Synthesis of 6-methyl-8H-dibenzo[a,g]quinolizin-8-imines via Reissert compounds

Article abstract of DOI:10.1007/s00706-007-0826-8

Alkylation of Reissert compounds derived from 3-methylisoquinolines with several 2-cyanobenzylbromides followed by hydrolytic cleavage provided the corresponding 1-benzyl-3-methylisoquinolines. Treatment of the latter with methylmagnesiumiodide caused cyclization to the title compounds rather than formation of 2-acetylbenzylisoquinolines.

Full text of DOI:10.1007/s00706-007-0826-8

Monatsh Chem 139, 673–684 (2008)
DOI 10.1007/s00706-007-0826-8
Printed in The Netherlands
Synthesis of 6-methyl-8H-dibenzo[a,g]quinolizin-8-imines
via Reissert compounds
ꢀ
Eberhard Reimann, Rainer Hertel , Ju¨rgen Krauss
¨
¨ ¨
Department Pharmazie – Zentrum fu¨r Pharmaforschung, Ludwig-Maximilians-Universitat Munchen, Munchen, Germany
Received 28 September 2007; Accepted 14 October 2007; Published online 19 May 2008
# Springer-Verlag 2008
Abstract Alkylation of Reissert compounds derived
from 3-methylisoquinolines with several 2-cyanoben-
zylbromides followed by hydrolytic cleavage provid-
ed the corresponding 1-benzyl-3-methylisoquinolines.
Treatment of the latter with methylmagnesiumiodide
caused cyclization to the title compounds rather than
formation of 2-acetylbenzylisoquinolines.
fluorescence in organic solvents and can be also iso-
lated as bright yellow crystals [1, 2] (Fig. 1).
On the other hand, coralyne (IIIa) has received
extensive attention because of its DNA-targeting
properties [3].
As it has been reported, the formation of modified
coralynes failed under certain structural conditions of
the educt, e.g., when starting from 3-methylpapaver-
ine (Ib) to afford 6-methylcoralyne (IIIb) [4, 5] or
from papaverine analogues without any donor func-
tion in the benzyl moiety as shown in the case of
1-benzyl-6,7-dimethoxyisoquinoline (Ic) to give 10,11-
didemethoxy-coralyne (IIIc) [5, 6]. This has been
explained by the steric hindrance of the 3-substituent
to complete the cyclization to the corresponding cor-
alyne analogue [5] or, in the latter cases, by the
precluded generation of the crucial 60-acetyl-inter-
mediate IIc [5, 6]. Nevertheless the demethoxy-
coralyne analogue IIIc was conveniently available
using our strategy via Reissert compounds [7]. As
well it was of interest wether our pathway would
also be blocked by a substituent at C3 in the corre-
sponding Reissert educts to give any 6-alkylproto-
berberine analogues. In this paper we would like to
report the results concerning these investigations.
Keywords Intramolecular cyclizations; 3-Methylisoquinoline
Reissert compounds; Rearrangement of Reissert compounds.
Introduction
Coralyne (IIIa, 2,3,10,11-tetramethoxy-8-methyl-
dibenzo[a,g]quinolizinium sulfoacetate or acetate,
ꢁ
Xꢁ ¼ HO3SCH2CO2 or CH3CO2ꢁ) possesses the
core of the protoberberine alkaloids, but it distin-
guishes itself from them in that it has not been iso-
lated from natural sources, hitherto; thus, it is a
purely synthetic member of this – probably most
widespread – alkaloid group. The compound is well
known firstly as the product of the ‘‘coralyne reac-
tion’’ commonly used as a sensitve analytical detec-
tion of the alkaloid papaverine Ia in drug analytics.
Thereby, the alkaloid is reacted with a mixture of
sulfuric acid and acetic anhydride yielding coralyne
sulfoacetate, which exhibits an intensive yellow green
Results and discussion
ꢀ
Part of PhD thesis, LMU Mu¨nchen, D
Correspondence: Eberhard Reimann, Department Phar-
mazie – Zentrum fu¨r Pharmaforschung, Ludwig-Maximil-
Educts
The required isoquinoline Reissert compounds 5
possessing an additional methyl group in the 3-posi-
¨
ians-Universitat Munchen, Munchen, Germany. E-mail:
ebrei@cup.uni-muenchen.de
¨
¨

674
E. Reimann et al.
Fig. 1 Coralyne reaction
Scheme 1
tion were prepared according to Scheme 1: Thus, the
benzaldehydes 1 were reacted with ꢀ-aminopropio-
naldehyddimethylacetal affording the Schiff bases
2, which were reduced with NaBH4 yielding the
amines 3. These could be cyclized by chlorosulfuric
acid immediately providing the 3-methylisoquino-
lines 4 in good total yields, which in turn could be
transformed to the Reissert compounds 5 by our well
established standard method. Since no procedure
was available from literature the benzylbromide 7b
was prepared from 4,5-dimethoxy-2-methylbenzoni-
trile (6); besides 7b, the dibromo-derivative 8 was
also formed (see Scheme 2); the educt 6 in turn was
available by an improved sequence according to Ref.
[8] (see Experimental section).
Alkylation of the Reissert compounds 5
First, the Reissert compound 5a was reacted with 2-
(2-bromomethylphenyl)-2-methyl-[1,3]dioxolane (9)
according to previous investigations [7], but instead
of the expected alkylation product IVa 1-benzoyl-
Scheme 2

Synthesis of 6-methyl-8H-dibenzo[a,g]quinolizin-8-imines
675
Scheme 3
3-methylisoquinoline (10), a product of the well
known rearrangement of Reissert compounds, was
formed as the main product [9–11] (Scheme 3).
Since these rearrangements are repressed by donor
substituents in the benzoyl moiety [10], consequent-
ly the alkylation was repeated with the p-toluoyl
Reissert compound 5c (Scheme 3) leading to a mix-
ture of the benzylated product 11 and the ethanone
derivative 12 emerged by rearrangement. Contrary to
the previous work mentioned above the expected
alkylation took place under a simultanous deprotec-
tion of the carbonyl group attached at the side chain,
though both the reaction and workup had been
accomplished under basic conditions (see Experi-
mental section). In addition, the formation of the
rearranged product 12 is noteworthy in that it has –
Scheme 4

676
E. Reimann et al.
to the best of our knowledge – not yet been observed
hitherto during an alkylation of an isoquinoline
Reissert compound. It may be explained by assum-
ing the generation of the expected, not isolated Reis-
sert product IVb followed by the formation of its
anion V, which would induce the rearrangement
via the intermediate VI under expulsion of cyanide
according to Scheme 4.
With the Reissert educt 11 in hand, our interest
was focused to its conversion to the benzylisoquino-
line IId, but despite all of our efforts the base in-
duced cleavage of 11, and hence its intended straight
cyclization to the 6-methylcoralyne analogue IIId
by improved methods used previously did not suc-
ceed (Scheme 5):
Obviously, the methyl group of the toluoyl moiety
admittedly allowed the approach to the desired
Reissert compound 11 but simultanously prevented
the consecutive cleavage of the amide function by
decreasing the reactivity of the carbonyl group; ad-
ditionally, the steric interaction of the 3-methyl- and
the amide function had to be taken in account.
Comparable examples of Reissert compounds being
uncleavable are – to the best of our knowledge – not
reported in literature. Thus, the general question
raised above concerning the preparation of 6-alkyl
Scheme 5
Scheme 6

Synthesis of 6-methyl-8H-dibenzo[a,g]quinolizin-8-imines
677
coralynes via the Reissert pathway remained unre-
solved.
methyl group inhibiting the cyclization as reported
in the case of 3-methylpapaverine (see above) could
not be observed, though the yield of the product 21c
was low, but this has to be also associated with the
decreased reactivity of the cyano group of the
dimethoxylated benzyl moiety of the educt 18c.
The analytical characterization revealed several
noteworthy properties of the new target compounds
21. Thus, on determing the melting point or on tem-
porary heating e.g., 21b to ca. 200ꢂC under N2, the
deep yellow amorphous solid changed to colorless
needles exhibiting the analytical data of the hydro-
chloride of the benzylisoquinoline educt 18b. Obvi-
ously, the latter is the thermodynamically more
stable structure isomer of the product. This thermal
recleavage was also to be expected under the record-
ing conditions of the mass spectra of the products
21; this was really confirmed by the fragmentation
patterns being nearly identical to those of the corre-
sponding educts 18 (see Experimental section).
Furthermore, a signal of one proton as well as of
one carbon atom were lacking in the NMR spectra of
the amidinium salts 21 recorded in solvents with
active deuterons, e.g., in deuteriotrifluoroacetic acid.
The comparison with those of the base of 21a mea-
sured in CDCl3 revealed that besides the protons of
the 8-iminium group, the proton attached at C13 was
also exchanged by deuterium. It is well known, that
the deuteration of exchangeable C–H to C–D can
result in a substantial diminution in the height of a
carbon signal [15, 16] up to its full deletion as it is
the case e.g., of C2 in the enol form of ethyl ben-
zoylacetate (ꢁ ¼ 87.40 ppm=CDCl3) [17]. Thus, a
signal applicable to C13 could not be observed in
the spectra of the products 21 recorded in solvents
with active deuterons. These visual differences
caused by deuteration can be used as a simple aid
to the assignment of 13C NMR spectra [15]. Similar-
ly, in the present case the chemical shifts of C13 and
H13 could unambiguously assigned (ꢁ ¼ 97.34,
6.78 ppm=CDCl3; see Experimental section). In con-
trast, the revised NMR spectra of structural related
8-methyldibenzo[a,g]quinolizinium salts, e.g., of
coralyne analogues [13] and of coralyne (IIIa) itself
[18], did not show a H,D-exchange at C13 and no
diminution of the intensities of the signals con-
cerned, in fact they exhibited the complete number
of protons and carbon atoms. This is also true for
5,6-dihydrodibenzoquinolizines, e.g., for berberine
chloride (Fig. 2) measured in D2O [19]. Due to lack-
Meanwhile, it was of interest whether any other
cyclizations of 3-methyl Reissert educts to proto-
berberine analogues other than coralynes could be
achieved at all. Thus, Reissert compounds of the
type 15 were found to be suitable educts for this
purpose, possessing a cyano instead of a carbonyl
group as the electrophilic reaction center. They
could be cleaved affording the 1-benzylisoquinolines
18 in satisfying yields (51–77%). In contrast to pre-
vious results obtained with 3-unsubstituted educts
[12, 13] the reaction exactly stopped at the stage
mentioned, i.e., no consecutive cyclizations to quin-
olizine derivatives 21 took place even though es-
sentially stronger reaction conditions were needed.
Additionally, bromobenzyl-3-methylisoquinoline 19
and 3-methylpapaverine 20 were prepared in the
same way serving as valuable NMR references with
respect to the products 18 (Scheme 6).
Finally, suitable conditions for the intended cycli-
zation 18 ! 21 were found during our attempts to
transform the nitrile function of the educts 18 by
Grignard reagents. Thus, treatment of the benzyli-
soquinolines 18 with methylmagnesium iodide
cleanly afforded the 8-iminodibenzoquinolizines 21
instead of the expected acetyl compounds of the
type IId (see Scheme 5). Obviously, the Grignard
reagent acted as a base rather than as a nucleophile
deprotonating 18 at the most C,H-acidic position
[14] to provide the anions VIIa and VIIb according
to Scheme 7.
In contrast, alcoholic KOH used as the approved
base in previous related investigations failed to give
the target compounds. A sterical influence of the 3-
Scheme 7

