Pictet-Spengler cyclization vs. Aminal formation: Competing reaction pathways of benzo[b][1,7]naphthyridines controlled by the configuration

Article abstract of DOI:10.1002/1522-2675(20010711)84:7<2064::AID-HLCA2064>3.0.CO;2-Y

Diastereoisomeric benzo[b][1,7]naphthyridines 13a,b were synthesized in nine steps from L-DOPA employing a Lewis acid-catalyzed cyclization of N-(4-methylpent-3-enyl)-a-amino aldehydes as the key step. Under aprotic Pictet-Spengler conditions, compounds 13a,b undergo different reaction pathways depending on the relative configuration. Whereas trans,cis-diastereoisomer 13a yielded the desired Pictet-Spengler cyclization product albeit in very low yield, the corresponding concave-shaped all-cis-diastereoisomer 13b undergoes intramolecular animal formation.

Full text of DOI:10.1002/1522-2675(20010711)84:7<2064::AID-HLCA2064>3.0.CO;2-Y

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Helvetica Chimica Acta ± Vol. 84 (2001)
Pictet-Spengler Cyclization vs. Aminal Formation:
Competing Reaction Pathways of Benzo[b][1,7]naphthyridines Controlled
by the Configuration
by Tim Dickner and Sabine Laschat*
Dedicated to Professor Burchard Franck on the occasion of his 75th birthday
Institut für Organische Chemie, Technische Universität Braunschweig, Hagenring 30, D-38106 Braunschweig
(Fax: ‡49-(0)531-3915388, e-mail: s.laschat@tu-bs.de)
Diastereoisomeric benzo[b][1,7]naphthyridines 13a,b were synthesized in nine steps from l-DOPA
employing a Lewis acid-catalyzed cyclization of N-(4-methylpent-3-enyl)-a-amino aldehydes as the key step.
Under aprotic Pictet-Spengler conditions, compounds 13a,b undergo different reaction pathways depending on
the relative configuration. Whereas trans,cis-diastereoisomer 13a yielded the desired Pictet-Spengler cyclization
product albeit in very low yield, the corresponding concave-shaped all-cis-diastereoisomer 13b undergoes
intramolecular aminal formation.
Introduction. ± There has been considerable interest in protoberberine alkaloids,
such as coralyne (1), berberine (2), and canadine (3) (Scheme 1), due to their
important pharmacological activities [1]. We considered that the structurally related
benz[b]isoquinolino[2,3-h]naphthyridine 5 might be potentially useful as a proto-
berberine mimic. During earlier studies, we observed that analogues of 5 display
promising in vitro cytotoxicity against human-brain-tumor cell lines [2]. Regarding the
synthesis of 5, we decided to apply a sequence of Lewis acid-catalyzed cyclization [3] of
l-DOPA-derived precursor 6, followed by Pictet-Spengler reaction [4] as the key steps.
It was anticipated that this route should be more amenable to variations of the
substitution pattern than the previously employed route with tetrahydroisoquinolinic
acid 4 as the precursor [2]. However, during our investigations we discovered that the
benzo[b][1,7]naphthyridines 13 obtained from the Lewis acid-catalyzed cyclization of 6
underwent different reaction pathways depending on the relative configuration. In
other words, either stereospecific aminal formation or Pictet-Spengler reaction was
observed. The results of this study are reported below.
Results and Discussion. ± To prepare the desired cyclization precursor 6, l-DOPA
was first converted to (S)-3-(3,4-dimethoxyphenyl)alanine (7) in 57% yield according
to the procedure of Tsuda et al. (Scheme 2) [5]. N-Alkylation of 7 was effected with 5-
bromo-2-methylpent-2-ene and CaO in DMF to give the amino acid derivative 8 in
57% yield. Further N-benzylation was achieved in the presence of K2CO3 and Bu4NI in
DMF in 93% yield. The resulting fully protected ester 9 was then reduced with LiAlH4
to give the alcohol 10. Swern oxidation of 10 proceeded without any event to give the
aldehyde 11 [6]. To prevent racemization, compound 11 was immediately submitted to

Helvetica Chimica Acta ± Vol. 84 (2001)
2065
Scheme 1
the one-pot imine formation/cyclization conditions. Thus, imine 6 was generated in situ
from 11 and 4-chloroaniline in the presence of 4-Š molecular sieves. After removal of
the molecular sieves, the mixture was treated with EtAlCl2 to induce the cyclization.
