Synthesis of 1-substituted 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10- diones

Article abstract of DOI:10.1039/c0ob00391c

1,2-Disubstituted 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-diones are prepared for the first time through an activated Pictet-Spengler reaction of the corresponding imines of 2-(1,4-dimethoxynaphth-2-yl)ethylamine in the presence of an acyl chloride and AlCl₃ followed by an oxidation with silver(ii) oxide in nitric acid. Depending on the reaction conditions the N-trichloroacetyl protecting group could be cleaved off, converted to an N-methoxycarbonyl group or transformed to an N-(2-oxoacetamide) moiety. The synthesized 1,2-disubstituted 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-diones constitute a new class of quinones, which has not been reported yet.

Full text of DOI:10.1039/c0ob00391c

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PAPER
Synthesis of 1-substituted 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-diones†
Ekaterina Shinkevich,a Jurgen Deblander,a Sandra Matthijs,b Jan Jacobs,c Norbert De Kimpec and
Kourosch Abbaspour Tehrani*a,d
Received 6th July 2010, Accepted 15th September 2010
DOI: 10.1039/c0ob00391c
1,2-Disubstituted 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-diones are prepared for the first time
through an activated Pictet–Spengler reaction of the corresponding imines of 2-(1,4-dimethoxyna-
phth-2-yl)ethylamine in the presence of an acyl chloride and AlCl3 followed by an oxidation with
silver(II) oxide in nitric acid . Depending on the reaction conditions the N-trichloroacetyl protecting
group could be cleaved off, converted to an N-methoxycarbonyl group or transformed to an
N-(2-oxoacetamide) moiety. The synthesized 1,2-disubstituted 1,2,3,4-tetrahydrobenz[g]isoquinoline-
5,10-diones constitute a new class of quinones, which has not been reported yet.
Introduction
Tetrahydroisoquinoline alkaloids have received much interest be-
cause of their tremendous structural diversity and broad spectrum
of biological and pharmaceutical activities.1 The most popular
synthetic approaches towards isoquinolines are the Bischler–
Napieralski reaction,2 the Pomeranz–Fritsch reaction followed
by reduction,3 and the Pictet–Spengler reaction,4 which often
require electron-donating groups at the benzene ring for successful
ring closure. On the other hand, quinones with annelated N-
heterocycles constitute an important research area in organic
synthesis due to the pronounced biological activities of several
natural products. In recent decades, a whole range of antibi-
Fig. 1
otics belonging to this family have been isolated. For instance,
lemonomycin 1, which was isolated from the fermentation broth
of Streptomyces candidus (LL-AP191)5,6 exhibited potent antibi-
otic activities against methicillin-resistant Staphylococcus aureus
(MRSA), Bacillus subtilis, and vancomycin-resistant Enterococcus
faecium (VREF) (Fig. 1).7 The renieramycins, saframycins 2 and
naphthyridinomycins are structurally related tetrahydroisoquino-
lines, and include potent cytotoxic agents that display a range of
antitumor activities, antimicrobial activity, and other biological
properties (Fig. 1).8
Considering these interesting biological activities, the
synthesis of 1-substituted 1,2,3,4-tetrahydrobenz[g]isoquinoline-
5,10-diones was envisaged as
a continuation of previous
work in which an entry towards 2-substituted 1,2,3,4-tetra-
hydrobenz[g]isoquinoline-5,10-diones was developed.9 Although
several 1-substituted 1,2,3,4-tetrahydroisoquinolines have
been synthesized, the synthesis of 1-substituted 1,2,3,4-
tetrahydrobenz[g]isoquinoline-5,10-diones has been reported
only once to the best of our knowledge.10 In this patent,
the reaction of 1,2,3,4-tetrahydroisoquinoline-5,8-diones with
Brassard dienes is described. Haloacyl 1-substituted 1,2,3,4-
tetrahydroisoquinolines have been found useful as antidotes for
protecting crop plants from herbicide injury.11
Because of the availability of the previously reported 2-(1,4-
dimethoxynaphth-2-yl)ethylamine,9 a strategy for the synthesis of
1-substituted 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-diones 3
was deployed based on the N-acyl-Pictet–Spengler reaction of
the corresponding aldimine derived from 5, followed by oxidative
demethylation of the ring closed product 4 (Fig. 2).
