LETTER 907 Desulfonylation of N-Sulfonyl Tetrahydroisoquinoline Derivatives by Potassium Fluoride on Alumina Under Microwave Irradiation: Selective Synthesis of 3,4-Dihydroisoquinolines and Isoquinolines a a a b DesulfonylationClaudio of N-Sulfonyl-Tetrahydroisoquinolines with KF/Al2O3 C. Silveira,* Carmem R. Bernardi, Antonio L. Braga, Teodoro S. Kaufman* a Departamento de Quimica, Universidade Federal de Santa Maria, 97105.900, Santa Maria, RS, Brazil Fax +55(55)2208754; E-mail: [email protected] b Instituto de Química Orgánica de Síntesis (CONICET-UNR) and Facultad de Ciencias Bioquímicas y Farmacéuticas, Suipacha 531, (S2002LRK) Rosario, Argentina Fax +54(341)4370477; E-mail: [email protected] Received 9 April 2002 Spengler synthesis11,12 and in many variations of the Po- Abstract: In a solvent-free system, the microwave irradiation of 13 mixtures of N-sulfonyl tetrahydroisoquinolines and 37% potassium merantz–Fritsch sequence. Removal of the sulfonyl fluoride supported on alumina selectively furnished 3,4-dihydroiso- moiety by taking advantage of the different oxidation quinolines or isoquinolines, depending upon the reaction time. states of sulfur has been employed to broaden the scope of Key words: isoquinolines, 3,4-dihydroisoquinolines, KF on alumi- these synthetic protocols, but only a few methods have 11,13 na, microwave-assisted desulfonylation been described. Herein, we wish to report the selective elaboration of 3,4- dihydroisoquinolines and isoquinolines (Scheme 1) by Chemical transformations carried out with supported re- the microwave-assisted oxidative desulfonylation and agents under dry conditions have several significant ad- subsequent dehydrogenation (for isoquinolines) of N-sul- vantages over reactions traditionally run in solution; they fonyl tetrahydroisoquinolines with KF/Al2O3 as solid sup- offer easier separation of the products, new or better selec- ported reagent, in non-solvent conditions. tivities, faster processes or milder reaction conditions, less waste problems and the possibility of working in a contin- uous way.1 Potassium fluoride on alumina (KF/Al2O3) has been re- ported as a solid supported reagent for alkylation,2 elimi- 3 4 5 nation, addition, condensation, enolization, desilyl- Scheme 1 Reagents and Conditions: a) 37% KF/Al2O3, Micro- 6 7 ation, coupling and other useful reactions. It has been waves (time: t1 < t2). shown that during the impregnation-activation procedure, the salt reacts with aluminium oxide forming K3AlF6 and Starting tetrahydroisoquinolines consigned in Table 1 an active mixture of KOH and potassium aluminate on the were prepared employing a modified activated Pictet– surface of the solid support,8 which would contribute to Spengler procedure, by reaction of a-phenylchalcogen-a- explain its reactivity. halocarbonyls as aldehyde surrogates with conveniently On the other hand, the enhancement of chemical transfor- substituted N-tosyl-b-phenethylamines, under Lewis ac- 11b,12 mations by microwave irradiation of organic molecules ids promotion. supported on inorganic solids has experienced an enor- As shown in Table 1, submission of the N-sulfonyl hetero- mous growth in recent years,9 as this technique is manip- cycles to microwave irradiation (490 Watts) provided ulatively simple, can be conducted rapidly and provides good yields of the corresponding 3,4-dihydroisoquino- products in high yields employing solvent-free condi- lines upon a short reaction period (10–20 s), uncontami- tions. nated with the related isoquinolines; interestingly, Recent work informed that under microwave assistance however, increasing the irradiation time completely trans- formed the starting materials into the corresponding iso- KF/Al2O3 cleaves sulfonamides to the corresponding amines in dry conditions.10 However, the irradiation of quinolines, providing a highly selective and convenient mixtures of N-sulfonyl isoquinoline derivatives and KF/ strategy to access both classes of compounds. In spite that hydrolytic cleavage of the N-S bond with formation of the Al2O3 has not been studied to date. desulfonylated tetrahydroisoquinolines10 could not be N-sulfonyl-type protecting groups are widely used in iso- completely ruled out, such compounds could neither be quinoline chemistry, specially in the N-activated Pictet– detected or isolated. In order to assure that these results were not due to a pure- Synlett 2002, No. 6, 04 06 2002. Article Identifier: ly thermal effect, conventional heating experiments were 1437-2096,E;2002,0,06,0907,0910,ftx,en;S09801ST.pdf. © Georg Thieme Verlag Stuttgart · New York performed. It has been reported that the temperature of an ISSN 0936-5214 908 C. C. Silveira et al. LETTER Table 1 Synthesis of 3,4-Dihydroisoquinolines and Isoquinolines by