Unfortunately, poor stereoselectivity was observed, and the diastereoisomers 12a and
12b were obtained in 28 and 26% yield, respectively. 4-Chloroaniline was used instead
of aniline, because the 7-Cl-substituted benzo[b][1,7]naphthyridines 12a,b could be
separated more easily by flash chromatography than the corresponding 7-H derivatives.
Debenzylation of the diastereoisomeric products 12a,b was achieved by catalytic
hydrogenation at elevated pressure according to a modified procedure by Jung et al.
[7]. Under these conditions, the Cl substituents were also removed [8], and the desired
compounds 13a,b were isolated in almost quantitative yield.
Our first attempts to perform the Pictet-Spengler cyclization under classical
conditions employing aqueous HCHO solution and HCOOH (or HCl) were
unsuccessful [4][9]. Only decomposition of starting material was observed. We
assumed that, at least partially, the trouble was caused by the secondary arylamine,
although it should be less basic and thus less nucleophilic. However, Cook and co-
workers reported the successful preparation of b-carbolines under aprotic conditions
employing N-benzyltryptophane derivatives with an unprotected indole N-atom [10].
Encouraged by these results, the diastereoisomeric benzo[b][1,7]naphthyridines 13a,b
were treated separately with paraformaldehyde and toluene at 1108. Remarkably, the
course of the reaction depended on the configuration. The cis,trans-configured
diastereomer 13a gave indeed the desired pentacyclic Pictet-Spengler adduct 5a,

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Helvetica Chimica Acta ± Vol. 84 (2001)
Scheme 2
a) Ac2O, HCO2H. b) Me2SO4, NaOH, H2O. c) AcCl, EtOH. d) BrCH2CH2CHˆC(CH3)2, CaO, DMF, r.t., 6 d.
e) BnBr, TBAI, K2CO3, DMF, 1008, 2d. f) LiAlH4, Et2O, r.t., 12 h. g) (COCl)2, DMSO, CH2Cl2, 458, Et3N, 6 h.
h) Mol. sieves (4 Š), 4-chloroaniline, CH2Cl2, r.t., 2 d; EtAlCl2, 788 ! r.t., 2 d. i) H2 (10 atm), Pd/C, EtOH,
608, 12 h. j) (CH2O)n, toluene, 1108, 15 h.
however, with a very low yield. Evidently, Pictet-Spengler cyclization was accompanied
by massive decomposition of the starting material. In contrast, similar treatment of the
all-cis-diastereoisomer 13b yielded the bridged aminal 14 in 44% yield. No trace of the

Helvetica Chimica Acta ± Vol. 84 (2001)
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corresponding Pictet-Spengler product was found in this case. Despite the presence of
an activated aromatic system, the initially formed iminium ion is exclusively attacked
by the aryl amine. Aminal formation and N-chloromethylation are common problems
in alkaloid chemistry, which usually occur during isolation and extraction from natural
sources [3a][11]. However, the above mentioned case seems to be the first example
where aminal formation competes with Pictet-Spengler cyclization. The configuration
dictates the pathway. In diastereoisomer 13a, the two N-atoms are antiperiplanarly
oriented, thus making the intramolecular aminal formation impossible. In contrast, in
diastereoisomer 13b, the N-atoms are oriented in a gauche position with respect to each
other, thus favoring the formation of the diazabicyclo[3.2.1]octane subunit.
In conclusion, despite suitable activation by two MeO groups aprotic Pictet-
Spengler cyclization of benzo[b][1,7]naphthyridines 13a,b is strongly retarded.
Depending on the relative configuration of 13, different pathways were observed.
The cis,trans-configured diastereoisomer 13a yielded the desired pentacyclic proto-
berberine analogue 5a only in small amounts. In contrast, under similar conditions the
corresponding all-cis-configured precursor 13b undergoes exclusively aminal formation
to the brigded compound 14.
Generous financial support by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen
Industrie is gratefully acknowlegded.
Experimental Part
General. All reactions were performed under N2 according to the standard Schlenk technique. 5-Bromo-2-
methylpent-2-ene was prepared according to [12]. M.p.: obtained by differential scanning calorimetry;
Rheometric Scientific DSC SP, heating rate: 10 K min 1. IR Spectra: Nicolet 320 FT-IR spectrometer. NMR
Spectra: Bruker AM-400; d in ppm and J in Hz. Configurational assignments are based on 2D NMR (COSY, CH
correlation) and 1D-NOE experiments. MS: Finnigan MAT 8430 (EI, 70 eV).