aLaboratory of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2,
B-1050, Brussels, Belgium
bInstitut en Recherches Microbiologiques – Wiame, Campus du CERIA, 1
avenue Emile Gryson, baˆt 4B, B-1070, Brussels, Belgium
cDepartment of Organic Chemistry, Faculty of Bioscience Engineering, Ghent
University, Coupure Links 653, B-9000, Ghent, Belgium
dOrganic Synthesis, Faculty of Sciences, University of Antwerp, Groe-
nenborgerlaan 171, B-2020, Antwerp, Belgium. E-mail: Kourosch.
abbaspourtehrani@ua.ac.be; Fax: +32 32653233; Tel: +32 32653226
† Electronic supplementary information (ESI) available: Copies of 1H
NMR and 13C NMR spectra for compounds 7c, 7d, 9, 12a–e, 13a, 14,
15, 21, 22, 23a–c, 24b, 25–27, 31 and 33; UPLC chromatograms for 13a,
14, 21, 22, 12c, 23a, 23b, 25, 26. See DOI: 10.1039/c0ob00391c
538 | Org. Biomol. Chem., 2011, 9, 538–548
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Fig. 2
Scheme 2 Synthesis of imine 10. Reagents and conditions: (i) 0.9 equiv.
2-(diphenylmethyleneamino)acetonitrile, 6.4 equiv. NaOH (2.5 M), 0.05
equiv. TEBA, CH2Cl2, rt, 24 h; (ii) 1 equiv. HCl (1 M), THF, rt, 16 h; (iii)
1 equiv. ArCHO, 3.3 equiv. MgSO4 (anhyd.), CH2Cl2, reflux, 4 h.
Results and discussion
The Pictet–Spengler reaction generally involves the cyclization of
imines or iminium ions formed by the dehydration reaction of
b-arylethyl amine derivatives with aldehydes.4 The electrophilicity
of the imine is of prime importance for the formation of the ring
closed product and can be enhanced by protonation of the imine by
means of strong Brønsted acids. But despite its wide application,
this strategy is not suitable for acid-labile functional groups. The
second strategy to enhance the electrophilic nature of the iminium
intermediate is the application of the more electrophilic N-
substituted iminium species such as N-acyliminium derivatives.12
For this purpose the imines 7a–d were prepared via condensation
of amine 59 with aldehydes in dichloromethane under reflux in the
presence of MgSO4 (Scheme 1). In order to achieve a complete
conversion of the b-naphthylethyl amine 5 to its corresponding
imines 7 an excess of the volatile aldehydes pivaldehyde (6c) and
isobutyraldehyde (6d) were used. In case of the reaction of 5 with
non-volatile aromatic aldehydes 6a and 6b only one equivalent of
the latter were added, giving rise to a 81–86% yield (1H NMR).
The addition of 2 equivalents of 6a did not lead to any substantial
increase of the yield, but caused purification problems of the
imine 7a.
dichloroethane, CH2Cl2) was evaluated. The best yield of com-
pound 12a was obtained by reaction of 7a with trichloroacetyl
chloride in 1,2-dichloroethane in the presence of AlCl3 (Scheme 3).
In all cases, after workup of the reaction mixture, partial hydrolysis
of the unreacted N-(trichloroacetyl)iminium ion intermediate 11a
was observed. Depending on the Lewis acid, solvent and the
reaction conditions the ratio of 6a/12a/13a varied from 85/0/15
to 30/65/5 (HPLC). Similar iminium ion hydrolyses in Pictet–
Spengler reactions using metal chloride Lewis acids have been
reported.12g Metal triflates, instead, have been reported to avoid
this side reaction12g but neither the use of Sc(OTf)3 nor AgOTf
led to better 12a/13a ratios. Fortunately, the N-trichloroacetyl
amide 13a could be separated from the ring-closed compound
and benzaldehyde by means of flash chromatography. In order to
confirm the structure of 13a, this compound was synthesized in
57% yield by reaction of 2-(1,4-dimethoxynaphth-2-yl)ethylamine
(5) with trichloroacetyl chloride (1.02 equiv.) in pyridine at room
temperature for 2 h.
Scheme 1 Synthesis of imines 7a–d. Reagents and conditions: (i) 1 equiv.
