Protoberberines from Reissert-Compounds VIII [1]. Oxazoloisoquinolines, New and Efficient Educts for the Synthesis of 8-Oxoprotoberberines

Article abstract of DOI:10.1007/s00706-003-0013-5

Certain benzylated oxazoloisoquinolinones readily available from Reissert compounds provided an efficient access to 8-oxoprotoberberines in three steps. A series of these new precursors as well as several oxoprotoberberines were prepared and the scope and limitation of this procedure were investigated.

Full text of DOI:10.1007/s00706-003-0013-5

Monatshefte f€ur Chemie 134, 991–1014 (2003)
DOI 10.1007/s00706-003-0013-5
Protoberberines from Reissert-Compounds
VIII ½1ꢀ. Oxazoloisoquinolines, New
and Efficient Educts for the Synthesis
of 8-Oxoprotoberberines
Eberhard Reimann , Fritz Grasbergera, and Kurt Polborn
ꢁ
€
Department Pharmazie – Zentrum fur Pharmaforschung,
€
€
Ludwig-Maximilians-Universitat Munchen, D-81377 Munchen, Germany
€
Received October 31, 2002; accepted November 5, 2002
Published online May 6, 2003 # Springer-Verlag 2003
Summary. Certain benzylated oxazoloisoquinolinones readily available from Reissert compounds
provided an efficient access to 8-oxoprotoberberines in three steps. A series of these new precursors
as well as several oxoprotoberberines were prepared and the scope and limitation of this procedure
were investigated.
Keywords. Oxazoloisoquinolinones; X-ray crystal structure; 13a-Carboxy-8-oxo-protoberberines;
8-Oxoprotoberberines.
Introduction
We previously reported the reduction of 1-benzylated Reissert compounds giving
oxazoloisoquinolines as the main products, which in turn could be readily
transformed to 8-oxoprotoberberines [1] (general formulae 4, 5, 14, and 15 in
Schemes 2, 3, and 6).
As part of our continuing investigations in this area we have checked the uses
of this pathway by synthesizing a series of new oxazoloisoquinolines 5 and several
further 8-oxoprotoberberines 14 and 15, which are known to possess biological
activity [2]. In this paper we would like to present the results concerning these
investigations.
ꢁ
Corresponding author. E-mail: ebrei@cup.uni-muenchen.de
a
€
Part of PhD thesis, LMU Munchen, D

992
E. Reimann et al.
Results and Discussion
The required starting substances, Reissert compounds 1 and 2-(bromomethyl)ben-
zoic acid esters 3 and 10 (Schemes 1 and 4), were synthesized according to stan-
dard procedures. Subsequent reaction of 1 and 3 as well as 1a and 10, according to
an efficient general procedure, afforded the benzylated Reissert compounds 4 and
11 in good yields (52–90%; see Schemes 2 and 4).
The reduction of compounds 4 was performed by an approved method [1]
leading to the desired oxazoloisoquinolines 5 summarized in Scheme 3. The yields
were found to depend on the ester group of the benzyl moiety. Thus, the ethyl (or
methyl) esters gave the best results; alkyl groups with larger steric demand caused
decreasing yields. Therefore, all the following reductions were performed using the
ethyl esters of the corresponding educts. In addition, it seemed that the substitution
pattern in both the isoquinoline and benzyl fragments of 4 hardly influenced the
reaction rate. Furthermore, according to Ref. [1] the by-products 6–9 could also be
isolated (Scheme 3).
In this connection it should be noted, that the reduction of Reissert compounds
11, lacking an ortho positioned carbalkoxy group, surprisingly did not take place in
the same manner. Instead of the expected oxazoloisoquinolines the aldehydes 12
were preferably formed as the main products (Scheme 4). A possible explanation
may be, that the formation of the intermediate Reissert salt, already containing the
unsaturated target oxazoloisoquinoline skeleton [1] is favored by an intramolecular
hydrogen bond between the ester and imino functions. However, this assumption is
not in line with the result obtained on the reduction of the o-nitrobenzyl derivative
11d. Although the NO2-group is also capable to form a corresponding hydrogen
Scheme 1

Protoberberines from Reissert-Compounds
993
Scheme 2
bond with the imino group, no formation of the desired oxazoloisoquinoline
occurred.
Treating the oxazoloisoquinolines 5 with ethanolic potassium hydroxide
according to Ref. [1] caused the generation of the new 8-oxoberbine carboxylic
acids 13 in exellent yields (Scheme 5). Their structures were fully characterized by
spectroscopic data and additionally confirmed by X-ray diffraction analysis of
compound 13b showing the trans configuration of the quinolizidine skeleton
(Fig. 1).
Finally, the carboxylic acids 13 were decarboxylated in an approved manner [1]
affording the title compounds in good yields (84–94%). Thus, in the cases 13a,
13b, 13d, and 13f mixtures of the ( ꢂ )-8-oxoprotoberberines 14a–d (among
others ( ꢂ )-gusanlung D (14c) [3], ( ꢂ )-8-oxodihydropalmatine (14d) [2, 4]) and
5,6-dihydrodibenzoquinolizin-8-ones 15a–d, easily identified by their blue fluores-
cence at ꢀ ¼ 365 nm, were obtained. In the cases 13h and 13i the 8-oxodihydrodi-
benzoquinolizines (berberin-8-one, berlambine, (15e) [5, 6] and 8-oxocoptisine
(15f) [7, 8]) were found to be the only products of the decarboxylation
(Scheme 6).

994
E. Reimann et al.
Scheme 3
In summary, we have shown the usefulness of the easily available 1-benzylated
Reissert compounds as educts for the synthesis of 8-oxoberberines. This sequence
represents a short route to the title compounds, which are of general interest
because of their natural occurence and remarkable antitumor and antileukemic
properties [2].

Protoberberines from Reissert-Compounds
995
Scheme 4
Scheme 5
Fig. 1. Crystal structure of 13b

Scheme 6
Table 1. Crystallographic data of 13ba
Formula
C20H19NO5
Formula weight
Temperature (ꢃK)
Color, shape
353.37
295
Pale yellow platelet
0.17 ꢄ 0.43 ꢄ 0.53
monoclinic
P21=c
Crystal dimensions (mm)
Crystal system
Space group
Cell dimensions:
˚
a=A
˚
b=A
11.064(4)
11.1823(14)
14.154(3)
101.87(2)
1713.7 (7)
˚
c=A
ꢁ=ꢃ
3
˚
V=A
˚
Radiaton
MoKꢂ (ꢀ ¼ 0.71073 A)
Z
4
F(000)
m=mmꢅ 1
744
0.099
Density=g cmꢅ 3
Reflections collected
Independent reflections
Observed reflections
No. of parameters refined
R-values
1.370
2806
2680 (Ri ¼ 0.0264)
2152 (I > 2ꢃI)
237=0
R1 (2ꢃI=all data)
wR2 (2ꢃI=all data)
Goodness of Fit
System used
0.0432=0.0574
0.1047=0.1139
1.181
SHELXS-86=SHELXL-93 [40]
a
Further details of the crystal structure determination are available from Cambridge Crystallographic
Data Center, 12 Union Road, GB Cambridge CB21EZ quoting the deposition number CCDC 159936
and the complete literature source (e-mail: deposit@ccdc.cam.ac.uk)

E. Reimann et al.: Protoberberines from Reissert-Compounds
997
Experimental
Melting points are measured with a Reichert hot-stage microscope and are uncorrected. IR: Perkin
Elmer FT-IR Paragon 1000 and Jasco FT-IR 410. NMR: Jeol GSX 400 and Jeol GSX 500 (1H: 400 and
500 MHz, 13C: 100 and 125 MHz, CDCl3 (unless otherwise stated), TMS as internal reference). MS
(70 eV): Hewlett Packard MS-Engine. Elemental analyses: Heraeus CHN-Rapid; the results are in
good agreement with the calculated values. Thin layer chromatography (TLC): aluminum sheets
Kieselgel 60 F254 (Merck), thickness of layer 0.2mm. Flash chromatography (FC): ICN-SiliTech
˚
32–36, 60 A. Compounds 10a–10d are commercial products. Reissert compound 1a was prepared
according to Ref. [9].
Reissert Compounds 1b–1g; General Procedure
To a solution of the isoquinoline in 120 cm3 of CH2Cl2 was added an aqueous solution of KCN and
then dropwise under vigorous stirring and ice cooling the corresponding quantity of benzoyl chloride.
Since the emulsion formed can warm up to boiling temperature the reaction flask should be equipped
with a reflux condenser. Stirring was continued for 2 h under cooling and for 5 h at ambient tempera-
ture. The beige coloured emulsion was diluted with 150 cm3 of CH2Cl2 and 200 cm3 of brine. The
organic layer was washed with 3 ꢄ 100 cm3 of H2O and dried with Na2SO4. After removing the solvent
in vacuo, the residue was recrystallized from EtOH. The crystals were collected by filtration, washed
with a small amount of EtOH, and dried at 60ꢃC in vacuo. The melting points of 1b–1d and 1g are
cited in Refs. [10–15] and are identical with those found; IR spectra were measured in KBr.
1,2-Dihydro-2-(4-methylbenzoyl)isoquinoline-1-carbonitrile (1b, [10])
Isoquinoline 63mmol, KCN 126 mmol, p-toluic acid chloride 240 mmol; yield: 68%; IR: ꢄꢀ¼ 1651
(C¼O)cmꢅ 1; TLC (n-hexane:petroleum ether ¼ 3:1): Rf ¼ 0.58.
1,2-Dihydro-2-(4-methoxybenzoyl)isoquinoline-1-carbonitrile (1c, [11])
Isoquinoline 63 mmol, KCN 126 mmol, 4-methoxybenzoyl chloride 240 mmol; yield: 82%; IR:
ꢄꢀ¼ 1662 (C¼O)cmꢅ 1; TLC (petroleum ether:EtOAc ¼ 3:2): Rf ¼ 0.50.
2-Benzoyl-1,2-dihydro-6,7-dimethoxyisoquinoline-1-carbonitrile (1d, [12, 13])
6,7-Dimethoxyisoquinoline 61 mmol, KCN 126 mmol, benzoyl chloride 244 mmol; yield: 74%; IR:
ꢄꢀ¼ 2237 (CꢆN), 1660 (C¼O)cmꢅ 1; TLC (n-hexane:EtOAc¼ 3:2): Rf ¼ 0.60.
2-Benzoyl-7-benzyloxy-1,2-dihydro-6-methoxyisoquinoline-1-carbonitrile (1e, [14])
7-Benzyloxy-6-methoxyisoquinoline 50.1mmol, KCN 180 mmol, benzoyl chloride 200 mmol; yield:
68%; IR: ꢄꢀ¼ 2239 (CꢆN), 1650 (C¼O)cmꢅ 1; TLC (n-hexane:EtOAc¼ 3:2): Rf ¼ 0.65.
1,2-Dihydro-6,7-dimethoxy-2-(4-methylbenzoyl)isoquinoline-1-carbonitrile
(1f, C20H18N2O3)
6,7-Dimethoxyisoquinoline 63 mmol, KCN 126mmol, p-toluic acid chloride 240 mmol; yield: 75%; IR:
ꢄꢀ¼ 2239 (CꢆN), 1658 (C¼O)cmꢅ 1; TLC (n-hexane:EtOAc¼ 3:2): Rf ¼ 0.60; MS(EI): m=z (%) ¼ 334
(Mþꢇ, 13), 119 (100), 91 (74); 1H NMR: ꢅ ¼ 7.43 and 7.19 (2d, each J ¼ 7.9Hz, each 2H), 6.77 and 6.65
(2s, 5-H, 8-H), 6.55–6.44 (m, 3-H), 6.40 (s, 1-H), 5.90 (d, J ¼ 7.7 Hz, 4-H), 3.85 and 3.84 (2s, 2 OCH3),