(S)-3-(3,4-Dimethoxyphenyl)alanine Ethyl Ester (7). To a soln. of l-DOPA (10.0 g, 50.0 mmol) in HCOOH
(90 ml, 90 wt%) was added Ac2O (30 ml), and the mixture was stirred for 3 h at r.t. The mixture was evaporated
to dryness, redissolved in H2O (50 ml), and the evaporation/solution procedure was repeated 7 Â . The residue
was dissolved in 10n NaOH (15 ml), and freshly dest. Me2SO4 (9.50 ml, 0.10 mol) was added dropwise under ice-
cooling, while adjusting pH to 5 ± 9 by simultaneous addition of 10n NaOH. After stirring for 30 min, Me2SO4
(28.5 ml, 0.30 mol) was added, and stirring was continued for 1.5 h. Then, the pH was adjusted to 2 by careful
addition of 8n H2SO4 (10 ml), the mixture was extracted with AcOEt (3 Â 200 ml) and evaporated. The residue
was dissolved in EtOH (130 ml). After addition of AcCl (28 ml), the mixture was stirred for 3 h at r.t. and then
evaporated. The residue was redissolved in H2O (50 ml), and the aq. layer was extracted with CH2Cl2 (3 Â
50 ml). The combined organic layers were dried (MgSO4) and evaporated to give 7 (7.23 g, 57%). Pale yellow
oil. 1H-NMR (400 MHz, CDCl3): 6.82 ± 6.73 (m, 3 H); 4.17 (q, J ˆ 7.4, 2 H); 3.87 (s, 3 H); 3.85 (s, 3 H); 3.73
(dd, J ˆ 7.4, 5.4, 1 H); 3.05 (dd, J ˆ 13.3, 5.4, 1 H); 2.86 (dd, J ˆ 13.3, 7.4, 1 H); 2.14 (s, 2 H); 1.26 (t, J ˆ 7.4, 3 H).
13C-NMR (100 MHz, CDCl3): 174.6; 148.9; 147.9; 129.4; 121.4; 112.4; 111.2; 61.0; 55.9; 55.8; 55.7; 40.2; 14.1.
(S)-N-(4-Methylpent-3-enyl)-3-(3,4-dimethoxyphenyl)alanine Ethyl Ester (8). To a soln. of 7 (6.32 g,
25.0 mmol) in DMF (25 ml) were added CaO (3.50 g, 62.5 mmol) and 5-bromo-2-methylpent-2-ene (4.48 g,
27.5 mmol), and the resulting mixture was stirred for 6 d at r.t. After filtration via Celite, the solvent was
evaporated and the crude product was purified by flash chromatography (FC) (SiO2; hexanes/AcOEt 5 :1, then
7:3) to give 8 (4.79 g, 57%). Colorless oil. IR (film) 3320, 1732. 1H-NMR (400 MHz, CDCl3): 6.80 ± 6.71
(m, 3 H); 5.02 (tq, J ˆ 7.1, 1.4, 1 H); 4.11 (dq, J ˆ 7.2, 2 H); 3.86 (s, 3 H); 3.85 (s, 3 H); 3.48 (t, J ˆ 6.9, 1 H); 2.89
(d, J ˆ 6.9, 2 H); 2.60 (dt, J ˆ 10.9, 7.3, 1 H); 2.47 (dt, J ˆ 10.9, 7.0, 1 H); 2.14 (ddd, J ˆ 7.0, 7.0, 7.0, 2 H); 1.66
(br. s, 1 H); 1.66, 1.59 (s, 6 H); 1.19 (t, J ˆ 7.2, 3 H). 13C-NMR (100 MHz, CDCl3): 174.5; 148.7; 147.7; 133.5;
‡
129.8; 121.5; 121.2; 112.3; 111.1; 63.2; 60.5; 55.8; 55.7; 47.9; 39.2; 28.7; 25.6; 17.7; 14.2. EI-MS: 335 (1, M ), 266
(100), 262 (20), 192 (44), 184 (56), 151 (31), 110 (30), 83 (17). EI-HR-MS: 335.2097 (calc. for C19H29NO4;
found: 335.2088).