R1CHO (6a,b) or 2 equiv. R1CHO (6c,d), 3.3 equiv. MgSO4 (anhyd.),
CH2Cl2, reflux, 4 h (6a,b) or 2 h (6c,d).
2-Amino-3-(1,4-dimethoxynaphthalen-2-yl)propanenitrile (9)
Scheme 3 Cyclization of imine 7a in the presence of CCl3COCl. Reagents
and conditions: (i) 1.1 equiv. CCl3COCl, 1,2-dichloroethane, rt, 0.5 h; (ii) 1
equiv. AlCl3, reflux, 3 h.
was synthesized according to
a slightly modified litera-
ture procedure13 by alkylation of 2-(diphenylmethyleneamino)-
acetonitrile with 2-(bromomethyl)-1,4-dimethoxynapthalene (8)14
under phase-transfer conditions, followed by hydrochloric acid
hydrolysis of the intermediate alkylated imine. The correspond-
ing imine of 9 and 4-chlorobenzaldehyde was prepared in
dichloromethane under reflux in the presence of MgSO4 (yield
60%, Scheme 2). Apart from unreacted 4-chlorobenzaldehyde no
other products were detected in the crude reaction mixture, which
could not be further purified and hence was used as such in the
following step.
Remarkably, in the absence of any Lewis acid or in the
presence of a weak Lewis acid like BF3·Et2O, the formation of
the ring-closed compound 12a was not observed. Instead, after
chromatography of the black tarry reaction mixture, the angular
derivative 14 and the acyclic trichloroacetamide 13a could be
isolated in 35% and 9% yield, respectively (Scheme 4).
The structure of compound 14 was established on the basis of
1
spectroscopic data. At room temperature the H and 13C NMR
In a preliminary study, the cyclization of imine 7a in the
presence of acetyl, chloroacetyl, dichloroacetyl or trichloroacetyl
chloride and a wide variety of Lewis acids (AlCl3, SnCl4, SbCl5,
TiCl4, BF3·Et2O, BF3·THF, AgOTf, Sc(OTf)3) and solvents (1,2-
spectra of this compound contained two sets of signals, due to
constrained rotation of the trichloroacetyl group. A variable-
temperature NMR investigation was made to simplify the NMR
spectra, and coalescence of signals was observed at 50 ◦C.
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methoxynaphthalen-2-yl)hydrazones has been reported to give
rise to benzo[e]indoles,17 and the treatment of 1-(2-(1-(1,4-
dimethoxynaphthalen-2-yl)ethyl)phenyl)ethanol with pTsOH also
led to an ipso-type displacement of methoxide.18 The oxidative
demethylation of 14 using cerium(IV) ammonium nitrate (CAN)
in aqueous acetonitrile afforded compound 15 in 62% yield
(Scheme 4). No rotameric phenomenon was observed in this case.
The reaction of enolizable imine 7d with acetyl chloride in the
absence of a Lewis acid resulted in the formation of enamide 21,
which could not be cyclized successfully (Scheme 6). Treatment
of the N-(arylidene)-1-cyano-2-naphthylethylamine 10 (Ar = 4-
ClC6H4) with acetyl chloride in the presence of the strongly
Lewis-acidic AlCl3 did not result in a ring-closed product, but
instead an acyclic enamide 22 was isolated in 22% yield after flash
chromatography.
Scheme 4 Synthesis and transformations of compound 14. Reagents and
conditions: (i) 1.1 equiv. CCl3COCl, 1,2-dichloroethane, rt, 0.5 h, then
reflux, 3 h; (ii) 3.3 equiv. CAN, MeOH/H2O (10/1), rt, 2 h; (iii) 10 equiv.
NaOH, MeOH/H2O (10/1), rt, 16 h.