678
E. Reimann et al.
Experimental
Melting points are measured with a Bu¨chi Melting Point B-
545. IR: Perkin Elmer FT-IR Paragon 1000. NMR: Jeol GSX
400 (1H: 400 MHz, 13C: 100 MHz, CDCl3, TMS as internal
reference); MS (70 eV): Hewlett Packard MS-Engine. UV:
Perkin-Elmer UV-Vis Lambda 20. Elemental analyses:
Heraeus CHN-Rapid; the results were in good agreement with
the calculated values. Thin layer chromatography (TLC): alu-
minium sheets Kieselgel 60 F254 (Merck), thickness of layer
0.2 mm. Flash chromatography (FC): ICN-SiliTech 32–36, 60
A. The following educts=compounds are commercial products:
3,4-dimethoxybenzaldehyde (1b), 3,4-dimethoxybenzylalko-
hol, 3,4-dimethoxytoluene, 1-bromo-2-bromomethylbenzene
(13), 2-bromomethylbenzonitrile (7a) [12], and 2,2-dimeth-
oxy-1-methylethylamin. 2-(2-Bromomethylphenyl)-2-methyl-
[1,3]dioxolane (9) was prepared according to Ref. [7]. An
improved procedure for 4-bromomethyl-1,2-dimethoxyben-
zene (14) [20] is given below.
Fig. 2 Berberine chloride
Coralyne sulfoacetate (IIIa)
Synthesis according to Ref. [18]. 13C NMR (F3CCO2D:
CDCl3 ¼ 1:1): ꢁ ¼ 158.18, 154.68, 154.23, 152.95 (4s, 4 arom
C–O), 144.69, 136.82, 135.59, 125.53, 123.96 (5s), 123.80 (d,
C-6), 123.22 (d, C-5), 121.56 (s), 117.32 (d, C-13), 109.21 (d,
C-12), 106.01 (d, C-4), 105.73 (d, C-1), 104.06 (d, C-9), 57.73,
57.34, 57.26, 57.14 (4q, 4 OCH3), 17.80 (q, C–CH3) ppm.
Scheme 8
ing data in literature, the 13C NMR spectrum of cor-
alyne IIIa is included in the Experimental part. The
easy H,D-exchange at C13 of the target compounds
21 was assumed to be favored by the presence of the
(de)-protonable heteroatom at C8 via the tautomer
VIII as indicated in Scheme 8.
General procedure for the synthesis of the Schiff bases 2
A mixture of the benzaldehyde 1 and 1,1-dimethoxy-2-propan-
amine (Fluka) in 200 cm3 toluene was refluxed with H2O sepa-
rationbya Dean-Stark trapfor 2 h. After evaporating the solvent
in vacuo the residual oil was purified by distillation.
Benzylidene-(2,2-dimethoxy-1-methylethyl)amine
(2a, C12H17NO2)
Benzaldehyde (1a) 21.75 cm3 (215.1 mmol), 1,1-dimethoxy-2-
propanamine 30.0 cm3 (236.7mmol). Yield 43.3g (97%), col-
orless oil, bp 88–90ꢂC=6 Pa; nD20 ¼ 1.5173; TLC (CHCl3:
MeOH:6N NH3 ¼ 19:1:0.1): Rf ¼ 0.70 (educt: Rf ¼ 0.40);
Conclusions
The results presented show, that – in contrast to the
coralyne reaction Ia ! IIIa, which is known to be in-
hibited by a 3-methyl substituent in the educt Ib –
the 1-benzylisoquinolines 18a–18c related to the
crucial intermediates II cyclize by means of meth-
ylmagnesium iodide yielding the target compounds
21a–21c rather than the expected acetophenone de-
rivatives of the type II. Moreover, the attempted
alkylation of the Reissert compound 5a with the
dioxolane 9 preferentially provides the 1-benzoyli-
soquinoline 10 by a well known pathway. Finally,
the same reaction with the N-toluoyl-Reissert educt
5c reveals besides the expected alkylation product 11
an unprecedented rearrangement affording the toluyl-
ethanone derivative 12. Further investigations on the
scope of the cyclization of related 3-methylbenzyli-
soquinolines are in progress.
þ
MS (CI): m=z (%) ¼ 208 (M ꢃþ 1, 15), 176 (20), 120 (9),
1
88 (100); H NMR (CDCl3): ꢁ ¼ 8.20 (s, N¼CH), 7.67–7.65
(m, 2 arom H), 7.32–7.29 (m, 3 arom H), 4.30 (d, J ¼ 6.8 Hz,
O–CH–O), 3.44–3.38 (m, ¼N–CHꢁ), 3.36, 3.28 (2s,
2OCH3), 1.19 (d, J ¼ 6.8 Hz, C–CH3) ppm; 13C NMR
(CDCl3): ꢁ ¼ 160.98 (N¼CH), 136.24 (C-10), 130.49 (C-40),
128.41 (2C), 128.13 (2C), 107.30 (O–C–O), 68.35 (¼N–C),
54.91, 54.47 (2OCH3), 17.80 (ꢁCH3) ppm.
(3,4-Dimethoxy-benzylidene)-(2,2-dimethoxy-1-methylethyl)-
amine (2b, C14H21NO4)
3,4-Dimethoxybenzaldehyde 1b 30.3g (182.3mmol), 1,1-di-
methoxy-2-propanamine 24.0cm3 (200.6mmol). Yield 46.8 g
(96%), colorless oil, bp 129–131ꢂC=10Pa; mp 48–50ꢂC; TLC
(CHCl3:MeOH:6N NH3 ¼ 19:1:0.1): Rf ¼ 0.90 (educt: Rf ¼
þ
0.4); MS (CI): m=z (%) ¼ 268 (M ꢃþ 1, 90), 236 (100), 192
(11), 130 (7); 1H NMR (CDCl3): ꢁ ¼ 8.27 (s, N¼CH), 7.49 (d,
J ¼ 1.7 Hz, 20-H), 7.25 (dd, J ¼ 8.1=1.7 Hz, 60-H), 6.94 (d,