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Helvetica Chimica Acta ± Vol. 84 (2001)
(S)-N-Benzyl-N-(4-methylpent-3-enyl)-3-(3,4-dimethoxyphenyl)alanine Ethyl Ester (9). To a soln. of 8
(1.68 g, 5.00 mmol) in DMF (5 ml) were added K2CO3 (0.69 g, 5.00 mmol), Bu4NI (1.81 g, 5.00 mmol) and BnBr
(0.86 g, 5.00 mmol), and the mixture was stirred for 4 h at r.t. and then heated for 2 d at 1008. After cooling to
r.t., toluene (25 ml) was added, and the solvent was azeotropically destilled in vacuo (3Â). The remaining
residue was dissolved in pentane (20 ml) and purified by FC (SiO2; pentane/AcOEt 30 :1) to give 3 (1.97 g,
93%). Pale yellow amorphous solid. 1H-NMR (400 MHz, CDCl3): 7.25 ± 7.16 (m, 5 H); 6.75 (d, J ˆ 8.3, 1 H);
6.67 (dd, J ˆ 8.3, 2.0, 1 H); 6.58 (d, J ˆ 2.0, 1 H); 5.04 (tq, J ˆ 7.1, 1.5, 1 H); 4.15 (dq, J ˆ 10.8, 7.2, 1 H); 4.11
(dq, J ˆ 10.8, 7.2, 1 H); 3.98 (d, J ˆ 14.3, 1 H); 3.86, 3.76 (2s, 6 H); 3.60 (d, J ˆ 14.3, 1 H); 3.57 (t, J ˆ 7.4, 1 H);
3.02 (dd, J ˆ 13.8, 7.4, 1 H); 2.84 (dd, J ˆ 13.8, 7.4, 1 H); 2.68 (ddd, J ˆ 13.0, 9.4, 6.9, 1 H); 2.50 (ddd, J ˆ 13.0, 9.1,
5.2, 1 H); 2.20 ± 2.00 (m, 2 H); 1.66 (s, 3 H); 1.55 (s, 3 H); 1.26 (t, J ˆ 7.2, 3 H). 13C-NMR (100 MHz, CDCl3):
172.6; 148.5; 147.4; 139.9; 132.4; 131.2; 128.6; 128.0; 126.7; 122.0; 121.4; 112.4; 110.9; 64.1; 60.1; 55.9; 55.6; 55.1;
‡
50.5; 35.7; 27.3; 25.7; 17.7; 14.5. EI-MS: 356 (100, M C5H9] ), 274 (42), 264 (8), 246 (3), 236 (7), 200 (11), 192
(14), 165 (4), 151 (38), 149 (2), 107 (4), 91 (82), 83 (9).
(S)-N-Benzyl-3-(3,4-dimethoxyphenyl)-N-(4-methylpent-3-enyl)alaninol (10). To a suspension of LiAlH4
(667 mg, 17.5 mmol) in Et2O (50 ml) was added dropwise a soln. of 9 (2.16 g, 5.00 mmol) in Et2O (5 ml) under
ice-cooling, and the resulting mixture was stirred at r.t. overnight. After careful hydrolysis with H2O (0.67 ml),
15% NaOH (0.67 ml), and H2O (2.0 ml), the soln. was filtered, dried (MgSO4), and concentrated in vacuo to
yield 10 (1.87 g, 98%). Colorless highly viscous oil. 1H-NMR (400 MHz, CDCl3): 7.32 ± 7.24 (m, 5 H); 6.77
(d, J ˆ 8.0, 1 H); 6.64 (dd, J ˆ 8.0, 2.0, 1 H); 6.58 (d, J ˆ 2.0, 1 H); 5.05 (tq, J ˆ 7.1, 1.5, 1 H); 3.95 (d, J ˆ 13.3,
1 H); 3.85 (s, 3 H); 3.83 (s, 3 H); 3.46 (d, J ˆ 13.3, 1 H); 3.39 (dd, J ˆ 10.6, 10.4, 1 H); 3.33 (dd, J ˆ 10.6, 4.8,
1 H); 3.06 ± 2.98 (m, 1 H); 2.94 (dd, J ˆ 13.4, 4.3, 1 H); 2.68 (dt, J ˆ 12.9, 8.2, 1 H); 2.52 (dt, J ˆ 12.9, 6.0, 1 H);
2.30 (dd, J ˆ 13.4, 9.6, 1 H); 2.17 (ddd, J ˆ 8.2, 7.1, 6.0, 2 H); 1.70 (d, J ˆ 1.3, 3 H); 1.59 (d, J ˆ 1.3, 3 H).