998
E. Reimann et al.
2.34 (s, CH3) ppm; 13C NMR: ꢅ ¼ 168.90, 150.32, 149.26, 142.69, 130.69, 129.65 (2C), 129.46, 129.34
(2C), 129.12, 124.79, 123.70, 116.75, 109.74, 108.77, 56.34, 56.20, 45.02, 21.66ppm.
(Bromomethyl)arene Derivatives 3a–3h and 10a–10f, General Procedures
Method A: A mixture of the o-toluic acid esters 2 or 1-methylnaphthalene or p-toluic acid t-butylester
[16], N-bromosuccinimide (NBS) and benzoyl peroxide was refluxed for 2 h. After cooling the
solid was filtered off. The filtrate was washed with 2ꢄ 50cm3 of H2O, dried with Na2SO4 and
evaporated under reduced pressure. The product thus obtained was purified by destillation or flash
chromatography.
Method B: To a refluxing solution of 2 in dry benzene, irradiated with a 500 W lamp, was added
dropwise a solution of Br2 in the same solvent. After the addition was complete the mixture was
heated under reflux for further 30 min without irradiation, after cooling to ambient temperature con-
secutively washed with 100 cm3 of ice cold water, 100 cm3 of saturated NaHCO3 solution and again
100 cm3 of H2O, and dried with Na2SO4. The solvent was removed in vacuo and the products were
purified by destillation or flash chromatography. Educts 2a and 2b are commercial products, 2c–2f,
2h and 2i are described in Refs. [17–24]. The bromomethyl derivatives 10a–10d are commercial
products.
3-Methoxy-2-methyl-benzoic acid ethylester (2g, C11H14O3)
A mixture of 2.0 g (12 mmol) of 3-methoxy-2-methyl-benzoic acid [25], 30cm3 of EtOH, and 2 cm3 of
conc. H2SO4 was refluxed for 12 h. After removing the solvent in vacuo, the oily residue was con-
secutively diluted with 10 cm3 of ice cold H2O and 20cm3 of Et2O. The aqueous layer was extracted
with 2 ꢄ 50 cm3 of Et2O, the combined organic phases were washed with 20cm3 of saturated NaHCO3
solution and 20cm3 of H2O, and dried with Na2SO4. After removing the solvent in vacuo a colourless
oil was obtained, which was used for the next step without further purification. Yield: 2.3 g (99%);
TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.70; IR (film): ꢄꢀ¼ 1726 (CO2R) cmꢅ 1; MS (EI): m=z (%) ¼ 194
(Mþꢇ, 39), 149 (Mþꢇ –OC2H5, 100), 91 (C7H7, 75); 1H NMR: ꢅ ¼ 7.39 (dd, J ¼ 7.9=3.1Hz, 6-H), 7.19
(br t, J ¼ 7.9Hz, 5-H), 6.96 (dd, J ¼ 7.9=0.9 Hz, 4-H), 4.35 (q, J ¼ 7.1 Hz, OCH2), 3.83 (s, OCH3), 2.42
(s, Ph-CH3), 1.38 (t, J ¼ 7.1 Hz, OC–CH3) ppm.
2-(Bromomethyl)benzoic acid methylester (3a)
Method A, yield: 86%, bp 90–94ꢃC=0.2 Pa [9]; TLC (n-hexane:EtOAc¼ 3:2): Rf ¼ 0.80.
2-(Bromomethyl)benzoic acid ethylester (3b)
Method A, yield: 93%, bp 98–100ꢃC=0.16 Pa [9]; TLC (n-hexane:EtOAc¼ 3:2): Rf ¼ 0.83.
2-(Bromomethyl)benzoic acid isopropylester (3c)
Method A, yield: 82%, bp 107–109ꢃC=0.15 Pa [26]; TLC (n-hexane:EtOAc¼ 3:2): Rf ¼ 0.86.
2-(Bromomethyl)benzoic acid t-butylester (3d, C12H15BrO2)
Method A, yield: 78%; TLC (petroleum ether:CHCl3 ¼ 2:1): Rf ¼ 0.77; IR (film): ꢄꢀ¼ 1712 (CO2R),
704 (C–Br)cmꢅ 1; MS (EI): m=z(%) ¼ 215 (Mþꢇ –C4H9, 4), 213 (Mþꢇ –C4H9, 4), 133 (100), 105 (46),
77 (43); 1H NMR: ꢅ ¼ 7.95 (m, 6-H), 7.68–7.50 (m, 3-H, 4-H, 5-H), 5.35 (s, CH2–Br), 1.63
(s, C(CH3)3) ppm.

Protoberberines from Reissert-Compounds
999
2-(Bromomethyl)-6-methoxybenzoic acid ethylester (3e)
Method B, yield: 95% [27]; TLC (n-hexane:EtOAc¼ 3:2): Rf ¼ 0.67.
2-(Bromomethyl)-4,5-dimethoxybenzoic acid ethylester (3f)
Method B, yield: 53%, mp 78–81ꢃC [20]; TLC (n-hexane:EtOAc¼ 3:2): Rf ¼ 0.69.
2-(Bromomethyl)-3-methoxybenzoic acid ethylester (3g, C11H13BrO3)
Method B, yield: 81%; TLC (n-hexane:EtOAc¼ 3:2): Rf ¼ 0.37; MS (EI): m=z(%) ¼ 274 (Mþꢇ, 5),
1
272 (Mþꢇ, 5), 193 (78), 165 (100), 77 (77); H NMR: ꢅ ¼ 7.51 (dd, J ¼ 8.0=1.1 Hz, 6-H), 7.33 (t,
J ¼ 8.0 Hz, 5-H), 7.05 (dd, J ¼ 8.0=1.1 Hz, 4-H), 5.05 (s, CH2–Br), 4.40 (q, J ¼ 7.1 Hz, OCH2), 3.92 (s,
OCH3), 1.42 (t, J ¼ 7.1 Hz, CH3) ppm.
6-(Bromomethyl)-2,3-(methylenedioxy)benzoic acid ethylester (3h)
Method B, yield: 96%, mp 67ꢃC [28]; TLC (n-hexane:EtOAc¼ 3:2): Rf ¼ 0.76.
6-(Chloromethyl)-2,3-dimethoxybenzoic acid ethylester (3i)
Educt is N-dimethoxybenzyl-N,N-dimethylamine; yield: 89%, bp 130ꢃC=0.05Pa [24]; TLC (n-
hexane:EtOAc¼ 3:2): Rf ¼ 0.65.
1-(Bromomethyl)naphthalene (10e)
Method A, yield: 85%, colourless liquid [29]; TLC (EtOAc:n-hexane¼ 3:1): Rf ¼ 0.78; MS (EI): m=z
1
(%) ¼ 221 (Mþꢇ –H, 100), 219 (Mþꢇ–H, 100), 141 (63); H NMR: ꢅ ¼ 8.10 (m, 4-H), 7.82–7.77 (m,
3H), 7.57–7.33 (m, 3H), 4.90 (s, CH2–Br) ppm.
4-(Bromomethyl)benzoic acid t-butylester (10f)
Method A, yield: 73%, colourless liquid [30]; TLC (petroleum ether:CHCl3 ¼ 2:1): Rf ¼ 0.70; IR
(film): ꢄꢀ¼ 1713 (CO2R), 704 (C–Br) cmꢅ 1; MS (CI): m=z (%) ¼ 273 (Mþꢇ þ 1, 12), 272 (Mþꢇ
,
1
100), 271 (Mþꢇ þ 1, 12), 269 (Mþꢇ, 98), 215 (29), 123 (67); H NMR: ꢅ ¼ 7.90 and 7.88 (2dd, each
J ¼ 6.5=1.7 Hz, 2-H, 6-H), 7.53 (dd, J ¼ 6.5=1.7 Hz, 1H, 3-H=5-H), 7.34 (br d, J ¼ 6.2Hz, 1H, 3-H=
5-H), 4.39 (s, CH2–Br), 1.51 (s, C(CH3)3) ppm.
Benzylated Reissert Compounds 4 and 11, General Procedures
Method A: According to Refs. [1, 9]; before extraction with benzene, the mixture was diluted with
20cm3 of H2O. The products were dried in vacuo at 60ꢃC.
Method B: A solution of the corresponding Reissert compound 1 in dry DMF was stirred for
30min under N2 at ambient temperature. After addition of NaH (60% dispersion in mineral oil) the
reaction flask was equipped with a septum, and a solution of the appropriate benzyl halogenide 3 or 10
in DMF was added dropwise over ca. 15min by a syringe under vigorous stirring. Stirring was
continued for several hours and then the mixture was quenched cautiously with 800cm3 of ice=H2O.
The aqueous layer was extracted with 4 ꢄ 200 cm3 of EtOAc and the combined organic extracts were
consecutively washed with 100 cm3 of H2O and 100 cm3 of brine and dried with Na2SO4. Further
workup was the same as described under Method A. For preparation and spectroscopic data of 4a, 4b,
4i, and 4l see Ref. [9].

1000
E. Reimann et al.
2-[[2-Benzoyl-1-cyano-1,2-dihydroisoquinolin-1-yl]methyl]benzoic acid isopropylester
(4c, C28H24N2O3)
Method A, 1a 31.9 mmol, 3c 33.9mmol, cetrimonium bromide 69mg, C6H6 100 cm3, 50% NaOH
solution 15cm3, 16h; yield: 65%, mp 155–156ꢃC; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.55; IR (KBr):
ꢄꢀ¼ 2240 (CꢆN), 1712, 1675 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 305 (10), 218 (52), 105 (100);
MS (CI): m=z (%) ¼ 437 (100), 306 (74), 105 (49).
2-[[2-Benzoyl-1-cyano-1,2-dihydroisoquinolin-1-yl]methyl]benzoic acid t-butylester
(4d, C29H26N2O3)
Method A, 1a 20mmol, 3d 16.6mmol, cetrimonium bromide 49mg, C6H6 50cm3, 50% NaOH
solution 7.5 cm3, 6 h; yield: 53%, mp 161–162ꢃC; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.70; IR
(KBr): ꢄꢀ¼ 2241 (CꢆN), 1713, 1684 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 218 (71), 105 (100), 84
(65); MS (CI): m=z (%) ¼ 451 (14), 395 (100), 368 (51).
2-[[1-Cyano-1,2-dihydro-2-(4-methylbenzoyl)isoquinolin-1-yl]methyl]benzoic
acid methylester (4e, C27H22N2O3)
Method A, 1b 14.2mmol, 3a 17.5mmol, cetrimonium bromide 50 mg, C6H6 50cm3, 50% NaOH
solution 7.5 cm3, 4 h; yield: 74%; mp 176–177ꢃC; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.54; IR (KBr):
ꢄꢀ¼ 1722, 1665 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 277 (5), 218 (29), 119 (100); MS (CI): m=z
(%) ¼ 423 (58), 278 (78), 119 (33).
2-[[1-Cyano-1,2-dihydro-2-(4-methylbenzoyl)isoquinolin-1-yl]methyl]benzoic
acid ethylester (4f, C28H24N2O3)
Method A, 1b 21.8mmol and 3b 24.7 mmol, cetrimonium bromide 53mg, C6H6 60 cm3, 50% NaOH
solution 10 cm3, 4 h; yield: 65%, mp 149ꢃC; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.59; IR (KBr):
ꢄꢀ¼ 1721, 1667 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 291 (12), 218 (58), 119 (100); MS (CI): m=z
(%) ¼ 437 (71), 292 (92), 119 (100).
2-[[1-Cyano-1,2-dihydro-2-(4-methoxybenzoyl)isoquinolin-1-yl]methyl]benzoic
acid methylester (4g, C27H22N2O4)
Method A, 1c 13.4mmol, 3a 17.5mmol, cetrimonium bromide 51 mg, C6H6 50cm3, 50% NaOH
solution 7.5 cm3, 4 h; yield: 52%, mp 168–169ꢃC; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.54; IR
(KBr): ꢄꢀ¼ 2242 (CꢆN), 1725, 1674 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 277 (11), 218 (44), 135
(100); MS (CI): m=z (%) ¼ 439 (100), 278 (41), 135 (38).
2-[[2-Benzoyl-1-cyano-1,2-dihydro-6,7-dimethoxyisoquinolin-1-yl]methyl]benzoic
acid methylester (4h, C28H24N2O5)
Method A, 1d 14 mmol, 3a 17.1mmol, cetrimonium bromide 50mg, C6H6 50cm3, 50% NaOH
solution 7.5 cm3, 4.5 h; yield: 90%, mp 162ꢃC; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.36; IR (KBr):
ꢄꢀ¼ 1727, 1672 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 337 (53), 305 (59), 278 (100); MS (CI): m=z
(%) ¼ 469 (12), 338 (90), 105 (100).
2-[[2-Benzoyl-7-benzyloxy-1-cyano-1,2-dihydro-6-methoxyisoquinolin-1-yl]methyl]benzoic
acid ethylester (4j, C35H30N2O5)
Method A, 1e 12.6 mmol, 3b 13mmol, cetrimonium bromide 40mg, C6H6 50cm3, 50% NaOH
solution 7.5cm3, 11 h; yield: 77%, mp 149ꢃC; TLC (n-hexane:EtOAc¼ 1:1): Rf ¼ 0.48; IR (KBr):

