SciELO - Scientific Electronic Library Online

Home Pagelista alfabética de revistas  

Servicios Personalizados




Links relacionados


Boletín de la Sociedad Chilena de Química

versión impresa ISSN 0366-1644

Bol. Soc. Chil. Quím. v.47 n.1 Concepción mar. 2002 



Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, (1113) Buenos Aires, Argentina. E-mail:

(Received: May 7, 2001 - Accepted: November 19, 2001)


Se intentó la síntesis de heterociclos nitrogenados conformacionalmente restringidos por medio de la reacción de Bischler-Napieralski y la modificación de Tsuda. Los resultados observados nos han llevado a especular sobre la naturaleza de los efectos que controlan el proceso de ciclación.

Palabras claves: Bischler-Napieralsky, Tsuda, heterociclos nitrogenados, ciclación, isoquinolonas, isoquinolinas.


An attempt was made to synthesize conformationally restricted nitrogen heterocycles by means of the Bischler-Napieralski reaction and Tsuda modification. Observed results prompted us to speculate on the nature of the effects which may be controlling such cyclization processes.

Key words: Bischler-Napieralsky, Tsuda, nitrogen heterocycles, cyclization, isoquinolones, isoquinolines.


Compounds of the benzylamine class are potent inhibitors of phenylethanolamine N-methyltransferase.1 Restriction of the amino methyl side chain through its incorporation into a ring framework as in 1,2,3,4-tetrahydroisoquinoline (THIQ) or 2,3,4,5-tetrahydro-1H-2-benzazepine (THAZ) enhances its potency as an inhibitor. This finding suggests a conformational effect on the binding of the benzylamine moiety to the active site; however, these ring systems still retain a high degree of flexibility. Full conformational restriction of the benzylamine side chain in analogues 1 leads to a loss in inhibitory potency. Conformational restriction of THIQ or THAZ employing a bridging unit not located above (or below) the ring system (as in 2) results in only slightly diminished activity as compared to THIQ itself (Figure 1).


Scheme 1
i) a-Bromoethylacetate, Zn; ii) H2, Pd/C (5%); iii) Curtius degradation; iv) Acylation reaction; v) EPP, 80ºC, 8 h; vi) Na2CO3, EtOH/H2O; vii) Cl2SO, NH4OH; viii) LiAlH4

Accordingly, our research was focused on the synthesis of compounds 3 and 4 (Scheme 1).

Flack and Lions2 have reported that isoquinolines such as 5 (Figure 2) may be obtained, in a low yield (15% R=CH3, 25% R=Ph), by refluxing a mixture of 1-acetyl or 1-benzoylamino-methylhydrindene and phosphorus pentoxide in dry xylene during 30 min or by heating the 1-acetyl-amine with phosphorous oxychloride and toluene under reflux for 50 min. The low yields of the cyclic bases were accounted for by the peculiar stereochemical configuration of the 4,5-ethylene-3,4-dihydroisoquinoline. Nevertheless, in 1973 it was documented that tricyclic amines 6 and 7 (Figure 3) were readily prepared by lithium aluminium hydride reduction of the corresponding lactams,3 synthesized in turn from the appropriate tricyclic ketones by Beckman rearrangement of the corresponding oxime or by Schmidt reaction.3



Sakane et al 4 resorted to a similar synthesis proposed by Rapoport and co-workers5 to prepare 7-carboxyindan-1-acetic acid 8 (Figure 4). This was converted into isoquinolone 9 in good yield. Likewise, Loewenthl et al 6 obtained 10.



Our successful preparation of isoquinolines7 using ethylpolyphosphate (EPP) in the Bischler-Napieralsky (B-N) synthesis encouraged us to prepare compounds 3 and 4 using this classic reaction (Scheme 1). Commercially available 5,6-dimethoxyindan-1-one was converted to the unsaturated ester 11 in a Reformatsky reaction with ethyl bromoacetate. Hydrogenation of 11 afforded 12, which was hydrolyzed to the acid 13 with potassium carbonate in ethanol/water. Acid 13 was converted, via its halide, to 14 which was reduced to 15 using lithium aluminium hydride and used in the following step without purification. Finally, acetyl and benzoyl derivatives 16 and 17 were obtained. The preparation of 18 was accomplished from 12 using a procedure previously described by us.8 Compounds 16, 17 and 18 were treated with EPP during 8 h at 80ºC.7 No reaction was observed for compounds 16 and 18. Compound 17 afforded the starting material together with decomposition products even at very different reaction conditions (1 h and 120ºC).