This unexpected result occurs because of ipso-type elec-
trophilic attack of the N-acyliminium cation 11a to the car-
bon bearing the 1-methoxy group to form the resonance-
stabilized 17. This cation further stabilizes itself by loss of
methanol and addition of chloride to the adjacent carbon to
produce the angular tetrahydrobenzo[h]isoquinoline 14. Based
on the NMR analysis only one diastereomer is formed, and
in view of the proposed mechanism the relative configura-
tion of the heterocyclic substituents is assigned as trans. Un-
der the present conditions an eventual epimerization of cis-
substituted tetrahydrobenzo[h]isoquinoline 20 via an intermediate
carbenium ion 19 cannot be excluded (Scheme 5).15 Similar
ipso-cyclizations with a displacement of a methoxy group on
carbon have only been rarely reported. Upon Bischler–Napieralski
reaction of (1,4-dimethoxynaphthalen-2-yl)ethylamides, in ad-
dition to the classical cyclization the formation of an angu-
lar derivative was observed, but this was not isolated pure
or characterized.16 Furthermore, the Fischer cyclisation of (1-
Scheme 6 Transformations of imines 7d and 10. Reagents and conditions:
(i) 1.1 equiv. CH3COCl, 1,2-dichloroethane, rt, 0.5 h, then reflux, 3 h; (ii)
1.1 equiv. CH3COCl, 1,2-dichloroethane, 0.04 equiv. KI, rt, 0.5 h; (iii) 1
equiv. AlCl3, reflux, 3 h.
In view of the above-mentioned results, Pictet–Spengler reac-
tions were limited to non-enolizable imines and to the use of
AlCl3 as Lewis acid. To avoid the formation of the side product
13a and to improve the yield, the reaction procedure was further
optimized by adding molecular sieves and a catalytic amount of
potassium iodide19 under argon atmosphere. Under these reaction
conditions N-acyl-1,2,3,4-tetrahydrobenz[g]isoquinolines 12a–e
were obtained in moderate yields after flash chromatography
(Scheme 7). The NMR spectra of the N-trichloroacetyl derivatives
12a–c showed one set of signals while the signals in the NMR spec-
tra of N-acetyl derivatives 12d and 12e were doubled. Presumably
rotamers of the N-acetyl tetrahydrobenz[g]isoquinolines 12d and
12e exist in solution because of hindered rotation of the amide C–
N bond. In order to simplify the 1H NMR spectrum, compound
12e was heated in an NMR tube in DMSO-d6 to 75 ◦C but no
Scheme 7 Synthesis of compounds 12a–e. Reagents and conditions: (i) 1.1
equiv. R2COCl, 1,2-dichloroethane, 0.04 equiv. KI, rt, 0.5 h; (ii) 1 equiv.
AlCl3, reflux, 3 h.
Scheme 5
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coalescence could be effected. Nevertheless, the composition of
compound 12e was confirmed by elemental analysis.
the COOMe singlets were reduced to two singlets (38/62 ratio).
A possible explanation for the latter doubling may be a slow
pyramidal inversion at nitrogen or rotamerism across the O C–
OMe single bond. For comparison, a detailed investigation of
the amide rotamers of N-acetyl-5-benzyloxy-6,8-dimethoxy-1,3-
trans-dimethyl-1,2,3,4-tetrahydroisoquinoline in toluene-d8 re-
vealed a convergence of the 1H NMR signals at 57 ◦C.23
The oxidative demethylation of 12e with CAN in aqueous
acetonitrile gave rise to inseparable reaction mixtures. Analogous
unselective oxidations of N-protected 5,10-dimethoxy-1,2,3,4-
tetrahydrobenz[g]isoquinolines with CAN were observed earlier
within our departments.9 The oxidation of compounds 12a–c to
the corresponding quinones could be successfully accomplished by
means of silver(II) oxide in 1,4-dioxane in the presence of nitric acid
(6 M) as a co-oxidant (Scheme 8). In contrast with N-alkyl-1,2,3,4-
tetrahydrobenz[g]isoquinoline-5,10-diones, which were not
air-stable, these N-acyl-1,2,3,4-tetrahydrobenz[g]isoquinoline-
5,10-diones 23a–c could be stored at room temperature under
air atmosphere without any noticeable degradation.9 Of course,
the electron-withdrawing trichloroacetyl group prevents these
unsaturated heterocycles oxidizing.
Most likely, the transformation of trichloroacetamide into
the methylcarbamate occurs via a haloform-like displacement of
the trichloromethyl group by methoxide. The intermediacy of a
[R2N
C
O]+ cation, formed by base-induced b-elimination of
chloroform (as has been reported for the reaction of secondary
trichloroacetamides in basic medium with alcohols in the presence
of CuCl and Bu4NCl22) is less likely. The treatment of the
angular N-trichloroacetyl tetrahydrobenz[h]isoquinoline 14 with
NaOH in methanol also led to a N-methoxycarbonyl-protected
analogue 16 (Scheme 4). Unfortunately, this compoundcompletely
decomposed upon standing at room temperature.
