Synthesis of heterocyclic compounds via 1,3-dipolar cycloaddition and 1,7-electrocyclisation reactions of azomethine ylides

Transcription

1 Synthesis of heterocyclic compounds via 1,3-dipolar cycloaddition and 1,7-electrocyclisation reactions of azomethine ylides D Thesis Andrea Virányi Supervisor: Miklós yerges, D, DSc Department of rganic Chemistry and Technology Budapest University of Technology and Economics 2007

2 Introduction and aims From the 80 s on the Technical University there have been much research carried out on 1,3-dipolar cycloaditions of azomethine-ylides. 1,3-dipoles were prepared from dihydroisoquinoline salts and their reactions examined. Meanwhile research on their electrocyclisations was started. In my work I have studied some new fields of application cycloadditions and electrocyclisations of these dipoles. My work can be divided to the following sections: Experiments on cycloadditions: -Synthesis of pyrrolo[3,4-c]quinolines A new route to the pyrrolo[3,4-c]quinoline (3) ring system has been developed. The synthesis proceeds stereoselectively in three steps, using 1,3-dipolar cycloaddition of azomethine ylides as the key step. -Synthesis of benzopirano[3,4-c]-pyrrolidines The abundance of naturally occuring chromene and chromane derivatives and their interesting physiological properties along with the known selective dopamine D3 receptor antagonist action of some benzopirano[3,4-c]pyrrolidine derivatives suggested the study of easily available 2-aryl-3-nitrochromene derivatives as 2π components in 1,3-dipolar cycloadditions of azomethine ylides. Experiments on electrocyclisations: -Synthesis of pyrrolo[3,4-c]quinolines by 1,5-electrocyclisation Among the quinolines 2-chloro-3-formylquinolines occupy a prominent position as they are key intermediates for further [b]-annelation of a wide variety of rings and for various functional group interconversions. The applications of these methodologies have yielded beside a large number of new quinoline derivatives new synthetic approaches for alkaloids such as camptothecin, luotonin A, or nothapodytine. -Synthesis of benz[5,6]azepino[4,3-b]indoles by 1,7-electrocyclisation In our expriments we have observed reaction of the analogous azomethine ylides formed from 2-aryl-indol-3-carbaldehydes. In these conjugated dipoles the 1,5-electrocyclisation pathway is not accessible. 2

3 -Synthesis of Indazole--oxides via 1,7-Electrocyclisation As part of our continuing work on the synthesis of the pyrrolo[3,2-c]quinoline ring system of the martinelline alkaloids (bradykinin receptor antagonist) we investigated the formation and reactions of a non-stabilised azomethine ylide. This azomethine ylide was formed by the reaction of o-nitrobenzaldehyde with sarcosine in refluxing benzene and, despite the presence of a large excess of active dipolarophiles, for example, ethyl acrylate or methyl vinyl ketone, we did not observe any trace of the expected cycloadduct in the 1 MR spectrum of the crude reaction mixture, but two products, an indazole--oxide and an oxazolidine were, isolated after chromatographic separation. In my work I made some experiments with these reactions. Results Dipolar cycloadditions of azomethine-ylides 1. A new route to the pyrrolo[3,4-c ]quinoline ring system has been developed. The synthesis proceeds stereoselectively in three steps, using 1,3-dipolar cycloaddition of azomethine ylides as a key step. 4,6 First, a series of 4-aryl-pyrrolidine-3-carboxylic acid was prepared from the appropriate cinnamic esters and a non-stabilised azomethine ylide (Scheme 1). The reduction of nitro group on the aromatic ring was followed by the acid catalyzed intramolecular lactame formation (Scheme 2). 4,6 RC 2 C 2 (C 2 )n R R 4 R 3 C 2 Et R 4 R R 3 C 2 Et Scheme 1 1 3

4 R R R R 4 R 3 2 C 2 Et 1 Pd/C 2 R 4 R 3 2 C 2 Et 2 Scheme 2 PTSA Et R ,3-dipolar cycloadditions of azomethine ylides with 2 - aryl nitrochromenes were used to develop a new procedure for the synthesis of benzopyrano[3,4-c]pyrrolidine derivatives. 8,12 The 3-nitrochromene derivatives (6) were prepared from the corresponding 2-aryl-nitroethylenes (5) by the treatment with salicylaldehyde (4) (Scheme 3). 8,12 Scheme 3 In the first set of experiments we used the most simple non-stabilized azomethine ylides, which were generated from paraformaldehyde and sarcosine or -benzyl-glycine using the decarboxylation method. The reaction of 3-nitrochromenes with these unstable intermediates in refluxing toluene proceeds smoothly to give the expected 3a-nitro-4-aryl-benzopirano[3,4-c]-pyrrolidines (7) (Scheme 4). 8,12 Scheme 4 4

