Protoberberines from Reissert- compounds. Part IX [1]. An alternative approach to dibenzoquinolizine- and isoquinonaphthyridin-13a-carboxylic acids, a novel synthesis of alangimarine

Article abstract of DOI:10.1007/s00706-004-0231-5

3,4-Dihydroisoquinoline-Reissert-compounds were alkylated to 1-benzyl- and 1-picolyl-derivatives, which in turn could selectively be hydrolized yielding various carboxylic acids, among others certain amino acids related to 3′,4′-deoxynorlaudanosoline carboxylic acid (DNLCA). These on treating with ethanolic KOH underwent cyclization to dibenzoquinolizine- and isoquinonaphthyridine-13a-carboxylic acids. Alternatively this cyclization also could be achieved by a more convenient one-pot procedure starting from the same dihydro-Reissert-compounds. Thermal decarboxylation afforded among others the alangia alkaloids alangimarine and dihydroalangimarine. Springer-Verlag 2004.

Full text of DOI:10.1007/s00706-004-0231-5

Monatshefte f€ur Chemie 136, 193–209 (2005)
DOI 10.1007/s00706-004-0231-5
Protoberberines from Reissert-Compounds.
Part IX ½1ꢀ. An Alternative Approach
to Dibenzoquinolizine- and
Isoquinonaphthyridin-13a-carboxylic
Acids, a Novel Synthesis of Alangimarine#
a
ꢁ
Eberhard Reimann and Fritz Grasberger
Department Pharmazie – Zentrum f€ur Pharmaforschung,
€
€
€
Ludwig-Maximilians-Universitat Munchen, D-81377 Munchen, Germany
Received May 13, 2004; accepted May 28, 2004
Published online September 24, 2004 # Springer-Verlag 2004
Summary. 3,4-Dihydroisoquinoline-Reissert-compounds were alkylated to 1-benzyl- and 1-picolyl-
derivatives, which in turn could selectively be hydrolized yielding various carboxylic acids, among
others certain amino acids related to 30,40-deoxynorlaudanosoline carboxylic acid (DNLCA). These on
treating with ethanolic KOH underwent cyclization to dibenzoquinolizine- and isoquinonaphthyridine-
13a-carboxylic acids. Alternatively this cyclization also could be achieved by a more convenient one-
pot procedure starting from the same dihydro-Reissert-compounds. Thermal decarboxylation afforded
among others the alangia alkaloids alangimarine and dihydroalangimarine.
Keywords. Alkaloids; Carboxylic acids; Cyclizations; Total synthesis.
Introduction
Starting from isoquinoline-Reissert-compounds we have previously synthesized
partially hydrogenated dibenzoquinolizine-13a-carboxylic acids, which in turn
were found to be very valuable precursors for the preparation of naturally occurring
protoberberines [1, 2]. However, the application of this strategy to the synthesis of
the corresponding 10-aza-analogues, the isoquinonaphthyridines, which represent
the framework of the pharmacologically active alangia alkaloids, e.g. 24c has
failed. The expected intermediate oxazoloisoquinoline derivative indicating that
#
Dedicated to Prof. C. Herdeis, W€urzburg, on the occasion of his 60th birthday
Corresponding author. E-mail: ebrei@cup.uni-muenchen.de
ꢁ
a
€
Part of PhD thesis, LMU Munchen, D

194
E. Reimann and F. Grasberger
the intended reduction of the Reissert educt had occured, was not observed [3].
Furthermore, it has been also found, that, in contrast to dibenzoquinolizinones [4],
the fully aromatic isoquinonaphthyridinone could not be reduced with complex
hydrides to afford the hydrogenation pattern of the alangia alkaloids 24c or 24b [5].
Therefore we envisaged that the reduction step required in our strategy should
be avoided, if 3,4-dihydro-Reissert-compounds of type 7 would be employed as
starting material. These are generally available from 3,4-dihydroisoquinolines 5 by
the known standard procedures [6] and their alkylation at the C-1 position proceeds
as readily as that of the classical Reissert-compounds [7, 8].
Results and Discussion
The 3,4-dihydroisoquinolines 5 were prepared by known but improved procedures
according to Scheme 1 starting from 1,2,3,4-tetrahydroisoquinoline 2 or from the
phenethylamines 3 via the formamides 4. They could be reacted with benzoyl
chloride and NaCN in the presence of NaHCO3 [6] affording the expected
dihydro-Reissert-compounds 7 in excellent yields. The formation of 6 as a possi-
ble side product reported [6] was detected in very small amounts only in the case
of 7c (see Scheme 2).
The sequential alkylation with the halogenides 8 and 9, prepared according to
Scheme 3, occured readily yielding the 1-benyzl- and 1-picolyl-dihydro-Reissert
derivatives 10 and 11. The reaction definitely stopped at this step. A further reac-
tion leading to the tetracyclic isoquinonaphthyridinone previously reported [5],
when classical Reissert compounds were employed as the educt, was not observed.
In contrast, 10 and 11 were markedly more stable towards hydrolysis. An expla-
nation may be that the complete aromatization cannot be achieved in the tetracyclic
target compounds of the type 21 and 22 (see Scheme 6).
This gave rise to a more systematic investigation to elaborate suitable cycliza-
tion conditions using 11a as educt. Thus it was hydrolyzed by ethanolic KOH to
give 16. On the other hand, more forced reaction conditions, e.g. KOH in mono-
ethylene glycol, additionally caused elimination of HCN affording 17. In contrast,
dilute sulfuric acid selectively converted the angular nitrile group to the corre-
sponding carboxylic acid 18, and finally with concentrated phosphoric acid the
Scheme 1

Protoberberines from Reissert-Compounds
195
Scheme 2
Scheme 3
amino acids 19 and 20 were obtained from the educts 10 and 11a under retention of
the aromatic ester function (see Schemes 4 and 5). These new amino acids, being
poorly soluble in the usual solvents, may be of biological interest due to their
structural relationship to 30,40-deoxynorlaudanosoline carboxylic acid (DNLCA,
19: R1¼R2¼OH, H instead of CO2Et), which in turn is known to inhibit several
enzymes, e.g. dihydropteridine reductase, tyrosine 3-monooxygenase, and dopa-
min-ꢀ-hydroxylase [9–11].
Concerning our present investigations the amino acids 19 and 20 obtained
turned out to be suitable precursors for the intended cyclizations. Thus treatment
of 19 with ethanolic potassium hydroxid solution afforded the oxoberbine-13a-
carboxylic acid 21 in excellent yields, being identical with that prepared previously
on an independent route (see Scheme 5) [1, 2].
The readily occurring cyclization of the amino acid 19 as well as its unequivocal
formation in phosphoric acid prompted us to combine the two steps in an one-pot

196
E. Reimann and F. Grasberger
Scheme 4
Scheme 5
procedure. Thus in a model reaction the 1-alkylated dihydro-Reissert-compound 10
first was treated with phosphoric acid and then – without isolating 19 – was reacted
with KOH. Indeed the berbinone carboxylic acid 21 was formed in 87% total yield
meaning a 14% increase in comparison to the single steps (see Scheme 6).
In the same manner the 3,4-dihydro-Reissert-compounds 11a, 11c, and 11d
could be cyclized to the azalogue carboxylic acids 22a, 22b, and 22c, whereby
in the case of 11c and 11d the benzylic ether group was also cleaved to provide the
corresponding phenols. Finally 21 and 22 underwent thermal decarboxylation

Protoberberines from Reissert-Compounds
197
Scheme 6
giving the alkaloids alangimarine (24c) and dihydroalangimarine (24b), whereas
from the educt 21 the 13,13a-dihydro-product, berbin-8-one (25), was preferen-
tially generated besides the corresponding dehydroderivative 23 [1, 2].
In conclusion, a novel route to partially hydrogenated 8-oxodibenzochino-
lizine-13a-carboxylic acids and the corresponding 10-aza analogues was designed
starting from 1-substituted dihydro-Reissert-compounds. This method provides a
convenient approach to the pharmacological attractive protoberberine- and alangia-
alkaloids from easily accessible starting materials. Furthermore, certain intermedi-
ate amino acids related to 30,40-deoxynorlaudanosoline carboxylic acid, which is
known as an enzyme inhibitor, are also available by this route. Further investiga-
tions concerning its applicability to natural product and drug synthesis are in pro-
gress in our laboratory.
Experimental
Melting points were measured with a Reichert hot-stage microscope. IR: Perkin Elmer FT-IR Paragon
1000 and Jasco FT-IR 410. UV=Vis: Jasco V-530. NMR: Jeol GSX 400 and Jeol GSX 500 (1H: 400
and 500MHz, 13C: 100 and 125 MHz, CDCl3, TMS as internal reference); MS (70 eV): Hewlett
Packard MS-Engine. Elemental analyses: Heraeus CHN-Rapid and Elementar Vario EL; the results
are in good agreement with the calculated values. Thin layer chromatography (TLC): Al sheets
Kieselgel 60 F254 (Merck) and Al sheets Aluminiumoxid F254 (Fluka), each thickness of layer
0.2 mm. Preparative Layer Chromatography (¼PLC): PSC-Fertigplatten Kieselgel 60 F254 (Merck),
thickness of layer 1 mm. Flash chromatography (FC): ICN-Sili Tech 32-63, 60 A and Aluminumoxid
Typ 507 C neutral 0.05–0.15 mm. Strongly basic ion-exchange resin: Amberlite IRA-400 (CI). 2 and
3a are commercial products. 1, 4a, 8, 9a, and 12a were prepared according to Refs. [12], [13], [2, 14],
[15], and [16].
2-(4-Benzyloxy-3-methoxyphenyl)ethylamine (3b)
To a suspension of 19.0g of LiAlH4 (0.5mol) in 500 cm3 of dry Et2O 25.8g of 4-(benzyloxy)-3-
methoxy-ꢀ-nitrostyrene (0.1mol) (1) were added under stirring and refluxing by continuous extraction