Protoberberines from Reissert-Compounds
1001
ꢄꢀ¼ 1717, 1676 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 427 (43), 354 (42), 91 (100); MS (CI): m=z
(%) ¼ 559 (2), 428 (13), 79 (100).
2-[[2-Benzoyl-1-cyano-1,2-dihydro-6,7-methylenedioxyisoquinolin-1-yl]methyl]benzoic
acid ethylester (4k, C28H22N2O5)
Method B, 1g 9.9 mmol, 3b 12 mmol, DMF 50cm3, 60% NaH dispersion 390 mg, 1 h; yield: 67%, mp
144ꢃC; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.44; IR (KBr): ꢄꢀ¼ 2242 (CꢆN), 1714, 1668
(C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 335 (19), 289 (57), 262 (100); MS (CI): m=z (%) ¼ 467 (2), 336
(72), 105 (100).
2-[[2-Benzoyl-1-cyano-1,2-dihydroisoquinolin-1-yl]methyl]-4,5-dimethoxybenzoic
acid ethylester (4m, C29H26N2O5)
Method A, 1a 2 mmol, 3f 1.9 mmol, cetrimonium bromide 10mg, C6H6 30 cm3, 50% NaOH solution
2.5 cm3, 7 h; yield: 61%, mp 181ꢃC; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.26; IR (KBr): ꢄꢀ¼ 2240
(CꢆN), 1710, 1676 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 305 (29), 278 (100), 105 (100); MS (CI): m=z
(%) ¼ 483 (100), 352 (100), 105 (29).
2-[[2-Benzoyl-1-cyano-1,2-dihydroisoquinolin-1-yl]methyl]-3-methoxy-benzoic
acid ethylester (4n, C28H24N2O4)
Method A, 1a 3.8 mmol, 3g 4.2 mmol, cetrimonium bromide 50 mg, C6H6 50cm3, 50% NaOH solution
7.5 cm3, 17 h; yield: 64%, mp 164ꢃC; TLC (n-hexane:EtOAc¼ 1:1): Rf ¼ 0.43; IR (KBr): ꢄꢀ¼ 2229
(CꢆN), 1714, 1677 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 259 (16), 105 (100), 77 (23); MS (CI): m=z
(%) ¼ 453 (22), 322 (100), 105 (53).
2-[[1-Cyano-1,2-dihydro-6,7-dimethoxy-2-(4-methylbenzoyl)isoquinolin-1-yl]methyl]-
6-methoxybenzoic acid ethylester (4o, C31H30N2O6)
Method B, 1d 12mmol, 3e 13.5mmol, DMF 100 cm3, 60% NaH dispersion 480 mg, 1 h; yield: 70%,
mp 168ꢃC; TLC (n-hexane:EtOAc¼ 1:1): Rf ¼ 0.41; IR (KBr): ꢄꢀ¼ 2236 (CꢆN), 1718, 1676
(C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 381 (5), 308 (100), 119 (29); MS (CI): m=z (%) ¼ 382 (100),
336 (13), 119 (72).
6-[[2-Benzoyl-1-cyano-1,2-dihydroisoquinolin-1-yl]methyl]-2,3-methylenedioxybenzoic
acid ethylester (4p, C28H22N2O5)
Method A, 1a 3.8 mmol, 3h 4.2 mmol, cetrimonium bromide 50mg, C6H6 50cm3, 50% NaOH solution
7.5 cm3, 12 h; yield: 71%, mp 152ꢃC; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.39; IR (KBr): ꢄꢀ¼ 2231
(CꢆN), 1715, 1676 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 335 (9), 262 (42), 105 (100); MS (CI): m=z
(%) ¼ 467 (33), 336 (58), 105 (100).
6-[[2-Benzoyl-1-cyano-1,2-dihydro-6,7-dimethoxyisoquinolin-1-yl]methyl]-
2,3-dimethoxybenzoic acid ethylester (4q, C31H30N2O7)
Method B, 1d 13.8mmol, 3i 14 mmol, DMF 100 cm3, 60% NaH dispersion 550mg, 1 h; yield: 71%,
mp 135–136ꢃC; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.37; IR (KBr): ꢄꢀ¼ 2243 (CꢆN), 1709, 1674
(C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 366 (13), 338 (100), 105 (19); MS (CI): m=z (%) ¼ 366 (10),
338 (11), 105 (100).

1002
E. Reimann et al.
6-[[1-Cyano-1,2-dihydro-6,7-dimethoxy-2-(4-methylbenzoyl)isoquinolin-1-yl]methyl]-
2,3-dimethoxybenzoic acid ethylester (4r, C32H32N2O7)
Method B, 1f 12.7mmol, 3i 13mmol, DMF 100 cm3, 60% NaH dispersion 508mg, 1 h; yield: 72%,
mp 155ꢃC; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.40; IR (KBr): ꢄꢀ¼ 2242 (CꢆN), 1714, 1663
(C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 366 (10), 338 (100), 119 (52); MS (CI): m=z (%) ¼ 557 (1), 412
(5), 195 (100).
6-[[2-Benzoyl-1-cyano-1,2-dihydro-6,7-methylenedioxyisoquinolin-1-yl]methyl]-
2,3-dimethoxybenzoic acid ethylester (4t, C30H26N2O7)
Method B, 1g 14.1mmol, 3i 14.3mmol, DMF 100 cm3, 60% NaH dispersion 550 mg, 1 h; yield: 74%,
mp 161ꢃC; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.56; IR (KBr): ꢄꢀ¼ 2239 (CꢆN), 1709, 1673
(C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 395 (2), 350 (12), 322 (100); MS (CI): m=z (%) ¼ 396 (34), 322
(10), 105 (100).
6-[[2-Benzoyl-1-cyano-1,2-dihydro-6,7-methylenedioxyisoquinolin-1-yl]methyl]-
2,3-methylenedioxybenzoic acid ethylester (4u, C29H22N2O7)
Method B, 1g 7.1 mmol, 3h mmol, DMF 50cm3, 60% NaH dispersion 283mg, 1 h; yield: 63%, mp
167ꢃC; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.65; IR (KBr): ꢄꢀ¼ 2243 (CꢆN), 1712, 1675
(C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 379 (16), 333 (16), 306 (100); MS (CI): m=z (%) ¼ 511 (2), 380
(31), 105 (100).
2-Benzoyl-1-benzyl-1,2-dihydroisoquinoline-1-carbonitrile (11a)
Method A, 1a 15.9mmol, 10a 16.3mmol, cetrimonium bromide 47mg, C6H6 50cm3, 50% NaOH
solution 7.5 cm3, 5 h; yield: 92%, TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.55; Ref. [31].
2-Benzoyl-1,2-dihydro-1-(2-methylbenzyl)isoquinoline-1-carbonitrile (11b)
Method A, 1a 15.3mmol, 10b 15.6mmol, cetrimonium bromide 44mg, C6H6 50cm3, 50% NaOH
solution 7.5 cm3, 3.5 h; yield: 88%; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.56; Ref. [31].
2-Benzoyl-1-(2-bromobenzyl)-1,2-dihydroisoquinoline-1-carbonitrile (11c, C24H17BrN2O)
Method A, 1a 15.3 mmol, 10c 15.6 mmol, cetrimonium bromide 51mg, C6H6 50 cm3, 50% NaOH
solution 7.5 cm3, 7 h; yield: 58%, mp 171ꢃC; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.63; IR (KBr):
ꢄꢀ¼ 1660 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 105 (100), 77 (47); MS (CI): m=z (%) ¼ 431 (1), 429
(1), 105 (24).
2-Benzoyl-1,2-dihydro-1-(2-nitrobenzyl)isoquinoline-1-carbonitrile (11d)
Method A, 1a 15.3mmol, 10d 15.6mmol, cetrimonium bromide 50mg, C6H6 50cm3, 50% NaOH
solution 7.5 cm3, 5.5 h; yield: 88%; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.49; Ref. [32].
2-Benzoyl-1,2-dihydro-1-(naphth-1-ylmethyl)isoquinoline-1-carbonitrile (11e, C28H20N2O)
Method A, 1a 15.3 mmol, 10e 15.6 mmol, cetrimonium bromide 50mg, C6H6 50 cm3, 50% NaOH
solution 7.5 cm3, 6 h; yield: 64%, mp 141ꢃC; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.49; IR (KBr):

Protoberberines from Reissert-Compounds
1003
ꢄꢀ¼ 1669 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 400 (3), 268 (100), 259 (91); MS (CI): m=z (%) ¼ 401
(100), 259 (80), 105 (78).
4-[[2-Benzoyl-1-cyano-1,2-dihydroisoquinolin-1-yl]methyl]benzoic acid t-butylester
(11f, C29H26N2O3)
Method A, 1a 15.9mmol, 10f 16.6 mmol, cetrimonium bromide 47 mg, C6H6 50cm3, 50% NaOH
solution 7.5 cm3, 6 h; yield: 42%, mp 160ꢃC; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.71; IR (KBr):
ꢄꢀ¼ 1712, 1677 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 262 (59), 105 (100), 84 (89); MS (CI): m=z
(%) ¼ 451 (60), 395 (100), 368 (44).
Oxazoloisoquinolines 5 and by-products 6–9
General procedure according to Ref. [1]. For isolation of the by-products 6–9 the reaction mixtures
were concentrated in vacuo and the residues separated by flash chromatography; eluents were the same
as indicated under TLC of compounds 5. For yields and analytical data of compounds 5b and 5h as
well as 6b and 6e see Ref. [1].
2-[(5,6-Dihydro-1-oxo-3-phenyloxazolo[4,3-a]isoquinolin-10b-yl)methyl]benzoic
acid methylester (5a, C26H23NO4)
4a 7.3 mmol, CH3CO2H 15 cm3, CF3CO2H 27 cm3, NaBH3CN 15.7mmol, 1 h; yield: 45%, mp 128ꢃC;
IR (KBr): ꢄꢀ¼ 1785, 1722 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 369 (4), 310 (46), 264 (53), 149 (100);
1
TLC (petroleum ether:EtOAc¼ 3:1): Rf ¼ 0.71; H NMR: ꢅ ¼ 7.86 (dd, J ¼ 7.7=1.4 Hz, 10-H), 7.81,
7.53, and 7.47 (3dd, each J ¼ 7.6=1.5 Hz, 3 arom H), 7.41–7.24 (m, 6 arom H), 7.17–7.12 (m, 7-H),
7.03–6.96 (m, 2 arom H), 5.67 (s, 3-H), 4.12 and 3.84 (AB, J ¼ 14.0Hz, benzyl-CH2), 3.72 (s, OCH3),
3.29 (ddd, J ¼ 14.3=12.9=4.3 Hz, 5-Ha), 3.14 (ddd, J ¼ 16.9=12.9=5.8Hz, 6-Ha), 2.84–2.75 (m, 5-Hb),
2.54 (dd, J ¼ 16.9=4.3 Hz, 6-Hb) ppm; 13C NMR: ꢅ ¼ 174.03, 168.78, 136.91, 135.62, 133.61, 133.58,
132.97, 131.16, 130.01, 129.72, 129.50, 128.24, 127.82, 127.72, 127.05, 126.74, 90,80, 66.86, 51.79,
40.58, 37.18, 21.82 ppm.
2-[(5,6-Dihydro-1-oxo-3-phenyloxazolo[4,3-a]isoquinolin-10b-yl)methyl]benzoic
acid isopropylester (5c, C28H27NO4)
4c 6.9 mmol, CH3CO2H 15 cm3, CF3CO2H 27cm3, NaBH3CN 15.7mmol, 1 h; yield: 32%, mp 131–
133ꢃC; IR (KBr): ꢄꢀ¼ 1776, 1705 (C¼O) cmꢅ 1; MS (EI): m=z (%) ¼ 397 (5), 310 (100), 91 (15); TLC
1
(petroleum ether:EtOAc¼ 3:1): Rf ¼ 0.78; H NMR: ꢅ ¼ 7.87 (dd, J ¼ 7.8=1.5 Hz, 10-H), 7.81 (dd,
J ¼ 7.7=1.6 Hz, 1 arom H), 7.53 (dd, J ¼ 7.7=1.2 Hz, 1 arom H), 7.45 (dt, J ¼ 7.7=1.6 Hz, 1 arom H),
7.39–7.23 and 7.16–7.11 (2m, 7 þ 2 arom H), 5.65 (s, 3-H), 5.08 (sept, J ¼ 6.2 Hz, 1 H), 4.20 and 3.79
(AB, J ¼ 14.1Hz, benzyl-CH2), 3.34 (ddd, J ¼ 14.6=13.1=4.6 Hz, 5-Ha), 3.13 (ddd, J ¼ 16.9=13.1=
6.1 Hz, 6-Ha), 2.78 (ddd, J ¼ 14.6=6.1=1.2 Hz, 5-Hb), 2.53 (dt, J ¼ 16.9=4.6 Hz, 6-Hb), 1.29 and 1.04
(2d, J ¼ 6.2 Hz, 2 CH3) ppm; 13C NMR: ꢅ ¼ 174.07, 167.76, 137.05, 135.60, 133.61, 133.56, 133.48,
133.14, 131.02, 129.96, 129.72, 129.46, 128.35 (2C), 128.22 (2C), 127.76, 127.67, 127.01, 126.63,
90.80, 67.98, 66.88, 40.40, 37.11, 21.84, 21.80, 21.67ppm.
2-[(5,6-Dihydro-1-oxo-3-phenyloxazolo[4,3-a]isoquinolin-10b-yl)methyl]benzoic
acid t-butylester (5d, C29H29NO4)
4d 6.7 mmol, CH3CO2H 15 cm3, CF3CO2H 20 cm3, NaBH3CN 15.7mmol, 10min; yield: 29%,
mp 135ꢃC; IR (KBr): ꢄꢀ¼ 1781, 1699 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 411 (8), 354 (12), 310
(100), 264 (76), 91 (60); TLC (petroleum ether:EtOAc¼ 3:1): Rf ¼ 0.88; 1H NMR: ꢅ ¼ 7.86 (d,

