Home PhotocatalysisNicewicz Photoredox Catalysts for Anti-Markovnik

Nicewicz Photoredox Catalysts for Anti-Markovnik

Introduction

While Markovnikov alkene reactivity is very well developed and utilized commonly in the synthesis of commodity and research chemicals, catalytic access to the anti-Markovnikov-selective adducts is a much less-developed endeavor. In collaboration with Professor David Nicewicz, Sigma-Aldrich is proud to offer a selection of photoexcitable acridinium salts that can facilitate various olefin hydrofunctionalizations with complete anti-Markovnikov selectivity.

The cationic organic oxidant 9-mesityl-10-methylacridinium perchlorate was originally designed by Shunichi Fukuzimi and co-workers.¹ Since its introduction, the Nicewicz group has demonstrated the wide utility of this material and related photoredox catalysts (794171, 793876, 793221) when used in conjunction with primarily thiol-containing hydrogen atom transfer co-catalysts.² Through the generation of alkene cation radical intermediates,³ this unique photoredox catalyst system affords hydrofunctionalization of an expansive range of activated and unactivated alkenes with diverse nucleophiles, such as carboxylic acids, amines, mineral acids, and propargylic and allylic alcohols.^2–3

Figure 1.Propargylic-and-allylic-alcohols

Advantages

Metal-free, visible light-mediated catalyst
Stable to air and moisture
Mild reaction conditions
Anti-Markovnikov selectivity
Superior oxidizing capabilities compared to Ru- and Ir-polypyridyl photoxidants
Straightforward excitation of acridinium salts with LED flood lights

Representative Applications

Hydroetherification

Complete regioselectivity was observed in over 10 examples of direct intramolecular anti-Markovnikov hydroetherification of alkenols when 9-mesityl-10-methylacridinium perchlorate was used with 2-phenylmalononitrile as a hydrogen atom donor.⁴

Hydroamination

Hydroamination of alkenes can be accessed using 9-mesityl-10-methylacridinium tetrafluoroborate (794171), with complete anti-Markovnikov selectivity in the presence of a thiol-containing co-catalyst. With thiophenol, intramolecular hydroamination of unsaturated amines provided access to several nitrogen-containing heterocycles.⁵ Furthermore, intermolecular hydroamination of aliphatic alkenes, α- and β-substituted styrenes, and heterocyclic amines were achieved with diphenyl disulfide.⁶

Figure 2.Diphenyl-disulfide

Hydrotrifluoromethylation

Diverse trifluoromethylated products have been obtained through this photoredox catalyst system. Single electron oxidation of the Langlois reagent (743232) by 9-mesityl-10-methylacridinium tetrafluoroborate (794171) and a thiol-containing co-catalyst (methyl thiosalicylate or thiophenol) results in the hydrotrifluoromethylation of styrenes and unactivated aliphatic alkenes with anti-Markovnikov selectivity. Nicewicz and co-workers provided 20 examples with 25–74% yields.⁷

Figure 3.Hydrotrifluoromethylation-of-styrenes

Hydroacetoxylation

Anti-Markovnikov-selective hydroacetoxylation of styrenes, enamides, and trisubstituted aliphatic amines is possible with a range of carboxylic acids when using 9-mesityl-10-methylacridinium tetrafluoroborate (794171) in combination with sodium benzene sulfinate or thiophenol. Seventeen reactions exhibited yields ranging from 29–99%.⁸

Figure 4.Sodium-benzene-sulfinate

Addition of Mineral Acids

The anti-Markovnikov addition of strong Brønsted acids to alkenes is achieved with complete regioselectivity using these photocatalysts. For hydrochlorination, 9-mesityl-10-methylacridinium tetrafluoroborate (794171) is used with thiophenol to generate the adduct. Hydrofluorination, hydrooxyphosphorylation and hydrooxysulfonylation are each effected by employing 9-mesityl-2,7-dimethyl-10-phenylacridinium tetrafluoroborate (793876) with the hydrogen-atom donors 4-nitrophenyl disulfide or 4-methoxythiophenol. Here, the inclusion of 2,6-lutidinium salts were found to provide the best reactivity through a nucleophilic couterion.⁹

Figure 5.Nucleophilic-couterion

Intramolecular Hydrofunctionalization of Amides

The anti-Markovnikov intramolecular cyclization of unsaturated allylic amides and thioamides furnishes the resultant 2-oxazolines and 2-thiazolines, respectively. These transformations utilize a photoredox catalyst system comprising 9-mesityl-10-methylacridinium tetrafluoroborate (794171) in combination with diphenyl disulfide. Through 17 examples, a range of 59–82% yields were observed.¹⁰

Figure 6.Combination-with-diphenyl-disulfide

Hydrodecarboxylation

The anti-Markovnikov hydrodecarboxylation of carboxylic and malonic acids is accomplished with 9-mesityl-10-phenylacridinium tetrafluoroborate (793221) and diphenyl disulfide. The decarboxylation reaction requires the inclusion of a base and a polar alcohol solvent, trifluoroethanol in order to afford good yields and scope. Eighteen examples were included to demonstrate the hydrodecarboxylation of primary, secondary, and tertiary carboxylic acids.¹¹

