The piperidine-based Takemoto catalyst has been successfully employed in a novel asymmetric transfer hydroxymethylation of activated isoindolinones, allowing us to prepare the enantioenriched hydroxymethylated adducts in good to excellent yields (48-96%) and enantiopurities (81:19-97:3 e.r.). To increase the reaction rate without compromising the selectivity, carefully optimized formaldehyde surrogates were employed, providing a convenient source of anhydrous formaldehyde with a base-triggered release. The substrate scope, including 34 entries, showed the considerable generality of the asymmetric transformation, and most entries exhibited complete conversions in 24-48 h. A scale-up experiment and multiple enantioselective downstream transformations were also carried out, suggesting the prospective synthetic utility of the products.

Department of Chemical Drugs Faculty of Pharmacy Masaryk University Palackeho 1 612 00 Brno Czechia

Institute of Organic Chemistry Johannes Kepler University Altenbergerstrasse 69 4040 Linz Austria

See more in PubMed

Li W.; Wu X.-F.. Formaldehyde as C1 Synthon in Organic Synthesis. In The Chemical Transformations of C1 Compounds, 1st ed.; Wu X.-F., Han B., Ding K., Liu Z., Eds.; Wiley-VCH: Weinheim, Germany, 2022; pp 157–248.

Desmons S.; Faure R.; Bontemps S. Formaldehyde as a Promising C1 Source: The Instrumental Role of Biocatalysis for Stereocontrolled Reactions. ACS Catal. 2019, 9, 9575.10.1021/acscatal.9b03128. DOI

Concepcion A. B.; Yamamoto H.; Boeckman R. K. Jr.; Biegasiewicz K. F.; Tusch D. J.. Formaldehyde. In Encyclopedia of Reagents for Organic Synthesis; Charette A. B., Ed.; Wiley-VCH: Weinheim, Germany, 2018.

Yamashita Y.; Yasukawa T.; Yoo W.-J.; Kitanosono T.; Kobayashi S. Catalytic Enantioselective Aldol Reactions. Chem. Soc. Rev. 2018, 47, 4388.10.1039/C7CS00824D. PubMed DOI

Meninno S.; Lattanzi A. Asymmetric Aldol Reaction with Formaldehyde: A Challenging Process. Chem. Rec. 2016, 16, 2016.10.1002/tcr.201600022. PubMed DOI

Li W.; Wu X.-F. The Applications of (Para)formaldehyde in Metal-Catalyzed Organic Synthesis. Adv. Synth. Catal. 2015, 357, 3393.10.1002/adsc.201500753. DOI

Franz A. W.; Kronemayer H.; Pfeiffer D.; Pilz R. D.; Reuss G.; Disteldorf W.; Gamer A. O.; Hilt A.. Formaldehyde. In Ullmann’s Encyclopedia of Industrial Chemistry; Ley C., Ed.; Wiley-VCH: Weinheim, Germany, 2016.

Gerberich H. R.; Seaman G. C.. Formaldehyde. In Kirk-Othmer Encyclopedia of Chemical Technology; Ley C., Ed.; Wiley-VCH: Weinheim, Germany, 2013.

Walker J. F.Formaldehyde, 3rd ed.; ACS Monograph Series, Vol. 159; R. E. Krieger: Huntington, NY, 1964.

Wu B.; Wen X.; Chen H.; Hu L. N-Nosyl-O-bromoethyl Hydroxylamine Acts as a Multifunctional Formaldehyde, Formaldimine, and 1,2-Oxazetidine Surrogate for C-C and C-O Bond-Forming Reactions. Org. Chem. Front. 2021, 8, 5124.10.1039/D1QO00748C. DOI

Asano N.; Sasaki K.; Chataigner I.; Shigeno M.; Kondo Y. Sodium Phenoxide Mediated Hydroxymethylation of Alkynylsilanes with N-[(Trimethylsiloxy)methyl]phthalimide. Eur. J. Org. Chem. 2017, 2017, 6926.10.1002/ejoc.201701440. DOI

Huang W.; Xu J. In Situ Generation of Formaldehyde and Triphenylphosphine from (Hydroxymethyl)triphenylphosphonium and Its Application in Wittig Olefination. Synth. Commun. 2015, 45, 1777.10.1080/00397911.2015.1043019. DOI

Priede M.; Kazak M.; Kalnins T.; Shubin K.; Suna E. Diastereoselective Hydroxymethylation of Cyclic N-tert-Butanesulfinylketimines Using Methoxymethanol as Formaldehyde Source. J. Org. Chem. 2014, 79, 3715.10.1021/jo500506u. PubMed DOI

Deguest G.; Bischoff L.; Fruit C.; Marsais F. Anionic, in Situ Generation of Formaldehyde: A Very Useful and Versatile Tool in Synthesis. Org. Lett. 2007, 9, 1165.10.1021/ol070145b. PubMed DOI