Therefore, by comparing these results with those observed by Flack and Lions,2 it is suggested that electronic factors, such as electron releasing groups in the benzenoid moiety, are not strong enough to achieve cyclization in these mild conditions. However, it cannot be ruled out that steric hindrance exerted by o-methoxy-group leads to the failure of the cyclization step. Our attention was then focused on common and uncommon structural features in 52 and 94 compounds. Thus, in both compounds the 5-membered ring is almost planar and lies in the plane of the benzene ring; C-1 should also lie in this plane, as well as C-3a. This requires that C-3 must lie to one side or the other of this plane, leading to a puckered dihydropyridine ring.

Quite likely, this peculiar stereochemical configuration could be obtained more easily from structure 9 rather than from 5. In view of this rationale, it appeared that a way to circumvent the cyclization problem could be found by replacing the C=N bond by the HN-C=O bond. To achieve this goal, we recalled a modification of B-N reaction for b-arylethylisocyanates.9 Treatment of acid 13 (Scheme 2) under Curtius conditions, with oxalyl chloride, sodium azide and refluxing benzene, afforded the isocyanate, which was cyclized by treatment with phosphorous oxychloride followed by stannic chloride, to the dihydroisoquinolone 19 in 18% yield. By means of this synthesis, C atom hybridization was changed in the intermediary implied in the cyclization step. In the B-N reaction this intermediary is a nitrilium ion (sp)10 (see Scheme 3). In the modification proposed by Tsuda,9 the reaction seems to proceed by initial activation of the isocyanate to an activated species (sp2) (see Scheme 2).

Scheme 2
i) (COCl)2, NaN3; ii) heat; iii) POCl3; iv) SnCl4; v) H2O

Scheme 3

This result is comparable to the one obtained by Flack and Lions2 using strong cyclodehydrating agents on amides in reactions mediated by the nitrilium ion.


Results achieved seem to indicate that neither the classic B-N (Scheme 1) reaction nor the modification proposed by Tsuda (Scheme 2) are adequate for the synthesis of these tricyclic amines. Apparently, these systems are only obtained with good yields from 1,7-disubstituted-indanes4-6 or by using concerted intramolecular rearrangements.3 Since the approach of the nucleophile (the aromatic ring) to the electrophile is similar for an endo dig (nitrilium) or endo trig process (C=N)11 and that, for both types of processes, tricyclic systems may be obtained by using strong cyclodehydrating agents, even though in low yields (19 and 5), the failure to obtain 3 and 4 is attributable to the use of a relatively mild cyclodehydrating agent (EPP). Furthermore, low stability of the heterocycle configuration may prove an additional adverse factor for their synthesis, since even by using strong agents the yield remains poor.



Infrared spectra were performed on a Jasco A200 spectrometer as mulls or neat. 1H NMR spectra were recorded on a Bruker AC 200 or Bruker MSL 300 spectrometer using CDCl3 as solvent. Chemical shifts are reported in ppm units, and coupling constants (J) are in Hz. Mass spectra were obtained on a VG-ZAB spectrometer. Melting points (uncorrected) were obtained on a Thomas Hoover apparatus. Merck silica gel 60 GF254 was used for preparative thin-layer chromatography (PTLC). Solvents and reagents were purified using standard procedures.

2-(5,6-Dimethoxyindanyl)acetic acid 13

A solution of the ester 128 (1g, 3.7 mmol), K2CO3 (1.8 g) in EtOH (17 ml) and H2O (14 ml) was heated at reflux for 15 h and then evaporated under reduced pressure. The residue was taken in aqueous NaOH (10%) and the basic extract was washed with CHCl3. The aqueous phase was made acid with HCl cc. until pH 1.0 and the solid obtained was filtered, washed with water and dried. The residue was recrystallized with EtOH:H2O (1:1) to give 13 (0.759 g, 85 %), mp 150-151ºC; nmax/cm-1 3200-3300 (OH), 1700 (C=O); dH1.80 (1H, m, HC-2´), 2.45 (2H, m), 3.55 (1H, m, HC-1´), 3.85 (3H, m), 3.90 (6H, s, OCH3), 6.70 (1H, s, ArH), 6.75 (1H, s, ArH) (Found: C, 66.32; H, 6.92. C13H16O4 requires C, 66.09; H, 6.83).