13C-NMR (100 MHz, CDCl3): 148.9; 147.4; 139.4; 133.4; 131.8; 128.9; 128.4; 127.1; 121.9; 120.8; 111.9; 111.3; 62.1;
‡
60.5; 55.9; 55.8; 54.1; 48.6; 31.4; 27.4; 25.7; 17.8. EI-MS: 352 (8, M ), 314 (88), 284 (2), 270 (2), 241 (3), 232
(100), 223 (3), 200 (2), 177 (4), 165 (6), 151 (54), 137 (2), 107 (4), 91 (72), 83 (16).
(S)-N-Benzyl-3-(3,4-dimethoxyphenyl)-N-(4-methylpent-3-enyl)alaninal (11). To a soln. of oxalyl chloride
(0.51 g, 4.00 mmol) in CH2Cl2 (15 ml) were added dropwise DMSO (0.63 g, 8.00 mmol) in CH2Cl2 (5 ml) at
458. After stirring for 10 min, 10 (778 mg, 2.00 mmol) was added dropwise, and the resulting soln. was stirred
for 6 h at 458. The mixture was hydrolyzed by addition of Et3N (1.50 ml), warmed to r.t. and washed with H2O
(3 Â 20 ml). The org. layer was dried (MgSO4) and evaporated to give 11 as a brown oil (775 mg, quant.), which
was immediately used for the imine condensation. 1H-NMR (200 MHz, CDCl3): 9.61 (s, 1 H); 7.30 ± 7.11
(m, 5 H); 6.77 ± 6.50 (m, 3 H); 5.00 (tq, J ˆ 7.1, 1.5, 1 H); 3.77 (d, J ˆ 14.0, 1 H); 3.76 (s, 3 H); 3.72 (s, 3 H); 3.55
(d, J ˆ 14.0, 1 H); 3.39 (t, J ˆ 6.8, 1 H); 2.95 (dd, J ˆ 13.9, 7.2, 1 H); 2.72 (dd, J ˆ 13.9, 5.8, 1 H); 2.64 ± 2.50
(m, 2 H); 2.09 (ddd, J ˆ 7.2, 7.2, 7.2, 2 H); 1.61 (s, 3 H); 1.49 (s, 3 H). 13C-NMR (50 MHz, CDCl3): 202.7; 148.8;
147.4; 139.3; 132.9; 131.9; 128.7; 128.3; 127.2; 121.7; 121.3; 112.4; 111.2; 70.0; 55.9; 55.7; 55.5; 50.8; 29.9; 27.7; 25.7;
17.8.
2-Benzyl-7-chloro-1-(3,4-dimethoxybenzyl)-1,2,3,4,4a,5,10,10a-octahydro-5,5-dimethylbenzo[b][1,7]naph-
thyridine (12a,b). To a mixture of 11 (388 mg, 1.00 mmol) and molecular sieves (4 Š) (1 g) in CH2Cl2 (10 ml)
was added 4-chloroaniline (128 mg, 1.00 mmol), and the mixture was stirred for 2 d at r.t. After removal of the
molecular sieves by filtration via Celite, the filtrate was cooled to 788 and treated with EtAlCl2 (2.6 ml,
2.6 mmol, 1m soln. in hexane) at 788. After warming to r.t. stirring was continued for 2 d. Then, the mixture was
poured onto ice-cold 2m NH4F (50 ml), and the aq. layer was separated with CH2Cl2 (3 Â 50 ml). The combined
org. layers were dried (MgSO4), concentrated, and purified by FC (SiO2; hexanes/CHCl3/Et3N 10 :1:1) to give
diastereoisomer 12b as the first fraction (127 mg, 26%) and diastereoisomer 12a as the second fraction (139 mg,
28%).