198
E. Reimann and F. Grasberger
in a Soxhlet apparatus for 30h. Then to the mixture 10 cm3 of H2O, 20 cm3 of 20% NaOH solution, and
37cm3 of H2O were consecutively added under vigorous stirring, ice cooling, and N2. After stirring for
further 30 min, the mixture was filtered over kieselguhr. The organic layer was separated and the H2O
phase extracted with 3ꢂ200 cm3 of Et2O. The combined organic extracts were dried (Na2SO4) and the
solvent was removed in vacuo. The remaining product was used without further purification. Yield:
20.6g (80%) colourless oil, which solidified on storing in the refrigerator; mp 58ꢃC (Ref. [17]:
1
60–62ꢃC); TLC (CHCl3:MeOH:25% NH3 ¼ 9:1:0.1): Rf ¼ 0.35; H NMR (400 MHz): ꢁ ¼ 7.47–7.25
(m, 5 arom H), 6.81 (d, J ¼ 8.3Hz, 5-H), 6.74 (d, J ¼ 1.6 Hz, 2-H), 6.67 (dd, J ¼ 1.6=8.3 Hz, 6-H), 5.12
(s, aryl–CH2O), 3.87 (s, CH3O), 2.92 (t, J ¼ 6.8 Hz, CH2–N), 2.67 (t, J ¼ 6.8Hz, aryl–CH2), 1.36
(s, NH2) ppm.
N-[2-(4-Benzyloxy-3-methoxyphenyl)ethyl]formamide (4b)
A mixture of 20.0g of 3b (78 mmol) and 46.9g of HCOOCH3 (780 mmol) freshly distilled before use
was stirred for 12 h at ambient temperature. After removing the volatile components in vacuo, a
colourless, viscous oil remained, which was used for the next step without further purification. Yield:
22.3g (100%) [18]; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.68; IR (film): ꢂꢀ¼ 1665 (C¼O) cmꢄ1; MS
1
(CI): m=z (%) ¼ 286 (Mþꢅ þ 1, 100); H NMR (400MHz): ꢁ ¼ 8.02 (d, J ¼ 1.2 Hz, N–CHO), 7.45–
7.25 (m, 5 arom H), 6.80 (d, J ¼ 8.2Hz, 5-H), 6.72 (d, J ¼ 1.9 Hz, 2-H), 6.64 (dd, J ¼ 8.2, 2.0 Hz, 6-H),
6.06 (br s, NH), 5.09 (s, aryl–CH2O), 3.83 (s, CH3O), 3.46 (dd, J ¼ 13.3, 7.0 Hz, CH2–N), 2.72 (t,
J ¼ 7.0 Hz, aryl–CH2) ppm; 13C NMR (100MHz): ꢁ ¼ 161.18, 149.92, 147.02, 137.25, 131.77, 128.53,
128.50, 127.85, 127.32, 127.14, 120.71, 114.54, 112.62, 71.26, 56.06, 39.24, 35.13 ppm.
3,4-Dihydroisoquinoline (5a) According to the General Procedure
for the Dehydrogenation of Benzylamines [19]
To a solution of 6.65 g of 2 (50 mmol) in 250cm3 of CH2Cl2 16.2g of HgO and 19.1g of I2 (each
75mmol) were added and the mixture was stirred for 1 h at ambient temperature. The solid was
removed by a glass frit P4 and washed with 3ꢂ20 cm3 of CH2Cl2. The combined filtrates were
consecutively washed with 500 cm3 of 5% Na2S2O3 solution and 500 cm3 of H2O and dried (Na2SO4).
After evaporating the solvent in vacuo the remaining product was used without further purification. An
analytical sample was obtained by FC (CHCl3:MeOH ¼ 9:1). Yield: 6.4 g (98%) colourless oil; TLC
(CHCl3:MeOH:25% NH3 ¼ 9:1:0.1): Rf ¼ 0.52; the 1H NMR spectrum was in line with that reported in
Ref. [20].
General Procedure for the Synthesis of 3,4-Dihydroisoquinolines 5b and 5c
by Bischler-Napieralski Cyclization
A mixture of the formamide 4, toluene, and freshly destilled POCl3 was heated for 1 h at 85ꢃC
(temperature of the oil bath) and then reacted for additional 4 h at ambient temperature. After removing
the excess POCl3 in vacuo, the mixture was rendered alkaline with 2N NaOH under ice cooling and
vigorous stirring and then was extracted with 3ꢂ50cm3 of CHCl3. The combined organic extracts
were dried (Na2SO4) and evaporated in vacuo. The residue was purified by FC (CHCl3:MeOH:25%
NH3 ¼ 9:1:0.1).
6,7-Dimethoxy-3,4-dihydroisoquinoline (5b)
From 5.0 g 4a (19 mmol), 150 cm3 toluene, 15 cm3 POCl3. Yield: 3.56 g (76%) pale yellow oil [13];
TLC (eluent see FC): Rf ¼ 0.43; 1H NMR (400MHz): ꢁ ¼ 8.23 (t, J ¼ 2.1 Hz, 1-H), 6.81 and 6.67 (2s,
8-H and 5-H), 3.91 and 3.90 (2s, 2OCH3), 3.76–3.70 and 2.72–2.63 (2m, 3-Hab and 4-Hab) ppm.

Protoberberines from Reissert-Compounds
199
7-Benzyloxy-6-methoxy-3,4-dihydroisoquinoline (5c)
From 4.0 g 4b (14 mmol), 150 cm3 toluene, 10cm3 POCl3. Yield: 3.21 g (86%) colourless oil, which
solidified on storing in the refrigerator; mp 92ꢃC, recrystallization of an analytical sample from
n-hexane: mp 99–100ꢃC (Ref. [21]: 101–101.5ꢃC); TLC (CHCl3:MeOH:25% NH3 ¼ 19:1:0.1):
1
Rf ¼ 0.49; MS (EI): m=z (%) ¼ 267 (Mþꢅ, 22), 176 (17), 91 (100); H NMR (400MHz): ꢁ ¼ 8.15
(t, J ¼ 2.2 Hz, 1-H), 7.47–7.23 (m, 5 arom H), 6.83 and 6.68 (2s, 8-H and 5-H), 5.14 (s, aryl–OCH2),
3.91 (s, OCH3), 3.71 (dt, J ¼ 8.0, 2.1Hz, 3-Hab), 2.67 (t, J ¼ 8.0 Hz, 4-Hab) ppm; 13C NMR (100MHz):
ꢁ ¼ 159.71, 152.17, 146.92, 136.80, 130.55, 128.61, 128.59, 127.99, 127.31, 127.01, 121.33, 113.42,
110.83, 71.34, 56.10, 47.11, 24.82 ppm.
General Procedure for the Synthesis of 3,4-Dihydroisoquinoline-Reissert-Compounds 7
A solution of NaCN, adjusted to pH 8, was added to a mixture of 5, NaHCO3, and CH2Cl2 under ice
cooling. Thereafter a solution of benzoyl chloride in CH2Cl2 was added dropwise during 30min under
vigorous stirring and further cooling. After stirring for additional 1.5 h at ambient temperature the
mixture was diluted with 20 cm3 of H2O and extracted with 3ꢂ25cm3 of CH2Cl2. The combined
organic extracts were consecutively washed with 20 cm3 of 2N HCl, 20cm3 of 2N NaOH, and
2ꢂ20 cm3 of H2O, dried (Na2SO4), and filtered. After removing the solvent in vacuo, the residue
was crystallized from 50 cm3 of MeOH. The solid was collected by filtration and dried in vacuo at
ambient temperature.
2-Benzoyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (7a)
From 6.0 g 5a (46 mmol), 150 cm3 CH2Cl2, 13.3g NaHCO3 (158mmol), 4.4 g NaCN
(92 mmol)=20cm3 H2O, 6.5 g C6H5COCl (69 mmol)=15cm3 CH2Cl2. Yield: 8.6 g (71%) colourless
crystals; mp 113ꢃC (Ref. [6]: 113–115ꢃC); TLC (n-hexane:EtOAc¼ 1:1): Rf ¼ 0.45; IR (KBr):
1
ꢂꢀ¼ 2238 (CN), 1643 (C¼O) cmꢄ1; MS (EI): m=z (%) ¼ 262 (Mþꢅ, 57), 105 (100), 77 (65); H
NMR (400 MHz): ꢁ ¼ 7.59–7.20 (m, 9 arom H), 6.46 (br s, 1-H), 4.23–3.90 and 3.72–3.36 (2 br s,
3-Ha and 3-Hb), 3.22–2.96 and 2.95–2.75 (2m, 4-Ha and 4-Hb) ppm; 13C NMR (100 MHz):
ꢁ ¼ 170.99, 133.90, 130.90, 129.55, 129.00, 128.81, 128.07, 127.48, 127.13 (5C), 117.78, 44.51, 43.29,
28.57 ppm.
2-Benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (7b)
From 3.5 g 5b (18 mmol), 100 cm3 CH2Cl2, 5.3 g NaHCO3 (63 mmol), 1.7g NaCN (36 mmol)=10cm3
H2O, 2.5g C6H5COCl (27 mmol)=10 cm3 CH2Cl2. Yield: 4.9 g (85%) colourless crystals; mp 205ꢃC
(Ref. [6]: 211–213ꢃC); TLC (n-hexane:EtOAc¼ 1:1): Rf ¼ 0.36; IR (KBr): ꢂꢀ¼ 2230 (CꢆN), 1628
(C¼O) cmꢄ1; MS (EI): m=z (%) ¼ 322 (Mþꢅ, 100), 307 (24), 105 (76), 77 (68); 1H NMR (400MHz):
ꢁ ¼ 7.57–7.43 (m, 5 arom H), 6.83 (br s, 8-H), 6.66 (s, 5-H), 6.42 (br s, 1-H), 4.12–3.95 (br s, 3-Ha),
3.88 (s, 2OCH3), 3.56 (br s, 3-Hb), 3.09–2.92 (m, 4-Ha), 2.74 (d, J ¼ 15.6Hz, 4-Hb) ppm; 13C NMR
(100 MHz): ꢁ ¼ 171.51, 149.69, 148.71, 134.11, 130.97, 128.92 (2C), 127.27 (3C), 119.75, 118.03,
111.67, 109.50, 56.23, 56.11, 44.36, 43.45, 28.18 ppm.
2-Benzoyl-7-benzyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (7c)
From 3.0 g 5c (11 mmol), 80cm3 CH2Cl2, 3.2 g NaHCO3 (38 mmol), 1.0 g NaCN (22 mmol)=8 cm3
H2O, 1.5 g C6H5COCl (17 mmol)=8 cm3 CH2Cl2. Yield: 4.0 g (91%); mp 180ꢃC (Ref. [22]:
178–180ꢃC); TLC (n-hexane:EtOAc¼ 1:1): Rf ¼ 0.43; IR (KBr): ꢂꢀ¼ 2233w (CꢆN), 1642 (C¼O)
1
cmꢄ1; MS (EI): m=z (%) ¼ 398 (Mþꢅ, 54), 105 (100), 91 (96); H NMR (400MHz): ꢁ ¼ 7.54–7.28
(m, 10 arom H), 6.85 (br s, 8-H), 6.67 (s, 5-H), 6.32 (br s, 1-H), 5.24–4.99 (m, OCH2), 4.08–3.91 (br s,