Synthesis of 6-methyl-8H-dibenzo[a,g]quinolizin-8-imines
679
J ¼ 8.1 Hz, 50-H), 4.44 (d, J ¼ 6.8 Hz, O–CH–O), 4.01, 3.98
(2s, 2Ar–OCH3), 3.56–3.53 (m, ¼N–CH), 3.52, 3.44 (2s,
2Alk–OCH3), 1.34 (d, J ¼ 6.4 Hz, C–CH3) ppm; 13C NMR
(CDCl3): ꢁ ¼ 160.55 (N¼CH), 151.28, 149.23 (C-40, C-50),
129.64 (C-10), 123.02, 110.41, 109.12, 107.42 (O–C–O),
68.23 (¼N–C), 55.98, 55.94 (2Ar–OCH3), 54.86, 54.59
(2Alk–OCH3), 17.98 (ꢁCH3) ppm.
ꢁ70ꢂC, then for 2 h at ambient temperature. After removing
the solvent in vacuo, the dark brown solution was poured on
ice. The mixture was washed twice with Et2O, rendered alka-
line by adding solid Na2CO3, and extracted twice with CHCl3.
The combined organic layers were concentrated to a smaller
volume and then washed with brine. Finally, the solvent was
removed in vacuo.
General procedure for the synthesis of the benzylamines 3
To an ice cold solution of the Schiff base 2 in 150 cm3 MeOH
was added portionwise NaBH4. The mixture was stirred under
ice cooling for 1 h, thereafter at ambient temperatur for 2.5 h.
After evaporating the solvent in vacuo, the residue was treated
with 50cm3 CH2Cl2 and the mixture was washed with 100 cm3
H2O. The aqueous layer was extracted with 3ꢄ50cm3
CH2Cl2. The combined organic phases were washed with
brine and dried (Na2SO4). After removing the solvent in vacuo
the raw product was purified by distillation (3a) or used
for the next step without further purification (3b).
3-Methylisoquinoline (4a)
From 450 cm3 CH2Cl2=145 cm3 ClSO3H, 3a 41.2 g
(196.8mmol)=CH2Cl2 450 cm3, ice 1 kg=Et2O 2ꢄ100 cm3,
CHCl3 2ꢄ1000 cm3. The residue (20.7 g) was purified by
distillation. Yield 19.5g (69%), bp 61–64ꢂC=133 Pa; mp
63–64ꢂC (Ref. [21]: 63–64ꢂC); TLC (n-hexane:CH2Cl2:
MeOH¼ 10:20:1): Rf ¼ 0.35 (educt: Rf ¼ 0.55); MS (EI):
1
þ
m=z (%) ¼ 143 (M ꢃ, 100), 129 (30), 115 (40), 100 (31); H
NMR: see Ref. [22]; 13C NMR: see Ref. [23].
6,7-Dimethoxy-3-methylisoquinoline (4b)
From 170 cm3 CH2Cl2=55 cm3 ClSO3H, 3b 20.0 g
(74.3 mmol)=CH2Cl2 170 cm3, ice 400 g=Et2O 2ꢄ50 cm3,
CHCl3 2ꢄ400 cm3. The ginger residue (9.2g) was crystal-
lized from 30cm3 acetone; crystallization of the residue of
the mother liquor from 10cm3 acetone afforded further prod-
uct. Total yield: 7.59g (50%), pale beige amorphous solid; mp
129–130ꢂC (Ref. [21]: 130–131ꢂC); TLC (CHCl3:MeOH:6N
NH3 ¼ 19:1:0.1): Rf ¼ 0.30 (educt: Rf ¼ 0.5); MS (EI): m=z
Benzyl-(2,2-dimethoxy-1-methylethyl)amine
(3a, C12H19NO2)
From 42.5g 2a (205mmol), NaBH4 15.5g (410 mmol). Yield
41.2g (96%), colorless oil, bp 90–95ꢂC=40Pa; nD20 ¼ 1.4941;
TLC (CHCl3:MeOH:6N NH3 ¼ 19:1: 0.1): Rf ¼ 0.50 (educt:
Rf ¼ 0.70); IR (film): ꢂꢀ¼ 3331 (NH) cmꢁ1; MS (EI): m=z
1
þ
(%) ¼ M ꢃ lacking, 178 (15), 134 (30), 91 (100); H NMR
þ
(%) ¼ 203 (M ꢃ, 100), 188 (30), 160 (40), 145 (13), 130
(CDCl3): ꢁ ¼ 7.31 (like a d, 4 arom H), 7.25–7.20 (m, 1 arom
H), 4.14 (d, J ¼ 6.0Hz, O–CH–O), 3.89, 3.69 (2d, AB-syst.,
J ¼ 12.8, 13.2Hz, N–CH2), 3.37, 3.34 (2s, 2OCH3), 2.86–2.80
(m, N–CH), 1.7 (br s, NH), 1.10 (d, J ¼ 6.4 Hz, C–CH3) ppm;
13C NMR (CDCl3): ꢁ ¼ 140.54 (C-10), 128.40 (2C, C-20=C-
60), 128.14 (2C, C-30=C-50), 126.86 (C-40), 107.96 (O–C–O),
54.70, 54.50 (2OCH3), 53.55 (N–CH), 51.21 (N–CH2), 15.00
(C–CH3) ppm.
1
(13), 117 (16); H NMR (CDCl3): ꢁ ¼ 8.95 (s, 1-H), 7.33 (s,
4-H), 7.15 (s, 8-H), 6.95 (5-H), 4.00 (s, 2OCH3), 2.65 (s, CH3)
ppm; 13C NMR (CDCl3): ꢁ ¼ 153.03 (C-6), 150.33, 149.65
(C-3, C-7), 149.34 (C-1), 133.34 (C-4a), 122.71 (C-8a),
117.46 (C-4), 105.17 (C-8), 104.02 (C-5), 56.02, 55.96
(2OCH3), 24.05 (CH3) ppm.
General procedure for the synthesis of the Reissert
compounds 5
(3,4-Dimethoxybenzyl)-(2,2-dimethoxy-1-methylethyl)amine
(3b, C14H23NO4)
To an ice cold solution of the corresponding 3-methylisoquin-
oline 4 in CH2Cl2 was added a solution of KCN in H2O
under vigorous stirring. After 5 min the benzoyl chloride
was added dropwise and stirring and cooling was continued
for a certain time. The mixture was diluted with CH2Cl2, then
the organic layer was washed three times with H2O and once
with brine, dried (Na2SO4) and evaporated in vacuo. After
dissolving the yellow oily residue in boiling MeOH, the solu-
tion was chilled in an ice bath for 30min and then immediate-
ly filtered. The mother liquor was filtered several times until
no further product separated. The combined solids were
washed with ice cold MeOH and dried in vacuo.
From 46.7g 2b (174.7 mmol), NaBH4 13.24 g (350mmol).
Yield 45.8g (97%), viscous oily raw product; TLC (CHCl3:
MeOH:6N NH3 ¼ 19:1:0.1): Rf ¼ 0.50 (educt: Rf ¼ 0.90);
IR (film): ꢂꢀ¼ 3330 (NH) cmꢁ1; MS (CI): m=z (%) ¼ 270
1H NMR
þ
(M ꢃþ 1, 100), 238 (30), 206 (40), 151 (30);
(CDCl3): ꢁ ¼ 6.88–6.80 (m, 3 arom H), 4.14 (d, J ¼ 6.4 Hz,
O–CH–O), 3.89, 3.86 (2s, 2ArOCH3), 3.86 (obscured), 3.64
(2d, AB-syst., J ¼ 12.8Hz, N–CH2), 3.38, 3.35 (2s, 2Alk–
OCH3), 2.86–2.80 (m, N–CH), 1.84 (br s, NH), 1.10 (d,
J ¼ 6.4 Hz, C–CH3) ppm; 13C NMR (CDCl3): ꢁ ¼ 148.92,
147.93, 133.14, 120.23, 111.37, 111.03, 107.88 (O–C–O),
55.89, 55.82 (2ArOCH3), 54.70, 54.54 (2AlkOCH3), 53.47
(N–CH), 50.97 (N–CH2), 14.98 (C–CH3) ppm.
2-Benzoyl-3-methyl-1,2-dihydroisoquinoline-1-carbonitrile
(5a)
From 5.0 g 4a (34.9 mmol)=CH2Cl2 85cm3, KCN 8.15g
(125.2 mol)=H2O 35 cm3, benzoyl chloride 10.0 g (71.1 mmol),
reaction time 1.5 h; CH2Cl2 100 cm3, boiling MeOH 60 cm3.
Yield 6.41g (67%), pale yellow crystals; mp 122–125ꢂC (Ref.
[24]: 127–128ꢂC); TLC (n-hexane:CH2Cl2:MeOH¼ 20:10:1):
Rf ¼ 0.40 (educt: Rf ¼ 0.30); IR (KBr): ꢂꢀ¼ 2234 (CꢅN), 1665
General procedure for the synthesis of the 3-methyliso-
quinolines 4
To CH2Cl2 cooled to ꢁ75ꢂC was added dropwise ClSO3H
followed under N2 by a solution of the corresponding benzyl-
amine 3 in CH2Cl2 cooled to the same temperature; the latter
should not exceed ꢁ70ꢂC. The mixture was stirred for 2 h at