(1S,4aR,10aS)-Diastereoisomer (12a): yellow solid. M.p. >2508 (dec.). [a]D22
ˆ
81.2 (c ˆ 0.50, CH2Cl2). IR
1
(film): 3396, 3391. H-NMR (400 MHz, CDCl3): 7.40 ± 7.32 (m, 4 H); 7.29 ± 7.26 (m, 1 H); 7.07 (d, J ˆ 2.3, 1 H);
6.91 (dd, J ˆ 8.4, 2.3, 1 H); 6.72 (d, J ˆ 8.3, 1 H); 6.58 (dd, J ˆ 8.3, 2.0, 1 H); 6.46 (d, J ˆ 2.0, 1 H); 6.44 (d, J ˆ 8.4,
1 H); 3.82 (s, 3 H); 3.76 (s, 3 H); 3.81 (s, 2 H); 3.37 (m, 1 H); 2.98 (dd, J ˆ 13.1, 3.5, 1 H); 2.90 (ddd, J ˆ 10.6, 3.0,
3.0, 1 H); 2.74 ± 2.70 (m, 1 H); 2.70 ± 2.63 (m, 2 H); 1.72 ± 1.66 (m, 1 H); 1.55 ± 1.48 (m, 1 H); 1.33 (s, 3 H); 1.15
(s, 3 H); 1.27 ± 1.22 (m, 1 H). 13C-NMR (100 MHz, CDCl3): 148.9; 147.3; 141.9; 139.2; 132.3; 130.5; 128.6; 128.4;
127.2; 126.4; 126.1; 121.5; 121.0; 116.0; 112.0; 111.3; 62.9; 58.7; 55.9; 55.7; 46.8; 46.1; 37.4; 35.6; 32.8; 25.9; 27.7;
‡
22.8. EI-MS: 490 (4, M ), 339 (100), 233 (11), 220 (10), 192 (4), 178 (12), 172 (4), 151 (17), 120 (14), 91 (34).
EI-HR-MS: 490.2387 (calc. for C30H35N2O2Cl; found: 490.2379).
(1S,4aS,10aS)-Diastereoisomer (12b): yellow solid. M.p. >2508 (dec.). [a]2D0 ˆ ‡40.4 (c ˆ 0.50; CH2Cl2). IR
(film): 3404; 3373. 1H-NMR (400 MHz, CDCl3): 7.25 ± 7.19 (m, 4 H); 7.16 ± 7.12 (m, 1 H); 6.97 (d, J ˆ 2.5, 1 H);

Helvetica Chimica Acta ± Vol. 84 (2001)
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6.97 (dd, J ˆ 8.6, 2.5, 1 H); 6.75 ± 6.69 (m, 2 H); 6.68 (dd, J ˆ 7.3, 1.3, 1 H); 6.52 (d, J ˆ 8.6, 1 H); 4.08 (d, J ˆ 13.9,
1 H); 3.74 (s, 4 H); 3.72 (s, 3 H); 3.26 (d, J ˆ 13.9, 1 H); 3.37 (s, 1 H); 3.16 (dd, J ˆ 13.9, 5.1, 1 H); 2.80 ± 2.72
(m, 1 H); 2.68 (dd, J ˆ 13.9, 9.9, 1 H); 2.52 (ddd, J ˆ 9.9, 5.1, 1.6, 1 H); 2.03 ± 1.97 (m, 1 H); 1.32 ± 1.27 (m, 1 H);
1.11 (s, 3 H); 0.93 (s, 3 H); 1.13 ± 1.05 (m, 2 H). 13C-NMR (100 MHz, CDCl3): 148.3; 147.1; 141.0; 139.0; 130.8;
130.6; 128.2; 127.8; 126.5; 125.9; 125.7; 121.4; 120.9; 116.3; 112.0; 110.7; 65.5; 56.7; 55.4; 55.3; 52.9; 47.0; 43.4;
‡
35.4; 35.2; 32.4; 25.5; 21.8. EI-MS: 490 (5, M ), 339 (100), 233 (7), 220 (16), 206 (3), 178 (6), 151 (6), 120 (12),
91 (14). EI-HR-MS: 490.2387 (calc. for C30H35N2O2Cl; found: 490.2379).
(1S,4aR,10aS)-1-(3,4-Dimethoxybenzyl)-1,2,3,4,4a,5,10,10a-octahydro-5,5-dimethylbenzo[b][1,7]naphthyr-
idine (13a). A soln. of 12a (490 mg, 1.00 mmol) in EtOH (10 ml) was treated with Pd/C (100 mg, 10 wt-%) and
hydrogenated at 10 atm and 608 for 12 h. Then, the catalyst was removed by filtration, and the mixture was
evaporated to give 13a (365 mg, quant.). Colorless solid. M.p. >2508 (dec.). [a]D22
ˆ
32.68 (c ˆ 1.00, CH2Cl2).