200
E. Reimann and F. Grasberger
3-Ha), 3.87 (s, OCH3), 3.62–3.38 (br s, 3-Hb), 3.07–2.90 (m, 4-Ha), 2.73 (d, J ¼ 15.7 Hz, 4-Hb) ppm;
13C NMR (100 MHz): ꢁ ¼ 170.81, 150.55, 147.89, 136.53, 134.20, 130.82, 128.83 (2C), 128.66 (2C),
128.13, 127.48 (3C), 127.18 (3C), 119.82, 117.82, 112.57, 112.42, 71.50, 56.19, 44.18, 28.11 ppm.
N-[2-(4-Benzyloxy-2-formyl-5-methoxyphenyl)ethyl]benzamide (6, C24H23NO4)
Separation by FC (CHCl3:MeOH ¼ 95:5) from the crude product 7c (see above). Yield: 86mg (2%)
colourless solid, mp 124ꢃC; TLC (eluent see FC): Rf ¼ 0.43; 1H NMR (400 MHz): ꢁ ¼ 10.01 (s, CHO),
7.74–7.68 (m, 2 arom H), 7.50–7.26 (m, 9 arom H), 6.81 (s, 1 arom H), 6.74–6.68 (like a t, NH), 5.16
(s, OCH2), 3.89 (s, OCH3), 3.71 (dd, J ¼ 12.7, 7.0 Hz, N–CH2), 3.31 (t, J ¼ 7.0, aryl–CH2) ppm.
5-Ethyl-4-methylnicotinonitrile (12b)
Preparation according to Ref. [23]. Yield: 11.3g (86%) colourless oil; bp 118–122ꢃC=9.0 ꢂ 102 Pa
(Ref. [23]: 120ꢃC=9.3ꢂ102 Pa); TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.56; IR (film): ꢂꢀ¼ 2227 (CꢆN)
cmꢄ1; MS (CI): m=z (%) ¼ 147 (Mþꢅ þ 1, 100); 1H NMR (400 MHz): ꢁ ¼ 8.55 and 8.43 (2s, 2-H and
6-H), 2.65 (q, J ¼ 7.7 Hz, CH2), 2.46 (s, ar-CH3), 1.18 (t, J ¼ 7.7 Hz, CH3) ppm; 13C NMR (100MHz):
ꢁ ¼ 152.37, 150.66, 148.56, 138.38, 116.54, 111.06, 23.98, 17.11, 14.09ppm.
4-Methyl-5-vinyl-nicotinonitrile (12c)
Preparation according to Ref. [24]. Yield: 6.6 g (52%) colourless oil; bp 96ꢃC=2.7ꢂ102 Pa (Ref. [23]:
98ꢃC=2.7ꢂ102 Pa) which solidified on storing in the refrigerator; TLC (n-hexane:EtOAc¼ 3:1):
Rf ¼ 0.34; IR (film): ꢂꢀ¼ 2229 (CꢆN) cmꢄ1; MS (EI): m=z (%) ¼ 144 (Mþꢅ, 22), 117 (26), 94
(100), 86 (53), 84 (72); 1H NMR (400MHz): ꢁ ¼ 8.75 and 8.69 (2s, 6-H and 2-H), 6.84 (dd,
J ¼ 11.2, 17.6Hz, ar-CH), 5.78 and 5.57 (2d, J ¼ 17.6 and 11.2Hz, C¼CH2), 2.56 (s, CH3) ppm;
13C NMR (100MHz): ꢁ ¼ 150.48, 149.02, 146.34, 132.62, 129.37, 119.25, 115.14, 110.05, 16.51 ppm.
General Procedure for the Preparation of Nicotinamides 13b and 13c
The ion-exchange resin was stored in 100 cm3 of H2O for 15h, then transferred to a chromatography
column and washed with ca. 1000 cm3 of 6N NaOH, until no more Clꢄ could be detected in the eluate.
The resin was filtered off and washed with 2ꢂ100 cm3 of H2O. A suspension of the resin thus prepared
and the nitrile 12 in H2O was refluxed for 16h. The resin was filtered off from the hot mixture and
washed with 2ꢂ50 cm3 of hot H2O. The combined filtrates were evaporated in vacuo affording the
solid product, which was used for the next step without further purification. An analytical sample was
recrystallized from EtOH.
5-Ethyl-4-methylnicotinamide (13b, C9H12N2O)
Ion-exchange resin 16.5g, 11.1g 12b (76 mmol), 150 cm3 H2O; yield: 11.6g (93%) colourless crystals;
mp 154ꢃC; TLC (CHCl3:MeOH ¼ 9:1): Rf ¼ 0.18; IR (KBr): ꢂꢀ¼ 1665 (C¼O) cmꢄ1; MS (EI):
m=z (%) ¼ 164 (Mþꢅ, 100), 148 (43), 147 (24), 120 (60); 1H NMR (CD3OD, 400 MHz): ꢁ ¼ 8.45 and
and 8.34 (2s, 2-H and 6-H), 4.95 (br s, NH2), 2.75 (q, J ¼ 7.6 Hz, ar-CH2), 2.43 (s, ar-CH3), 1.24 (t,
J ¼ 7.6 Hz, CH3) ppm; 13C NMR (CD3OD, 100 MHz): ꢁ ¼ 172.83, 150.44, 145.64, 145.16, 140.51,
134.78, 24.60, 15.52, 14.65 ppm.
4-Methyl-5-vinylnicotinamide (13c, C9H10N2O)
Ion-exchange resin 8.5 g, 6.5 g 12c (45 mmol), 100 cm3 H2O; yield: 6.5 g (89%) colourless
crystals; mp 143ꢃC; TLC (CHCl3:MeOH ¼ 9:1): Rf ¼ 0.19; IR (KBr): ꢂꢀ¼ 1667 (C¼O) cmꢄ1; MS (EI):