Figure 7.Tertiary-carboxylic-acids

Polar Radical Crossover Cycloadditions

In a tandem addition-cyclization sequence, polar radical crossover cycloadditions use variations of the photoredox catalyst system to generate the following products from alkenes: g-butyrolactones (with α,β-unsaturated carboxylic acids),¹² tetrahydrofurans (with allylic alcohols),¹³ g-lactams (with unsaturated amides), and pyrrolidines (with unsaturated amines).¹⁴

Figure 8.Unsaturated-amines

Photooxygenation

Prior to Nicewicz’s reports, Griesbeck and Cho used 9-mesityl-10-methylacridinium perchlorate in the presence of O₂ as a visible-light mediated catalyst for Type II and electron-transfer photooxygenation reactions.¹⁵

Figure 9.Photooxygenation-reactions

Materials

References

Fukuzumi S, Kotani H, Ohkubo K, Ogo S, Tkachenko NV, Lemmetyinen H. 2004. Electron-Transfer State of 9-Mesityl-10-methylacridinium Ion with a Much Longer Lifetime and Higher Energy Than That of the Natural Photosynthetic Reaction Center. J. Am. Chem. Soc.. 126(6):1600-1601. https://doi.org/10.1021/ja038656q

Nicewicz D, Hamilton D. Organic Photoredox Catalysis as a General Strategy for Anti-Markovnikov Alkene Hydrofunctionalization. Synlett. 25(09):1191-1196. https://doi.org/10.1055/s-0033-1340738

Romero NA, Nicewicz DA. 2014. Mechanistic Insight into the Photoredox Catalysis of Anti-Markovnikov Alkene Hydrofunctionalization Reactions. J. Am. Chem. Soc.. 136(49):17024-17035. https://doi.org/10.1021/ja506228u

Hamilton DS, Nicewicz DA. 2012. Direct Catalytic Anti-Markovnikov Hydroetherification of Alkenols. J. Am. Chem. Soc.. 134(45):18577-18580. https://doi.org/10.1021/ja309635w

Nguyen TM, Nicewicz DA. 2013. Anti-Markovnikov Hydroamination of Alkenes Catalyzed by an Organic Photoredox System. J. Am. Chem. Soc.. 135(26):9588-9591. https://doi.org/10.1021/ja4031616

Nguyen TM, Manohar N, Nicewicz DA. 2014. anti-Markovnikov Hydroamination of Alkenes Catalyzed by a Two-Component Organic Photoredox System: Direct Access to Phenethylamine Derivatives. Angew. Chem. Int. Ed.. 53(24):6198-6201. https://doi.org/10.1002/anie.201402443

Wilger DJ, Gesmundo NJ, Nicewicz DA. 2013. Catalytic hydrotrifluoromethylation of styrenes and unactivated aliphatic alkenes via an organic photoredox system. Chem. Sci.. 4(8):3160. https://doi.org/10.1039/c3sc51209f

Perkowski AJ, Nicewicz DA. 2013. Direct Catalytic Anti-Markovnikov Addition of Carboxylic Acids to Alkenes. J. Am. Chem. Soc.. 135(28):10334-10337. https://doi.org/10.1021/ja4057294

Wilger DJ, Grandjean JM, Lammert TR, Nicewicz DA. 2014. The direct anti-Markovnikov addition of mineral acids to styrenes. Nature Chem. 6(8):720-726. https://doi.org/10.1038/nchem.2000

10.

Morse PD, Nicewicz DA. Divergent regioselectivity in photoredox-catalyzed hydrofunctionalization reactions of unsaturated amides and thioamides. Chem. Sci.. 6(1):270-274. https://doi.org/10.1039/c4sc02331e

11.

Griffin JD, Zeller MA, Nicewicz DA. 2015. Hydrodecarboxylation of Carboxylic and Malonic Acid Derivatives via Organic Photoredox Catalysis: Substrate Scope and Mechanistic Insight. J. Am. Chem. Soc.. 137(35):11340-11348. https://doi.org/10.1021/jacs.5b07770

12.

Zeller MA, Riener M, Nicewicz DA. 2014. Butyrolactone Synthesis via Polar Radical Crossover Cycloaddition Reactions: Diastereoselective Syntheses of Methylenolactocin and Protolichesterinic Acid. Org. Lett.. 16(18):4810-4813. https://doi.org/10.1021/ol5022993

13.

Grandjean JM, Nicewicz DA. 2013. Synthesis of Highly Substituted Tetrahydrofurans by Catalytic Polar-Radical-Crossover Cycloadditions of Alkenes and Alkenols. Angew. Chem. Int. Ed.. 52(14):3967-3971. https://doi.org/10.1002/anie.201210111

14.

Gesmundo NJ, Grandjean JM, Nicewicz DA. 2015. Amide and Amine Nucleophiles in Polar Radical Crossover Cycloadditions: Synthesis of ?-Lactams and Pyrrolidines. Org. Lett.. 17(5):1316-1319. https://doi.org/10.1021/acs.orglett.5b00316

15.

Griesbeck AG, Cho M. 2007. 9-Mesityl-10-methylacridinium: An Efficient Type II and Electron-Transfer Photooxygenation Catalyst. Org. Lett.. 9(4):611-613. https://doi.org/10.1021/ol0628661

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