1004
E. Reimann et al.
J ¼ 7.7 Hz, 10-H), 7.84 and 7.53 (2d, J ¼ 8.1 and 7.7Hz, 2 arom H), 7.43 (t, J ¼ 7.7 Hz, 1 arom H),
7.36–7.25 (m, 7 arom H), 7.13 (d, J ¼ 7.3Hz, 7-H), 7.00 (dd, J ¼ 8.1=0.9 Hz, 2 arom H), 5.66 (s, 3-H),
4.26 and 3.75 (AB, J ¼ 14.1Hz, benzyl-CH2), 3.40 (dt, J ¼ 14.8=4.7Hz, 5-Ha), 3.12 (dt,
J ¼ 17.3=4.9 Hz, 6-Ha), 2.82 (dd, J ¼ 14.8=4.9 Hz, 5-Hb), 2.54 (dd, J ¼ 17.3=4.7 Hz, 6-Hb), 1.46 (s,
3 CH3) ppm.
2-[[5,6-Dihydro-3-(4-methylphenyl)-1-oxooxazolo[4,3-a]isoquinolin-10b-yl]methyl]benzoic
acid methylester (5e, C27H25NO4)
4e 7.1 mmol, CH3CO2H 15 cm3, CF3CO2H 20cm3, NaBH3CN 15.7mmol, 1 h; yield: 43%, mp 111–
113ꢃC; IR (KBr): ꢄꢀ¼ 1776, 1717 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 383 (14), 324 (100), 105 (19), 84
1
(39); TLC (petroleum ether:EtOAc¼ 4:1): Rf ¼ 0.73; H NMR: ꢅ ¼ 7.78 (dd, J ¼ 7.8=1.9 Hz, 10-H),
7.75 and 7.45 (2dd, each J ¼ 7.7=1.5 Hz, 1 arom H), 7.39 and 7.29 (2dt, each J ¼ 7.7=1.5 Hz, 2 arom
H), 7.27–7.17 (m, 8-H, 9-H), 7.09–6.00 (m, 3 arom H), 6.86–6.81 (m, 2 arom H), 5.57 (s, 3-H), 4.03
and 3.79 (AB, J ¼ 14 Hz, benzyl-CH2), 3.68 (s, CH3), 3.20 (ddd, J ¼ 14.4=13.1=4.5 Hz, 5-Ha), 3.05
(ddd, J ¼ 16.8=13.1=5.7 Hz, 6-Ha), 2.72 (ddd, J ¼ 14.4=5.7=1.3 Hz, 5-Hb), 2.45 (dd, J ¼ 16.8=4.5 Hz,
6-Hb), 2.28 (s, CH3) ppm; 13C NMR: ꢅ ¼ 173.06, 167.76, 139.03, 135.98, 132.59, 132.50, 131.99,
131.88, 131.57, 130.11, 128.70, 128.44, 128.00 (2C), 127.23 (2C), 126.74, 126.70, 125.97, 125.66,
89.76, 65.84, 50.81, 39.51, 36.12, 20.76, 20.28 ppm.
2-[[5,6-Dihydro-3-(4-methylphenyl)-1-oxooxazolo[4,3-a]isoquinolin-10b-yl]methyl]benzoic
acid ethylester (5f, C28H27NO4)
4f 6.9 mmol, CH3CO2H 15cm3, CF3CO2H 27cm3, NaBH3CN 15.7mmol, 1 h; yield: 47%, mp 139ꢃC;
IR (KBr): ꢄꢀ¼ 1776, 1709 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 397 (9), 324 (100), 105 (18); TLC
(petroleum ether:EtOAc¼ 4:1): Rf ¼ 0.79; 1H NMR: ꢅ ¼ 7.87–7.77 (m, 2 arom H), 7.51, (d, J ¼ 8.0 Hz,
arom H), 7.43 and 7.34 (2t, each J ¼ 8.0 Hz, 2 arom H), 7.31–7.19 (m, 3 arom H), 7.11 (d, J ¼ 7.9 Hz,
7-H), 7.09–7.01 and 6.91–6.83 (2m, each 2 arom H), 5.61 (s, 3-H), 4.29–4.06 (m, 3 H), 3.80 (d,
J ¼ 14.0Hz, 1 H), 3.28 (dt, J ¼ 14.1=4.2 Hz, 5-Ha), 3.09 (ddd, J ¼ 17.3=12.6=5.6 Hz, 6-Ha), 2.76 (dd,
J ¼ 14.1=5.6 Hz, 5-Hb), 2.50 (dd, J ¼ 17.3=4.2Hz, 6-Hb), 2.32 (s, CH3), 1.20 (t, J ¼ 7.2 Hz, CH3) ppm;
13C NMR: ꢅ ¼ 174.02, 168.29, 139.91, 136.93, 133.60, 133.49, 133.22, 133.02, 132.58, 130.97,
129.62, 129.41, 128.85, 128.37, 128.26, 127.68, 127.64, 126.91, 126.60, 90.72, 66.83, 60.60, 40.42,
37.06, 21.73, 21.22, 14.00 ppm.
2-[[5,6-Dihydro-3-(4-methoxyphenyl)-1-oxooxazolo[4,3-a]isoquinolin-
10b-yl]methyl]benzoic acid methylester (5g, C27H25NO5)
4g 6.8 mmol, CH3CO2H 15 cm3, CF3CO2H 27 cm3, NaBH3CN 15.7mmol, 1 h; yield: 27%, mp 156ꢃC;
IR (KBr): ꢄꢀ¼ 1783, 1707 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 399 (18), 340 (68), 121 (100); TLC
(petroleum ether:EtOAc¼ 4:1): Rf ¼ 0.68; 1H NMR: ꢅ ¼ 7.86–7.79 (m, 2 arom H), 7.52 (dd,
J ¼ 7.5=1.5 Hz, 1 arom H), 7.45 and 7.35 (2dt, each J ¼ 7.5=1.5 Hz, 2 arom H), 7.32–7.22 and
7.14–7.10 (2m, 2 þ 1 arom H), 6.93 and 6.78 (2d, each J ¼ 8.8Hz, each 2 arom H), 5.62 (s, 3-H),
4.10 and 3.83 (AB, J ¼ 14.0Hz, benzyl-CH2), 3.79 and 3.75 (2s, 2 CH3), 3.26 (ddd,
J ¼ 14.3=13.2=4.5 Hz, 5-Ha), 3.15-3.03 (m, 6-Ha), 2.76 (ddd, J ¼ 14.3=5.8=1.1 Hz, 5-Hb), 2.51 (dd,
J ¼ 16.9=4.5 Hz, 6-Hb) ppm.
2-[(9-Benzyloxy-5,6-dihydro-8-methoxy-1-oxo-3-phenyloxazolo[4,3-a]isoquinolin-
10b-yl)methyl]benzoic acid ethylester (5i, C35H33NO6)
4j 1.8 mmol, CH3CO2H 5 cm3, CF3CO2H 9 cm3, NaBH3CN 5.2mmol, 15min; yield: 30%, mp 168ꢃC;
IR (KBr): ꢄꢀ¼ 1785, 1722 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 519 (9), 446 (10), 400 (14), 355 (21), 91

Protoberberines from Reissert-Compounds
1005
(100); TLC (n-hexane:EtOAc ¼ 1:1): Rf ¼ 0.85; 1H NMR: ꢅ ¼ 7.79 and 7.56–7.52 (2m, 1 þ 2 arom H),
7.46–7.24 and 7.07–7.02 (2m, 10þ 2 arom H), 6.59 and 5.63 (2s, 7-H and 3-H), 5.22 and 5.16 (2d,
each J ¼ 12.0 Hz, OBn), 4.24–4.04 (m, OCH2), 4.04 and 3.64 (AB, J ¼ 14.0Hz, benzyl-CH2), 3.89 (s,
OCH3), 3.23 (ddd, J ¼ 14.3=13.0=4.6 Hz, 5-Ha), 3.04 (ddd, J ¼ 16.8=13.0=5.8 Hz, 6-Ha), 2.74 (dd,
J ¼ 14.3=5.8 Hz, 5-Hb), 2.40 (dd, J ¼ 16.8=4.6 Hz, 6-Hb), 1.19 (t, J ¼ 7.2 Hz, CH3) ppm; 13C NMR
(CDCl3): ꢅ ¼ 174.09, 168.28, 149.44, 147.02, 136.95, 136.93, 135.69, 133.54, 133.29, 131.00, 129.97,
129.61, 128.54 (2C), 128.34 (2C), 128.22 (2C), 127.95, 127.85, 126.63, 126.45, 124.36, 112.81,
111.96, 90.74, 71.13, 66.39, 60.58, 56.02, 40.40, 37.22, 21.38, 14.06 ppm.
2-[(5,6-Dihydro-8,9-methylenedioxy-1-oxo-3-phenyloxazolo[4,3-a]isoquinolin-
10b-ylethyl]benzoic acid ethylester (5j, C28H25NO6)
4k 1.8 mmol, CH3CO2H 5 cm3, CF3CO2H 9 cm3, NaBH3CN 5.2 mmol, 1 h; yield: 37%, mp 134ꢃC; IR
(KBr): ꢄꢀ¼ 1783, 1716 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 427 (12), 354 (100), 308 (6), 91 (10); TLC
(n-hexane:EtOAc¼ 3:1): Rf ¼ 0.81; 1H NMR: ꢅ ¼ 7.81 (dd, J ¼ 7.7=1.5 Hz, arom H), 7.51 (dd,
J ¼ 7.7=1.4 Hz, arom H), 7.45 (dt, J ¼ 7.7=1.5 Hz, arom H), 7.38–7.32 (m, 2 arom H), 7.32 (s, 10-
H), 7.29–7.24 and 7.01–6.97 (2m, 2 þ 2 arom H), 6.57 (s, 7-H), 5.97 and 5.94 (2d, each J ¼ 1.5 Hz,
OCH2O), 5.62 (s, 3-H), 4.28–4.05 (m, OCH2), 4.11 and 3.73 (AB, J ¼ 14.0Hz, benzyl-CH2), 3.23
(ddd, J ¼ 14.5=13.1=4.7 Hz, 5-Ha), 3.03 (ddd, J ¼ 16.8=13.1=5.8 Hz, 6-Ha), 2.73 (ddd, J ¼ 14.5=
5.8=1.1 Hz, 5-Hb), 2.41 (dd, J ¼ 16.8=4.7 Hz, 6-Hb), 1.19 (t, J ¼ 7.1 Hz, CH3) ppm; 13C NMR:
ꢅ ¼ 174.00, 168.31, 147.42, 146.47, 136.89, 135.66, 133.41, 133.31, 131.02, 129.95, 129.68, 128.29
(2C), 128.21 (2C), 127.31, 126.66, 125.95, 108.66, 107.47, 101.08, 90.75, 66.88, 60.62, 40.46, 37.24,
22.09, 14.06 ppm.
6-[(5,6-Dihydro-1-oxo-3-phenyloxazolo[4,3-a]isoquinolin-10b-yl)methyl]-2-methoxy-
benzoic acid ethylester (5k, C28H27NO5)
4l 2.2 mmol, CH3CO2H 5 cm3, CF3CO2H 9 cm3, NaBH3CN 5.2 mmol, 1 h; yield: 29%, mp 152ꢃC; IR
(KBr): ꢄꢀ¼ 1783, 1716 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 413 (4), 340 (100), 264 (19), 91 (16); TLC
(n-hexane:EtOAc¼ 3:1): Rf ¼ 0.61; 1H NMR: ꢅ ¼ 7.82 (dd, J ¼ 7.6=1.5 Hz, 10-H), 7.39–7.33 and
7.32–7.22 (2m, 1 þ 5 arom H), 7.19–7.14 (m, 2 arom H), 7.11 (dd, J ¼ 7.5=1.5 Hz, arom H), 6.97
and 6.86 (2dd, each J ¼ 8.0=0.7 Hz, 2 arom H), 5.70 (s, 3-H), 4.32–4.17 (m, OCH2), 3.83 (s, OCH3),
3.67 and 3.42 (AB, J ¼ 14.7Hz, benzyl-CH2), 3.18–3.01 (m, 5-Ha and 6-Ha), 2.83–2.72 (m, 6-Hb),
2.51–2.39 (m, 5-Hb), 1.20 (t, J ¼ 7.2 Hz, CH3) ppm; 13C NMR: ꢅ ¼ 174.54, 168.19, 156.94, 135.62,
135.57, 133.67, 132.97, 130.13, 130.02, 129.60, 128.47 (2C), 128.30 (2C), 127.85, 127.45, 127.04,
125.88, 123.44, 110.02, 90.93, 66.03, 61.01, 56.21, 41.60, 37.48, 21.69, 14.03 ppm.
6-[(5,6-Dihydro-1-oxo-3-phenyloxazolo[4,3-a]isoquinolin-10b-yl)methyl]-
2,3-methylenedioxy-benzoic acid ethylester (5l, C28H25NO6)
4k 2.1 mmol, CH3CO2H 5 cm3, CF3CO2H 9 cm3, NaBH3CN 5.2 mmol, 1 h; yield: 45%, mp 147ꢃC; IR
(KBr): ꢄꢀ¼ 1777, 1710 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 427 (9), 354 (100), 91 (12); TLC
(n-hexane:EtOAc¼ 3:1): Rf ¼ 0.61; 1H NMR: ꢅ ¼ 7.81 (d, J ¼ 7.7=1.5 Hz, 10-H), 7.40–7.35 and
7.34–7.29 (2m, 1 þ 2 arom H), 7.28–7.23 (m, 8-H and 9-H), 7.17–7.10 (m, 3 arom H), 6.94 and
6.85 (2d, each J ¼ 7.9 Hz, 2 arom H), 6.05 and 6.02 (2d, each J ¼ 1.5 Hz, OCH2O), 5.68 (s, 3-H), 4.21
(dq, J ¼ 10.9=7.2 Hz, OCH2), 3.82 and 3.71 (2d, each J ¼ 14.1Hz, benzyl-CH2), 3.20 (dt, J ¼ 13.1=
4.9 Hz, 5-Ha), 3.11 (dt, J ¼ 12.8=4.9 Hz, 6-Ha), 2.85–2.78 (m, 5-Hb), 2.55–2.47 (m, 6-Hb), 1.19 (t,
J ¼ 7.1 Hz, CH3) ppm; 13C NMR: ꢅ ¼ 174.00, 165,73, 147.23, 146.98, 135.75, 133.62, 132.91, 129.98,
129.42, 129.06, 128.26 (4C), 127.77, 127.66, 127.02, 126.33, 116.74, 109.96, 101.47, 90.82, 66.77,
60.89, 40.31, 37.39, 21.85, 14.02 ppm.