Microwave-Assisted Reaction of N-Sulfonyl Tetrahydroisoquinoline Derivatives with KF Supported on Alumina22 Entry R1 R2 R3 Dihydroisoquinolines Isoquinolines a b a b Time (t1, s) Yield (%) Time (t2, s) Yield (%) c 1 HHC6H5 10 60 20 56 2 HHtBu 15 71 30 73 3 -OCH2O- C6H5 10 87 30 86 d 4 -OCH2O- 3-MeO-C6H4 20 92 60 69 e 5 -OCH2O- 4-MeO-C6H4 ––12049 f 6 MeO MeO 4-MeO-C6H4 10 77 – – a Irradiation time at 490 W in a domestic microwave oven. b Isolated yield after column chromatography. c The resulting isoquinoline has been previously synthesized.14 d Conventional heating of the N-sulfonyl tetrahydroisoquinoline with KF/Al2O3 in toluene afforded the related 3,4-dihydroisoquinoline after a 48 h reflux period. e The resulting isoquinoline is a natural product isolated from Oocotea pulcella, mp 152–154 ºC (Lit.15 152–153 ºC). f The resulting 3,4-dihydroisoquinoline is O,O-dimethyl longifolonine, mp 91–92 ºC; IR and 1H NMR spectra are in agreement with those re- ported in the literature.16b alumina bath (heat sink) inside a Sears Kenmore micro- and submitted to microwave irradiation, with the results wave oven equipped with a turntable at full power (900 consigned in Table 2. » 17 W) was found to be 65 ºC after 30 s of irradiation; In the cases of N-sulfonyl N,S- and N,O- acetals (entries 1 therefore, the tetrahydroisoquinoline depicted in entry 4 and 2), it was observed that while the thio compound fur- of Table 1 was mixed with KF/Al2O3 and aliquots of the nished an isoquinoline with concomitant loss of the 1- resulting powder were heated at 90 ºC in an oil bath or thiophenyl moiety, the 3-methoxy tetrahydroisoquinoline heated under reflux in toluene. In the first case, no reac- quickly lost methanol, giving the related N-sulfonyl-1,2- tion was observed after heating for 24 h; in the experiment dihydroisoquinoline in good yield, but no isoquinoline employing toluene as solvent, however, it was noticed that was produced, even under prolonged microwave heating, at the same time the reaction consisted of a 2:1 mixture of which caused complete product decomposition. The 1- the 3,4-dihydroisoquinoline and the starting tetrahy- phenyl tetrahydroisoquinoline of entry 3, however, fur- droisoquinoline. Complete consumption of the starting nished the expected isoquinoline in moderate yield after 6 material was achieved in 48 h, but no 1-benzoylisoquino- minutes of irradiation. line could be detected, 3,4-dihydroisoquinoline being the the only reaction product. In addition, no reaction was ob- In contrast with the known base-promoted desulfonyla- served when the tetrahydroisoquinoline was submitted to tion of N-sulfonyl-1,2-dihydroisoquinolines in solu- 13a microwave irradiation in the absence of KF/Al O . tion, when compounds of entries 4–7 were irradiated, 2 3 poor yields of the corresponding isoquinolines were ob- Many 1-benzoylisoquinolines and 1-benzoyl-3,4-dihy- tained after comparatively long reaction times. Interest- droisoquinolines have been isolated from different plants. ingly, it has been reported the easy conversion of the N- Noteworthy, this strategy provides new alternatives for benzylsulfonyl dihydroisoquinolines of entries 5 and 6 the syntheses of these type of natural products and their into isoquinolines when treated with Raney Nickel.13c derivatives, as illustrated by the convenient elaboration of the unnamed base isolated from Oocotea pulcella,15 de- Not quite unexpectedly, a base-promoted retroaldol-like 20 picted in entry 5 and of O,O-dimethyl longifolonine,16 ob- reaction leading to an isoquinoline with simultaneous tained as shown in entry 6. dehydroxymethylation was observed when the 1-hy- droxymethyl-substituted dihydro- isoquinoline derivative In order to explore more in depth the scope of the above of entry 7 was exposed to microwave irradiation, hoping transformations, a series of N-sulfonyl-1,2-dihydroiso- to promote desulfonylation by assistance from the neigh- quinolines and N-sulfonyl-1,2,3,4-tetrahydroisoquino- 18 13 boring carbinolic oxygen. Isoquinolines obtained as lines was synthesized following Jackson’s protocol shown in entries 1 and 4–7 are known natural produts.13a,c,19 Synlett 2002, No. 6, 907–910 ISSN 0936-5214 © Thieme Stuttgart · New York LETTER Desulfonylation of N-Sulfonyl Tetrahydroisoquinolines with KF/Al2O3 909 Table 2 Synthesis of Isoquinolines by Microwave-Assisted Reaction of N-Sulfonyl Dihydro- and Tetrahydroisoquinoline Derivatives with KF Supported on Alumina Entry Substrate Time (s)a Product Yield (%)b 1c 30 63d 2 60 86e 3 360 65 4c 210 32f 5c 180 24g 6c 210 34f 7c 600 16d a Irradiation time at 490 W in a domestic microwave oven. b Isolated yield after column chromatography. c The resulting isoquinolines are natural products, displaying spectral data in agreement