The oxidation of compound 25 to the targeted quinone deriva-
tive 26 was accomplished by silver(II) oxide in the presence of nitric
acid. Also in this case, the COO◦Me protons displayed doubling
1
in the H NMR spectrum at 25 C. Variable-temperature NMR
experiments brought about coalescence of these signals at 50 ◦C,
and more interestingly, extra doubling of the COOMe NMR
signals into four singlets occurred at -30 C, as was the case for
compound 25 at room temperature.
Scheme 8 Oxidation of compounds 12a–c. Reagents and conditions: (i)
◦
4 equiv. AgO, dioxane, 6 M HNO3, 50 ◦C, 16 h.
Since trichloroacetamides can be deprotected under acidic hy-
drolytic conditions,20–22 1,2,3,4-tetrahydrobenz[g]isoquinoline 12b
was refluxed with 12 M HCl in methanol. After 8 h the reaction
mixture was worked up, showing a 57% conversion of 12b (1H
NMR) to a demethylated compound. After flash chromatography
of the black tarry residue a 10% yield of the aromatized 2-
azaanthraquinone 24b was obtained (Scheme 9).
A reported one-pot synthesis of ureas by reaction of N-
monosubstituted trichloroacetamides with morpholine,24 or the
analogous reactions of trichloroacetamides with carboxamides
to form N-acylureas,25 inspired us to examine the reaction of
12c with an excess of propylamine. Instead of the expected
propyl urea derivative and in contrast with the literature, the 2-
oxoacetamide 27 was isolated in good yield (Scheme 11). The
presence of the extra carbonyl function was confirmed by HRMS
and 13C NMR spectroscopy. The mechanism of this conversion
may be interpreted as a Favorskii-type rearrangement, as reported
for a comparable reaction of trichloromethanesulfinamides with
Scheme 9 Deprotection of compound 12b. Reagents and conditions:
(i) HCl 12 M, MeOH, reflux, 8 h.
The synthetic utility of the trichloroacetyl group was further
explored by a reaction of compound 12a with NaOH in aqueous
methanol. Quite unexpectedly, instead of the N-deprotected
compound, the product 25 of a haloform-type reaction was
1
obtained in 71% yield (Scheme 10). In the H NMR spectra of
compound 25 at room temperature two sets of signals appeared,
and the MeO-signal of the carboxylic ester even appeared as
four singlets in a 19/25/31/25 ratio. The singlets of H-1 of
these presumable carbamate rotamers merged at 50 ◦C while
Scheme 10 Transformations of compound 12a. Reagents and conditions:
(i) 3 equiv. NaOH, MeOH/H2O (10/1), reflux, 0.5 h; (ii) 4 equiv. AgO,
dioxane, 6 M HNO3, 50 ◦C, 16 h.
Scheme 11 Transformations of compound 12c. Reagents and conditions:
(i) excess PrNH2, 50 ◦C, 21 h; (ii) 4 equiv. AgO, dioxane, 6 M HNO3, 50 ◦C,
16 h.
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morpholine in the presence of triethylamine.26 This mechanism
involves the formation of a three-membered cyclic intermediate
28, with subsequent attack of propylamine on the carbonyl
carbon atom, followed by ring-opening and hydrolysis of the
CCl2 moiety to give the observed product 27. The spectroscopic
analysis of compound 27 was hampered because of rotamerism
in solution (25 ◦C). Unfortunately, variable-temperature NMR
could not induce any coalescence at 45 ◦C. The corresponding
quinone derivative 31 was obtained in 63% yield by the standard
silver(II) oxide oxidation. The NMR spectra of this compound also
displayed double sets of signals due to restricted rotation across
the amide bond.
Finally, the cleavage of the trichloroacetyl group in 12b was
accomplished by means of NaOH in 5/1 acetonitrile/water
under reflux (Scheme 12). Upon attempted chromatography on
silica gel of this 1,2,3,4-tetrahydrobenz[g]isoquinoline degradation
occurred, and therefore, in view of its high purity (NMR), it
was used as such in the next step. After aqueous basic workup
a complex reaction mixture was obtained in which compound
24b could be distinguished as well as quinone 33 (tentatively).