1006
E. Reimann et al.
6-[(5,6-Dihydro-8,9-dimethoxy-1-oxo-3-phenyloxazolo[4,3-a]isoquinolin-10b-yl)methyl]-
2,3-dimethoxybenzoic acid ethylester (5m, C31H33NO8)
4q 1.8 mmol, CH3CO2H 5 cm3, CF3CO2H 9 cm3, NaBH3CN 5.2 mmol, 25min; yield: 40%, mp 143ꢃC;
IR (KBr): ꢄꢀ¼ 1782, 1710 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 430 (100), 322 (22), 105 (77); TLC
(n-hexane:EtOAc¼ 3:1): Rf ¼ 0.52; 1H NMR: ꢅ ¼ 7.40–7.34 and 7.32–7.26 (2m, 1 þ 2 arom H), 7.29
(s, 10-H), 7.22–7.16 (m, 3 arom H), 6.92 (d, J ¼ 7.7 Hz, arom H), 6.58 and 5.70 (2s, 7-H and 3-H),
4.21 (dq, J ¼ 10.7=7.2 Hz, OCH2), 3.94 and 3.91 (2s, 2 OCH3), 3.89 (s, 2 OCH3), 3.52 and 3.48 (AB,
J ¼ 14.6Hz, benzyl-CH2), 3.19–2.98 (m, 5-Ha and 6-Ha), 2.84–2.75 and 2.44–2.35 (2m, 5-Hb and
6-Hb), 1.19 (t, J ¼ 7.2 Hz, CH3) ppm; 13C NMR: ꢅ ¼ 174.51, 167.73, 151.73, 148.90, 148.13, 146.57,
135.67, 130.99, 130.06, 128.54, 128.26, 127.69, 126.98 (2C), 125.99 (2C), 124.54, 113.50, 111.61,
109.87, 90.90, 66.32, 61.42, 60.99, 56.14, 55.93 (2C), 40.53, 37.60, 21.42, 14.0 ppm.
6-[[5,6-Dihydro-8,9-dimethoxy-3-(4-methylphenyl)-1-oxooxazolo[4,3-a]isoquinolin-
10b-yl]methyl]-2,3-dimethoxybenzoic acid ethylester (5n, C32H35NO8)
4r 1.8 mmol, CH3CO2H 5 cm3, CF3CO2H 9 cm3, NaBH3CN 5.2mmol, 25min; yield: 37%, mp 141ꢃC;
IR (KBr): ꢄꢀ¼ 1783, 1709 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 517 (5), 444 (100), 338 (9), 105 (12);
TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.55; 1H NMR: ꢅ ¼ 7.28–7.25 (m, 2 arom H), 7.17 (d, J ¼ 8.7 Hz,
arom H), 7.10–7.08 (m, 3 arom H), 6.91 (d, J ¼ 8.7 Hz, arom H), 6.57 and 5.67 (2s, 7-H and 3-H), 4.22
(dq, J ¼ 10.8=7.1 Hz, OCH2), 3.94 and 3.92 (2s, 2 OCH3), 3.87 (s, 2 OCH3), 3.53–3.44 (m, benzyl-
CH2), 3.17–2.95 (m, 5-Ha and 6-Ha), 2.83–2.75 and 2.46–2.31 (2m, 5-Hb and 6-Hb), 2.34 (s, CH3),
1.19 (t, J ¼ 7.2 Hz, CH3) ppm; 13C NMR: ꢅ ¼ 174.56, 167.72, 151.66, 148.77, 148.00, 146.45, 140.10,
135.56, 130.92, 128.94 (2C), 128.49 (2C), 127.72, 126.93, 125.97, 124.47, 113.39, 111.48, 109.77,
90.82, 66.32, 61.46, 61.42, 56.09, 55.90, 40.45, 37.51, 21.37, 21.31, 14.01 ppm.
6-[(5,6-Dihydro-8,9-dimethoxy-1-oxo-3-phenyloxazolo[4,3-a]isoquinolin-10b-yl)methyl]-
2,3-methylenedioxybenzoic acid ethylester (5o, C30H29NO8)
4s 1.9 mmol, CH3CO2H 5 cm3, CF3CO2H 9 cm3, NaBH3CN 5.2 mmol, 25 min; yield: 35%, mp 144ꢃC;
IR (KBr): ꢄꢀ¼ 1779, 1709 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 487 (6), 414 (100), 91 (12); TLC
(n-hexane:EtOAc¼ 1:1): Rf ¼ 0.78; 1H NMR: ꢅ ¼ 7.41–7.36 and 7.35–7.30 (2m, 1 þ 2 arom H), 7.24
(s, 10-H), 7.21–7.16 (m, 2 arom H), 6.93 and 6.84 (2d, each J ¼ 8.2 Hz, 2 arom H), 6.56 (s, 7-H), 6.05
and 6.02 (2d, each J ¼ 1.3 Hz, OCH2O), 5.64 (s, 3-H), 4.19 (dq, J ¼ 10.7=7.2 Hz, OCH2), 3.93 and 3.88
(2s, 2 OCH3), 3.78 and 3.71 (AB, J ¼ 14.1Hz, benzyl-CH2), 3.14 (dt, J ¼ 13.2=5.0 Hz, 5-Ha), 3.04 (dt,
J ¼ 16.4=5.0 Hz, 6-Ha), 2.84–2.75 and 2.44–2.35 (2m, 5-Hb and 6-Hb), 1.20 (t, J ¼ 7.2 Hz, CH3) ppm;
13C NMR: ꢅ ¼ 174.30, 165.80, 148.86, 148.06, 147.26, 146.98, 135.78, 130.03, 129.12, 128.32 (4C),
126.27, 126.00, 124.33, 116.74, 111.46, 110.08, 109.93, 101.48, 90.82, 66.35, 60.87, 56.07, 55.90,
40.12, 37.39, 21.40, 14.04 ppm.
6-[(5,6-Dihydro-8,9-methylenedioxy-1-oxo-3-phenyloxazolo[4,3-a]isoquinolin-10b-yl)methyl]-
2,3-dimethoxybenzoic acid ethylester (5p, C30H29NO8)
4t 1.9 mmol, CH3CO2H 5 cm3, CF3CO2H 9 cm3, NaBH3CN 5.2mmol, 25min; yield: 41%, mp 146ꢃC;
IR (KBr): ꢄꢀ¼ 1778, 1708 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 487 (4), 414 (100), 322 (27), 105 (33),
1
91 (12); TLC (n-hexane:EtOAc¼ 1:1): Rf ¼ 0.81; H NMR: ꢅ ¼ 7.37–7.32 and 7.31–7.24 (2m, 1 þ 2
arom H), 7.29 (s, 10-H), 7.18–7.12 (m, 3 arom H), 6.91 (d, J ¼ 8.8 Hz, arom H), 6.56 (s, 7-H), 5.97 and
5.94 (2d, each J ¼ 1.6 Hz, OCH2O), 5.66 (s, 3-H), 4.20 (dq, J ¼ 10.7=7.2Hz, OCH2), 3.90 and 3.88 (2s,
2 OCH3), 3.48 and 3.44 (AB, J ¼ 14.1Hz, benzyl-CH2), 3.14–2.95 (m, 5-Ha and 6-Ha), 2.80–2.73 and
2.41–2.33 (2m, 6-Hb and 5-Hb), 1.17 (t, J ¼ 7.2 Hz, CH3) ppm; 13C NMR: ꢅ ¼ 174.31, 167.74, 151.76,
147.45, 146.79, 146.57, 135.62, 130.95, 130.05, 128.51 (2C), 128.24 (2C), 127.80, 127.32, 126.91,

Protoberberines from Reissert-Compounds
1007
125.81, 113.53, 108.73, 107.32, 101.48, 90.86, 66.68, 61.42, 60.99, 55.94, 40.60, 37.57, 22.09,
14.01 ppm.
6-[(5,6-Dihydro-8,9-methylenedioxy-1-oxo-3-phenyloxazolo[4,3-a]isoquinolin-
10b-yl)methyl]-2,3-methylenedioxybenzoic acid ethylester (5q, C29H25NO8)
4u 2.0 mmol, CH3CO2H 5 cm3, CF3CO2H 9 cm3, NaBH3CN 5.2 mmol, 45min; yield: 49%, mp 171ꢃC;
IR (KBr): ꢄꢀ¼ 1780, 1702 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 471 (10), 398 (100), 91 (12); TLC
(n-hexane:EtOAc¼ 1:1): Rf ¼ 0.55; 1H NMR: ꢅ ¼ 7.41–7.35 and 7.35–7.28 (2m, 1 þ 2 arom H), 7.29
(s, 10-H), 7.18–7.12 (m, 2 arom H), 6.92 and 6.85 (2d, each J ¼ 7.9Hz, 2 arom H), 6.56 (s, 7-H), 6.05,
6.02, 5.97, and 5.94 (4d, each J ¼ 1.4 Hz, 2 OCH2O), 5.64 (s, 3-H), 4.21 (dq, J ¼ 10.9=7.2 Hz, OCH2),
3.78 and 3.64 (AB, J ¼ 14.4Hz, benzyl-CH2), 3.12 (dt, J ¼ 13.1=4.8Hz, 5-Ha), 3.02 (dt,
J ¼ 16.4=4.8 Hz, 6-Ha), 2.82–2.73 and 2.44–2.35 (2m, 5-Hb and 6-Hb), 1.20 (t, J ¼ 7.2 Hz, CH3)
ppm; 13C NMR: ꢅ ¼ 174.13, 166.02, 147.46, 147.29, 147.04, 146.80, 135.75, 130.10, 129.04,
128.36 (4C), 127.39, 126.41, 125.73, 116.76, 110.04, 108.71, 107.47, 101.56, 101.17, 90.68, 66.69,
60.95, 40.00, 37.30, 22.09, 13.98 ppm.
Aldehydes 6 2-[(2-Benzoyl-1-formyl-1,2-dihydroisoquinolin-1-yl)methyl]benzoic
acid methylester (6a, C26H21NO4)
Yield: 16%, colourless solid, mp 113–115ꢃC (n-hexane); IR (KBr): ꢄꢀ¼ 1725, 1658 (C¼O)cmꢅ 1; MS
(CI): m=z (%) ¼ 440 (6), 412 (100), 382 (28), 105 (54); TLC (petroleum ether:EtOAc¼ 3:1): Rf ¼ 0.55;
1H NMR: ꢅ ¼ 9.59 (s, CHO), 7.65–7.61 (m, 2 arom H), 7.56 (dd, J ¼ 7.7=1.5 Hz, arom H), 7.53–7.49
and 7.48–7.41 (2m, 1 þ 2 arom H), 7.29–7.24 and 7.19–7.16 (2m, 2 þ 1 arom H), 7.14 (dd,
J ¼ 7.7=1.3 Hz, arom H), 7.08 (dt, J ¼ 7.7=1.5Hz, arom H), 6.93–6.88 (m, arom H), 6.66 (dd,
J ¼ 7.7=1.3 Hz, arom H), 6.22 and 5.19 (2d, each J ¼ 7.9Hz, 3-H and 4-H), 4.26 and 3.83 (AB,
J ¼ 14.0Hz, benzyl-CH2), 3.67 (s, OCH3) ppm; 13C NMR: ꢅ ¼ 191.22, 170.19, 168.25, 136.56,
133.65, 132.77, 132.27, 131.45, 131.33, 130.50, 129.88, 128.95 (2C), 128.53 (2C), 127.72, 127.41,
127.25 (2C), 126.46 (2C), 125.58, 107.94, 72.42, 51.96, 37.95 ppm.
2-[[1-Formyl-1,2-dihydro-2-(4-methylbenzoyl)isoquinolin-1-yl]methyl]benzoic
acid methylester (6c, C27H23NO4)
Yield: 9%, colourless resin; IR (film): ꢄꢀ¼ 1723, 1657 (C¼O)cmꢅ 1; MS (CI): m=z (%) ¼ 426 (24),
1
155 (49), 137 (100), 119 (38); TLC (petroleum ether:EtOAc¼ 4:1): Rf ¼ 0.53; H NMR: ꢅ ¼ 9.50 (s,
CHO), 7.49–7.43 and 7.23–7.16 (2m, 3 þ 4 arom H), 7.12–7.08 (m, arom H), 7.06 (dd, J ¼ 7.7=1.2 Hz,
arom H), 7.00 (dt, J ¼ 7.5=1.5 Hz, arom H), 6.84–6.80 (m, arom H), 6.58 (dd, J ¼ 7.7=1.2Hz, arom H),
6.16 and 5.10 (2d, each J ¼ 7.9 Hz, 2 arom H), 4.15 and 3.74 (AB, J ¼ 14.0Hz, benzyl-CH2), 3.59 and
2.34 (2s, 2 CH3) ppm.
2-[[1-Formyl-1,2-dihydro-2-(4-methoxybenzoyl)isoquinolin-1-yl]methyl]benzoic
acid methylester (6d, C27H23NO5)
Yield: 7%, colourless resin; IR (film): ꢄꢀ¼ 1720, 1655 (C¼O)cmꢅ 1; MS (CI): m=z (%) ¼ 442 (49),
153 (100); TLC (petroleum ether:EtOAc¼ 4:1): Rf ¼ 0.69; 1H NMR: ꢅ ¼ 9.55 (s, CHO), 7.63–7.59 (m,
2 arom H), 7.53 (dd, J ¼ 7.8=1.5 Hz, arom H), 7.29–7.25 and 7.19–7.12 (2m, 3 þ 1 arom H), 7.06 (dt,
J ¼ 7.8=1.5 Hz, arom H), 6.97–6.93 and 6.91–6.88 (2m, 2 þ 1 arom H), 6.62 (dd, J ¼ 7.8=1.1 Hz, arom
H), 6.27 and 5.18 (2d, each J ¼ 7.9 Hz, 2 arom H), 4.23 and 3.79 (AB, J ¼ 14.3Hz, benzyl-CH2), 3.86
(s, OCH3), 3.66 (s, CH3) ppm.