2-(5,6-Dimethoxyindanyl)acetamide 14

To a solution of 13 (1 g, 4.2 mmol) in dry benzene (20 ml) was added SOCl2 (1.5 ml). The solution was stirred at reflux for 3 h and then concentrated in vacuo. The residue thus obtained was dissolved in THF (25 ml) and then poured over an aqueous solution of NH4OH (28%) (20 ml). The mixture was stirred at room temperature for 1 h, concentrated in vacuo to yield 14 as a solid, which was recrystallized from EtOH:H2O (1:1) (0.838 g, 85%), mp 166-167ºC;nmax/cm-1 3100-3500 (NH), 1650 (C=O); dH 1.85 (1H, m), 2.40 (2H, m), 2.65 (1H, dd, J 6.5 and 15.0), 2.90 (2H, m), 3.60 (1H, m) 3,90 (6H, s), 5.45 (2H, brs), 6.78 (1H, s), 6.79 (1H, s); m/z 236 (M++1, 10.1%), 235 (M+, 61,1), 177 (100) (Found: C, 66.51, H, 7.19; N, 6.01. C13H17NO3 requires C, 66.36; H, 7.28; N, 5.95).

N-Acetyl-(5,6-dimethoxyindanyl)methylamine 18

To a solution of (5,6-dimethoxyindanyl)methylamine8 (0.55g, 2.26 mmol) in benzene (5 ml) was added (C2H5)3N (0.4 ml) and distilled acetyl chloride (0.4 ml). The mixture was stirred at reflux for 2h, then cooled, diluted with water and extracted with CHCl3 (3x30 ml). The organic phase was washed with aqueous NaOH (5%) (10 ml), aqueous HCl (5%) (10 ml), H2O (10 ml), dried (MgSO4) and concentrated in vacuo to render 18 as an oil (330 mg, 45%); dH 1.70-2.40 (2H, m), 1.90 (3H, s), 2.70-3.00 (2H, m), 3.30 (2H, m), 3.60 (1H, m), 3.90 (6H, s), 5.70 (1H, brs), 6.80 (2H, brs) (Found: C, 67.30, H, 7.48; N, 5.57. C14H19NO3 requires C, 67.45; H 7.68; N 5.62).

7,8-Dimethoxy-3, 3a, 4, 5-tetrahydrocyclopent[de]isoquinolin-1(2H)-one 19

To a solution of 13 (400 mg, 1.69 mmol) in dry benzene (15 ml) was added oxalyl chloride (1.5 ml). The mixture was stirred at room temperature for 12 h and then concentrated in vacuo. The residue thus obtained was dissolved in acetone (10 ml) and the solution dropped on a stirred and cooled (0 ºC) solution of sodium azide (4 g) in H2O (10 ml). After one hour, the mixture was extracted with benzene (3x10 ml). The organic phase was washed with H2O, dried (MgSO4) and concentrated in vacuo to render the isocyanate which, without further purification, was treated with phosphorous oxychloride (6.5 ml) and heated at 90 ºC for 1h. The excess of the reactive was removed in vacuo and the residue dissolved in CH2Cl2 (10 ml). To the solution was added SnCl4 (200 mg) in CH2Cl2 (2 ml) and the mixture stirred at room temperature for 2 h. The solution was diluted with CH2Cl2, washed with aqueous HCl (5%), aqueous NaHCO3 (5%), H20, dried (MgSO4) and evaporated in vacuo. Purification by PTLC (CHCl3:MeOH) (9:1) yielded 19 as an oil (75.74 mg, 18%); dH(acetone-d6) 2.35 (2H, m), 2.90-3.70 (5H, m), 3.80 (3H, s), 3.85 (3H, s), 6.60 (1H, brs, NH), 7.10 (1H, s); m/z 234 (M++1 5.6 %), 233(M+ 54.9), 218 (15.5), 205 (15.1), 104 (100.0), 177 (7.1) (Found: C, 66.78, H, 6.40; N, 5.79. C13H15NO3 requires C, 66.94; H 6.48; N, 6.00).

2-(5,6-Dimethoxyindanyl)ethylamine 15

A mixture of 14 (500 mg, 2.12 mmol) and LiAlH4 (300 mg) in dry THF (20 ml) was heated at reflux for 8 h. The reaction was stopped by adding EtOH-H2O (caution). The mixture was filtered through Celite and the filtrate extracted with CHCl3 (3x50 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure to render 15 (300 mg, 64%), which was used without further purification.