Protoberberines from Reissert-Compounds
201
1
m=z (%) ¼ 162 (Mþꢅ, 92), 144 (45), 118 (100), 91 (84), 65 (48); H NMR (CD3OD, 400 MHz):
ꢁ ¼ 8.55 and 8.41 (2s, 6-H and 2-H), 6.95 (dd, J ¼ 17.5, 11.0Hz, ar-CH¼), 5.75 and 5.51 (2d,
J ¼ 17.5 and 11.0 Hz, CH2¼), 5.37–4.84 (br s, NH2), 2.42 (s, CH3) ppm; 13C NMR (CD3OD,
100 MHz): ꢁ ¼ 170.38, 147.30, 145.12, 143.12, 134.28, 132.18, 131.14, 118.87, 15.55 ppm.
General Procedure for the Synthesis of Nicotinic Acid Ethyl Ester 14b and 14c
A solution of the amide 13 in anhydrous EtOH was heated under reflux. Simultaneously a weak stream
of dry HCl was passed into the mixture until no more NH4Cl precipitated (ca. 5 h). Refluxing was
continued for further 31 h. After evaporating the solvent in vacuo, the residue was triturated with
200 cm3 of H2O. The solution was rendered neutral with solid Na2CO3 and extracted with 3ꢂ100 cm3
of Et2O. The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The remaining
product was used for the next step without further purification. An analytical sample was obtained by
FC (n-hexane:EtOAc¼ 3:1).
5-Ethyl-4-methylnicotinic Acid Ethyl Ester (14b)
From 11.5 g 13b (70 mmol), 700 cm3 EtOH. Yield: 12.6g (93%) colourless liquid (Ref. [25]); TLC
(n-hexane:EtOAc¼ 3:1): Rf ¼ 0.72; IR (film): ꢂꢀ¼ 1721 (C¼O) cmꢄ1; MS (EI): m=z (%) ¼ 193
1
(Mþꢅ, 16), 165 (100), 150 (94), 120 (57); H NMR (400 MHz): ꢁ ¼ 8.84 and 8.45 (2s, 2-H and
6-H), 4.39 (q, J ¼ 7.1 Hz, OCH2), 2.71 (q, J ¼ 7.5 Hz, ar-CH2), 2.54 (s, ar-CH3), 1.41 (t, J ¼ 7.1 Hz,
OC–CH3), 1.23 (t, J ¼ 7.5 Hz, C–CH3) ppm; 13C NMR (100 MHz): ꢁ ¼ 166.92, 151.90, 148.99,
146.31, 138.42, 126.89, 61.30, 24.03, 15.65, 14.51, 14.29 ppm.
4-Methyl-5-vinylnicotinic Acid Ethyl Ester (14c, C11H13NO2)
From 6.5 g 13c (40 mmol), 500 cm3 EtOH. Yield: 6.7g (88%) colourless liquid; TLC (n-hexane:
EtOAc¼ 3:1): Rf ¼ 0.84; IR (film): ꢂꢀ¼ 1721 (C¼O) cmꢄ1; MS (CI): m=z (%) ¼ 192 (Mþꢅ þ 1, 34);
1H NMR (400MHz): ꢁ ¼ 8.86 and 8.63 (2s, 2-H and 6-H), 6.88 (dd, J ¼ 17.4, 11.1 Hz, ar-CH¼), 5.64
and 5.44 (2d, J ¼ 17.4 and 11.1Hz, CH2¼), 4.36 (q, J ¼ 7.2Hz, OCH2), 2.52 (s, ar-CH3), 1.37
(t, J ¼ 7.2 Hz, OC–CH3) ppm; 13C NMR (100MHz): ꢁ ¼ 166.61, 150.03, 149.71, 145.49, 134.38,
131.92, 126.68, 119.03, 61.32, 16.32, 14.26 ppm.
General Procedure for the Synthesis of the N-Oxides 15b and 15c
A mixture of 14, glacial acetic acid, and 30% H2O2 was heated for 3 h at 80ꢃC (bath temperature) and,
after addition of further 30% H2O2, for additional 12h at 75ꢃC. The solution was concentrated in vacuo
to one half of its volume, then 20 cm3 of H2O were added and the remaining acetic acid was evaporated
in vacuo. After triturating with 50 cm3 of CHCl3 the residue was neutralized with 30cm3 of a saturated
NaHCO3 solution. The CHCl3 layer was separated and the aqueous phase was extracted with
6ꢂ20 cm3 of CHCl3 (TLC monitoring). After drying the combined organic extracts (Na2SO4) the
solvent was removed in vacuo. The product was used for the next step without further purification. An
analytical sample was obtained by FC (CHCl3:MeOH ¼ 9:1).
5-Ethyl-4-methyl-1-oxynicotinic Acid Ethyl Ester (15b, C11H15NO3)
From 11.5g 14b (60 mmol), 50 cm3 CH3CO2H, 5.0þ 2.5 cm3 30% H2O2. Yield: 9.8 g (78%) pale
yellow oil; TLC (eluent see FC): Rf ¼ 0.36; IR (film): ꢂꢀ¼ 1727 (C¼O), 1306 (NO) cmꢄ1; MS (EI):
m=z (%) ¼ 209 (Mþꢅ, 15), 193 (92), 148 (100), 120 (82); 1H NMR (CD3OD, 400 MHz): ꢁ ¼ 8.52 and
8.27 (2s, 2-H and 6-H); 4.41 (q, J ¼ 7.1 Hz, OCH2), 2.78 (q, J ¼ 7.6 Hz, ar-CH2), 2.55 (s, ar-CH3),

202
E. Reimann and F. Grasberger
1.40 (t, J ¼ 7.1 Hz, OC–CH3), 1.26 (t, J ¼ 7.6 Hz, C–CH3) ppm; 13C NMR (CD3OD, 100 MHz):
ꢁ ¼ 165.17, 144.83, 142.33, 140.87, 138.44, 131.40, 63.30, 24.88, 15.53, 14.37, 13.86 ppm.
4-Methyl-1-oxy-5-vinylnicotinic Acid Ethyl Ester (15c, C11H13NO3)
From 6.6 g 14c (35 mmol), 25cm3 CH3CO2H, 2.5 þ 1.25cm3 30% H2O2. The crude product was
purified by FC (CHCl3:MeOH ¼ 9:1). Yield: 4.0g (56%) pale yellow oil, which should be stored in
the refrigerator under N2 or immediately used in the next step. TLC (eluent see FC): Rf ¼ 0.38; IR
(film): ꢂꢀ¼ 1725 (C¼O), 1304 (NO) cmꢄ1; MS (EI): m=z (%) ¼ 207 (Mþꢅ, 100), 191 (44), 162 (89),
1
146 (51), 118 (85), 91 (63); H NMR (400MHz): ꢁ ¼ 8.59 and 8.33 (2d, each J ¼ 2.1 Hz, 2-H and
6-H), 6.81 (dd, J ¼ 17.4, 11.0Hz, ar-CH¼), 5.70 and 5.58 (2d, J ¼ 17.4 and 11.0 Hz, CH2¼), 4.39
(q, J ¼ 7.1 Hz, OCH2), 2.52 (s, ar-CH3), 1.40 (t, J ¼ 7.1 Hz, OC–CH3) ppm; 13C NMR (100MHz):
ꢁ ¼ 163.87, 138.96, 138.27, 137.94, 136.64, 130.08, 129.48, 121.24, 62.14, 15.64, 14.12ppm.
General Procedure for the Synthesis of 4-Chloromethylnicotinic
Acid Esters 9b- and 9c-HCl
A solution of the N-oxide 15 and p-toluenesulfonyl chloride in dry dioxane was heated under reflux for
1.5 h. After cooling to ambient temperature the black mixture was diluted with 10% HCl, stirred for
15min, and then washed with 5ꢂ20cm3 of Et2O. After adding 30cm3 of ice-cold Et2O the aqueous
phase was cautiously neutralized with solid NaHCO3. The unstable base was rapidly extracted with
3ꢂ20 cm3 of ice-cold Et2O. The combined extracts were dried (Na2SO4), stored in the refrigerator, and
filtered. Thereafter a weak stream of dry HCl was passed into the filtrate under ice cooling until the
precipitation of the reddish brown oil was complete (ca. 30–45min). After evaporating the solvent
in vacuo the residual product was immediately used in the next step.
4-Chloromethyl-3-ethoxycarbonyl-5-ethylpyridinium Hydrochloride
(9b, C11H15Cl2NO2)
From 9.8 g 15b (47 mmol), 18.3g p-toluenesulfonyl chloride (94 mmol), 50cm3 dioxane, 50cm3 10%
HCl. The crude oil was crystallized from 200 cm3 of EtOAc, the crystals were washed with a small
volume of the same solvent, and dried at ambient temperature in vacuo. Yield: 9.8 g (79%) pink solid;
mp 45ꢃC; TLC (CHCl3:MeOH:25% NH3 ¼ 90:10:1): Rf ¼ 0.78; IR (KBr): ꢂꢀ¼ 1733 (C¼O) cmꢄ1; MS
(EI): m=z (%) ¼ 229 (Mþꢅ ꢄ H, 11), 227 (Mþꢅ ꢄ H, 37), 192 (23), 182 (42), 162 (100), 118 (99);
1H NMR (CD3OD, 400 MHz): ꢁ ¼ 9.18 and 8.96 (2s, 2-H and 6-H), 4.92 (s, CH2Cl), 4.52
(q, J ¼ 7.1 Hz, OCH2), 3.09 (q, J ¼ 7.6Hz, ar-CH2), 1.46 (t, J ¼ 7.1 Hz, OC–CH3), 1.41 (t, J ¼
C–CH3) ppm; 13C NMR (CD3OD, 100 MHz): ꢁ ¼ 163.67, 156.25, 145.47, 145.44, 143.21, 130.68,
64.31, 37.29, 24.09, 14.52, 14.28 ppm.
4-Chloromethyl-3-ethoxycarbonyl-5-vinylpyridinium Hydrochloride
(9c, C11H13Cl2NO2)
From 4.0 g 15c (19 mmol), 7.4g p-toluenesulfonyl chloride (39 mmol), 30cm3 dioxane, 30cm3 10%
HCl. The crude product was used for the next step without further purification. An analytical sample
was obtained by FC (CHCl3:MeOH:25% NH3 ¼ 90:10:1). Yield: 3.5 g (71%) pink oil; TLC (eluent see
FC): Rf ¼ 0.74; IR (film): ꢂꢀ¼ 1730 (C¼O) cmꢄ1; MS (CI): m=z (%) ¼ 228 (Mþꢅ þ 1, 42), 226
1
(Mþꢅ þ 1, 100), 190 (24), 162 (14); H NMR (400 MHz): ꢁ ¼ 9.04 and 8.82 (2s, 2-H and 6-H);
7.06 (dd, J ¼ 17.5, 11.2 Hz, ar-CH¼), 5.82 and 5.62 (2d, J ¼ 17.5 and 11.2Hz, CH2¼), 5.02
(s, CH2Cl), 4.45 (q, J ¼ 7.1 Hz, OCH2), 1.44 (t, J ¼ 7.1 Hz, C–CH3) ppm; 13C NMR (100MHz):
ꢁ ¼ 165.50, 151.26, 150.87, 142.95, 134.04, 130.28, 124.95, 121.04, 61.89, 37.73, 14.17ppm.