1008
E. Reimann et al.
2-[(2-Benzoyl-7-benzyloxy-1-formyl-1,2-dihydro-6-methoxyisoquinolin-1-yl)methyl]benzoic
acid ethylester (6f, C35H31NO6)
Yield: 8%, colourless crystals, mp 176ꢃC (n-hexane); IR (KBr): ꢄꢀ¼ 1719, 1659 (C¼O) cmꢅ 1; TLC
(n-hexane:EtOAc¼ 1:1): Rf ¼ 0.65; 1H NMR (CDCl3): ꢅ ¼ 9.50 (s, CHO), 7.65–7.28 (m, 11 arom H),
7.13 and 7.01 (2dt, J ¼ 7.6=1.2 and 7.6=1.4 Hz, 2 arom H), 6.75 (s, arom H), 6.44–6.40 (m, 2 arom H),
6.12 (d, J ¼ 7.9Hz, arom H), 5.11 and 5.07 (2d, each J ¼ 7.8 Hz, OBn), 4.20 and 3.69 (AB,
J ¼ 14.0Hz, benzyl-CH2), 4.17–4.10 (m, OCH2), 3.86 (s, OCH3), 1.32 (t, J ¼ 7.0 Hz, CH3) ppm.
2-[(2-Benzoyl-1-formyl-1,2-dihydro-6,7-methylenedioxyisoquinolin-1-yl)methyl]benzoic
acid ethylester (6g, C28H23NO6)
Yield: 13%, colourless resin; IR (film): ꢄꢀ¼ 1736, 1691 (C¼O)cmꢅ 1; TLC (n-hexane:EtOAc¼ 3:1):
Rf ¼ 0.62; MS (CI): m=z ¼ 498 (4), 470 (100), 105 (54); 1H NMR: ꢅ ¼ 9.53 (s, CHO), 7.63–7.58 (m, 2
arom H), 7.55 (dd, J ¼ 7.6=1.6 Hz, arom H), 7.52–7.47 and 7.46–7.42 (2m, 1þ 2 arom H), 7.16 and
7.12 (2 dt, J ¼ 7.6=1.5 and 7.6=1.6 Hz, 2 arom H), 6.76 (dd, J ¼ 7.=1.5 Hz, arom H), 6.69 and 6.37 (2s,
2 arom H), 6.10 (d, J ¼ 7.8 Hz, 1H), 6.02 and 5.96 (2d, each J ¼ 1.5 Hz, OCH2O), 5.04 (d, J ¼ 7,8 Hz,
1H), 4.20–4.17 (m, OCH2), 4.15 and 3.81 (AB, J ¼ 14.0 Hz, benzyl-CH2), 1.29 (t, J ¼ 7.2 Hz, CH3)
ppm.
2-[(2-Benzoyl-1-formyl-1,2-dihydroisoquinolin-1-yl)methyl]-6-methoxybenzoic
acid ethylester (6h, C28H25NO5)
Yield: 16%, colourless oil; IR (film): ꢄꢀ¼ 1726, 1656 (C¼O)cmꢅ 1; TLC (n-hexane:EtOAc¼ 3:1):
Rf ¼ 0.42; MS (CI): m=z ¼ 456 (26), 382 (81), 322 (100), 212 (91); 1H NMR: ꢅ ¼ 9.54 (s, CHO), 7.71–
7.67 and 7.51–7.38 (2m, 2 þ 3 arom H), 7.34–7.28, 7.23–7.20, and 6.94–6.91 (3m, 2 þ 1 þ 1 arom H),
6.81 (t, J ¼ 7.9Hz, arom H), 6.65 and 6.45 (2d, each J ¼ 7.9 Hz, 2 arom H), 5.67 and 5.19 (2d, each
J ¼ 7.8 Hz, 2 arom H), 4.41 (dq, J ¼ 7.1=10.7 Hz, OCH2), 3.75 and 3.31 (AB, J ¼ 14.5Hz, benzyl-
CH2), 3.72 (s, OCH3), 1.39 (t, J ¼ 7.1 Hz, CH3) ppm; 13C NMR: ꢅ ¼ 191.67, 170.78, 168.07, 155.71,
134.27, 133.95, 132.45, 131.21, 129.62 (2C), 129.03, 128.74, 128.62, 128.25 (2C), 127.61, 126.72,
126.51, 125.56, 125.49, 123.04, 108.94, 107.47, 72.13, 61.48, 55.76, 38.57, 14.17ppm.
2-[[1-Formyl-1,2-dihydro-6,7-dimethoxy-2-(4-methylbenzoyl)isoquinolin-1-yl]methyl]-
6-methoxybenzoic acid ethylester (6i, C31H31NO7)
Yield: 22%, yellowish oil; IR (film): ꢄꢀ¼ 1726, 1622 (C¼O)cmꢅ 1; TLC (n-hexane:EtOAc¼ 1:1):
1
Rf ¼ 0.63; MS (CI): m=z ¼ 530 (100), 500 (12), 336 (55); H NMR: ꢅ ¼ 9.49 (s, CHO), 7.58 and
7.23 (2d, each J ¼ 8.2 Hz, 2 þ 2 arom H), 6.84 (t, J ¼ 8.2Hz, arom H), 6.72 (s, arom H), 6.66 (d,
J ¼ 8.2 Hz, arom H), 6.45 (s, arom H), 6.38 (d, J ¼ 7.9 Hz, 1H), 5.78 (d, J ¼ 8.2 Hz, arom H), 5.12
(d, J ¼ 7.9 Hz, 1H), 4.39 (q, J ¼ 7.2 Hz, OCH2), 3.92 and 3.88 (2s, 2 OCH3), 3.71 and 3.32 (AB,
J ¼ 14.5Hz, benzyl-CH2), 3.70 (s, OCH3), 2.38 (s, CH3), 1.38 (t, J ¼ 7.2, CH3) ppm.
6-[[1-Formyl-1,2-dihydro-6,7-dimethoxy-2-(4-methylbenzoyl)isoquinolin-1-yl]methyl]-
2,3-dimethoxybenzoic acid ethylester (6k, C31H31NO7)
Yield: 10%, yellowish resin; IR (film): ꢄꢀ¼ 1731, 1658 (C¼O)cmꢅ 1; TLC (n-hexane:EtOAc¼ 3:1):
Rf ¼ 0.31; MS (CI): m=z ¼ 560 (16), 336 (16), 215 (100), 119 (39); 1H NMR: ꢅ ¼ 9.50 (s, CHO), 7.56
and 7.24 (2d, each J ¼ 8.2 Hz, 2 þ 2 arom H), 6.70 (s, arom H), 6.66 (d, J ¼ 8.6 Hz, 5-H), 6.47 (s, 8-H),
6.37 (d, J ¼ 7.9 Hz, 3-H), 5.99 and 5.17 (2d, J ¼ 8.6 and 7.9 Hz, arom H and 4-H), 4.35 (q, J ¼ 7.2 Hz,
OCH2), 3.91, 3.89, 3.76, and 3.72 (4s, 4 OCH3), 3.62 and 3.30 (AB, J ¼ 14.8Hz, benzyl-CH2), 2.40 (s,
CH3), 1.35 (t, J ¼ 7.2 Hz, CH3) ppm; 13C NMR: ꢅ ¼ 192.38, 170.59, 167.27, 151.20, 149.25, 148.44,

Protoberberines from Reissert-Compounds
1009
145.38, 141.70, 131.11, 129.53 (3C), 128.92 (2C), 127.15, 126.85, 125.87, 125.46, 118.56, 112.48,
109.79, 108.43, 107.07, 72.16, 61.33, 61.31, 56.23, 56.01, 55.87, 37.15, 21.56, 14.21 ppm.
2-[(2-Benzyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]benzoic acid ethylester (7a)
Yield: 3%, light yellow oil. Analytical and spectroscopic data were in line with those published in
Ref. [1].
2-[(2-Benzyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]-6-methoxybenzoic acid ethylester
(7b, C27H29NO3)
Yield: 13%, colourless oil; TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.81; IR (film): ꢄꢀ¼ 1721 (C¼O)cmꢅ 1
;
MS (CI): m=z (%) ¼ 444 (Mþꢇ þ 29, 10), 416 (Mþꢇ þ 1, 100), 222 (51); 1H NMR: ꢅ ¼ 7.25–7.00 (m,
9 arom H), 6.87, 6.80, and 6.74 (3d, each J ¼ 8.3Hz, 3 arom H), 4.32 (q, J ¼ 7.1 Hz, OCH2), 3.96 (dd,
J ¼ 9.0=5.0 Hz, 1-H), 3.83 (s, OCH3), 3.73 and 3.60 (AB, J ¼ 13.6Hz, N-benzyl-CH2), 3.30 (dt,
J ¼ 12.5=4.8 Hz, 1H), 3.12 (dd, J ¼ 14.00=10.5Hz, 3-Ha), 3.00 (ddd, J ¼ 16.7=10.5=6.3 Hz, 4-Ha),
2.90–2.78 (m, 3-Hb þ 1H), 2.52 (dd, J ¼ 16.7=4.1 Hz, 4-Hb), 1.29 (t, J ¼ 7.1 Hz, CH3) ppm;
13C NMR: ꢅ ¼ 168.62 (C¼O), 156.30, 139.62, and 138.62 (3s, 3C) 138.06 (s, C-4a), 134.12 (s, C-8a),
129.45 and 128.93 (2d, 2C), 128.64 (d, 2C), 128.31 (d, C-5), 127.91 (d, 2C), 126.57, 126.07, and
125.54 (3d, C-6, C-8, C-7), 124.62 (s, 1C), 123.59, 108.83, and 62.17 (3d, 2C, C-1), 60.99 and 57.74
(2t, OCH2, N-CH2), 55.96 (q, OCH3), 41.79, 39.66, and 23.67 (3t, benzyl-CH2, C-3, C-4), 14.20 (q,
CH3) ppm.
2-[[1,2,3,4-Tetrahydro-6,7-dimethoxy-2-(4-methylbenzyl)isoquinolin-1-yl]methyl]-
6-methoxybenzoic acid ethylester (7c, C30H35NO5)
Yield: 2%, colourless oil; TLC (n-hexane:EtOAc ¼ 1:1) Rf ¼ 0.79; IR (film): ꢄꢀ¼ 1716 (C¼O)cmꢅ 1
;
1
MS (CI): m=z (%) ¼ 490 (Mþꢇ þ 1, 49), 296 (100); H NMR: ꢅ ¼ 7.21 (t, J ¼ 7.9 Hz, arom H), 7.07
and 7.03 (2d, each J ¼ 7.8 Hz, 4 arom H), 6.80 (d, J ¼ 7.9Hz, arom H), 6.69 (br d, J ¼ 7.9 Hz, arom H),
6.58 and 6.21 (2s, 8-H, 5-H), 4.28 (q, J ¼ 7.2 Hz, OCH2), 3.93–3.86 (m, 1-H), 3.85 and 3.83 (2s,
2 OCH3), 3.72 (d, J ¼ 13.5Hz, 1H, N-CH2), 3.64 (s, OCH3), 3.60 (d, J ¼ 13.5Hz, 1H, N-CH2), 3.28–
3.18 (m, 1H), 3.13 (dd, J ¼ 13.7=8.0 Hz, 3-Ha), 2.97–2.87 (m, 4-Ha), 2.87–2.77 (m, 3-Hb þ 1H), 2.46–
2.39 (m, 4-Hb), 2.32 (s, CH3), 1.29 (t, J ¼ 7.2 Hz, CH3) ppm.
2-[(6,7-Dimethoxyisoquinolin-1-yl)methyl]benzoic acid ethylester (8a)
Yield: 13%, light yellow oil. Analytical and spectroscopic data were in line with those published in
Ref. [1].
2-[(6,7-Methylenedioxyisoquinolin-1-yl)methyl]benzoic acid ethylester (8b, C20H17NO4)
1
Yield: 5%, colourless oil; TLC (n-hexane:EtOAc¼ 3:1) Rf ¼ 0.34; H NMR: ꢅ ¼ 8.30 (d, J ¼ 5.7 Hz,
3-H), 7.96 (dd, J ¼ 7.7=1.6 Hz, arom H), 7.42 (s, 8-H), 7.38 (d, J ¼ 5.7 Hz, 4-H), 7.32 (dt,
J ¼ 7.7=1.8 Hz, arom H), 7.26 (dt, J ¼ 7.7=1.6 Hz, arom H), 7.06 (s, 5-H), 7.03–6.99 (m, arom H),
6.05 (s, OCH2O), 4.96 (s, CH2), 4.31 (q, J ¼ 7.1Hz, OCH2), 1.30 (t, J ¼ 7.1 Hz, CH3) ppm.
6,7-Dimethoxyisoquinoline-1-carbonitrile (9a)
Yield: 15%, TLC (petroleum ether:EtOAc¼ 3:1): Rf ¼ 0.48 (blue fluorescent, ꢀ ¼ 365 nm); IR (KBr):
1
ꢄꢀ¼ 2227 (CN)cmꢅ 1; MS (EI): m=z (%) ¼ 214 (Mþꢇ, 100), 199 (13), 184 (5); mp and H NMR data
were in line with those published in Ref. [33].