680
E. Reimann et al.
(C¼O) cmꢁ1
moist yellowish solid, which was crystallized from 50cm3
MeOH. The product was washed with a small volume of
petroleum ether and dried in vacuo. Yield 10.7 g (45%), pale
yellow needles; mp 116–117ꢂC (Ref. [26]: 119–120ꢂC); TLC
(EtOAc:n-hexane¼ 1:1): Rf ¼ 0.80 (educt: Rf ¼ 0.50); MS
þ
; MS (CI): m=z (%) ¼ 275 (M ꢃþ 1, 60), 248
1
(100), 144 (7), 105 (9); H NMR (CDCl3): ꢁ ¼ 7.56–7.52,
7.43–7.36, 7.24–7.21 (3m, 3ꢄ3 arom H), 6.53 (s, 1-H),
6.26 (s, 4-H), 1.80 (s, CH3) ppm; 13C NMR (CDCl3):
ꢁ ¼ 169.01 (C¼O), 135.58, 135.25, 132.29, 131.46, 130.26,
128.99 (2C), 128.72 (2C), 128.19, 126.41, 126.01, 125.50,
117.07 (CN), 115.90 (C-4), 47.25 (C-1), 22.26 (CH3) ppm.
þ
(EI): m=z (%) ¼ 197 (M ꢃ, 60), 180 (100), 152 (25), 136 (18),
1
121 (18); H NMR (CDCl3): ꢁ ¼ 7.57, 6.64 (2s, each 1 arom
H), 3.89, 3.85 (2s, 2OCH3), 2.54 (s, C–CH3) ppm.
2-Benzoyl-6,7-dimethoxy-3-methyl-1,2-dihydroisoquinoline-
1-carbonitrile (5b, C20H18N2O3)
B) 4,5-Dimethoxy-2-methylaniline
A dark green mixture of 18.3 g (92.6 mmol) of the above nitro
compound, 1.0 g Adams catalyst (PtO2–H2O), and 200cm3
EtOH was hydrogenated at ambient temperatur under nor-
mal pressure. After 2 h, 7.5 dm3 (theory: 6.3 dm3) H2 were
absorbed. The gray suspension was diluted with an adequate
volume of MeOH to dissolve of some product. Now, the cata-
lyst was centrifuged off, and the solvents were evaporated
in vacuo with most 30ꢂC. The residue was dried in vacuo at
ambient temperatur. Yield 15.3 g (99%), pale beige solid; mp
106–107ꢂC (Ref. [27]: 108ꢂC); TLC (EtOAc:n-hexane ¼ 1:1):
From 10.0g 4b (49.2 mmol)=CH2Cl2 120 cm3, KCN 11.4g
(175 mmol)=H2O 50 cm3, benzoyl chloride 11.6 cm3
(100 mmol), reaction time: 1.5 h, CH2Cl2 100 cm3. Differing
from the general procedure the raw product was crystallized
from 160 cm3 EtOAc and the residue of the evaporated
mother liquor was crystallized from 40cm3 EtOAc. Total
yield: 11.7 g (71%), colorless crystals; mp 171–173ꢂC; TLC
(n-hexane:CH2Cl2:MeOH¼ 20:10:1): Rf ¼ 0.50 (educt: Rf ¼
0.30); IR (KBr): ꢂꢀ¼ 1656 (C¼O), (lacking CꢅN) cmꢁ1
;
þ
MS (EI): m=z (%) ¼ 334 (M ꢃ, 20), 229 (15), 203 (52), 160
Rf ¼ 0.30 (educt: Rf ¼ 0.80); IR (KBr): ꢂꢀ¼ 3395 (NH) cmꢁ1
;
1
(14), 131 (13), 105 (100); H NMR (CDCl3): ꢁ ¼ 7.57–7.51
þ
MS (EI): m=z (%) ¼ 167 (M ꢃ, 100), 152 (90), 124 (50), 109
C) 4,5-Dimethoxy-2-methyl-benzonitrile (6)
(m, 3 arom H), 7.51–7.41 (m, 2 arom H), 6.82, 6.75, 6.49,
6.19 (4s, each 1H, 8-H, 5-H, 1-H, 4-H), 3.91, 3.89 (2s, each
OCH3), 1.77 (s, CH3) ppm; 13C NMR (CDCl3): ꢁ ¼ 168.76
(C¼O), 150.13 (C-6), 148.79 (C-7), 135.11 (C-3), 133.36 (C-
10), 131.93, 128.69 (2C), 128.42 (2C), 124.54 (C-4a), 118.40
(C-8a), 117.06 (CꢅN), 115.58 (C-4), 108.87 (C-8), 108.30 (C-
5), 56.18, 56.07 (each OCH3), 46.76 (C-1), 21.80 (CH3) ppm.
1
(31); H NMR: see Ref. [27].
To a solution of 5.0g (30 mmol) of the preceding aniline
derivative in 50cm3 2 N HCl cooled to 5ꢂC was dropwise
added a solution of 2.15g NaNO2 in 5 cm3 H2O. The mixture
was stirred for 10min under cooling and then adjusted to pH 7
with ca. 16 cm3 conc. Na2CO3 (solution A). Generation of
CuCN: To a solution of 9.38g CuSO4 and 2.44 g NaCl in
30cm3 hot H2O was added a solution of 2.0 g Na2S2O5 and
1.31g NaOH in 15cm3 H2O under N2. After decantation the
solid was repeatedly washed with 10cm3 portions of H2O,
until the supernatant was colorless. To the residue a mixture
of 4.88g NaCN, 7.5 cm3 H2O, and 5 cm3 toluene was added
followed by solution A (see above) under stirring and ice
cooling. The mixture was stirred under cooling for 30min,
thereafter for 60min at 20ꢂC, and finally for 10min at 80ꢂC.
After cooling to ambient temperatur the solids were removed
by filtration. Then the deep red filtrate was saturated with
NaCl and extracted with 3ꢄ300 cm3 Et2O. After concentrat-
ing the combined extracts the residue was purified by steam
distillation. The distillate (ca. 1.5 dm3) was saturated with
NaCl and extracted with 4ꢄ300 cm3 Et2O. The combined
organic phases were concentrated to a volume of 300cm3,
washed with brine, and evaporated in vacuo. Yield 2.31g
(43%), beige crystals; mp 78–80ꢂC (Ref. [28]: mp 79–80ꢂC);
3-Methyl-2-(4-toluoyl)-1,2-dihydroisoquinoline-1-carbo-
nitrile (5c)
From 1.65g 4a (11.5mmol)=CH2Cl2 17 cm3, KCN 2.7 g
(41.5 mmol)=H2O 11 cm3, p-toluoyl chloride 6.1 cm3
(38.8 mmol), reaction time: 2.5 h=ice cooling and 15 h=
20ꢂC; CH2Cl2 30cm3, boiling MeOH ca. 20 cm3. Yield
2.47g (75%), pale beige crystals; mp 116–117ꢂC (Ref. [10]:
139–140, 128–129.5ꢂC); TLC (n-hexane: CH2Cl2:MeOH¼
20:20:1): Rf ¼ 0.50 (educt: Rf ¼ 0.30); IR (KBr): ꢂꢀ¼ 1661
(C¼O), (lacking CꢅN) cmꢁ1; MS (EI): m=z (%) ¼ 288
1H NMR: see Ref. [25]; 13C NMR
þ
(M ꢃ, 5), 119 (100);
(CDCl3): ꢁ ¼ 168.82 (C¼O), 142.76 (C-40), 135.57, 132.15,
131,29, 129.96, 129.37 (2C), 128.62 (2C), 126.18, 125.75
(2C), 125.18, 116.92 (CN), 115.36 (C-4), 47.11 (C-1), 22.02
(Isoquin-CH3), 21.62 (Tol–CH3) ppm.
2-Bromomethyl-4,5-dimethoxybenzonitrile (7b)
A) 1,2-Dimethoxy-4-methyl-5-nitrobenzene
TLC (EtOAc:n-hexane¼ 1:1): Rf ¼ 0.80 (educt: Rf ¼ 0.30); IR
(KBr): ꢂꢀ¼ 2215 (CꢅN) cmꢁ1
þ
To a solution of 18.4g (121 mmol) 3,4-dimethoxytoluene in
90cm3 glacial acetic acid, cooled to 5–10ꢂC, a mixture of
9 cm3 (ca. 120 mmol) conc. HNO3 and 50 cm3 glacial acetic
acid was added dropwise under stirring. After further stir-
ring and cooling for 30 min the suspension was poured into
600 cm3 H2O. The dark red mixture was extracted with
2ꢄ500 cm3 Et2O. The combined yellow organic layers were
washed with 2ꢄ400 cm3 brine and evaporated in vacuo.
The residue was taken up in 200 cm3 CH2Cl2 and washed
with 3ꢄ50 cm3 of a saturated solution of NaHCO3. Drying
(Na2SO4) and removing the solvent afforded ca. 15g of a
; MS (EI): m=z (%) ¼ 177 (M ꢃ,
1
100), 162 (40), 134 (15); H NMR: see Ref. [28].
D) 2-Bromomethyl-4,5-dimethoxybenzonitrile (7b,
C10H10BrNO2) and 2-Dibromomethyl-4,5-dimeth-
oxybenzonitrile (8, C10H9Br2NO2)
A suspension of 770 mg (4.3 mmol) N-bromosuccini-
mide, 691 mg (3.9 mmol) 6 and 20 mg (0.08 mmol) diben-
zoylperoxide in 20 cm3 CCl4 was refluxed for 3 h. After
filtering off the solid, the filtrate was washed with a saturat-
ed solution of NaHCO3 and brine, dried (Na2SO4) and