Boeckman R. K. Jr.; Biegasiewicz K. F.; Tusch D. J.; Miller J. R. Organocatalytic Enantioselective α-Hydroxymethylation of Aldehydes: Mechanistic Aspects and Optimization. J. Org. Chem. 2015, 80, 4030.10.1021/acs.joc.5b00380. PubMed DOI

Chen A.; Xu J.; Chiang W.; Chai C. L. L. L-Threonine-Catalysed Asymmetric α-Hydroxymethylation of Cyclohexanone: Application to the Synthesis of Pharmaceutical Compounds and Natural Products. Tetrahedron. 2010, 66, 1489.10.1016/j.tet.2009.11.100. DOI

Aratake S.; Itoh T.; Okano T.; Nagae N.; Sumiya T.; Shoji M.; Hayashi Y. Highly Diastereo- and Enantioselective Direct Aldol Reactions of Aldehydes and Ketones Catalyzed by Siloxyproline in the Presence of Water. Chem. - Eur. J. 2007, 13, 10246.10.1002/chem.200700363. PubMed DOI

Torii H.; Nakadai M.; Ishihara K.; Saito S.; Yamamoto H. Asymmetric Direct Aldol Reaction Assisted by Water and a Proline-Derived Tetrazole Catalyst. Angew. Chem., Int. Ed. 2004, 43, 1983.10.1002/anie.200352724. PubMed DOI

Kanemitsu T.; Ozasa E.; Murase Y.; Sakaue S.; Miyazaki M.; Nagata K.; Itoh T. Asymmetric Construction of All-Carbon Quaternary Stereocenters via Organocatalytic α-Hydroxymethylation of Malonic Diesters Using Aqueous Formaldehyde. Asian J. Org. Chem. 2022, 11, e202200101.10.1002/ajoc.202200101. DOI

Shirakawa S.; Ota K.; Terao S. J.; Maruoka K. The Direct Catalytic Asymmetric Aldol Reaction of α-Substituted Nitroacetates with Aqueous Formaldehyde Under Base-Free Neutral Phase-Transfer Conditions. Org. Biomol. Chem. 2012, 10, 5753.10.1039/c2ob07193b. PubMed DOI

Zhu B.; Li F.; Lu B.; Chang J.; Jiang Z. Synthesis of 2-Oxindoles Sharing Vicinal All-Carbon Quaternary Stereocenters via Organocatalytic Aldol Reaction. J. Org. Chem. 2018, 83, 11350.10.1021/acs.joc.8b01573. PubMed DOI

Scorzelli F.; Di Mola A.; Filosa R.; Massa A. Organocatalytic Asymmetric Hydroxymethylation of Isoindolinones with Paraformaldehyde. Monatsh. Chem. 2018, 149, 723.10.1007/s00706-017-2070-1. DOI

Sonsona I. G.; Vicenzi A.; Guidotti M.; Bisag G. D.; Fochi M.; Herrera R. P.; Bernardi L. Investigation of Squaramide Catalysts in the Aldol Reaction En Route to Funapide. Eur. J. Org. Chem. 2022, 2022, e202101254.10.1002/ejoc.202101254. DOI

Jiang Y.; Yu S.-W.; Yang Y.; Liu Y.-L.; Xu X.-Y.; Zhang X.-M.; Yuan W.-C. Synthesis of Polycyclic Spirooxindoles via an Asymmetric Catalytic One-Pot Stepwise Aldol/Chloroetherification/Aromatization Procedure. Org. Biomol. Chem. 2018, 16, 6647.10.1039/C8OB01713A. PubMed DOI

Bhunia S.; Chaudhuri S.; De S.; Babu K. N.; Bisai A. An Expeditious Route to the Synthesis of the Enantioenriched Tetracyclic Core of Ergot Alkaloids via an Organocatalytic Aldol Reaction. Org. Biomol. Chem. 2018, 16, 2427.10.1039/C7OB03069J. PubMed DOI

Zhao J.; Ren X.; Zheng B.; Ji J.; Qiu Z.; Li Y. Cinchona-Alkaloid-Catalyzed Enantioselective Hydroxymethylation of 3-Fluorooxindoles with Paraformaldehyde. J. Fluorine Chem. 2018, 215, 44.10.1016/j.jfluchem.2018.09.004. DOI

Gao X.; Han J.; Wang L. Tartrate-Derived Iminophosphorane Catalyzed Asymmetric Hydroxymethylation of 3-Substituted Oxindoles with Paraformaldehyde. Org. Chem. Front. 2016, 3, 656.10.1039/C6QO00074F. DOI