1010
E. Reimann et al.
7-Benzyloxy-6-methoxyisoquinoline-1-carbonitrile (9b)
Yield: 52%; TLC (n-hexane:EtOAc¼ 1:1): Rf ¼ 0.42 (blue fluorescent, ꢀ ¼ 365 nm); mp and spectro-
scopic data were in line with those published in Ref. [34].
6,7-Methylenedioxyisoquinoline-1-carbonitrile ( ¼ [1,3]-Dioxolo[4,5-g]isoquinoline-
1-carbonitrile, 9c)
Yield: 25%, TLC (n-hexane:EtOAc¼ 3:1): Rf ¼ 0.41 (blue fluorescent, ꢀ ¼ 365 nm); IR (KBr):
1
ꢄꢀ¼ 2226 (CN)cmꢅ 1; mp, MS, and H NMR data were in line with those published in Ref. [35].
The aldehydes 12 were prepared by the general procedure according to Ref. [1] starting from
0.6–0.7 mmol 11a–11e=2.5 cm3 of AcOH, 4.5 cm3 of F3CCO2H, and 1.2–1.4 mmol of NaCNBH3;
reaction time: 45min (12a, 12b), 60 min (12c–12e).
2-Benzoyl-1-benzyl-1,2-dihydroisoquinoline-1-carbaldehyde (12a, C24H19NO2)
Yield: 46%, mp 106ꢃC (n-hexane); IR (KBr): ꢄꢀ¼ 1726, 1656 (C¼O)cmꢅ 1; MS (CI): m=z (%) ¼ 354
(100), 324 (10), 262 (3), 105 (4); TLC (petroleum ether:EtOAc¼ 3:1): Rf ¼ 0.70; 1H NMR: ꢅ ¼ 9.69 (s,
CHO), 7.55–7.44 and 7.32–7.25 (2m, 5 þ 3 arom H), 7.18–7.12 and 7.11–7.05 (2m, 1þ 2 arom H),
6.97–6.93 (m, 5-H), 6.80–6.75 (m, 5-H þ 2 arom H), 6.30 and 5.26 (2d, each J ¼ 7.9 Hz, 3-H, 4-H),
3.83 and 3.30 (AB, J ¼ 13.9Hz, Ar–CH2) ppm; 13C NMR: ꢅ ¼ 191.67 (d, CHO), 170.05 (s, CO),
135.89 and 133.51 (2s, 2C), 131.17 (d, 1C), 131.11 (s, C-4a), 130.35 (d, C-8), 128.87 (d, C-6=C-7),
128.68, 128.59, and 128.33 (3d, each2C), 127.80, 127.75 (2d, 2C), 127.38 (s, C-8a), 126.82 (d, C-6=C-7),
126.74 (d, C-3), 126.58 (d, 1C), 125.50 and 107.58 (2d, C-5, C-4), 72.65 (s, C-1), 41.69 (t, Ar–CH2)
ppm.
2-Benzoyl-1,2-dihydro-1-(2-methylbenzyl)isoquinoline-1-carbaldehyde (12b, C25H21NO2)
Yield: 24%, colourless resin; IR (KBr): ꢄꢀ¼ 1730, 1648 (C¼O)cmꢅ 1
; TLC (petroleum
1
ether:EtOAc¼ 3:1): Rf ¼ 0.69; H NMR (CDCl3): ꢅ ¼ 9.63 (s, CHO), 7.56–7.44 and 7.31–7.22 (2m,
5 þ 4 arom H), 7.18–7.12 and 7.11–7.05 (2m, 2 arom H), 6.97–6.93 (m, 5-H), 6.53 (d, J ¼ 7.7 Hz,
arom H), 6.25, 5.23 (2d, each J ¼ 7.9Hz, 3-H, 4-H), 3.92 and 3.30 (AB, J ¼ 13.9Hz, Ar–CH2), 1.88 (s,
CH3) ppm.
2-Benzoyl-1-(2-bromobenzyl)-1,2-dihydroisoquinoline-1-carbaldehyde (12c, C24H18BrNO2)
Yield: 32%, light yellow resin; IR (KBr): ꢄꢀ¼ 1735, 1659 (C¼O)cmꢅ 1; MS (CI): m=z (%) ¼ 434
(100), 432 (98), 404 (12), 402 (12); TLC (petroleum ether:EtOAc¼ 5:1): Rf ¼ 0.50; 1H NMR: ꢅ ¼ 9.59
(s, CHO), 7.63–7.60 and 7.55–7.50 (2m, 1 þ 2 arom H), 7.49–7.44 and 7.34–7.22 (2m, 2 þ 3 arom H),
6.95–6.89 (m, 3 arom H), 6.79 (dt, J ¼ 7.6=1.6 Hz, arom H), 6.43 (d, J ¼ 7.9Hz, 3-H), 6.24 (dd,
J ¼ 7.6=1.6 Hz, arom H), 5.22 (d, J ¼ 7.9 Hz, 4-H), 4.12 and 3.37 (AB, J ¼ 14.4Hz, Ar–CH2) ppm;
13C NMR: ꢅ ¼ 191.36, 170.38, 136.03, 133.74, 132.55, 132.40, 132.10, 131.57, 129.27, 129.22,
128.72, 128.32, 128.01, 127.68, 127.04, 126.41, 125.82, 125.77, 108.28, 71.65, 40.35 ppm.
2-Benzoyl-1,2-dihydro-1-(2-nitrobenzyl)isoquinoline-1-carbaldehyde (12d, C24H18N2O4)
Yield: 28%, light yellow resin; IR (KBr): ꢄꢀ¼ 1731, 1631 (C¼O)cmꢅ 1; MS (CI): m=z (%) ¼ 399
(100), 369 (8), 105 (47); TLC (petroleum ether:EtOAc¼ 5:1): Rf ¼ 0.65; 1H NMR: ꢅ ¼ 9.45 (s, CHO),
7.56–7.35 and 7.23–7.03 (2m, 3 þ 8 arom H), 6.84–6.81 (m, 5-H), 6.55 (dd, J ¼ 7.9=1.4Hz, arom H),
6.25 and 5.19 (2d, each J ¼ 7.9 Hz, 3-H, 4-H), 4.17 and 3.57 (AB, J ¼ 14.1Hz, Ar–CH2) ppm.

Protoberberines from Reissert-Compounds
1011
2-Benzoyl-1,2-dihydro-1-(naphth-1-ylmethyl)isoquinoline-1-carbaldehyde (12e, C28H21NO2)
Yield: 12%, light yellow resin; TLC (petroleum ether:EtOAc¼ 5:1): Rf ¼ 0.56; 1H NMR: ꢅ ¼ 9.63 (s,
CHO), 7.84–7.70 (m, 3H), 7.68–7.17 (m, 11H), 6.98 and 6.96 (2d, each J ¼ 7.1Hz, 2H), 5.62 and 4.83
(2d, each J ¼ 7.9 Hz, 3-H, 4-H), 4.45 and 3.51 (AB, each J ¼ 14.5Hz, CH2) ppm.
The 8-oxoprotoberberine carboxylic acids 13 were prepared by the general procedure according to
Ref. [1] starting from 0.5–2.4mmol of 5; the crude product was dried in vacuo at ambient temperature
and recrystallized. Analytical and spectroscopic data of the compounds 13a and 13b are listed in
Ref. [1].
2-Benzyloxy-5,6,8,13-tetrahydro-3-methoxy-8-oxo-13aH-dibenzo[a,g]quinolizine-
13a-carboxylic acid (13c, C26H23NO5)
Yield: 88%, mp 231ꢃC (EtOAc); TLC (CHCl3:CH3OH¼ 9:1): Rf ¼ 0.47; IR (KBr): ꢄꢀ¼ 1719, 1601
(C¼O)cmꢅ 1; MS (CI): m=z (%) ¼ 414 (4), 386 (37), 384 (100), 374 (61), 282 (58); 1H NMR (DMSO-
d6): ꢅ ¼ 13.16 (s, CO2H), 7.92 (d, J ¼ 7.7 Hz, 9-H), 7.56–7.30 (m, 9 arom H), 6.86 (s, 4-H), 5.14 and
5.04 (AB, J ¼ 11.8Hz, benzyl-CH2), 4.77 (dt, J ¼ 12.5=3.5 Hz, 6-Ha), 3.86 (d, J ¼ 15.5Hz, 13-Ha),
3.80 (s, OCH3), 3.23 (dt, J ¼ 12.5=8.0 Hz, 6-Hb), 3.01 (d, J ¼ 15.5Hz, 13-Hb), 2.84 (m, 5-Hab) ppm;
13C NMR (DMSO-d6): ꢅ ¼ 173.23, 163.57, 148.89, 146.25, 136.90, 136.21, 132.10, 128.29 (2C),
128.15, 127.92 (2C), 127.87, 127.80, 127.59, 127.39, 127.08, 125.83, 112.13, 111.89, 70.43, 63.92,
55.35, 40.43, 37.19, 27.60 ppm.
5,6,8,13-Tetrahydro-2,3-methylenedioxy-8-oxo-13aH-dibenzo[a,g]quinolizine-
13a-carboxylic acid (13d, C19H15NO5)
Yield: 97%, mp 224ꢃC (EtOAc); TLC (CHCl3:CH3OH¼ 9:1): Rf ¼ 0.35; IR (KBr): ꢄꢀ¼ 1705, 1635
1
(C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 292 (7), 291 (9), 276 (16); H NMR (DMSO-d6): ꢅ ¼ 13.27 (s,
CO2H), 7.91 (dd, J ¼ 7.5=1.3Hz, 9-H), 7.52 (dt, J ¼ 7.5=1.4Hz, 11-H), 7.43–7.35 (m, 10-H, 12-H),
7.25 (s, 1-H), 6.83 (s, 4-H), 6.05–6.02 (m, OCH2O), 4.69 (dt, J ¼ 12.6=3.5 Hz, 6-Ha), 3.89 (d,
J ¼ 15.6Hz, 13-Ha), 3.30–3.20 (m, 6-Hb), 3.09 (d, J ¼ 15.6Hz, 13-Hb), 2.86–2.79 (m, 5-Hab) ppm;
13C NMR (DMSO-d6): ꢅ ¼ 172.97, 163.56, 146.64, 146.22, 135.97, 131.97, 128.71, 128.12, 127.54,
127.24, 127.18, 127.11, 108.22, 106.15, 101.10, 64.39, 41.03, 38.10, 28.25 ppm.
5,6,8,13-Tetrahydro-9-methoxy-8-oxo-13aH-dibenzo[a,g]quinolizine-13a-carboxylic
acid (13e, C19H17NO2)
Yield: 96%, mp 229ꢃC (CH3OH); TLC (CHCl3:CH3OH¼ 9:1): Rf ¼ 0.41; IR (KBr): ꢄꢀ¼ 1719, 1618
(C¼O)cmꢅ 1; MS(EI):m=z (%) ¼ 280 (26), 279(27),278(56), 277 (45), 248(34);1H NMR (DMSO-d6):
ꢅ ¼ 13.07 (s, CO2H), 7.72–7.68 (br d, J ¼ 7.6 Hz, 1-H), 7.46–7.41 (m, 2-H, 3-H), 7.36–7.26 (m, 4-H,
11-H), 7.01 and 6.94 (2d, each J ¼ 7.9 Hz, 12-H, 10-H), 4.68 (dt, J ¼ 12.7=4.2 Hz, 6-Ha), 3.80 (s,
OCH3), 3.77 (d, J ¼ 15.7Hz, 13-Ha), 3.35–3.23 (m, 6-Hb), 3.05 (d, J ¼ 15.7Hz, 13-Hb), 2.98–2.83 (m,
5-Hab) ppm; 13C NMR (DMSO-d6): ꢅ ¼ 172.93, 161.32, 159.33, 138.63, 135.95, 132.59, 128.82,
127.39, 126.65, 125.82, 119.61, 116.94, 111.64, 55.74, 49.14, 42.08, 37.49, 28.54 ppm.
5,6,8,13-Tetrahydro-2,3,9,10-tetramethoxy-8-oxo-13aH-dibenzo[a,g]quinolizine-
13a-carboxylic acid (13f, C22H23NO7)
Yield: 95%, mp 218ꢃC (EtOAc); TLC (CHCl3:CH3OH¼ 9:1): Rf ¼ 0.23; IR (KBr): ꢄꢀ¼ 1709, 1638
1
(C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 428 (30), 414 (70), 370 (48), 369 (27), 368 (100); H NMR
(DMSO-d6): ꢅ ¼ 13.03 (s, CO2H), 7.22 (s, 1-H), 7.18 and 7.08 (2d, each J ¼ 8.2 Hz, 11-H, 12-H)
6.84 (s, 4-H), 4.69 (dt, J ¼ 12.9=4.2 Hz, 6-Ha), 3.80 (s, OCH3), 3.79–3.76 (m, 13-Ha, 2 OCH3), 3.75