Synthesis of 6-methyl-8H-dibenzo[a,g]quinolizin-8-imines
681
1
evaporated in vacuo. The products were separated by FC (n-
hexane:EtOAc ¼ 3:1).
(90), 105 (50); H NMR (CDCl3): ꢁ ¼ 8.07–8.04, 7.97–7.94,
7.83–7.81, 7.69–7.58, 7.50–7.45 (each m, 1 þ 2 þ 1 þ 3 þ 3
H), 2.73 (s, CH3) ppm.
7b: Yield 658 mg (66%), colorless crystals; mr 122–125ꢂC;
TLC (see FC): Rf ¼ 0.40; IR (KBr): ꢂꢀ¼ 2224 (CꢅN), 582 (C–
þ
þ
Br) cmꢁ1
; MS (CI): m=z (%) ¼ 257 (M ꢃ, 20), 255 (M ꢃ, 15),
1-(2-Acetylbenzyl)-3-methyl-2-(4-toluoyl)-1,2-dihydroiso-
quinoline-1-carbonitrile (11, C28H24N2O2) and 2-[2-(2-
methyl-[1,3]dioxolan-2-yl)-phenyl]-2-(3-methyl-isoquinolin-
1-yl)-1-p-tolyl-ethanone (12, C29H27NO3)
176 (100); 1H NMR (CDCl3): ꢁ ¼ 7.05 (s, 6-H), 7.00 (s, 3-H),
4.63 (s, CH2), 3.96, 3.91 (2s, 2OCH3) ppm; 13C NMR
(CDCl3): ꢁ ¼ 152.73, 149.07 (C-3, C-4), 135.19 (C-2),
117.07 (CꢅN), 114.03 (C-6), 112.57 (C-3), 103.70 (C-1),
56.21, 56.15 (2OCH3), 29.89 (CH2) ppm.
From 580 mg (2 mmol) 5c, 9 1.6 g (6.2mmol), TEBA 100 mg
(0.44 mmol), benzene 1.5 cm3, KOH 0.3 cm3. Method B: the
components were separated by repeated FC (n-hexane:
CH2Cl2:MeOH ¼ 20:10:1), followed by PTLC.
8: Yield 433 mg (33%), colorless crystals; mr 140–145ꢂC;
TLC (see FC): Rf ¼ 0.60; IR (KBr): ꢂꢀ¼ 2222 (CꢅN), 584 (C–
þ
Br) cmꢁ1
256=254 (90=100), 206 (26), 176 (80); H NMR (CDCl3):
; MS (EI): m=z (%) ¼ 337, 335, 333 (M ꢃ, 5–10),
1
12 (1, fraction): Yield 75mg (14%), colorless crystals;
mp 208–212ꢂC (MeOH); TLC (n-hexane:CH2Cl2:MeOH¼
20:10:1): Rf ¼ 0.45 (edcuct: Rf ¼ 0.50); IR (KBr): ꢂꢀ¼ 1670
(C¼O), 1039 (C–O dioxolane) cmꢁ1; MS (EI): m=z (%) ¼
ꢁ ¼ 7.44 (s, 3-H), 6.99 (s, CHBr2), 6.94 (s, 6-H), 4.03, 3.93
(2s, 2OCH3) ppm; 13C NMR (CDCl3): ꢁ ¼ 153.44, 150.07 (C-
4, C-5), 138.62 (C-2), 116.24 (CꢅN), 112.49 (C-6), 111.94
(C-3), 99.58 (C-1), 56.44, 56.24 (2OCH3), 36.03 (CHBr2) ppm.
þ
437 (M ꢃ, 15), 394 (35), 350 (60), 318 (15), 274 (65), 231
(20), 119 (100), 91 (65); 1H NMR (CDCl3): ꢁ ¼ 8.08 (d,
J ¼ 8.6 Hz, 1 arom H), 7.70 (d, J ¼ 8.1 Hz, 2 arom H), 7.64–
7.60 (m, 2 arom H), 7.51–7.47 (m, 1 arom H), 7.42 (s, 1 arom
H), 7.35–7.31 (m, 1 arom H), 7.26 (s, 1 arom H), 7.18–7.12
(m, 1 arom H), 7.04–7.01 (m, 3 arom H), 6.88 (d, J ¼ 7.7 Hz,
1 arom H), 3.99–3.93, 3.79–3.74, 3.62–3.57 (3m, 1H, 2H, 1H,
2OCH2), 2.43 (s, Isoquin–CH3), 2.24 (s, Tol–CH3), 1.78 (s,
Dioxol–CH3) ppm; 13C NMR (CDCl3): ꢁ ¼ 197.15 (C¼O),
159.03, 150.55, 142.15, 140.12, 137.60, 135.90, 135.75,
131.78, 129.61, 128.97 (2C), 128.35 (2C), 128.02, 126.96
(2C), 126.30 (2C), 125.09, 125.00, 117.72, 109.44 (C(O)O),
64.59, 64.28 (2CH2–O), 55.14, 27.93 (Dioxol–CH3), 24.12
(Isoquin–CH3), 21.53 (Tol–CH3) ppm.
4-Bromomethyl-1,2-dimethoxybenzene (14)
To a solution of 1.0 (6mmol) 3,4-dimethoxybenzylalkohol in
30cm3 Et2O cooled with dry ice=acetone was dropwise added
a mixture of 0.62 cm3 (6.5mmol) PBr3 in 10 cm3 Et2O. After
stirring for1 h under cooling the mixturewas allowed tocometo
ambient temperature and then poured on ice. The separated
organic layer was washed with brine, dried (Na2SO4) and evap-
orated in vacuo. Yield 1.23 g (90%), colorless crystals quickly
adopting a pale purple color cast; mp 56–58ꢂC (Ref. [20]:
56ꢂC); IR (KBr): ꢂꢀ¼ 652 (C–Br) cmꢁ1; MS (EI): m=z (%) ¼
1
þ
232=230 (M ꢃ, 2–5), 151 (100); H NMR: see Ref. [20].
11 (2, fraction): Yield 165 mg (20%), dark yellow oil; TLC
(n-hexane:CH2Cl2: MeOH¼ 20:10:1): Rf ¼ 0.40; IR (film):
ꢂꢀ¼ 2253 (CꢅN), 1683 (C¼O), 1669 (C(O)N) cmꢁ1; MS (CI):
General procedure for the synthesis of the alkylated Reissert
compounds 15, 16, and 17
1
þ
m=z (%) ¼ 421 (M ꢃþ 1, 30), 394 (10), 276 (100), 119 (80); H
To a mixture of the Reissert compound 5, the corresponding
benzylbromide, and cetrimoniumbromide (CTAB) or triethyl-
benzylammoniumchloride (TEBA) in toluene or benzene was
added dropwise 50% KOH. The mixture protected against
light was vigorously stirred for 24 h. Workup: Products being
sparingly soluble in toluene precipitated and were filtered off
and washed and=or recrystallized (method A) or alternatively,
the reaction mixture was diluted with H2O (300 cm3) and
EtOAc (200cm3), then the aqueous phase was extracted with
EtOAc. The combined organic layers were washed with brine,
dried (Na2SO4) and evaporated in vacuo; residual toluene or
benzene were removed by repeated evaporation with small
volumes of CH2Cl2 (method B).
NMR (CDCl3): ꢁ ¼ 7.61 (br s, 2 arom H), 7.52–7.41 (m, 2 arom
H), 7.34–7.19 (m, 4 arom H), 7.11–6.98 (m, 1 arom H), 6.78
(d, J ¼ 7.8 Hz, 1 arom H), 5.98 (s, 4-H), 4.56–4.53, 3.74–3.71
(2d, AB-syst., each J ¼ 12.8Hz, CH2), 2.39 (s, (Tol–CH3), 2.01
(s, Ac–CH3), 1.71 (s, Isoquin–CH3) ppm; 13C NMR (CDCl3):
ꢁ ¼ 201.52 (C¼O), 170.02 (NHC¼O), 143.45, 139.65, 134.14,
133.52, 132.70, 132.53, 131.02, 130.67, 129.44 (2C), 129.21
(2C), 129.06, 128.55, 127.63, 127.49, 127.36, 126.44, 124.29,
117.65, 111.96 (C-4), 64.17, 35.66 (CH2), 28.88 (Ac–CH3),
24.05 (Isoquin–CH3), 21.65 (Tol–CH3) ppm.
2-Benzoyl-1-(2-cyano-benzyl)-3-methyl-1,2-dihydroiso-
quinoline-1-carbonitrile (15a, C26H19N3O)
1-Benzoyl-3-methylisoquinoline (10, C17H13NO)
From 1.0 g (3.6mmol) 5a, 7a 920 mg (4.7mmol), CTAB
50mg (0.14 mmol), toluene 10 cm3, KOH 3 cm3. Method B:
the raw product was crystallized from 30cm3 MeOH. Yield
1.12g (81%), colorless crystals; mp 180–183ꢂC; TLC (n-
hexane:CH2Cl2:MeOH ¼ 20:10:1): Rf ¼ 0.20 (edcuct: Rf ¼
0.40); IR (KBr): ꢂꢀ¼ 2228 (CꢅN), 1674 (C¼O) cmꢁ1; MS
(50); 1H NMR (CDCl3): ꢁ ¼ 7.65–7.63 (m, 3 arom H), 7.53–
7.45 (m, 2 arom H), 7.37–7.25 (m, 5 arom H), 7.06–7.04 (d,
J ¼ 7.3Hz, 1 arom H), 6.97–6.93 (m, 1 arom H), 6.77–6.75
(d, J ¼ 7.7Hz, 1 arom H), 5.97 (s, 4-H), 3.84–3.80, 3.67–3.64
A mixture of 100 mg (0.36 mmol) 5a, 250 mg (1 mmol) 9,
90mg TEBA (0.4mmol), 0.2 cm3 50% NaOH, and 1 cm3 ben-
zene was stirred for 3 h under ice cooling and thereafter
poured into a mixture of 50 cm3 EtOAc and 50 cm3 H2O.
The organic layer was washed with 2ꢄ100 cm3 H2O and
dried (Na2SO4). After removing of the solvent in vacuo the
residue was purified by FC (n-hexane:CH2Cl2:MeOH¼
20:20:1). Yield 76 mg (85%), colorless crystals; mp 101–
þ
(CI): m=z (%) ¼ 390 (M ꢃþ 1, 100), 363 (30), 259 (50), 105
103ꢂC (Ref. [29]: 103ꢂC); IR (KBr): ꢂꢀ¼ 1673 (C¼O)
þ
cmꢁ1
; MS (EI): m=z (%) ¼ 247 (M ꢃ, 60), 246 (80), 218