De S.; Das M. K.; Bhunia S.; Bisai A. Unified Approach to the Spiro(pyrrolidinyl-oxindole) and Hexahydropyrrolo[2,3-b]indole Alkaloids: Total Syntheses of Pseudophrynamines 270 and 272A. Org. Lett. 2015, 17, 5922.10.1021/acs.orglett.5b03082. PubMed DOI

Liu X.-L.; Liao Y.-H.; Wu Z.-J.; Cun L.-F.; Zhang X.-M.; Yuan W.-C. Organocatalytic Enantioselective Hydroxymethylation of Oxindoles with Paraformaldehyde as C1 Unit. J. Org. Chem. 2010, 75, 4872.10.1021/jo100769n. PubMed DOI

Chen L.; Zou Y.-X. Recent Advances in the Direct Functionalization of Isoindolinones for the Synthesis of 3,3-Disubstituted Isoindolinones. Adv. Synth. Catal. 2021, 363, 4159.10.1002/adsc.202100522. DOI

Topolovcan N.; Gredicak M. Synthesis and Stereoselective Catalytic Transformations of 3-Hydroxyisoindolinones. Org. Biomol. Chem. 2021, 19, 4637.10.1039/D1OB00164G. PubMed DOI

Gao W.; Chen M.; Ding Q.; Peng Y. Catalytic Asymmetric Synthesis of Isoindolinones. Chem. - Asian J. 2019, 14, 1306.10.1002/asia.201900080. PubMed DOI

Svestka D.; Otevrel J.; Bobal P. Asymmetric Organocatalyzed Friedel-Crafts Reaction of Trihaloacetaldehydes and Phenols. Adv. Synth. Catal. 2022, 364, 2174.10.1002/adsc.202200180. DOI

Otevrel J.; Svestka D.; Bobal P. Bianthryl-Based Organocatalysts for the Asymmetric Henry Reaction of Fluoroketones. Org. Biomol. Chem. 2019, 17, 5244.10.1039/C9OB00884E. PubMed DOI

Otevrel J.; Bobal P. Diamine-Tethered Bis(thiourea) Organocatalyst for Asymmetric Henry Reaction. J. Org. Chem. 2017, 82, 8342.10.1021/acs.joc.7b00079. PubMed DOI

Koppel I.; Koppel J.; Leito I.; Pihl V.; Grahn L.; Ragnarsson U. The Acidity of Some Neutral NH-Acids in Water and Dimethyl Sulfoxide. J. Chem. Res. 1994, 6, 1173.

Tanaka Y.; Velen S. R.; Miller S. I. Syntheses and Properties of H-1,2,3-Triazoles. Tetrahedron. 1973, 29, 3271.10.1016/S0040-4020(01)93480-5. DOI

Wood J. K. The Acidic Constants of Some Ureides and Uric Acid Derivatives. J. Chem. Soc., Trans. 1906, 89, 1831.10.1039/CT9068901831. DOI

Kalisiak J.; Sharpless K. B.; Fokin V. V. Efficient Synthesis of 2-Substituted-1,2,3-Triazoles. Org. Lett. 2008, 10, 3171.10.1021/ol8006748. PubMed DOI

Abdireimov K. B.; Mukhamedov N. S.; Aiymbetov M. Z.; Shakhidoyatov K. M. Benzazoles 5*. Synthesis and Arylsulfonylation of 1-Hydroxymethylbenzimidazole. Chem. Heterocycl. Compd. 2012, 48, 458.10.1007/s10593-012-1015-1. DOI

Cul A.; Chihab-Eddine A.; Pesquet A.; Marchalin S.; Daich A. Evaluation of N-Hydroxymethylphthalimide in Alkaline Medium: Novel Entry to the Tricyclic [1,3]Oxazepine Core via an Intramolecular π and O-Cationic Cyclization. J. Heterocyclic Chem. 2003, 40, 499.10.1002/jhet.5570400314. DOI

Gaylord N. G. Displacement Reactions in the Benzotriazole Series. J. Am. Chem. Soc. 1954, 76, 285.10.1021/ja01630a081. DOI

Herrmann A. Dynamic Combinatorial/Covalent Chemistry: A Tool to Read, Generate and Modulate the Bioactivity of Compounds and Compound Mixtures. Chem. Soc. Rev. 2014, 43, 1899.10.1039/C3CS60336A. PubMed DOI

Lehn J.-M. Dynamic Combinatorial Chemistry and Virtual Combinatorial Libraries. Chem. - Eur. J. 1999, 5, 2455.10.1002/(SICI)1521-3765(19990903)5:9<2455::AID-CHEM2455>3.0.CO;2-H. DOI

Katritzky A. R.; Perumal S.; Savage G. P. An NMR Study of the Equilibria Involved with Benzotriazole, Carbonyl Compounds, and Their Adducts. J. Chem. Soc., Perkin Trans. 2 1990, 921.10.1039/p29900000921. DOI