generated the alkene products in high yields (Fig. 5, 49–53). Decarboxylative elimination of these carboxylic acids was recently reported using either photoredox/synergistic catalysis35,36 or palladium catalysis under light37. Facile access to alkenes expands the synthetic utility of this low-cost and mild decarboxylative iodination protocol.
The products of decarboxylative iodination can be further used to construct C–O, C–N, C–F, and C–SCN bonds, allowing their subsequent use without requiring the expensive transition metals38–41. As exemplified by the reaction of oleic acid, shown in Scheme 2, a gram-scale decarboxylative iodination reaction produced the corresponding iodide in 80% yield. The primary iodide underwent SN2-type reaction with oxygen, fluorine, nitrogen, and sulfur nucleophiles to generate ethers (54, 55), fluoride (56), amine (57, 59), and thiocyanate (58). Subsequent formation of C–N and C–SCN bonds can also be achieved in one pot in good yields without isolation of alkyl iodides (Scheme 3). The procedures thus provide alternative methods for decarboxylative oxygenation, amination, fluorination, and thiocyanation. These additional examples highlight the synthetic utility of the new photodecarboxylative iodination protocol and underline its wide applicability to various synthetic tasks.
Scheme 2 Further transformations for decarboxylative construction of C–O, C–N, C–F, and C–SCN bonds. aThe yield was determined by 1H NMR spectroscopic analysis using diphenylmethane as internal standard.
Scheme 3 One-pot decarboxylative thiocyanation and amination.
In summary, a PPh3-catalyzed iododecarboxylation protocol for use with aliphatic carboxylates and lithium iodide under irradiation with blue light has been developed. The reaction uses lithium iodide as iodine source, proceeds under mild, redox-neutral conditions, and hence is suitable for modification of complex natural products and pharmaceuticals. The activation principle of this protocol is based on the photoactivation of an EDA encounter complex in a solvent cage, and a catalyst for this process facilitates electron transfer and suppresses back electron transfer. The protocol has the advantages of low cost and simplicity, and allows versatile follow-up transformations to be applied, thereby expanding the use of aliphatic carboxylic acids in organic synthesis.
General procedure for iododecarboxylation. Redox-active esters (1.0 equiv., 0.2 mmol) (if solid), LiI (1.5 equiv., 0.3 mmol), and PPh3 (10 mol%) were added to a 10 mL transparent Schlenk tube equipped with a stirring bar. The tube was evacuated and filled with argon (three cycles). To these solids, redox-active esters (1.0 equiv., 0.2 mmol) (if liquid) and acetone (2.0 mL) were added under argon atmosphere. The reaction mixture was stirred under irradiation with blue LEDs (Kessil, PR160–456 nm) maintained at approximately room temperature. After 24 h, the mixture was transferred to a round-bottom flask and concentrated with a rotary evaporator. The product was purified by flash column chromatography on silica gel.
Author contributions
R.S. conceived the concept, guided the project, and wrote the manuscript; M.-C.F. and J.-X.W. performed the experiments; and M.-C.F., and R.S. analyzed the data and participated in the preparation of the manuscript.
Competing financial interests.
The authors declare no competing financial interests.
Acknowledgements
We are grateful for the support from the National Natural Science Foundation of China (GG2065010002), KY (2060000119), Natural Science Foundation of Anhui (2008085MB40) and the USTC Research Funds of the Double First-Class Initia-tive (YD2060002003).
- Qin, T. et al. A general alkyl-alkyl cross-coupling enabled by redox-active esters and alkylzinc reagents. Science 352, 801–805 (2016).
- Liang, Y., Zhang, X., MacMillan, D. W. C. Decarboxylative sp3 C–N coupling via dual copper and photoredox catalysis. Nature 559, 83–88 (2018).
- Edwards, J. T. et al. Decarboxylative alkenylation. Nature 545, 213–218 (2017).
- Zhang, X. et al. Copper-mediated synthesis of drug-like bicyclopentanes. Nature https://doi.org/10.1038/s41586-020-2060-z (2020).