682
E. Reimann et al.
(2d, AB-syst., J ¼ 12.8=13.3Hz, Ar–CH2), 1.63 (s, CH3) ppm;
13C NMR (CDCl3): ꢁ ¼ 170.23 (C¼O), 136.49, 136.03,
133.29, 132.76, 132.39, 132.32, 132.16, 130.62, 129.69,
129.30 (2C), 128.74, 128.10 (2C), 126.93, 126.73, 124.97,
117.16, 116.47 (2CꢅN), 114.47, 112.53, 63.47, 39.38
(CH2), 24.02 (CH3) ppm.
mp 167–169ꢂC; TLC (n-hexane:CH2Cl2:MeOH¼ 20:10:1):
Rf ¼ 0.40 (edcuct: Rf ¼ 0.40); IR (KBr): ꢂꢀ¼ (CꢅN) lacking,
1674 (C¼O), 1026 (C–Br) cmꢁ1; MS (CI): m=z (%) ¼ 445=
þ
443 (each M ꢃþ 1, each 100), 418=416 (each 40), 314=312
1
(each 50), 273 (22), 151 (19), 105 (100); H NMR (CDCl3):
ꢁ ¼ 7.72 (br s, 2 arom H), 7.55–7.51 (m, 1 arom H), 7.43–7.20
(m, 6 arom H), 7.10–7.03 (m, 3 arom H), 6.98–6.96 (m, 1
arom H), 5.92 (s, 4-H), 3.99–3.96, 3.67–3.64 (2d, AB-syst.,
J ¼ 13.3=12.8Hz, Ar–CH2), 1.67 (s, CH3) ppm; 13C NMR
(CDCl3): ꢁ ¼ 170.19 (C¼O), 136.32, 133.58, 132.92, 132.66,
132.57, 130.70, 129.41, 129.30 (2C), 129.11, 128.75 (2C),
127.61, 127.32, 127.16, 127.05, 126.94, 126.88, 124.32, 117.67
(CꢅN), 112.42, 63.68 (C-1), 40.42 (CH2), 24.06 (CH3) ppm.
2-Benzoyl-1-(2-cyanobenzyl)-6,7-dimethoxy-3-methyl-1,2-
dihydroisoquinoline-1-carbonitrile (15b, C28H23N3O3)
From 898 mg (2.7 mmol) 5b, 7a 683 mg (3.5mmol), CTAB
74mg (0.2mmol), toluene 10cm3, KOH 3 cm3. Method A:
after consecutively washing with Et2O, MeOH (2x), and
Et2O the product was dried in vacuo giving 842 mg; the moth-
er liquor of the original reaction mixture provided further
61mg. Total yield: 903 mg (74%) citreous crystals; mp 166–
168ꢂC; TLC (n-hexane:CH2Cl2:MeOH ¼ 20:10:1): Rf ¼ 0.30
2-Benzoyl-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3-methyl-
1,2-dihydroisoquinoline-1-carbonitrile (17, C29H28N2O5)
From 1.0g (3mmol) 5b, 14 920 mg (4mmol), CTAB 50 mg
(0.14 mmol), toluene 10cm3, KOH 3 cm3. Method A:
Washing with 5 cm3 H2O and with 2ꢄ20cm3 Et2O and drying
in vacuo gave 978 mg of pale yellow raw product, which was
crystallized from 20cm3 EtOAc=4 cm3 MeOH. Repeated
evaporation and crystallization of the residue of the mother
liquor provided additional substance. Total yield: 724mg
(50%), pale yellow crystals; mp 154–156ꢂC; TLC (n-
hexane:CH2Cl2:MeOH¼ 20:10:1): Rf ¼ 0.40 (edcuct: Rf ¼
0.50); IR (KBr): ꢂꢀ¼ 2224 (CꢅN), 1669 (C¼O) cmꢁ1; MS:
(edcuct: Rf ¼ 0.40); IR (KBr): ꢂꢀ¼ 2226 (CꢅN), 1665
þ
(C¼O) cmꢁ1
; MS (EI): m=z (%) ¼ M ꢃ lacking, 422 (30),
1
405 (45), 394 (25), 345 (10), 317 (60), 105 (100); H NMR
(CDCl3): ꢁ ¼ 7.72–7.20 (m, 9 arom H), 6.56 (s, 5-H), 6.14 (s,
8-H), 5.92 (s, 4-H), 3.84 (s, OCH3), 3.79–3.76, 3.68–3.65 (2d,
AB-syst., each J ¼ 12.8 Hz, CH2), 3.40 (s, OCH3), 1.62 (s,
CH3) ppm; 13C NMR (CDCl3): ꢁ ¼ 170.29 (C¼O), 149.81,
147.45, 136.80, 136.05, 132.72, 132.39, 132.34, 132.05,
131.37, 129.30 (2C), 128.72, 127.91 (2C), 124.11, 118.72,
117.45, 116.36, 114.86, 112.59, 110.36, 107.78, 63.36 (C-1),
55.95 (OCH3), 55.71 (OCH3), 39.14 (CH2), 23.86 (CH3) ppm.
þ
a) EI: m=z (%) ¼ M ꢃ lacking, 457 (20), 465 (50), 352 (100),
þ
338 (30), 320 (16), 228 (17), 105 (10); b) CI: 485 (M ꢃþ 1, 2),
1
458 (40), 354 (20), 229 (100), 151 (10), 105 (20); H NMR
2-Benzoyl-1-(2-cyano-4,5-dimethoxybenzyl)-6,7-dimethoxy-
3-methyl-1,2-dihydroisoquinoline-1-carbonitrile
(CDCl3): ꢁ ¼ 7.71 (br s, 2 arom H), 7.55–7.51 (m, 1 arom H),
7.43–7.39 (m, 2 arom H), 6.69–6.67 (d, J ¼ 8.1 Hz, 1 arom H),
6.61 (s, 1 arom H), 6.50 (s, 1 arom H), 6.46–6.41 (m, 2 arom
H), 5.83 (s, 4-H), 3.91, 3.83, 3.73, 3.58 (4s, 4OCH3), 3.50–
3.46, 3.41–3.38 (2d, AB-syst., each J ¼ 12.8Hz, CH2), 1.63 (s,
CH3) ppm; 13C NMR (CDCl3): ꢁ ¼ 170.03 (C¼O), 149.31,
148.34, 148.09, 147.34, 136.27, 132.50, 131.75, 129.18 (2C),
128.61, 128.44, 125.79, 123.36, 122.94, 120.49, 117.78 (CꢅN),
114.00, 111.88, 111.35, 110.43, 107.01, 63.91 (C-1), 55.93,
55.82, 55.75, 55.62 (4OCH3), 41.50 (CH2), 23.80 (CH3) ppm.
(15c, C30H27N3O5)
From 3.0 g (9.0mmol) 5b, 7b 2.56 (10 mmol), CTAB 100 mg
(0.27 mmol), toluene 20 cm3, KOH 6 cm3. Method B: the semi
solid light brown raw product (ca. 5.8g) was treated with
10cm3 hot MeOH affording 3.0 g (64%) yellow solid which
was used for the next step without further purification.
Repeating the treatment with the same solvent gave an analyti-
cal pure product, mp 155–157ꢂC; TLC (n-hexane:CH2Cl2:
MeOH¼ 20:10:1): Rf ¼ 0.30 (edcuct: Rf ¼ 0.50); IR (KBr):
ꢂꢀ¼ 2219 (CꢅN), 1668 (C¼O) cmꢁ1; MS: a) EI: m=z (%) ¼
þ
M ꢃlacking, 482 (50), 465 (50), 377 (100), 105 (50); b) CI: 510 General procedure for the synthesis of the 1-benzyl-3-
þ
(M ꢃþ 1, 40), 483 (100), 379 (50), 333 (15), 229 (5), 105 (45);
methylisoquinolines 18, 19, and 20
1H NMR (CDCl3): ꢁ ¼ 7.67 (br s, 2 arom H), 7.50–7.46 (m, 1
arom H), 7.38–7.34 (m, 2 arom H), 7.18 (s, 1 arom H), 6.73 (s, 1
arom H), 6.57 (s, 5-H), 6.23 (s, 8-H), 5.94 (s, 4-H), 3.93, 3.84,
3.77 (3s, 3OCH3), 3.73–3.69, 3.59–3.56 (2d, AB-syst., J ¼
12.8, 13.3 Hz, CH2), 3.46 (s, OCH3), 1.63 (s, CH3) ppm; 13C
NMR (CDCl3): ꢁ ¼ 170.21 (C¼O), 152.05, 149.81, 148.45,
147.45, 136.03, 132.71, 131.37, 131.00, 129.29 (2C), 128.72
(2C), 124.11, 118.97, 117.82, 116.76 (2CꢅN), 114.33, 113.49,
112.64, 110.27, 107.72, 105.95, 63.38 (C-1), 56.32, 56.17,
55.93, 55.86 (4OCH3), 39.00 (CH2), 23.82 (CH3) ppm.
A mixture of the alkylated Reissert compound 15, 16, or 17,
KOH, and FeSO4 in MeOH- or EtOH=H2O was refluxed for 3 h.
After removing the solids by filtration the solvent was evapo-
rated in vacuo, and the yellow residue was partitioned between
EtOAc and H2O (each 300 cm3). The aqueous layer was sa-
turated with NaCl and extracted again with EtOAc. The com-
bined organic phases were extracted five times with 2 N HCl,
then the combined acidic extracts were rendered alkaline with
2 N NaOH and extracted with 3ꢄ100 cm3 EtOAc. The com-
bined extracts were dried (Na2SO4) and evaporated in vacuo.
2-Benzoyl-1-(2-bromobenzyl)-3-methyl-1,2-dihydroiso-
quinoline-1-carbonitrile (16, C25H19BrN2O)
2-(3-Methyl-isoquinolin-1-ylmethyl)-benzonitrile
(18a, C18H14N2)
From 4.0g (14.6 (mmol) 5a, 13 4.74g (19.0 mmol), CTAB
100 mg (0.27 mmol), toluene 30cm3, KOH 6 cm3. Method B:
the raw product was crystallized from 40cm3 EtOAc and
4 cm3 MeOH. Yield 4.6g (71%), pale yellow crystals;
From 1.0 g (2.6mmol) 15a, KOH 800mg (14.3mmol), FeSO4
500 mg (3.3mmol), MeOH 100 cm3, H2O 5 cm3. The tawny
oily residue (589mg) was used for the next step without
further purification. An analytical pure sample was obtained