5 Cycloaddition of 6 to azomethine ylides derived from the imines of ethyl glycinate or phenylalanine ethylester in the presence of AgAc and Et 3 gives pure benzopirano[3,4-c]-pyrrolidine derivatives 9 in 60 77% yield (Scheme 5). 8,12 Scheme 5 Subsequently I prepared the azomethine ylides from sarcosine methyl ester and benzaldehyde (Sheme 6). 8,12 MeC 2 C 2 Me +C - 2 Me 2 C Me Me C 2 Me Scheme ,3-Dipolar cycloadditions of azomethine ylides derived from the isoquinolinium salt (11) by deprotonation have previously been studied by us. Cycloaddition of 3-nitrochromenes with the azomethine ylide derived from the isoquinolinium salt 11 gave rise to cycloadducts (12) in virtually quantitative yield as a single diastereoisomer. owever, as observed during the early experiments, in the presence of oxygen, the solution of 12 transforms into the pyrrole derivative 13 at room temperature in a short period of time (Scheme 7). 8,12 5

6 6 2 + Me Me 11 Br C 2 Me Et 3 Me 2 C 2 Me Me = = - 2 Me 2 C Me Me 12 Scheme 7 13 Electrocyclisations of azomethine ylides 3. I synthetized pyrrolo[3,4-c]quinolines from 2-chloro-3-formylquinolines by a 1,5-electrocyclisation reaction. 5,10 The quinolines 14a c were prepared from the corresponding acetanilides. The non-stabilized azomethine ylides 15 were generated from the aldehydes 14a c by decarboxylation. The reaction of 2-chloro-3-formylquinolines (14a c) with sarcosine gave 2-methyl-2,4,5,9b-tetrahydro-1-pyrrolo[3,4-c]-quinolin-4-ones (16a c) in acceptable yields via the expected 1,5-electrocyclisation reaction accompanied by hydrolysis of the chlorine function under the applied reaction conditions in the presence of the water formed in the first step. The reaction of the quinolines 17a c with sarcosine gave 2-methyl-4-phenyl-1-pyrrolo[3,4-c]quinolines as products in moderate yields. The 1,5-electrocyclisations in these cases were followed by full aromatisation to the tetrahydro-1-pyrrolo[3,4-c]quinoline (18a c) ring system (Scheme 8). 5,10 6

7 Scheme 8 The intermediacy of azomethine ylides 15 was shown by trapping the proposed dipoles with -phenylmaleimide to give the two isomeric cycloadducts 231 and 242 (endo exo ratio -1:1) in a quantitative yield (Scheme 9). 5,10 227a-c 236b C Me C 2 =Cl = Me Me Scheme 9 7

8 4. I synthetized benz[5,6]azepino[4,3-b]indoles from 2-aryl-3-formylindoles by 1,7-electrocyclisation reaction. 9 In our next expriments we have observed the reaction of the analogous azomethine ylides formed from 2-aryl-indol-3-carbaldehydes 21 and 22. In these conjugated dipoles the 1,5-electrocyclisation pathway is not accessible. The nonstabilised azomethine ylides were generated from the aldehydes in refluxing xylene using the method of decarboxylative condensation with sarcosine or -benzyl-glycine. The azomethine ylide intermediates reacted via the expected 1,7-electrocyclisation reaction to azepines, and finally by a 1,5-hydrogen shift to give the products 23 (Scheme 10). C C 2 C 2 C 2 = Me,Bn 21 = 22 =Me 23 Scheme I realized successfully the synthesis of indazole- -oxides by electrocyclisation of 6,7-dimethoxy-dihydroisoquinolines. 7 To our surprise, in spite of the presence of a large excess of active dipolarophiles, such as ethyl acrylate or methyl vinyl ketone, we could not observe any trace of the expected cycloadducts in the 1 MR spectrum of the crude reaction mixture. owever, two products, an indazole--oxide (25) and an oxazolidine (24) were isolated by chromatography (Scheme 11). C 3 C 2 + C 3 C 2 C C 3 Scheme 11 8