- Fawcett, A. et al. Photoinduced decarboxylative borylation of carboxylic acids. Science 357, 283–286 (2017).
- Li, C. et al. Decarboxylative borylation. Science 356, eaam7355 (2017).
- The Hunsdiecker and Related Reactions in Comprehensive Organic Synthesis, vol. 7 (Ed.: B. M. Trost, I. Fleming), Pergamon Press, Oxford, 1991, p. 717.
- Kochi, J. K. A new method for halodecarboxylation of acids using lead(IV) acetate. J. Am. Chem. Soc. 87, 2500–2502 (1965).
- Barton, D. H. R., Crich, D., Motherwell, W. B. New and improved methods for the radical decarboxylation of acids. J. Chem. Soc., Chem. Commun. 939–941 (1983).
- Cristol, S. J., Firth, W. C. Jr. Communications. A convenient synthesis of alkyl halides from carboxylic acids. J. Org. Chem. 26, 280–280 (1961).
- Wang, Z. et al. Silver-catalyzed decarboxylative chlorination of aliphatic carboxylic acids. J. Am. Chem. Soc. 134, 4258–4263 (2012).
- Yin, F., Wang, Z., Li, Z., Li, C. Silver-catalyzed decarboxylative fluorination of aliphatic carboxylic acids in aqueous solution. J. Am. Chem. Soc. 134, 10401–10404 (2012).
- Johnson, R. G., Ingham, R. K. The degradation of carboxylic acid salts by means of halogen-the Hunsdiecker reaction. Chem. Rev. 56, 219–269 (1956).
- Barton, D. H. R., Lacher, B., Zard, S. Z. The invention of radical reactions: Part XVI. Radical decarboxylative bromination and iodination of aromatic acids. Tetrahedron 43, 4321–4328 (1987).
- Patra, T., Mukherjee, S., Ma, J., Strieth-Kalthoff, F., Glorius, F. Visible-light-photosensitized aryl and alkyl decarboxylative functionalization reactions. Angew. Chem. Int. Ed. 58, 10514–10520 (2019).
- Perry, G. J. P., Quibell, J. M., Panigrahi, A., Larrosa, I. Transition-metal-free decarboxylative iodination: New routes for decarboxylative oxidative cross-couplings. J. Am. Chem. Soc. 139, 11527–11536 (2017).
- Barton, D. H. R., Crich, D., Motherwell, W. B. The invention of new radical chain reactions. Part VIII. Radical chemistry of thiohydroxamic esters: A new method for the generation of carbon radicals from carboxylic acids. Tetrahedron 41, 3901–3924 (1985).
- Concepcion, J. I. et al. Iodosobenzene diacetate, an efficient reagent for the oxidative decarboxylation of carboxylic acids. J. Org. Chem. 51, 402–404 (1986).
- Abeywickrema, R. S., Della, E. W. Decarboxylative iodination: A convenient synthesis of bridgehead iodides. J. Org. Chem. 45, 4226–4229 (1980).
- Candish, L., Standley, E. A., Gómez-Suárez, A., Mukherjee, S., Glorius, F. Catalytic access to alkyl bromides, chlorides and iodides via visible light-promoted decarboxylative halogenation. Chem. Eur. J. 22, 9971–9974 (2016).
- Narobe, R., Düsel, S. J. S., Iskra, J., König, B. Photocatalytic oxidative iodination of electron-rich arenes. Adv. Synth. Catal. 361, 3998–4004 (2019).
- Fu, M.-C., Shang, R., Zhao, B., Wang, B., Fu, Y. Photocatalytic decarboxylative alkylations mediated by triphenylphosphine and sodium iodide. Science 363, 1429–1434 (2019).
- Lima, C. G. S., Lima, T. de M., Duarte, M., Jurberg, I. D., Paixão, M. W. Organic synthesis enabled by light-irradiation of EDA complexes: Theoretical background and synthetic applications. ACS Catal. 6, 1389–1407 (2016).