Unfortunately, the crude reaction mixture completely degraded
upon attempted chromatography on silica gel.
tetrahydrobenz[g]isoquinolines 12a–c, 25 and 27 were all oxida-
tively demethylated in good yields to the envisaged N-protected
1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-diones 23a–c, 26 and
31 by silver(II) oxide in nitric acid.
Experimental
General experimental
1H NMR spectra were recorded on a Bruker Avance DRX 250
spectrometer at 250 MHz, or a Bruker Avance II 500 spectrometer
at 500 MHz with internal standard TMS. 13C NMR spectra were
recorded on a Bruker Avance DRX 250 spectrometer at 63 MHz,
Bruker Avance II 500 spectrometer at 125 MHz with internal
standard CDCl3 (dC = 77). Coupling constants (J values) are
reported in Hz. 13C NMR assignments were made using DEPT
spectra. Melting points were determined on a Buchi melting
point apparatus B-540 and are uncorrected. GC-MS analyses were
performed using an Intersience GC 8000 series gas chromatograph
with a ECTM-5 column (length: 30 m, internal diameter: 0.32 mm,
film t◦hickness: 0.25 mm). Products were injected in a split injector
(250 C); the inert carrier gas is helium. The mass spectrometer
was a Fisons Instruments MD 800 using electron impact (70 eV)
as ionization method. HRMS was measured with a VGQuattro
II mass spectrometer. Elemental analyses were executed with
Perkin Elmer Series II CHNS/O Analyzer 2400. UPLC analyses
were obtained with an Acquity (Waters) with a reverse-phase
C-18 column (Halo, 2.1 ¥ 30 mm, 2.7 mm). The mobile phase
(water/acetonitrile) contained 0.1% formic acid. The standard
gradient consisted of a 1.5 min run from 5% to 95% acetonitrile at a
flow of 0.6 ml/min with diode array UV detection. Infrared spectra
were recorded with an Avatar 370 FT-IR apparatus (Thermo
Nicolet), using the attenuated total reflection technology. Column
chromatography was performed using Merck silica (diameter
40–63 mm). TLC-analysis was performed on glass-backed plates
¨
Scheme 12 Transformations of compound 12b. Reagents and conditions:
(i) 5 equiv. NaOH, MeCN/H2O (5/1), reflux, 2 h; (ii) 4 equiv. AgO,
dioxane, 6 M HNO3, 50 ◦C, 16 h.
(Merck) coated with 0.2 mm silica 60F254
.
Synthesis of 2-amino-3-(1,4-dimethoxynaphthalen-2-
yl)propanenitrile 9
Conclusion
For the first time, the synthesis of N-acyl 1-substituted 1,2,3,4-
tetrahydrobenz[g]isoquinolines 12a–e has been achieved through
an activated Pictet–Spengler reaction of the corresponding imine
of 2-(1,4-dimethoxynaphth-2-yl)ethylamine in the presence of
AlCl3. In the absence of Lewis acids, a remarkable ipso-
cyclisation with concomitant displacement of the methoxy group
of the intermediate N-acyliminium ion is observed, leading to a
tetrahydrobenzo[h]isoquinoline. The problematic ring closure is
surprising in view of the fact that similar methoxy-substituted
electron-rich phenethylamines are the textbook examples for
Pictet–Spengler cyclizations, and therefore (a priori) no problems
were expected with this method.