9 We next chose to form the azomethine ylides from 6,7-dimethoxy-3,4-dihydro--(2-nitrobenzyl)isoquinolinium chloride 27 by dehydrohalogenation with triethylamine (Scheme 12). In the presence of -phenylmaleimide a 2:1 mixture of the cycloadduct 29 and indazole--oxide 31 was obtained, while in the absence of the dipolarophile the -oxide 31 was formed in quantitative yield. In contrast to the example described above, in this case the aldehyde arising from the fragmentation (which in this example is attached to the indazole component) is not sufficiently reactive to act as a dipolarophile in a 1,3-dipolar cycloaddition process in competition with the 1,7-electrocyclisation. Me Me 27 Cl 2 Et 3 Me Me 28 2 Me Me 30 Me Me 26 Me Me 2 29 Scheme 12 Me Me C In support of the proposed mechanism I performed the next series of experiments with 6,7-diethoxy-3,4-dihydro-1-(2-nitrophenyl)--substitutedisoquinolinium bromides. 7 In all experiments the isoquinoline fused indazole--oxide was formed. In one case (R=C2C3) the competitive formation of the 1,3-dipolar cycloadduct 37 as a single isomer due to the high reactivity of the electron-deficient C= double bond of the byproduct aldehyde was found. 9

10 Scheme I prepared indazole- -oxides in annellation with β -carbolines by electrocyclisation. 7,11 We also formed the azomethine ylide 41 from 2-allyl-1-(2-nitrophenyl)-4,9- dihydro-3-β-carbolinium bromides 40 by dehydrohalogenation with triethylamine. The reaction of the quaternary salts 40 with triethylamine at room temperature in ethanol provided the expected products i.e. 3,13-dihydro-7-indazolo[3,2-a]-βcarboline-5--oxides 43 (scheme 14). PCl C 2 =CC 2 Br Br 2 Et 3 2 -C 2 =CC Scheme 14 10

11 PUBLICATIS 1. yerges, M.; Fejes, I.; Virányi, A.; Groundwater, P.W.; Tõke, L.; A ew Convenient Synthesis of 2-Dimethylamino-1-Arylethanols Synthesis 2001, 1479.(IF:1.985) 2. yerges, M.; Fejes, I.; Virányi, A.; Groundwater, P.W.; Tõke, L.; Synthesis of Indazole--xides via the 1,7-Electrocyclisation of Azomethine Ylides Tetrahedron Lett. 2001, 42, (IF:2.280) 3. yerges, M.; Virányi, A.; Pintér, Á.; Tõke, L.; 1,7-Electrocyclisations of Stabilised Azomethine Ylides Tetrahedron Lett., 2003, 44, 793. (IF:2.326) 4. Pintér, Á.; yerges, M.; Virányi, A.; Tõke, L.; Synthesis of Pyrrolo[3,4- c]quinolines by 1,5-Electrocyclisation of on-stabilised Azomethine Ylides Tetrahedron Lett., 2003, 44, (IF:2.326) 5. yerges, M.; Virányi, A.; Tõke, L.; A Convenient Synthesis of Pyrrolo[3,4- c]quinolines eterocyclic Communication, 2003, 239. (IF:0.342) 6. Virányi, A.; yerges, M.; Blaskó, G.; Tőke L.; A Convenient Synthesis of Pyrrolo[3,4-c]quinolines Synthesis 2003, (IF:2.074) 7. yerges, M.; Virányi, A.; Zhang, W.; Groundwater, P.W.; Blaskó, G.; Tõke, L.; Synthesis of Indazole--xides via the 1,7-Electrocyclisation of Azomethine Ylides - Tetrahedron 2004, 60, (IF:2.643) 8. yerges, M.; Virányi, A.; Marth G.; Dancsó A.; Blaskó G.; Tőke L.; 3- itrochromene Derivatives as 2π Components in 1,3-Dipolar Cycloadditions of Azomethine Ylides Synlett 2004, (IF:2.738) 9. yerges M., Pintér, Á. Virányi A., Bitter I., Tőke L.; Synthesis of Benz[5,6]azepino[4,3-b]indoles by 1,7-Electrocyclisation of Azomethine Ylides Tetrahedron Lett., 2005, 46, 377. (IF:2.477) 10. yerges, M.; Pintér, Á.; Virányi, A.; Blaskó, G.; Tõke, L.; Synthesis of Pyrrolo[3,4-c]quinolines by 1,5-Electrocyclisation of on-stabilised Azomethine Ylides Tetrahedron 2005, 61, (IF:2.477) 11. yerges, M.; Virányi, A.; Tóth, J.; Blaskó, G.; Tõke, L.; Synthesis of ew β- Carboline Derivatives via 1,7-Electrocyclisation of Azomethine Ylides - Synthesis 2006, (IF:2.333) 12. Virányi, A.; Marth G.; Dancsó A.; Blaskó G.; Tőke L.; yerges, M.; 3- itrochromene Derivatives as 2π Components in 1,3-Dipolar Cycloadditions of Azomethine Ylides Tetrahedron 2006, 62, (IF:2.817) 11

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