Synthesis of 6-methyl-8H-dibenzo[a,g]quinolizin-8-imines
683
by FC (n-hexane:CH2Cl2:MeOH¼ 10:20:1). Yield 520mg
(77%), colorless oil; hydrochloride: mp 259ꢂC; TLC (see
FC): Rf ¼ 0.50 (educt: 0.80); IR (film): ꢂꢀ¼ 2222 (CꢅN)
1H NMR (CDCl3): ꢁ ¼ 7.41, 7.28 (2s, 8-H, 4-H), 7.02, 7.03
(2s, 30-H, 60-H), 6.96 (s, 5-H), 4.69 (s, CH2), 4.04, 3.98, 3.85,
3.74 (4s, 4OCH3), 2.68 (s, CH3) ppm; 13C NMR (CDCl3):
ꢁ ¼ 155.63 (C-1), 152.82, 152.76, 149.76, 149.19, 147.82,
137.84 (C-10), 134.23 (C-4a), 120.79 (C-8a), 119.17 (CꢅN),
117.30 (C-4), 113.35 (C-30), 112.18 (C-60), 104.74 (C-5),
103.53 (C-8), 102.85 (C-20), 56.47, 56.13, 55.96, 55.85
(4OCH3), 39.43 (CH2), 24.20 (CH3) ppm.
þ
þ
cmꢁ1
; MS (EI): m=z (%) ¼ 258 (M ꢃ, 30), 257 (M ꢃꢁ 1,
1
100), 232 (5), 195 (10), 167 (9), 149 (15), 115 (9); H NMR
(CDCl3): ꢁ ¼ 8.00 (d, J ¼ 8.6 Hz, 8-H), 7.74–7.57 (3m, each
1H), 7.48–7.23 (3m, 2 þ 1 þ 1H), 7.10 (d, J ¼ 8.6 Hz, 1H),
4.86 (s, CH2), 2.69 (s, CH3) ppm; 13C NMR (CDCl3):
ꢁ ¼ 157.33, 150.66, 143.27, 137.31, 132.72 (2C), 130.05,
129.53, 126.86, 126.77, 126.66, 126.57, 125.24, 118.27
(2C), 112.42, 39.70 (CH2), 24.23 (CH3) ppm.
1-(2-Bromobenzyl)-3-methyl-isoquinoline (19, C17H14BrN)
From 720 mg (1.62 mmol) 16, KOH 520mg (9.3mmol),
FeSO4 320 mg (2.1mmol), EtOH 70 cm3, H2O 3 cm3. The
yellow oily residue (482 mg) was purified by FC (n-
hexane:CH2Cl2: MeOH ¼ 10:20:1). Yield 387 mg (77%), pale
yellow oil; HCl: mp 139–141ꢂC; TLC (see FC): Rf ¼ 0.60
(educt: 0.80); IR (film): ꢂꢀ¼ 1024 (C–Br) cmꢁ1; MS (CI): m=z
2-(6,7-Dimethoxy-3-methylisoquinolin-1-ylmethyl)-benzo-
nitrile (18b, C18H20N2O2)
A) From 2.48g (5.5mmol) 15b, KOH 2 g (35.7 mmol), FeSO4
1.25g (8.2mmol), MeOH 250 cm3, H2O 13 cm3. During the
acidic extraction 18b ꢃ HCl separated. Therefore the aqueous
suspension was separated, rendered alkaline, and extracted
with EtOAc. The organic extracts were evaporated in vacuo
and the light brown residue smelling according as vanillin was
crystallized from 20 cm3 MeOH. Yield 892 mg (51%), color-
less crystals; mp 154–156ꢂC; 18b ꢃ HCl: mp 219–221ꢂC; TLC
(n-hexane:CH2Cl2:MeOH¼ 20:10:1): Rf ¼ 0.50 (educt: 0.80);
IR (KBr): ꢂꢀ¼ 2222 (CꢅN) cmꢁ1; MS (EI): m=z (%) ¼ 318
þ
(%) ¼ 314=312 (M ꢃþ 1, 100), 232 (20), 117 (20), 91 (42);
1H NMR (CDCl3): ꢁ ¼ 7.83 (d, J ¼ 8.5Hz, 1 arom H), 7.64 (d,
J ¼ 7.9Hz, 1 arom H), 7.52–7.47, 7.34–7.29, 6.96–6.91 (3m,
each 2 arom H), 6.67–6.65 (m, 1 arom H), 4.65 (s, CH2), 2.62
(s, CH3) ppm; 13C NMR (CDCl3): ꢁ ¼ 157.01 (C-1), 149.02
(C-3), 137.61 (C-4a), 135.76, 131.13, 128.59, 128.53, 126.38,
125.93, 125.35 (C-5), 125.06 (C-7), 124.37 (C-8), 124.13 (C-
8a), 122.99, 116.77 (C-4), 41.48 (CH2), 24.03 (CH3) ppm.
1
þ
(M ꢃ, 70), 317 (100), 303 (53), 259 (20), 135 (10); H NMR
1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3-methyl-
(CDCl3): ꢁ ¼ 7.67–7.65 (m, 1 arom H), 7.41–7.24 (m, 5 arom
H), 6.96 (s, 5-H), 4.78 (s, CH2), 3.98, 3.96 (2s, 2OCH3), 2.67
(s, CH3) ppm; 13C NMR (CDCl3): ꢁ ¼ 155.16 (C-1), 152.69
(C-6), 149.69 (C-3), 149.41 (C-7), 143.34, 134.23 (C-4a),
132.88, 132.50, 129.77, 126.88, 120.83 (C-8a), 118.54
(CꢅN), 117.37, 112.07, 104.77 (C-5), 103.40 (C-8), 56.27
(OCH3), 55.98 (OCH3), 39.92, 24.16 (CH3) ppm.
isoquinoline (3-Methylpapaverine 20)
From 100 mg (0.2 mmol) 17, KOH 80mg (1.4mmol), FeSO4
50mg (0.3mmol), EtOH 10cm3, H2O 0.5 cm3, refluxing time:
1 h. The residue was crystallized from 0.5cm3 EtOH. Yield
51mg (72%), colorless crystals; mp 132–134ꢂC (Ref. [30]:
136ꢂC); TLC (CH2Cl2:MeOH¼ 20:1): Rf ¼ 0.40 (educt: Rf ¼
þ
0.70); MS (EI): m=z (%) ¼ 353 (M ꢃ, 60), 338 (100), 322
B) From 21b (see below): 42mg (0.12 mmol) 21b were
heated to 200ꢂC under N2 for 1 min. From ca. 180ꢂC decol-
oration of the educt began. After cooling to ambient tempera-
ture the solid was treated with a mixture of EtOAc and 2 N
NaOH (each 10 cm3). The organic layer was separated,
washed with brine, and dried with Na2SO4. After evaporating
the solvent in vacuo, the residue was purified by FC (eluent
see TLC under A). Mp, TLC and the spectroscopic data were
identical to those given under A.
(20); 1H NMR (CDCl3): ꢁ ¼ 7.27 (s, 8-H), 7.26 (s, 4-H),
6.95 (s, 5-H), 6.84–6.73 (m, 3 arom H), 4.51 (s, CH2), 3.97,
3.86, 3.81, 3.77 (4s, 4OCH3), 2.67 (s, CH3) ppm; 13C NMR
(CDCl3): ꢁ ¼ 157.24 (C-1), 152.43 (C-6), 149.29 (C-7),
149.07 (C-3), 148.94 (C-30), 147.44 (C-40), 134.23 (C-4a),
132.42 (C-10), 120.88 (C-8a), 120.43 (C-60), 116.93 (C-4),
111.87 (C-20), 111.12 (C-50), 104.70 (C-5), 104.30 (C-8),
55.91, 55.83, 55.78 (4OCH3), 42.32 (CH2), 24.21 (CH3) ppm.
General procedure for the synthesis of the dibenzoquinolizine
derivatives 21
2-(6,7-Dimethoxy-3-methylisoquinolin-1-ylmethyl)-4,5-
dimethoxybenzonitrile (18c, C22H22N2O4)
To a solution of 1.38g (2.7 mmol) 15c in 10 cm3 DMF was
added dropwise 2.8 cm3 Triton B (40% benzyltrimethylammo-
nium hydroxide in MeOH). After stirring for 15h at ambient
temperatur the red brown suspension formed was diluted with
300 cm3 EtOAc and 500 cm3 H2O. The yellow organic layer
was extracted with 1 dm3, thereafter with 2ꢄ200 cm3 2 N
HCl. The combined acidic phases were rendered alkaline with
solid Na2CO3 and extracted with 3ꢄ200 cm3 EtOAc. After
washing with brine and drying (Na2SO4) the organic extracts
were evaporated in vacuo affording 1.3 g beige orange solid,
which was recrystallized from 8 cm3 EtOAc. Crystallization of
the residue of the mother liquor gave additional substance.
Total yield: 752 mg (74%), pale yellow, fine needles; mp
169–171ꢂC; TLC (CH2Cl2:MeOH¼ 20:1): Rf ¼ 0.60 (educt:
Rf ¼ 0.90); IR (KBr): ꢂꢀ¼ 2214 (CꢅN) cmꢁ1; MS (EI): m=z
To a solution of the cyanobenzylisoquinoline 18 in anhydrous
THF cooled by an ice bath was added a 1.6 M solution of
methylmagnesiumbromide in Et2O. Stirring and cooling was
continued for 1 h, then further MeMgBr was added. The dark
red solution was allowed to warm up to ambient temperature
and stirred for additional 15h. The mixture was diluted with
MeOH, followed by 2 N HCl causing a deep yellow precipi-
tate, which was filtered off and consecutively washed with
acetone, H2O, acetone, and CHCl3 and dried in vacuo.
8-Amino-6-methyldibenzo[a,g]quinoliziniumchloride
(21a, C18H15ClN2)
From 100mg (0.38 mmol) 18a, THF 5 cm3, CH3MgBr
0.2=0.4 cm3 (0.32=0.64mmol), MeOH 1 cm3, HCl 10cm3.
Yield 54mg (47%), deep yellow, amorphous solid; mr from
192ꢂC (decompn.), 264–266ꢂC (decompn., from MeOH,
þ
þ
(%) ¼ 378 (M ꢃ, 90), 377 (M ꢃꢁ 1, 100), 363 (50), 347 (20);

