Russian Chemical Bulletin, International Edition, Vol. 64, No. 1, pp. 112—126, January, 2015 112 Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0112—0125, January, 2015. 1066-5285/15/6401-0112 © 2015 Springer Science+Business Media, Inc. Continuous-flow catalytic hydrogenation of 3a,6-epoxyisoindoles V. P. Zaytsev, a,b F. I. Zubkov, a D. F. Mertsalov, a D. N. Orlova, a E. A. Sorokina, a E. V. Nikitina, a and A. V. Varlamov a a Deparment of Organic Chemistry, People´s Friendship University of Russia, 6 ul. Miklukho-Maklaya, 117198 Moscow, Russian Federation. Fax: +7 (495) 955 0779. E-mail: vzaitsev@sci.pfu.edu.ru b Shared Research and Educational Center of Physico-Chemical Studies of New Materials, Substances, and Catalytic Systems", 3 ul. Ordzhonikidze, 115419 Moscow, Russian Federation. Fax: +7 (495) 952 2644. E-mail: ckp_fhi@sci.pfu.edu.ru Selective catalytic (10% Pd/C) hydrogenation of the double bond in the oxabicyclo- [2.2.1]heptene fragment of substituted fused 1-oxo-3a,6-epoxyisoindoles is described. A con- tinuous-flow hydrogenation device that incorporates in situ hydrogen generation by electrolysis of water was used. Changing the hydrogen source from water to deuterium oxide provides possibility to synthesize deuterated oxoepoxyisoindolones. Hydrogenation is stereoselective to give exclusively exo-cis deuterated derivatives. Key words: continuous-flow reactor, heterogeneous catalytic hydrogenation, reduction, 3a,6-epoxyisoindoles, deuteration. Addition of the molecular hydrogen to multiple bonds of the organic compounds occurring on metal surfaces is widely used in the organic synthesis. 1—7 Recently, a great attention was paid to continuous- flow hydrogenation technology. An H-Cube Pro TM con- tinuous-flow hydrogenation reactor combining in situ hy- drogen generation with a disposable cartridge system pre- loaded with a metal catalyst gives the possibility to fast and safe hydrogenation of various compounds. 8—10 In the present work, we describe the results of the selective hy- drogenation of the double bond in the 7-oxabicyclo[2.2.1]- heptene fragment fused with different azaheterocycles. Continuous-flow hydrogenation was studied on the ex- amples of readily available adducts of intramolecular [2+4] cycloaddition between unsaturated acid derivatives and compounds bearing the furfurylamine moiety, namely, 3a,6-epoxyisoindol-1-ones, 11—15 6b,9-epoxyisoindolo- [2,1-a]quinolines, 16,17 11,13a- or 12,14a-epoxyisoindo- lo[3,2-c]quinolines, 16,18 10,12a-epoxyisoindolo[1,2-a]- isoquinolines, 19 8,10a-epoxy[1,3]oxazino[2,3-a]iso- indoles, 20,21 and 2,4a-epoxyisoindolo[1,2-b]quinazol- ines. 21 The main structural motif of all mentioned hetero- cycles is the oxabicyclo[2.2.1]heptene fragment. This moiety undergoes aromatization under both basic and acidic conditions, 11,13,14,17,18,22 its reaction with com- plex hydrides can lead to a retro Diels—Alder reac- tion giving the starting furfurylamines. 23 Moreover, the conventional hydrogenation techniques with hydro- gen gas are time consuming and require high pressure of hydrogen. Only four works devoted to the conventional hydroge- nation of the double bond in epoxyisoindoles are avail- able. 23—26 Hydrogenation of these compounds under con- tinuous-flow conditions has not been studied. Reactions of furfurylamines 1a—l with acid anhydrides (acid halides) of ,-unsaturated carboxylic acids 11,12,14,15 and allylfurfurylamine 1g (R 1 = All, R 2 = H) with arylsul- fonyl chlorides 27,28 carried out following the known pro- cedures produced 3a,6-epoxyisoindoles 2—5 (Scheme 1). To increase the solubility, the corresponding carboxylic acids were transformed into methyl esters 3g—j. The conditions of continuous-flow hydrogenation (sol- vent, reaction temperature, catalyst) of the C=C bond using the H-Cube Pro TM reactor were optimized. It was found that the double bond in the oxabicycloheptene frag- ment of epoxyisoindoles 2—5 is completely hydrogenated under continuous-flow conditions (TLC and GC/MS monitoring); while, other functional groups remain intact (Scheme 2). The optimum conditions for the synthesis are as follows: H 2 (full mode); disposable cartridge packed with 10% Pd/C; 0.025 M solution of isoindole in either EtOH (for 2a—g, 3g—j) or CH 2 Cl 2 (for 3a—f, 4a—d, 5a,b, 8—13); room temperature; atmosphere pressure; flow rate of 1 mL min –1 . All perhydroepoxyisoindoles 6a—w were obtained in nearly quantitative yields as well-shaped crys- tals and viscous or glassy oils (Table 1). It is known that deuterated compounds are widely used for the study of the reaction mechanisms, for structural characterization of compounds by NMR spectroscopy, and as standards for both mass spectrometry and monitor-