1
IR (KBr): 3411, 3400. H-NMR (400 MHz, CDCl3): 7.06 (dd, J ˆ 7.8, 1.3, 1 H); 6.93 (dd, J ˆ 7.8, 7.8, 1 H); 6.85
(s, 1 H); 6.78 (d, J ˆ 8.1, 1 H); 6.75 (d, J ˆ 8.1, 1 H); 6.65 ± 6.59 (m, 2 H); 4.83 (br. s, 1 H); 4.04 ± 4.00 (m, 1 H);
3.84 (s, 3 H); 3.82 (s, 3 H); 3.66 (s, 1 H); 3.57 ± 3.50 (m, 1 H); 3.40 ± 3.32 (m, 1 H); 3.13 ± 2.96 (m, 2 H); 1.84 ±
1.78 (m, 1 H); 1.71 ± 1.63 (m, 1 H); 1.58 ± 1.46 (m, 1 H); 1.33 (s, 3 H); 1.16 (s, 3 H). 13C-NMR (100 MHz,
CDCl3): 149.2; 148.2; 141.4; 128.0; 126.9; 126.8; 125.9; 121.2; 117.6; 114.6; 112.3; 111.4; 57.3; 55.9; 55.8; 45.1; 38.7;
‡
36.8; 35.1; 33.5; 32.4; 25.6; 19.7. EI-MS: 366 (32, M ), 351 (15), 215 (100), 194 (9), 186 (41), 170 (14), 151 (48),
144 (66), 130 (15), 106 (9), 91 (10). HR-MS: 366.2300 (calc. for C23H30N2O2; found: 366.2299).
(1S,4aS,10aS)-1-(3,4-Dimethoxybenzyl)-1,2,3,4,4a,5,10,10a-octahydro-5,5-dimethylbenzo[b][1,7]naphthyr-
idine (13b). According to the same procedure as described for 13a, hydrogenation of 12b yielded 13b (366 mg,
quant.). Colorless solid. M.p. 2548. [a]2D2 ˆ ‡58.6 (c ˆ 1.00; CH2Cl2). IR (KBr): 3408, 3400. 1H-NMR (400 MHz,
CDCl3): 7.08 (dd, J ˆ 7.8, 1.5, 1 H); 7.03 (ddd, J ˆ 7.8, 7.4, 1.5, 1 H); 6.92 (dd, J ˆ 7.8, 1.2, 1 H); 6.88 (d, J ˆ 1.8,
1 H); 6.82 (dd, J ˆ 8.1, 1.8, 1 H); 6.73 (d, J ˆ 8.1, 1 H); 6.68 (ddd, J ˆ 7.4, 7.4, 1.2, 1 H); 4.87 (br. s, 1 H); 3.84
(s, 3 H); 3.83 (s, 3 H); 3.59 (br. s, 1 H); 3.51 ± 3.44 (m, 2 H); 3.33 ± 3.27 (m, 2 H); 2.92 (ddd, J ˆ 13.1, 13.1, 3.5,
1 H); 1.68 ± 1.60 (m, 1 H); 1.50 ± 1.44 (m, 1 H); 1.40 ± 1.34 (m, 1 H); 1.26 (s, 3 H); 1.08 (s, 3 H). 13C-NMR
(100 MHz, CDCl3): 149.1; 148.1; 140.9; 127.5; 127.2; 127.0; 125.9; 121.5; 118.0; 115.4; 112.2; 111.4; 60.8; 56.0;
‡
55.8; 44.5; 44.3; 43.1; 35.4; 34.4; 33.3; 25.6; 19.7. EI-MS: 366 (32, M ), 351 (14), 243 (5), 215 (100), 194 (8), 186
(49), 170 (11), 158 (26), 151 (22), 144 (32), 130 (9), 121 (3), 106 (3), 91 (5). EI-HR-MS: 366.2300 (calc. for
C23H30N2O2; found: 366.2299).