Protoberberines from Reissert-Compounds
203
2-(2-Benzoyl-1-cyano-1,2,3,4-tetrahydroisoquinolin-1-ylmethyl)benzoic Acid Ethyl Ester
(10, C27H24N2O3)
Preparation according to Ref. [1], Meth. B, using 7a and the following workup, The combined dry
EtOAc extracts were evaporated in vacuo and the residue was crystallized from EtOH. The product was
collected by filtration, washed with a small volume of ice-cold EtOH and dried at 60ꢃC in vacuo. If the
crystallization fails to occur and=or the mother liquor affords no more product, the solvent was
removed in vacuo and the residue was purified by FC (n-hexane:EtOAc¼ 3:1).
From 8.0 g 7a (30 mmol)=100 cm3 dry DMF, 1.2 g 60% NaH (30 mmol), 7.5g 8 (31 mmol)=10cm3
DMF, reaction time 1 h. Yield: 11.7g (92%); mp 148ꢃC (EtOH); TLC (n-hexane:EtOAc¼ 3:1):
Rf ¼ 0.62; IR (KBr): ꢂꢀ¼ 2234 (CꢆN), 1716 (CO2R), 1651 (CONR2) cmꢄ1; MS (CI): m=z (%) ¼
425 (Mþꢅ þ 1, 27), 263 (100), 236 (44); 1H NMR (500MHz): ꢁ ¼ 7.67–7.63 and 7.54–7.50 (2m, 1þ 2
arom H), 7.49–7.44 (m, 5 arom H), 7.32 (ddd, J ¼ 8.0, 6.7, 2.0 Hz, 1 arom H), 7.25 (dt, J ¼ 7.6, 1.6 Hz,
6-H), 7.20 (dd, J ¼ 7.6, 1.6 Hz, 8-H), 7.19–7.15 (m, 7-H), 7.06 (dd, J ¼ 7.6, 0.5 Hz, 5-H), 4.65 and 4.35
(2d, each J ¼ 13.4Hz, each 1H, ar-CH2), 4.00–3.85 (m, OCH2), 3.68 and 3.35 (2ddd, J ¼ 12.9, 5.0, 4.1
and 12.9, 10.4, 3.3 Hz, 3-Hab), 2.64 (ddd, J ¼ 15.7, 5.0, 3.3 Hz, 4-Ha), 2.33 (m, 4-Hb), 1.23
(t, J ¼ 7.1 Hz, OC–CH3) ppm; 13C NMR (125MHz): ꢁ ¼ 171.69, 166.95, 136.03, 135.27, 134.72,
133.54, 132.14, 131.90, 131.29, 130.39, 130.23, 128.67 (2C), 128.49, 128.27, 127.97, 127.53,
127.05 (2C), 126.81, 119.28, 60.73, 60.03, 45.88, 40.06, 29.12, 13.92 ppm.
General Procedure for the Synthesis of 1-Substituted 3,4-Dihydroisoquinoline-
Reissert-Compounds 11
To a solution of 7 in dry DMF K-t-OC4H9 was added at ꢄ56ꢃC under N2 and vigorous stirring. After
stirring for additional 2 min a solution of 9 in DMF was added dropwise as slowly as the colour of the
suspension disappeared at no time (ca. 15min). Stirring was continued at ꢄ56ꢃC for 30min and
thereafter for 15min at ambient temperature. The suspension was cautiously poured into a mixture
of 200 cm3 of EtOAc and 800 cm3 of H2O and extracted with 4ꢂ200 cm3 of EtOAc. The combined
organic phases were dried (Na2SO4), filtered, and evaporated in vacuo. The yellowish, semi-solid
residue was purified by FC (n-hexane:EtOAc ¼ 1:1) followed by recrystallization from MeOH.
4-(2-Benzoyl-1-cyano-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-ylmethyl)nicotinic
Acid Ethyl Ester (11a, C28H27N3O5)
From 3.0 g 7b (9.3mmol), 300 cm3 dry DMF, 2.1 g K-t-OC4H9 (18.6 mmol), 1.9 g 9a
(9.4mmol)=10cm3 DMF. Yield: 3.6 g (79%) colourless crystals; mp 160ꢃC; TLC (n-
hexane:EtOAc¼ 1:1): Rf ¼ 0.45; IR (KBr): ꢂꢀ¼ 2228 (CꢆN), 1721 (CO2R), 1645 (CONR2) cmꢄ1
;
MS (CI): m=z (%) ¼ 486 (Mþꢅ þ 1, 100), 321 (72); 1H NMR (400 MHz): ꢁ ¼ 8.83 (s, 1 arom H), 8.64
(d, J ¼ 5.0 Hz, 1 arom H), 7.53–7.40 (m, 6 arom H), 6.51 and 6.50 (2s, 5-H and 8-H), 4.52 and 4.32
(2d, each J ¼ 12.6Hz, ar-CH2), 3.99–3.90 (m, OCH2), 3.83 and 3.63 (2s, 2OCH3), 3.72 and 3.36
(2ddd, J ¼ 13.0, 4.9, 4.2 and 13.0, 10.1, 3.3 Hz, 3-Ha and 3-Hb), 2.58 (ddd, J ¼ 15.8, 4.9, 3.3 Hz, 4-Ha),
2.38 (m, 4-Hb), 1.21 (t, J ¼ 7.1 Hz, CH3) ppm; 13C NMR (100MHz): ꢁ ¼ 172.03, 165.21, 151.65,
150.77, 149.13, 147.54, 144.41, 135.61, 130.75, 128.80 (2C), 128.04, 127.81, 127.59, 127.16 (2C),
122.78, 118.78, 111.14, 110.57, 61.26, 59.19, 55.93, 55.77, 45.90, 39.22, 28.80, 13.82 ppm.
4-(2-Benzoyl-1-cyano-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-ylmethyl)-5-
ethylnicotinic Acid Ethyl Ester (11b, C30H31N3O5)
From 1.0 g 7b (3.1mmol), 100 cm3 dry DMF, 0.7 g K-t-OC4H9 (6.2mmol), 0.7 g 9b (2.7mmol)=5 cm3
DMF. Yield: 1.2 g (73%) colourless crystals; mp 164ꢃC; TLC (n-hexane:EtOAc¼ 1:1): Rf ¼ 0.29; IR
(KBr): ꢂꢀ¼ 2232 (CꢆN), 1703 (CO2R), 1652 (CONR2) cmꢄ1; MS (CI): m=z (%) ¼ 542 (Mþꢅ þ 29, 4),