1012
E. Reimann et al.
(s, OCH3), 3.23 (ddd, J ¼ 12.9=10.1=4.9 Hz, 6-Hb), 2.91 (d, J ¼ 15.1 Hz, 13-Hb), 2.87–2.74 (m, 5-Hab)
ppm; 13C NMR (DMSO-d6): ꢅ ¼ 173.69, 162.12, 152.99, 148.99, 148.24, 147.43, 129.06, 127.64,
125.91, 122.73, 122.32, 115.88, 111.74, 109.69, 63.73, 60.64, 55.85, 55.72, 55.44, 41.51, 37.77,
28.00 ppm.
5,6,8,13-Tetrahydro-2,3-dimethoxy-9,10-methylenedioxy-8-oxo-13aH-dibenzo[a,g]
quinolizine-13a-carboxylic acid (13g, C21H19NO7)
Yield: 95%, mp 210ꢃC (CH3OH); TLC (CHCl3:CH3OH¼ 9:1): Rf ¼ 0.21; IR (KBr): ꢄꢀ¼ 1725, 1622
1
(C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 412 (39), 398 (12), 354 (60), 353 (29), 352 (100); H NMR
(DMSO-d6): ꢅ ¼ 13.18 (s, CO2H), 7.23 (s, 1-H), 7.01 (d, J ¼ 7.6 Hz, 12-H), 6.82 (s, 4-H), 6.81
(d, J ¼ 7.6Hz, 11-H), 6.15 and 6.08 (2s, OCH2O), 4.72 (dt, J ¼ 12.9=4.0 Hz, 13-Ha), 3.84 (d,
J ¼ 15.6Hz, 6-Ha), 3.78 and 3.77 (2s, 2 OCH3), 3.22–3.13 (m, 13-Hb), 2.93 (d, J ¼ 15.6Hz, 6-Hb),
2.85–2.78 (m, 5-Hab) ppm; 13C NMR (DMSO-d6): ꢅ ¼ 173.09, 161.25, 148.31, 147.54, 147.42, 147.15,
129.07, 127.51, 125.81, 119.83, 111.87, 111.74, 111.14, 109.89, 101.91, 64.29, 55.78, 55.48, 40.57,
36.97, 27.88 ppm.
5,6,8,13-Tetrahydro-9,10-dimethoxy-2,3-methylenedioxy-8-oxo-13aH-dibenzo[a,g]
quinolizine-13a-carboxylic acid (13h, C21H19NO7)
Yield: 95%, mp 226ꢃC (CH3OH); TLC (CHCl3:CH3OH¼ 9:1): Rf ¼ 0.28; IR (KBr): ꢄꢀ¼ 1727, 1616
1
(C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 412 (39), 398 (100), 354 (69), 352 (100); H NMR (DMSO-d6):
ꢅ ¼ 13.10 (s, CO2H), 7.21 (s, 1-H), 7.17 and 7.06 (2d, each J ¼ 8.4 Hz, 12-H, 11-H), 6.82 (s, 4-H),
6.04–6.00 (m, OCH2O), 4.57 (dt, J ¼ 12.9=4.4 Hz, 6-Ha), 3.80 (s, OCH3), 3.75–3.69 (m, OCH3,
13-Ha), 3.44–3.23 (m, 6-Hb), 2.93 (d, J ¼ 15.2Hz, 13-Hb), 2.86–2.72 (m, 5-Hab) ppm; 13C NMR
(DMSO-d6): ꢅ ¼ 173.00, 161.55, 152.45, 148.93, 146.63, 146.24, 129.07, 128.86, 127.27, 122.81,
122.31, 115.90, 108.26, 106.03, 101.12, 64.04, 60.67, 55.87, 40.69, 37.26, 28.37 ppm.
5,6,8,13-Tetrahydro-2,3,9,10-di(methylenedioxy)-8-oxo-13aH-dibenzo[a,g]quinolizine-
13a-carboxylic acid (13i, C20H15NO7)
Yield: 98%, mp 218ꢃC (EtOAc); TLC (CHCl3:CH3OH¼ 9:1): Rf ¼ 0.25; IR (KBr): ꢄꢀ¼ 1720, 1636
1
(C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 382 (41), 338 (80), 337 (42), 336 (100), 335 (36); H NMR
(DMSO-d6): ꢅ ¼ 13.24 (s, CO2H), 7.23 (s, 1-H), 7.01 and 6.83–6.77 (2d, each J ¼ 8.0 Hz, 12-H,
11-H), 6.80 (s, 4-H), 6.15, 6.09, and 6.02 (3s, 2 OCH2O), 4.63 (dt, J ¼ 12.8=4.3 Hz, 6-Ha), 3.79 (d,
J ¼ 15.5Hz, 13-Ha), 3.25–3.14 (m, 6-Hb), 2.93 (d, J ¼ 15.5 Hz, 13-Hb), 2.84–2.74 (m, 5-Hab) ppm; 13
C
NMR (DMSO-d6): ꢅ ¼ 172.86, 161.23, 147.56, 147.09, 146.68, 146.25, 128.75, 127.77, 127.14,
119.78, 111.80, 111.03, 108.19, 106.22, 101.88, 101.11, 64.54, 41.23, 38.02, 28.30 ppm.
Tetra- and Dihydro-8H-dibenzoquinolizin-8-ones 14=15, General Procedure
The acids 13 were decarboxylated by heating them to the melting temperature in vacuo (water pump).
The products 14=15 were separated by FC.
5,6,13,13a-Tetrahydro-8H-dibenzo[a,g]quinolizin-8-one (Berbin-8-one, 14a)
and 5,6-Dihydro-8H-dibenzo[a,g]quinolizin-8-one (15a)
From 500 mg (1.7 mmol) of 13a; reaction time: 15 min; yields: 14a 61%, 15a 26%; for NMR and MS
data see Ref. [1].

Protoberberines from Reissert-Compounds
1013
5,6,13,13a-Tetrahydro-2,3-dimethoxy-8H-dibenzo[a,g]quinolizin-8-one
(2,3-Dimethoxy-berbin-8-one, 14b) and 5,6-Dihyro-2,3-dimethoxy-8H-dibenzo[a,g]
quinolizin-8-one (15b)
From 300 mg (0.9 mmol) of 13b; reaction time: 15min; yields: 14b 54%, 15b 31%; for NMR and MS
data see Ref. [1].
5,6,13,13a-Tetrahydro-2,3-methylenedioxy-8H-dibenzo[a,g]quinolizin-8-one
(2,3-Methylenedioxyberbin-8-one, Gusanlung D, 14c) and 5,6-Dihydro-
2,3-methylenedioxy-8H-dibenzo[a,g]quinolizin-8-one (15c)
From 150 mg (0.4mmol) of 13d; reaction time: 10 min; 14c: yield: 27%; TLC (EtOAc:
n-hexane ¼ 2:1): Rf ¼ 0.50; 13C NMR: ꢅ ¼ 158.67, 146.77, 146.57, 137.24, 132.33, 131.81, 128.85,
128.60, 128.55, 127.37, 126.87, 108.81, 105.97, 101.00, 55.18, 38.49, 37.78, 29.61 ppm; mp, IR, MS,
1H, and 13C NMR data were in line with those published in Refs. [3, 36]; 15c: yield: 58%; TLC
(EtOAc:n-hexane ¼ 2:1): Rf ¼ 0.33; MS (EI): m=z (%) ¼ 291 (Mþꢇ, 66), 276 (100); 13C NMR:
ꢅ ¼ 162.10, 148.71, 147.43, 137.40, 136.65, 132.27, 130.29, 127.94, 126.27, 126.01, 124.57, 123.73,
107.96, 105.06, 101.89, 101.48, 39.69, 28.57 ppm; mp, IR, and 1H NMR data were in line with those
published in Ref. [37].
5,6,13,13a-Tetrahydro-2,3,9,10-tetramethoxy-8H-dibenzo[a,g]quinolizin-8-one
(Di-hydropalmatin-8-one, 14d) and 5,6-Dihydro-2,3,9,10-tetramethoxy-8H-dibenzo[a,g]
quinolizin-8-one (Oxypalmatine, 15d)
From 240 mg (0.6 mmol) of 13f; reaction time: 15 min; 14d: yield: 47%; TLC (EtOAc:n-hexane¼ 2:1):
Rf ¼ 0.48; IR (KBr): ꢄꢀ¼ 1640 (C¼O)cmꢅ 1; MS (EI): m=z (%) ¼ 369 (Mþꢇ, 93), 368 (50), 354 (23),
192 (46), 178 (100), 163 (21); mp, 1H and 13C NMR data were in line with those published in Ref. [2];
15d: yield: 47%; TLC (EtOAc:n-hexane¼ 2:1): Rf ¼ 0.32; MS (EI): m=z (%) ¼ 367 (Mþꢇ, 100), 352
(70), 338 (47), 324 (24), 308 (21), 280 (9); 13C NMR: ꢅ ¼ 160.22, 151.32, 150.05, 149.53, 148.37,
135.61, 132.37, 128.48, 122.32, 122.13, 119.33, 118.98, 110.45, 107.52, 100.87, 61.59, 56.85, 56.23,
1
56.01, 39.39, 28.22 ppm; mp and H NMR data were in line with those published in Ref. [5].
5,6-Dihydro-9,10-dimethoxy-2,3-methylenedioxy-8H-dibenzo[a,g]quinolizin-8-one
(Berberin-8-one, Oxyberberine, Berlambin, 15e)
From 200 mg (0.5 mmol) of 13h; reaction time: 10min; purification of the crude product by FC; yield:
1
81%; TLC (EtOAc:n-hexane¼ 2:1): Rf ¼ 0.36; IR (KBr): ꢄꢀ¼ 1643 (C¼O)cmꢅ 1; mp, MS, H, and
13C NMR data were in line with those published in Refs. [3, 5, 38].
5,6-Dihydro-2,3,9,10-di(methylenedioxy)-8H-dibenzo[a,g]quinolizin-8-one
(Coptisin-8-one, 15f)
From 300 mg (0.78 mmol) of 13i; reaction time: 30min; purification of the crude product by FC (n-
hexane:EtOAc¼ 2:1); yield: 73%; TLC (CHCl3:CH3OH¼ 9:1): Rf ¼ 0.35; mp, IR, MS, 1H, and
13C NMR data were in line with those published in Ref. [39].
References
[1] VII: Reimann E, Grasberger F, Polborn K (2000) Monatsh Chem 131: 73
[2] Matulenko MA, Meyers AJ (1996) J Org Chem 61: 573 and further lit cited therein
[3] Zhang JS, le Men-Olivier L, Massiot G (1995) Phytochemistry 39: 439

1014
E. Reimann et al.: Protoberberines from Reissert-Compounds
[4] Nimgirawath S, Ponghusabun O (1994) Austr J Chem 47: 951
[5] Grigg R, Sridharan V, Stevenson P, Sukhirthalingam S, Worakun T (1990) Tetrahedron 46: 4003
[6] Huang WJ, Singh OV, Chen CH, Chion SY, Lee SS (2002) Helv Chim Acta 85: 1069
[7] Lou ZC, Gao CY, Lin FT, Zhang J, Lin MC, Sharaf M, Wong LK, Slatkin DJ, Schiff PL Jr (1992)
Planta Medica 58: 114
[8] Leete E, Murril JB (1967) Phytochemistry 6: 231
[9] Reimann E, Benend H (1992) Monatsh Chem 123: 939
[10] Gibson HW (1970) J Heterocyclic Chem 7: 1169
[11] Cook MJ, Katritzky AR, Page AD (1977) J Am Chem Soc 99: 165
[12] Jackson YA, Stephenson EK, Cava M (1993) Heterocycles 36: 1047
[13] Cava MP, Noguchi J (1972) J Org Chem 37: 2936
[14] Kido K, Watanabe Y (1980) Heterocycles 14: 1151
[15] Chantimakorn V, Nimgirawath S (1989) Austr J Chem 42: 209
[16] Tilley JW, Danho W, Lovey K, Wagner R, Swistok J, Makofske R, Michalewsky J, Triscari J,
Nelson D, Weatherford S (1991) J Med Chem 34: 1125
[17] Jones JA (1964) J Org Chem 29: 3531
[18] Roclofsen DP, DeGraaf JWM, Hagendoorn JA, Verschoor HM, Van Bekkum H (1970) Recl Trav
Chim Pays-Bas 89: 193
[19] Hauser FM, Pogany SA (1980) Synthesis, 814
[20] Grethe G, Lee HL, Uskokovic M, Brossi A (1968) J Org Chem 33: 494
[21] Cushman M, Choong T, Valko JT, Koleck MP (1980) J Org Chem 45: 5067
[22] Ziegler FE, Fowler KW (1976) J Org Chem 41: 1564
[23] Eliel EL, Ferdinand TN, Carolyn SRM (1954) J Org Chem 19: 1693
[24] Dean RT, Rappoport H (1978) J Org Chem 43: 2115
[25] Meyers AJ, Gabel R, Mihelich E (1978) J Org Chem 43: 1372
[26] Jahangir, Fisher LE, Clark RD, Muchowski JM (1989) J Org Chem 54: 2992
[27] Eicher T, Tiefensee K, Pick R (1988) Synthesis, 525
[28] Ollero L, Castedo L, Domingez D (1999) Tetrahedron 55: 4445
[29] Lutz RE, Bailey PS, Rowlett RJ Jr, Wilson JW, Allison RK, Clark MT, Leake NH, Jordan RH,
Keller RJ, Nicodemus KC (1947) J Org Chem 12: 760
[30] Wang W, Obeyesekere NU, McMurray JS (1996) Tetrahedron Letters 37: 6661
€
€
[31] Reimann E, Hoglmuller A (1985) Arch Pharm (Weinheim) 318: 487
[32] Neumeyer JL, Oh KH, Weinhardt KK, Neustadt BR (1969) J Org Chem 34: 3786
[33] Ruchirawat S (1978) Heterocycles 9: 1345
[34] Reimann E, Renz H (1993) Arch Pharm (Weinheim) 323: 253
[35] Hung TV, Mooney BA, Prager RH (1981) Austr J Chem 34: 151
[36] Kessar VS, Singh P, Vohra R, Kaur NP, Venugopal D (1992) J Org Chem 57: 6716
[37] Ruchirawat S, Lertwanawatana W, Thepchumrune P (1980) Tetrahedron Letters 21: 189
[38] Jahangir, MacLean DB, Holland H (1987) Can J Chem 65: 727
[39] Li M, Chen X, Tang QM, Zhang JS (2001) Planta Medica 67: 189
€
[40] Sheldrick GM, Programs for the Solution and Refinement of Crystal Structures, Gottingen, 1990
and 1993