(8aR,14aS,14bS)-5,6,7,8,8a,9,14,14a,14b,15-Decahydro-2,3-dimethoxy-9,9-dimethylbenz[b]isoquinoli-
no[2,3-h]naphthyridine (5a). A mixture of 13a (183 mg, 0.50 mmol) and paraformaldehyde (150 mg) in toluene
(30 ml) was refluxed in a Dean-Stark trap filled with molecular sieves (4 Š) for 15 h. Then, the solvent was
removed in vacuo, and the crude product was purified by FC (SiO2; hexanes/CHCl3/Et3N 10 :1:1) to give 5a
1
(15 mg, 8%). Colorless solid. M.p. >2008 (dec.). [a]D22
ˆ
106.8 (c ˆ 0.50, CH2Cl2). IR (KBr): 3419. H-NMR
(400 MHz, CDCl3): 7.14 (dd, J ˆ 7.8, 1.5, 1 H); 7.04 (ddd, J ˆ 7.8, 7.8, 1.5, 1 H); 6.67 ± 6.63 (m, 2 H); 6.62 (s, 1 H);
6.55 (s, 1 H); 4.38 (br. s, 1 H); 3.86 (s, 6 H); 3.80 ± 3.68 (m, 2 H); 3.56 ± 3.50 (m, 1 H); 3.13 ± 3.04 (m, 2 H); 2.83 ±
2.72 (m, 2 H); 2.64 ± 2.57 (m, 2 H); 1.70 ± 1.58 (m, 3 H); 1.34 (s, 3 H); 1.27 (s, 3 H). 13C-NMR (100 MHz,
CDCl3): 148.0; 147.9; 142.4; 127.9; 127.6; 126.7; 125.9; 123.5; 117.2; 114.7; 111.4; 109.4; 57.6; 55.9; 55.9; 55.8; 49.9;
‡
46.3; 37.9; 35.0; 33.7; 25.9; 24.4; 22.8. EI-MS: 378 (24, M ), 345 (7), 244 (7), 229 (4), 218 (10), 206 (100), 191 (8),
164 (13), 149 (7), 144 (12), 121 (4), 110 (4), 97 (4). EI-HR-MS: 378.2307 (calc. for C24H30N2O2; found:
378.2300).
(1S,4aS,10aS)-1-(3,4-Dimethoxybenzyl)-1,2,3,4,4a,5,10,10a-octahydro-5,5-dimethyl-2,10-methanoben-
zo[b][1,7]naphthyridine (14). A mixture of 13b (183 mg, 0.50 mmol) and paraformaldehyde (150 mg) in
toluene (30 ml) was refluxed in a Dean-Stark trap filled with molecular sieves (4 Š) for 15 h. Then, the solvent
was removed in vacuo, and the crude product was purified by FC (SiO2; hexanes/CHCl3/Et3N 20 :1:1) to give 14
(85 mg, 44%). Colorless solid. M.p. >2008 (dec.). [a]2D2 ˆ ‡69.4 (c ˆ 0.50, CH2Cl2). 1H-NMR (400 MHz,
CDCl3): 7.14 (dd, J ˆ 7.6, 1.3, 1 H); 7.04 (ddd, J ˆ 7.6, 7.6, 1.5, 1 H); 6.76 (ddd, J ˆ 7.6, 7.6, 1.3, 1 H); 6.75 ± 6.70
(m, 3 H); 6.68 (dd, J ˆ 7.6, 1.5, 1 H); 4.72 (d, J ˆ 8.6, 1 H); 3.79 (s, 3 H); 3.77 (s, 3 H); 3.71 (d, J ˆ 8.6, 1 H); 3.32
(s, 1 H); 3.06 (dd, J ˆ 7.3. 7.3, 1 H); 2.90 ± 2.82 (m, 2 H); 2.76 ± 2.70 (m, 2 H); 1.49 (dd, J ˆ 10.5, 6.4, 1 H); 1.36 ±
1.28 (m, 1 H); 1.14 (s, 3 H); 1.11 (s, 3 H); 0.84 ± 0.77 (m, 1 H). 13C-NMR (100 MHz, CDCl3): 148.7; 147.3; 145.3;
132.2; 131.9; 126.6; 126.4; 121.0; 119.8; 119.5; 112.2; 111.2; 75.2; 72.2; 55.9; 55.8; 55.5; 53.9; 43.0; 37.5; 37.0; 31.2;
‡
26.0; 21.7. EI-MS: 378 (100, M ), 363 (29), 345 (9), 334 (11), 306 (8), 290 (6), 227 (23), 206 (90), 199 (10), 186
(17), 170 (25), 151 (66), 144 (34), 115 (10), 107 (8), 91 (10). EI-HR-MS: 378.2307 (calc. for C24H30N2O2; found:
378.2300).

2070
Helvetica Chimica Acta ± Vol. 84 (2001)
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Received March 10, 2001