204
E. Reimann and F. Grasberger
514 (Mþꢅ þ 1, 100), 321 (100); 1H NMR (ꢄ20ꢃC, 400 MHz): ꢁ ¼ 8.74 and 8.71 (2s, each 1 arom H),
7.63–7.47 (m, 5 arom H), 6.67 and 6.00 (2s, 5-H and 8-H), 4.53 and 4.44 (2d, each J ¼ 12.5Hz,
ar-CH2), 4.03–3.81 and 3.90 (br m and s, OCH2 and OCH3), 3.67–3.54 (m, 3-Hab), 3.45 (s, OCH3),
3.23–3.09 and 3.04–2.84 (2m, C–CH2 and 4-Hab), 1.33 and 1.24 (2 br t, each J ¼ 7.3 Hz, OC–CH3 and
CH3) ppm; 13C NMR (100 MHz): ꢁ ¼ 172.15, 165.97, 153.97, 149.24, 148.37, 147.07, 142.17, 141.68,
135.80, 130.79, 128.88 (2C), 128.64, 127.44, 127.20 (2C), 122.57, 118.70, 111.84, 110.58, 61.07,
59.22, 55.63, 45.87, 33.41, 29.02, 24.20, 16.18, 13.75ppm.
4-(2-Benzoyl-7-benzyloxy-1-cyano-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-
ylmethyl)-5-ethylnicotinic Acid Ethyl Ester (11c, C36H35N3O5)
From 3.0 g 7c (7.5mmol), 300 cm3 dry DMF, 1.7 g K-t-OC4H9 (15.0 mmol), 1.6 g 9b
(7.5mmol)=10cm3 DMF. Yield: 3.1 g (70%) colourless crystals; mp 164ꢃC; TLC (n-
hexane:EtOAc¼ 1:2): Rf ¼ 0.57; IR (KBr): ꢂꢀ¼ 2225 (CꢆN), 1715 (CO2R), 1640 (CONR2) cmꢄ1
;
MS (CI): m=z (%) ¼ 590 (Mþꢅ þ 1, 26), 397 (28), 74 (100); 1H NMR (ꢄ20ꢃC, 400 MHz): ꢁ ¼ 8.76 and
8.73 (2s, each 1 arom H), 7.63–7.45 and 7.44–7.29 (2m, each 5 arom H), 6.68 and 6.12 (2s, 8-H and
5-H), 4.60 (s, ar-OCH2-ar), 4.49 and 4.43 (2d, each J ¼ 12.8 Hz, ar-CH2), 4.03–3.79 and 3.88 (br m
and s, OCH2 and OCH3), 3.71–3.50 (m, 3-Hab), 3.20–2.77 (m, C–CH2 and 4-Hab), 1.33 (t, J ¼ 7.1 Hz,
OC–CH3), 1.28 (t, J ¼ 7.4 Hz, CH3) ppm; 13C NMR (100 MHz): ꢁ ¼ 172.19, 166.18, 154.30, 149.29,
148.28, 146.11, 142.40, 141.37, 136.07, 135.61, 130.90, 128.95 (2C), 128.75 (2C), 128.55, 128.29,
127.94 (2C), 127.71, 127.28 (2C), 122.07, 118.40, 113.14, 110.49, 70.58, 61.28, 59.18, 55.95, 46.19,
33.69, 29.02, 24.25, 16.55, 13.75 ppm.
4-(2-Benzoyl-7-benzyloxy-1-cyano-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-
ylmethyl)-5-vinylnicotinic Acid Ethyl Ester (11d, C36H33N3O5)
From 1.5 g 7c (3.8mmol), 300 cm3 dry DMF, 842mg K-t-OC4H9 (7.5mmol), 1.0g 9c
(3.8mmol)=10cm3 DMF. Yield: 1.3 g (61%) colourless crystals; mp 174ꢃC; TLC (n-
hexane:EtOAc¼ 1:1): Rf ¼ 0.39; IR (KBr): ꢂꢀ¼ 2219 (CꢆN), 1717 (CO2R), 1639 (CONR2) cmꢄ1
;
1
MS (CI): m=z (%) ¼ 588 (Mþꢅ þ 1, 21), 397 (26), 192 (100); H NMR (ꢄ20ꢃC, 400 MHz): ꢁ ¼ 9.04
and 8.77 (2s, each 1 arom H), 8.03 (dd, J ¼ 17.3, 11.0Hz, 1 arom H), 7.59–7.48 and 7.42–7.32 (2m,
each 5 arom H), 6.69 and 6.31 (2s, 8-H and 5-H), 5.91 and 5.74 (2d, J ¼ 17.3 and 11.0Hz, CH2¼),
4.71–4.62 (m, ar-CH2O-ar), 4.52 and 4.47 (2d, each J ¼ 12.9Hz, ar-CH2), 4.05–3.95 (m, 3-Ha),
3.94–3.80 (m and s, OCH2 and OCH3), 3.74–3.63 (m, 3-Hb), 3.60–3.49 and 3.00–2.80 (2m,
4-Hab), 1.29 (t, J ¼ 7.2 Hz, CH3) ppm; 13C NMR (100MHz): ꢁ ¼ 171.92, 165.66, 150.55, 149.08
(2C), 146.01, 140.39, 136.08, 135.79, 135.26, 131.99, 130.67, 128.68 (2C), 128.53 (3C), 128.08,
127.69 (2C), 121.94, 120.13, 118.03, 112.72, 110.31, 70.36, 61.20, 58.65, 55.73, 45.94, 33.81,
28.73, 13.53 ppm.
4-(2-Benzoyl-1-cyano-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-
ylmethyl)nicotinic Acid (16, C26H23N3O5)
To a solution of 101 mg of 11a (0.2mmol) in 10cm3 of hot EtOH a solution of 42mg KOH (0.6mmol)
in 0.5 cm3 of H2O was added. The mixture was refluxed for 2 h and then adjusted to pH ¼ 6–7 with 2N
HCl under ice-cooling. The colorless solid was filtered off, washed with 2ꢂ5 cm3 of H2O, and dried in
vacuo. Yield: 87 mg (96%); mp 177ꢃC; TLC (CHCl3:MeOH¼ 9:1): Rf ¼ 0.24; IR (KBr): ꢂꢀ¼ 3300–
2800 (OH), 2218 (w, CꢆN), 1711 (CO2H), 1638 (CONR2) cmꢄ1; MS (EI): m=z (%) ¼ 412
1
(Mþꢅ ꢄ CO2, 100), 397 (73), 105 (50), 77 (43); H NMR (CD3OD, 400MHz): ꢁ ¼ 8.81 (s, 2-H),
8.51 (d, J ¼ 5.1 Hz, 6-H), 7.42 (m, 5 arom H), 7.31 (d, J ¼ 4.5 Hz, 1 arom H), 6.55 and 6.51 (2s, each 1
arom H), 4.52 and 4.27 (2d, each J ¼ 12.6Hz, ar-CH2), 3.79 (s, OCH3), 3.62 (m, OCH3 þ 1H), 3.35