684
E. Reimann et al.
þ
several months); MS (EI): m=z (%) ¼ 258 (M ꢃ, 100), 257
153.23, 152.35, 138.09 (C-13a), 135.49 (C-4a), 133.18 (C-6),
126.33 (C-5), 125.47 (C-12a), 122.10 (C-13b), 113.38 (C-12),
110.25 (C-8a), 108.37 (C-9), 107.54 (C-1), 104.47 (C-4),
58.17, 57.91, 57.75, 57.51 (4CO3), 22.50 (CH3) ppm.
1
þ
(M ꢃꢁ 1, 93), 232 (15), 149 (10), 128 (12), 115 (10); H
NMR (F3CCO2D): ꢁ ¼ 8.48–8.46, 8.35 (2m, 9-H, 1-H),
8.12–8.09 (m, 2H, 11-H, 12-H), 7.92–7.91 (m, 10-H), 7.72–
7.67 (m, 3 arom H), 7.20 (s, 5-H), 2.81 (s, CH3) ppm; 13C
NMR (F3CCO2D): ꢁ ¼ 156.31 (C¼N), 138.97 (C-13a), 137.83
(C-11), 137.69 (C-4a), 133.84 (C-6), 133.80, 132.32, 132.03
(C-10), 130.73, 130.22, 129.58, 127.93 (C-12a), 126.84,
125.95 (C-1), 125.55 (C-9), 119.23 (C-8a), 22.55 (CH3)
ppm. Free base of 21a (C18H14N2): 230 mg (0.78 mmol) of
the salt was stirred in a mixture of 2 N NaOH and CHCl3.
After usual workup the crude product was purified by FC
(EtOAc:n-hexane:MeOH¼ 4:1:0.1). Yield 96 mg (47%), semi-
References
1. Schneider W, Schroeter K (1920) Ber Dtsch Chem Ges
53:1459
2. Awe W (1936) Pharmaz Zentralhalle Deutschland 77:157
3. Ihmels H, Salbach A (2006) Photochem Photobiol
82:1572 and further lit. cited herein
4. Wiegrebe W, Pohl L (1965) Z Naturforsch 20b:1032
5. Wiegrebe W, Sasse D, Reinhart H, Faber L (1970)
Z Naturforsch 25b:1408
6. Zee-Cheng KY, Paull KD, Cheng CC (1974) J Med Chem
17:347
7. Reimann E, Renz H (1993) Arch Pharm (Weinheim)
326:253
8. Luff BDW, Perkin WH, Robinson R (1910) J Chem Soc:
1131
9. McEwen WE, Cobb RL (1955) Chem Rev 55:511
10. Gibson HW (1970) J Heterocyclic Chem 7:1169
11. Wolf AP, McEwen WE, Glazier RH (1956) J Am Chem
Soc 78:861
¨
¨
12. Reimann E, Hoglmuller A (1985) Arch Pharm (Weinheim)
318:487
þ
solid yellow compound. MS (EI): m=z (%) ¼ 258 (M ꢃ, 100),
1
257 (70), 243 (14), 232 (15); H NMR (CDCl3): ꢁ ¼ 7.84 (d,
J ¼ 8.1 Hz, 9-H), 7.80 (d, J ¼ 7.7 Hz, 1-H), 7.50 (m, 1 arom
H), 7.44 (d, J ¼ 7.5 Hz, 12-H), 7.39–7.29 (m, 3 arom H), 7.24
(d, J ¼ 7.6 Hz, 4-H), 6.78 (s, 13-H), 6.14 (s, 5-H), 2.42 (s,
CH3) ppm; 13C NMR (CDCl3): ꢁ ¼ 159.69 (C¼N), 137.97
(C-4a), 136.26, 133.47 (C-6), 131.05, 130.65, 129.30,
127.01, 126.85, 125.75, 125.44 (C-12), 125.35, 125.18 (C-
4), 124.36 (C-9), 123.18 (C-1), 113.14 (C-5), 97.34 (C-13),
21.14 (CH3) ppm. Bromide (C18H15BrN2): Gaseous HBr was
passed into a solution of the above base in acetone. The
crystalline product was filtered off and dried. Mr: 244–260
(decompn.); UV (c ¼ 5.896ꢄ10ꢁ5 mol dmꢁ3, MeOH): lmax
("ꢄ10ꢁ3) ¼ 407 (11.00), 381 (10.50) nm (molꢁ1 dm3 cm).
13. Reimann E, Benend H (1992) Monatsh Chem 123:939
14. Awe W, Halpaap H, Hertel O (1960) Arzneim Forsch=
Drug Res 10:936
8-Amino-2,3-dimethoxy-6-methyldibenzo[a,g]-
quinoliziniumchloride (21b, C20H19ClN2O2)
From 500 mg (2.4mmol) 18b, THF 30cm3, CH3MgBr 1.5=
1.5 cm3 (2.4=2.4 mmol), MeOH 5 cm3, HCl 30cm3. Yield
380 mg (69%), yellow amorphous solid, from ca. 180ꢂC
up to 200ꢂC converting to colorless needles; mr 218–230ꢂC
(decompn.); UV (c ¼ 5.636ꢄ10ꢁ5 mol dmꢁ3, MeOH): lmax
("ꢄ10ꢁ3) ¼ 428 (11.75), 394 (13.49), 290 (28.18), 276–270
15. O’Brien JE, McMurry TBH, O’Callaghan CN (1998) J
Chem Res (S):448
16. Reduced peak of C2 in the 13C NMR spectrum of thia-
mine hydrochloride in D2O: Adeyemo A, Shamim A,
Turner A (1984) Inorgan Chim Acta 91:L23; see also:
http:==riodb.ibase.aist.go.jp, Spectral Database for Or-
ganic Compounds, spectrum No. 1619
3
þ
(30.20) nm (þmolꢁ1
dm cm); MS (EI): m=z (%) ¼ 318 (M ꢃ,
1
80), 317 (M ꢃꢁ 1, 100), 303 (60), 259 (20), 169 (16); H
17. Katritzky AR, Wang Z, Wang M, Wilkerson CR, Hall CD,
Akhmedov NG (2004) J Org Chem 69:6617
18. Zee-Cheng KY, Cheng CC (1972) J Pharm Sci 61:969
19. Tripathi AN, Chauhan L, Thankachan PP, Barthwal R
(2007) Magn Reson Chem 45:647
20. v. Angerer E, Wiegrebe W (1979) Arch Pharm (Weinheim)
312:385
21. Kido K, Watanabe Y (1987) Chem Pharm Bull 35:4964
22. Abraham RJ, Reid M (2002) J Chem Soc Perkin Trans
2:1081
NMR (F3CCO2D): ꢁ ¼ 8.45 (d, J ¼ 8.6 Hz, 9-H), 8.14–8.05
(m, 2H, 11-H=12-H), 7.89–7.86 (m, 2H, 1-H=10-H), 7.21 (s,
2H, 5-H=4-H), 4.21, 4.13 (2s, 2OCH3), 2.83 (s, CH3) ppm;
13C NMR (F3CCO2D): ꢁ ¼ 156.20, 154.25, 152.74, 138.69
(C-13a), 137.82 (C-4a), 137.68 (C-11), 133.35 (C-6), 131.73
(C-10), 130.2 (C-12), 126.63 (C-5), 126.23, 125.39, 121.26,
118.64 (C-8a), 110.77 (C-4), 108.20 (C-1), 58.19 (OCH3),
57.91 (OCH3), 22.63 (CH3) ppm.
8-Amino-2,3,10,11-tetramethoxy-6-methyldibenzo[a,g]-
quinoliziniumchloride (21c, C22H23ClN2O4)
23. Su J-A, Siew E, Brown EV, Smith SL (1977) Org Magn
Reson 10:122
From 100 mg (0.26 mmol) 18c, THF 5 cm3, CH3MgBr
0.2=0.4 cm3 (0.32=0.64 mmol), MeOH 1 cm3, HCl 10cm3.
Yield 7 mg (7%), yellow solid; mr 202–207ꢂC (decompn.);
UV (c ¼ 4.821ꢄ10ꢁ5 mol dmꢁ3, MeOH): lmax ("ꢄ10ꢁ3) ¼
434 (9.12), 389 (8.51), 312 (29.51), 290 (29.51) nm
24. Elliott IW (1955) J Am Chem Soc 77:4408
25. Uff BC, Kershaw JR, Chhabra SR (1974) J Chem Soc
Perkin Trans 1:1146
26. Boyer JH, Morgan LR Jr (1961) J Org Chem 26:1654
27. Brieskorn CH, Mosandl A (1973) Arch Pharm (Wein-
heim) 306:164
28. Davis FA, Mohanty P (2002) J Org Chem 67:1290
29. Hung TV, Mooney BA, Prager RH (1981) Austr J Chem
34:151
3
þ
(molꢁ1
dm cm); MS (CI): m=z (%) ¼ 378 (M ꢃ, 100), 363
1
(22), 149 (6); H NMR (F3CCO2D): ꢁ ¼ 7.60, 7.51, 7.21 (3s,
each 1H, 9-H, 1-H, 5-H), 6.95, 6.93 (2s, each 1H, 4-H, 12-H),
3.96 (s, 2OCH3), 3.92, 3.86 (2s, 2OCH3), 2.54 (s, CH3) ppm;
13C NMR (F3CCO2D): ꢁ ¼ 158.13 (C¼N), 153.79, 153.68,
30. Dobrowsky A (1951) Monatsh Chem 82:122