- Kysel, O., Juhász, G., Mach, P., Košík, G. Theoretical study of solvent effect on π-EDA complexation II. Complex between TCNE and two benzene molecules. Chem. Pap. 61, 66–72 (2007).
- Litwinienko, G., Beckwith, A. L. J., Ingold, K. U. The frequently overlooked importance of solvent in free radical syntheses. Chem. Soc. Rev. 40, 2157–2163 (2011).
- Weaver, M. J., McManis, G. E. III. Dynamical solvent effects on electron-transfer processes: Recent progress and perspectives. Acc. Chem. Res. 23, 294–300 (1990).
- Li, X., Ogihara, T., Abe, M., Nakamura, Y., Yamago, S. The effect of viscosity on the diffusion and termination reaction of organic radical pairs. Chem. Eur. J. 25, 9846–9850 (2019).
- Kavarnos, G. J., Turro, N. J. Photosensitization by reversible electron transfer: Theories, experimental evidence, and examples. Chem. Rev. 86, 401–449 (1986).
- 10.26434/chemrxiv.12130011.v2McClain, E., Monos, T., Mori, M., Beatty, J., Stephenson, C. Overcoming back electron transfer facilitates the implementation of electron donor-acceptor complexes in catalysis. ChemRxiv. Preprint at https://doi.org/10.26434/chemrxiv.12130011.v2 (2020).
- Kochi, J. K. Electron transfer and charge transfer: Twin themes in unifying the mechanisms of organic and organometallic reactions. Angew. Chem. Int. Ed. Engl. 27, 1227–1266 (1988).
- Fukin, G. K., Lindeman, S. V., Kochi, J. K. Molecular structures of cation… π(arene) interactions for alkali metals with π- and σ-modalities.J. Am. Chem. Soc. 124, 8329–8336 (2002).
- Lindeman, S. V., Kochi, J. K. Fresh look at electron-transfer mechanisms via the donor/acceptor bindings in the critical encounter complex. Acc. Chem. Res. 41, 641–653 (2008).
- Crisenza, G. E. M., Mazzarella, D., Melchiorre, P. Synthetic methods driven by the photoactivity of electron donor–acceptor complexes. J. Am. Chem. Soc. https://dx.doi.org/10.1021/jacs.0c01416 (2020).
- Blanksby, S. J., Barney Ellison, G. Bond dissociation energies of organic molecules. Acc. Chem. Res. 36, 255–263 (2003).
- Sun, X., Chen, J., Ritter, T. Catalytic dehydrogenative decarboxyolefination of carboxylic acids. Nat. Chem. 10, 1229–1233 (2018).
- Tlahuext-Aca, A., Candish, L., Garza-Sanchez, R. A., Glorius, F. Decarboxylative olefination of activated aliphatic acids enabled by dual organophotoredox/copper catalysis. ACS Catal. 8, 1715–1719 (2018).
- Cheng, W.-M., Shang, R., Fu, Y. Irradiation-induced palladium-catalyzed decarboxylative desaturation enabled by a dual ligand system. Nat. Commun. 9, 5215 (2018).
- Mao, R., Balon, J., Hu, X. Decarboxylative C(sp3)-O cross-coupling. Angew. Chem. Int. Ed. 57, 13624–13628 (2018).
- Mao, R., Frey, A., Balon, J., Hu, X. Decarboxylative C(sp3)–N cross-coupling via synergetic photoredox and copper catalysis. Nat. Catal. 1, 120–126 (2018).
- Liang, Y., Zhang, X., MacMillan, D. W. C. Decarboxylative sp3 C–N coupling via dual copper and photoredox catalysis. Nature 559, 83–88 (2018).
- Webb, E. W. et al. Nucleophilic (radio)fluorination of redox-active esters via radical-polar crossover enabled by photoredox catalysis. J. Am. Chem. Soc. https://doi.org/10.1021/jacs.0c03125 (2020).
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Supplementary file