Protoberberines from Reissert-Compounds
205
(ddd, J ¼ 13.5, 9.8, 3.5Hz, 1H), 2.57 and 2.37 (2ddd, J ¼ 15.7, 4.9, 3.5 and 13.5, 9.8, 3.8 Hz, each 1H)
ppm; 13C NMR (CD3OD, 100 MHz): ꢁ ¼ 173.95, 168.95, 151.98, 151.61, 151.13, 149.10, 146.69,
137.02, 131.77, 130.01, 129.92 (2C), 129.63, 129.27, 127.97 (2C), 123.94, 120.01, 112.71, 112.57,
60.57, 56.49, 56.38, 47.01, 40.63, 29.32 ppm.
4-(2-Benzoyl-6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-ylidenemethyl)nicotinic
Acid (17, C25H22N2O5)
A mixture of 70mg of 11a (0.14 mmol), 23mg of powdered KOH (0.4mmol), and 10cm3 of mono-
ethyleneglycol was refluxed for 3 h. The cold solution was diluted with 20cm3 of H2O, and adjusted to
pH¼ 6–7 with 2N HCl under ice-cooling. The solid was filtered off and after drying recrystallized
from 10 cm3 of EtOH. The colourless crystals were washed with a small volume of EtOH and dried in
1
vacuo. Yield: 32 mg (62%); mp 199ꢃC; TLC (CHCl3:MeOH ¼ 1:1): Rf ¼ 0.15; H NMR (400MHz):
ꢁ ¼ 9.16 (s, 2-H), 8.71 (br s, 6-H), 7.74 (s, ar-CH¼), 7.72 (d, J ¼ 5.1 Hz, 5-H), 7.64–7.62 (m, 2 arom
H), 7.36 (t, J ¼ 7.3 Hz, 1 arom H), 7.28 (t, J ¼ 7.6 Hz, 2 arom H), 6.83 and 6.80 (2s, each 1 arom H),
3.79 and 3.76 (2s, 2OCH3), 3.57 and 3.01 (2t, each J ¼ 7.8 Hz, each 2H) ppm.
2-Benzoyl-1-(3-ethoxycarbonylpyridin-4-ylmethyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline-1-carboxylic Acid (18, C28H28N2O7)
A solution of 70 mg of 11a (0.14 mmol) in 5 cm3 of 20% H2SO4 was refluxed for 3 h and then adjusted
to pH¼ 7 with NH4OH under ice-cooling. The precipitated colourless solid was filtered off, washed
with 2ꢂ5 cm3 of H2O, and dried in vacuo. Yield: 40mg (56%); mp 232ꢃC; TLC (CHCl3:MeOH¼ 9:1):
Rf ¼ 0.22; IR (KBr): ꢂꢀ¼ 3300–2800 (OH), 1722 (CO2R and CO2H), 1636 (CONR2) cmꢄ1; MS (CI):
m=z (%) ¼ 533 (Mþꢅ þ 29, 7), 505 (Mþꢅ þ 1, 52), 487 (Mþꢅ ꢄ OH, 57), 459 (Mþꢅ ꢄ CO2, 54), 296
1
(84), 105 (100); H NMR (CD3OD, 400 MHz): ꢁ ¼ 8.61 (s, heteroarom 2-H), 8.48 (d, J ¼ 5.1 Hz,
heteroarom 6-H), 7.51–7.47 (m, 5 arom H), 7.21 (d, J ¼ 5.1 Hz, heteroarom 5-H), 7.12 and 6.58 (2s,
5-H and 8-H), 4.51 and 4.43 (2d, each J ¼ 13.3Hz, aryl–CH2), 4.04 (dq, J ¼ 10.7, 7.1 Hz, OCH2), 3.87
and 3.81 (2s, 2OCH3), 3.40 and 2.89 (2ddd, J ¼ 11.3, 8.0, 3.6 and 12.8, 7.2, 3.7 Hz, 3-Hab), 2.52 and
1.77 (2ddd, J ¼ 11.3, 7.2, 3.6 and 12.8, 8.0, 3.6 Hz, 4-Hab), 1.23 (t, J ¼ 7.1 Hz, CH3) ppm.
General Procedure for the Preparation of 1,2,3,4-Tetrahydroisoquinoline-1-
carboxylic Acids 19 and 20
85% H3PO4 was heated to 100ꢃC (bath temperature) under stirring and then 10 or 11a were added.
Stirring was continued for additional 15 min causing sublimation of benzoic acid. The mixture was
diluted with 10 cm3 of ice=H2O under ice-cooling and adjusted to pH¼ 7 with NH4OH. Cooling was
continued for 2–4 h causing a nearly colourless gelatinous precipitate, which was filtered off and dried
in vacuo.
1-(2-Ethoxycarbonylbenzyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic Acid
(19, C20H21NO4)
From 3.0 g 10 (7.1mmol), 20cm3 H3PO4. Yield: 1.8 g (76%) colourless solid; mp 191ꢃC; TLC (RP8,
MeOH:H2O ¼ 1:1): Rf ¼ 0.54; IR (KBr): ꢂꢀ¼ 3411 (NH), 3000–2600 (OH), 1714 (CO2R), 1676
1
(CO2H) cmꢄ1; MS (CI): m=z (%) ¼ 340 (Mþꢅ þ 1, 75), 322 (12), 294 (48), 248 (100); H NMR
(CD3OD:F3CCO2D ¼ 5:1, 400 MHz): ꢁ ¼ 7.97 (dd, J ¼ 7.9, 1.4 Hz, 1 arom H), 7.95–7.90 (m, 1 arom
H), 7.61 and 7.53 (2dt, J ¼ 7.6, 1.5 and 7.7, 1.1 Hz, each 1 arom H), 7.48 (dd, J ¼ 7.7, 1.0 Hz, 1 arom
H), 7.44–7.38 (m, 2 arom H), 7.34–7.28 (m, 1 arom H), 4.49–4.35 (m, OCH2), 4.32 and 3.70 (2d, each
J ¼ 14.4Hz, aryl–CH2), 3.53–3.46 (m, 3-Hab), 3.28–3.16 (m, 4-Ha), 3.10 (dt, J ¼ 17.3, 4.2 Hz, 4-Hb),
1.41 (t, J ¼ 7.2 Hz, CH3) ppm; 13C NMR (CD3OD:F3CCO2D ¼ 5:1, 100 MHz): ꢁ ¼ 172.28, 171.57,

206
E. Reimann and F. Grasberger
134.99, 134.36, 133.57, 133.49, 132.94, 132.50, 131.68, 130.49, 130.24, 129.99, 129.44, 128.86, 68.00,
63.94, 43.08, 41.45, 26.56, 14.10 ppm.
1-(3-Ethoxycarbonylpyridin-4-ylmethyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline-1-carboxylic Acid (20, C21H24N2O6)
From 1.5 g 11a (3.1mmol), 10cm3 H3PO4. Yield: 844 mg (68%) yellowish solid; mp 167–170ꢃC; TLC
(RP8, MeOH:H2O ¼ 1:1): Rf ¼ 0.61; IR (KBr): ꢂꢀ¼ 3421 (NH), 3000–2600 (OH), 1719 (CO2R) cmꢄ1
;
1
MS (CI): m=z (%) ¼ 309 (Mþꢅ ꢄ OH, –CO, –OEt, 100), 236 (Mþꢅ ꢄ C7H7, 79), 192 (65); H NMR
(F3CCO2D, 400 MHz): ꢁ ¼ 9.45 (s, heteroarom 2-H), 9.00 and 8.21 (2d, each J ¼ 6.2 Hz, heteroarom
6-H and 5-H), 7.50 and 6.92 (2s, arom 8-H and 5-H), 4.68 (q, J ¼ 7.2 Hz, OCH2), 4.57 and 4.35 (2d,
each J ¼ 14.2 Hz, aryl–CH2), 4.04 and 4.02 (2s, 2OCH3), 3.86–3.74 and 3.61–3.51 (2m, 3-Hab), 3.25–
3.15 (m, 4-Hab), 1.54 (t, J ¼ 7.2 Hz, CH3) ppm; 13C NMR (F3CCO2D, 100MHz): ꢁ ¼ 172.51, 167.95,
157.91, 152.90, 151.00, 146.46, 146.06, 134.47, 134.27, 128.76, 120.63, 114.51, 112.61, 69.17, 68.99,
58.23, 57.59, 44.03, 43.73, 26.96, 14.49 ppm.
8-Oxo-5,6,8,13-tetrahydrodibenzo[a,g]quinolizine-13a-carboxylic
Acid (8-oxoberbine-13a-carboxylic Acid, 21)
From 19: To a solution of 4.0 g of KOH (71 mmol) in 40cm3 of 50% EtOH 1.7 g of 19 (5.0mmol) were
added and the mixture was refluxed for 2 h. After removing the EtOH invacuo, the solution was acidified
with conc. HCl under ice-cooling. The colourless solid was filtered off, dried in vacuo at ambient
temperature, and crystallized from EtOAc. Additional product could be obtained by concentrating the
mother liquor. Yield: 1.4 g (96%); the analytical data are completely in line with those given in Ref. [2].
General One-Pot Procedure for the Preparation of Oxocarboxylic Acids
21 and 22 from 10 and 11
The educts 10 and 11 were added to 10cm3 of hot 85% H3PO4 (100ꢃC bath temperature) under
stirring. Heating and stirring was continued for 15 min causing sublimation of benzoic acid. The
mixture was placed into an ice bath, diluted with 10cm3 of ice=H2O, and stirred for additional
15min. After rendering alkaline with 6N NaOH the mixture was heated to 80ꢃC (bath temperature)
under N2 for 15 min. In the case of 21 conc. HCl was added under ice-cooling until a colourless
precipitation occurred. Further workup was the same as already given (see above 21). In the case of 22
the cold alkaline solution was justified to pH¼ 6–7 with 2N HCl and extracted with 10–12ꢂ30cm3 of
EtOAc until no more product was detected in the aqueous phase (TLC monitoring). The combined
organic extracts were dried (Na2SO4), filtered, and evaporated in vacuo. The residue was crystallized
from the solvent indicated. The acids thus obtained were poorly soluble in Et2O, CHCl3, MeOH,
acetone, DMSO, DMF, and H2O). Chromatographical purification could be achieved only by PLC
(CHCl3:MeOH ¼ 4:1), but this method was found to cause marked loss of the product.
8-Oxo-5,6,8,13-tetrahydrodibenzo[a,g]quinolizine-13a-carboxylic Acid
(8-oxoberbine-13a-carboxylic Acid, 21)
From 1.0 g 10 (2.4mmol). Yield: 670 mg (87%); analytical data are in line with those already given
(see above).
2,3-Dimethoxy-8-oxo-5,6,13,13a-tetrahydro-8H-isoquino[2,1-b][2,7]naphthyridin-
13a-carboxylic Acid (22a, C19H18N2O5)
From 1.1 g 11a (2.1mmol). The residue was crystallized from MeOH (4 days). Yield: 476 mg (64%)
beige crystals; mp 211ꢃC; TLC (CHCl3:MeOH ¼ 4:1): Rf ¼ 0.16; IR (KBr): ꢂꢀ¼ 3000–2600 (OH),