N-Acetyl-2-(5,6-Dimethoxyindanyl)ethylamine 16

To a solution of the amine 15 (500 mg, 2.26 mmol) in dry benzene (5 ml) was added acetic anhydride (0.5 ml) with stirring at room temperature during 2 h, then concentrated in vacuo. The residue was taken in CH2Cl2 and washed with aqueous NaOH (5%) (3x20 ml), H2O (2x10 ml), dried (MgSO4) and concentrated in vacuo to render 16 as an oil (500 mg, 85%); dH 1.55 (1H, m), 1.65 (1H, m), 2.00 (3H, s), 2.20 (3H, s), 2.20 (2H, m), 2.80 (2H, m), 3.10 (1H, m), 3.30-3.40 (2H, m) 3.82 (3H, s), 3.83 (3H, s), 5.80 (1H, brs), 6.73 (1H, s), 6.74 (1H, s); m/z 234 (M++1 12.7 %), 263(M+ 66.3), 117 (100) (Found: C, 68.60; H, 8.12; N, 5.25. C15H21NO3 requires C, 68.42; H, 8.04; N, 5.32).

N-Benzoyl -2-(5,6-Dimethoxyindanyl)ethylamine 17

To a solution of the amine 15 (500 mg, 2.26 mmol) in dry benzene (5 ml) was added benzoyl chloride (1.0 ml) with stirring at room temperature during 2 h, then concentrated in vacuo. The residue was taken in CH2Cl2 and washed with aqueous NaOH (5%) (3x20 ml), H2O (2x10 ml), dried (MgSO4) and concentrated in vacuo to render 17 as an oil (350 mg, 47%); dH 1.75 (2H, m), 2.15 (1H, m), 2.35 (1H, m), 2.85 (2H, m), 3.20 (1H, m), 3.55-3.65 (2H, m), 3.83 (3H, s), 3.84 (3H, s), 6.25 (1H, brs), 6.80 (2H, s), 7.40 (3H, m), 7.70 (2H, dd, J 8.0 and 1.5); m/z 326 (M++1 23.0 %), 325(M+ 100), 177 (50.6) (Found: C, 73.93, H, 7.23; N, 4.23. C20H23NO3 requires C, 73.82; H, 7.12; N, 4.30.


Financial support from SECYT (Universidad de Buenos Aires) through grant Nº. FA 056 and from CONICET (Argentina) is gratefully recognized.


1) Grunewald, G. L; Sall, D. J.; Monn, J. A.; J. Med. Chem. 1988, 31, 433.        [ Links ]

2) Flack, A.; Lions F.; J. Proc. Roy. Soc. N. S. Wales, 1949, 253.        [ Links ]

3) Evans, A. D.; Weale, J.; Weyell, D. J.; Aust. J. Chem., 1973, 26, 1333.        [ Links ]

4) Sakane, K.; Oda, S.; Haruki, E.; Otsuji, Y.; Imoto, E.; Bull. Chem. Soc. Japan, 1974, 47, 2515.        [ Links ]

5) Rapoport, H.; Pasky, J. Z.; J. Am. Chem. Soc., 1956, 78, 3788.         [ Links ]

6) Eli Loewenthal, H. J.; Schatzmiller, S; J. Chem. Soc. Perkin I, 1976, 944.        [ Links ]

7) Alesso, E. N.;. Aguirre, J. M;. Tombari, D. G; Ibañez, A. F.; Moltrasio Iglesias, G.Y. ; Trends in Heterocyclic Chemistry, 1993, 3, 95.        [ Links ]

8) Tombari, D. G.; Moglioni, A. G.; Dominici, F. P.; G. Y. Moltrasio Iglesias; Organic Preparation and Procedures International; 1992, 24(1), 45.        [ Links ]

9) Tsuda, Y.; Isobe, K.; Toda, J.; Taga, J.; Heterocycles, 1976, 5, 157.        [ Links ]

10) Nagubandi, S.; Fodor, G.; J. Het. Chem., 1980, 17, 1457.         [ Links ]

11) Baldwin, J. E.; J. Chem. Soc., Chem. Comm.,1976, 734.        [ Links ]

Creative Commons License Todo el contenido de esta revista, excepto dónde está identificado, está bajo una Licencia Creative Commons