Protoberberines from Reissert-Compounds
207
1
1716 (CO2H), 1661 (CONR2) cmꢄ1; MS (CI): m=z (%) ¼ 355 (Mþꢅ þ 1, 3), 310 (100), 309 (61); H
NMR (CD3OD, 400 MHz): ꢁ ¼ 9.00 (s, 9-H), 8.53 (d, J ¼ 5.2 Hz, 11-H), 7.51 (s, 1-H), 7.40 (d,
J ¼ 5.2 Hz, 12-H), 6.75 (s, 4-H), 4.81 (m, 6-Ha, superimposed by H2O), 3.99 (d, J ¼ 16.0Hz, 13-
Ha), 3.87 and 3.83 (2s, 2OCH3), 3.55 (ddd, J ¼ 12.9, 10.6, 5.3 Hz, 6-Hb), 3.02 (d, J ¼ 16.1Hz, 13-Hb),
2.95–1.81 (m, 5-Hab) ppm; 13C NMR (CD3OD, 100 MHz): ꢁ ¼ 178.54, 164.91, 152.11, 149.41,
149.26, 149.03, 148.94, 129.94, 128.25, 126.55, 123.85, 112.33, 111.32, 67.64, 56.60, 56.38, 42.25,
39.20, 29.38 ppm.
12-Ethyl-2-hydroxy-3-methoxy-8-oxo-5,6,13,13a-tetrahydro-8H-
isoquino[2,1-b][2,7]naphthyridin-13a-carboxylic Acid (22b, C20H20N2O5)
From 1.1 g 11c (1.7mmol). The residue was crystallized from MeOH:H2O ¼ 9:1 (14 days). Yield:
384 mg (61%) beige crystals; mp 221ꢃC; TLC (CHCl3:MeOH ¼ 4:1): Rf ¼ 0.20; IR (KBr): ꢂꢀ¼ 3000–
2600 (OH), 1709 (w, CO2H), 1657 (CONR2) cmꢄ1; MS (CI): m=z (%) ¼ 397 (Mþꢅ þ 29, 9), 369
(Mþꢅ þ 1, 12), 325 (45), 324 (26), 323 (100); 1H NMR F3CCO2D, 400 MHz): ꢁ ¼ 9.46, 8.79, 7.45, and
6.95 (4s, 9-H, 11-H, 1-H, and 4-H), 5.12–5.03 (m, 6-Ha), 4.56 (d, J ¼ 17.6 Hz, 13-Ha), 4.06 (s, OCH3),
3.84–3.74 (m, 6-Hb), 3.49 (d, J ¼ 17.6 Hz, 13-Hb), 3.29–3.01 (m, 5-Hab and CH2), 1.54 (t, J ¼ 7.5 Hz,
CH3) ppm; 13C NMR (F3CCO2D, 100 MHz): ꢁ ¼ 177.19, 163–164, 158.43, 149.96, 145.75, 145.56,
143.78, 141.94, 130.14, 129.74, 124.62, 115.34, 115.08, 66.30, 57.49, 41.69, 39.24, 29.28, 25.06,
13.57 ppm.
2-Hydroxy-3-methoxy-8-oxo-12-vinyl-5,6,13,13a-tetrahydro-8H-
isoquino[2,1-b][2,7]naphthyridin-13a-carboxylic Acid (22c, C20H18N2O5)
From 1.1 g 11d (1.7mmol). The residue was crystallized from MeOH (ca. 14 days). Yield: 398 mg
(64%) pale yellow crystals; mp 212ꢃC; TLC (CHCl3:MeOH¼ 4:1): Rf ¼ 0.21; IR (CHCl3=film):
ꢂꢀ¼ 3418 (aryl–OH), 3300–2700 (OH), 1726 (CO2H), 1645 (CONR2) cmꢄ1; MS: (FAB): m=z
(%) ¼ 367 (Mþꢅ þ 1, 23); (EI): m=z (%) ¼ 322 (Mþꢅ ꢄ CO2, 93), 307 (100), 305 (49), 293 (89),
1
176 (20); H NMR (500 MHz; CD3OD): ꢁ ¼ 8.93, 8.67, and 7.32 (3s, 9-H, 11-H, 1-H), 7.02 (dd,
J ¼ 11.3, 11.4Hz, vinyl–CH¼), 6.75 (s, 4-H), 5.84 and 5.59 (2d, J ¼ 17.3 and 11.3Hz, vinyl–CH2¼),
4.82–4.76 (m, 6-Ha), 4.16 and 2.91 (2d, each J ¼ 16.5Hz, 13Hab), 3.86 (s, OCH3), 3.52–3.47 (m, 6-
Hb), 2.88–2.82 (m, 5-Hab) ppm; 13C NMR (100MHz; CD3OD): ꢁ ¼ 177.70, 165.20, 150.34, 148.63,
148.56, 146.40, 145.51, 133.22, 131.42, 128.88, 127.17, 126.03, 120.46, 114.33, 112.45, 66.45, 56.40,
39.75, 38.95, 29.35 ppm.
General Procedure for the Decarboxylation of Compounds 21 and 22
According to Ref. [1]
The crude products were purified by FC or PLC.
5,6,13,13a-Tetrahydro-8H-dibenzo[a,g]quinolizin-8-one (Berbin-8-one, 25) and 5,6-
Dihydro-8H-dibenzo[a,g]quinolizin-8-one (23)
For preparation and analytical data see Ref. [1].
2,3-Dimethoxy-5,6-dihydro-8H-isoquino[2,1-b][2,7]naphthyridin-8-one (24a)
From 410 mg 22a (1.2mmol), reaction time 15min, FC (CHCl3:MeOH¼ 9:1). Yield: 228 mg
(64%) yellow crystals; mp 161–165ꢃC (MeOH, Ref. [26]: mp 169–170ꢃC); TLC (eluent see FC):
Rf ¼ 0.48 (blue fluorescence, lem ¼ 365 nm); IR (KBr): ꢂꢀ¼ 1651 (CONR2) cmꢄ 1
; UV
(c ¼ 3.243ꢂ10ꢄ5 mol dmꢄ3, 0.1N HCl in EtOH): lmax ("ꢂ10ꢄ3) ¼ 252 (23.34), 373 (26.46), 418

208
E. Reimann and F. Grasberger
1
(33.33) nm (molꢄ 1 dm3 cm); MS (EI): m=z (%) ¼ 308 (Mþꢅ, 87), 293 (100); H NMR: Data were in
line with those published in Ref. [26]; 13C NMR (100MHz): ꢁ ¼ 161.45, 151.65, 150.29, 148.72,
148.67, 143.53, 142.72, 129.87, 121.10, 119.37, 119.19, 110.50, 108.31, 98.95, 56.32, 56.15, 39.60,
27.76 ppm.
12-Ethyl-2-hydroxy-3-methoxy-5,6-dihydro-8H-isoquino[2,1-b][2,7]naphthyridin-8-
one (Dihydroalangimarine, 24b)
From 156 mg 22b (0.4mmol), reaction time 10min, PLC (CHCl3:MeOH¼ 9:1). Yield: 80 mg (61%)
yellow crystals; mp 208–212ꢃC (MeOH, Ref. [27]: mp 222ꢃC); TLC (eluent see FC): Rf ¼ 0.33 (blue
fluorescence, lem ¼ 365 nm); IR (KBr): ꢂꢀ¼ 3421 (OH), 1657 (CONR2) cmꢄ 1
;
UV
(c ¼ 3.7224ꢂ10ꢄ5 mol dmꢄ3, 0.1 N HCl in EtOH): lmax ("ꢂ10ꢄ3) ¼ 224 (32.24), 266 (18.91), 420
(34.92) nm (molꢄ 1 dm3 cm); MS (EI): m=z (%) ¼ 322 (Mþꢅ, 66), 307 (100), 292 (12); 1H NMR: Data
were in line with those published in Ref. [27]; 13C NMR (100 MHz): ꢁ ¼ 161.73, 149.03, 148.12,
147.05, 146.92, 145.30, 143.05, 141.46, 129.01, 122.13, 119.14, 111.64, 109.96, 96.01, 56.20, 39.68,
27.83, 23.04, 14.62 ppm.
2-Hydroxy-3-methoxy-12-vinyl-5,6-dihydro-8H-isoquino[2,1-b][2,7]naphthyridin-8-
one (Alangimarine, 24c)
From 333 mg 22c (0.9mmol), reaction time 15min, FC (CHCl3:MeOH¼ 9:1). Yield: 177mg (61%)
yellow crystals; mp 242–244ꢃC (MeOH, Ref. [28]: mp 245–247ꢃC); TLC (eluent see FC): Rf ¼ 0.34
(blue fluorescent, lem ¼ 365 nm); IR (KBr): ꢂꢀ¼ 3508 (OH), 1655 (CONR2) cmꢄ 1
; UV
(c ¼ 2.4973ꢂ10ꢄ5 mol dmꢄ3, EtOH): lmax ("ꢂ10ꢄ3) ¼ 261 (19.77), 290 (10.69), 365 (25.26), 380
1
(21.96) nm (molꢄ 1 dm3 cm); MS (EI): m=z (%) ¼ 320 (Mþꢅ, 78), 305 (100), 290 (10); H NMR:
Data were in line with those published in Ref. [28]; 13C NMR (125MHz): ꢁ ¼ 160.85, 149.68 (2C),
148.09, 146.95, 144.27, 138.53, 129.50, 128.05, 126.91, 121.45, 118.56, 118.03, 110.59, 108.06, 95.33,
55.25, 38.71, 26.98 ppm.
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[6] Jackson YA, Stephenson EK, Cava MP (1993) Heterocycles 36: 1047 and Refs cited herein
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Protoberberines from Reissert-Compounds
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[21] Kametani T, Ohkubo K (1967) Chem Pharm Bull 15: 608
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