The N-trichloroacetyl group of the N-acyl-1,2,3,4-tetrahydro-
benz[g]isoquinoline 12b could be cleaved under the action of
NaOH in acetonitrile, or converted to an N-methoxycarbonyl
protecting group by means of NaOH in methanol. The reaction of
N-trichloroacetyl-1,2,3,4-tetrahydrobenz[g]isoquinoline 12c with
propylamine unexpectedly gave rise to an 2-oxoacetamide. The
N-acyl-, N-methoxycarbonyl- or N-(2-oxoacetamide)-1,2,3,4-
To a solution of 2-(diphenylmethyleneamino)acetonitrile (1.56 g,
7.09 mmol), 2-(bromomethyl)-1,4-dimethoxynapthalene (8, 2.2 g,
7.83 mmol) and TEBA (0.08 g, 0.35 mmol) in CH2Cl2 (20 ml),
2.5 M NaOH solution was added (20 ml). After 24 h of vigorous
stirring, the layers were separated and the aqueous phase was
extracted with CH2Cl2 (2 ¥ 10 ml). The combined organic layers
were washed with water (2 ¥ 10 ml) and evaporated. The residue
was solved in THF (30 ml) and 1 M HCl (7.8 ml) was added
dropwise. After overnight stirring, the THF was evaporated, water
was added and the organic material was taken into ether (3 ¥
10 ml). The aqueous layer was made alkaline by a saturated
solution of NaHCO3 and extracted with ether (3 ¥ 25 ml). The
combined extracts were dried (Na2SO4) and evaporated to afford
the amine 9 (1.16 g, 64%) as a brown oil. dH (500 MHz; CDCl3) 1.74
(2H, br s, NH2), 3.21 (2H, dd, CH2), 3.90 (3H, s, OCH3), 3.99 (3H,
s, OCH3), 4.11 (1H, t, CHCN), 6.69 (1H, s, H-3), 7.47–7.56 (2H,
m, H-6 and H-7), 8.01–8.03 (1H, m, H-8), 8.23–8.25 (1H, m, H-5);
dC (125 MHz; CDCl3) 36.3 (CH2), 44.0 (CH), 55.7 (OCH3), 62.1
(OCH3), 105.4 (C-3), 121.8 ( CH), 121.9 (CN), 122.4 ( CH),
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123.0 ( Cquat), 125.5 ( CH), 126.3 ( Cquat), 126.8 ( CH), 128.3
(%)): 299 (63) [M], 268 (82), 200 (54), 185 (88), 170 (65), 127 (96),
115 (61), 98 (95), 69 (67), 56 (100).
(
Cquat), 148.1 and 152.1 (2 ¥ C–OMe). IR (ATR): n = 1594, 1627,
2229 (CN), 2837, 2937, 3061, 3318, 3386 (NH2) cm-1. MS (ESI):
m/z (%) = 257 (76) [M + H+], 241 (12) [M - NH2 + 1], 240 (100)
[M - NH2], 231 (12) [M - CN + 1], 230 (91) [M - CN].
N - (2-Methylpropylidene)-2-(1,4-dimethoxynaphthalen-2-yl)-
ethanamine 7d. Colorless oil. dH (250 MHz; CDCl3) 1.01 (6H, d,
J = 6.8 Hz, (CH3)2CH), 2.38 (1H, m, (CH3)2CH), 3.09 (2H, t, J =
7.4 Hz, CH2), 3.69 (2H, t, J = 7.4 Hz, CH2N), 3.89 (3H, s, OCH3),
3.96 (3H, s, OCH3), 6.63 (1H, s, H-3), 7.41–7.44 (2H, m, H-6,
H-7), 7.49 (1H, m, HC N), 8.01 (1H, d, J = 8.3 Hz, H-8), 8.19
(1H, d, J = 8.3 Hz, H-5). dC (125 MHz; CDCl3) 19.2 ((CH3)2CH),
31.9 (CH2), 33.9 ((CH3)2CH), 55.6 (OCH3), 61.8 (CH2N), 62.1
(OCH3), 106.3 (C-3), 121.7 and 122.2 (C-5, C-8), 124.8 and 126.4
(C-6, C-7), 125.6 ( Cquat), 127.7 ( Cquat), 128.6 ( Cquat), 147.3
and 151.5 (2 ¥ C–OMe), 170.3 (CH N). IR (ATR): n 1596, 1669
(C N), 2836, 2936, 2958 cm-1. MS (70 eV, m/z (%)): 287 (48) [M
+ H+ + 1], 286 (100) [M + H+], 232 (81), 215 (43), 200 (33).
Synthesis of imines 7a–d and 10
Typical procedure. To a mixture of 5 (0.50 g, 2.16 mmol)
and anhydrous MgSO4 (0.78 g, 6.50 mmol) in CH2Cl2 (10 ml),
benzaldehyde (0.23 g, 2.17 mmol) was added (2 equivalents of
aldehyde for imines 7c and 7d). After refluxing for 4 h (2 h
for imines 7c and 7d), the reaction mixture was filtered and
concentrated in vacuo to give the crude imine 7a which was used in
the next step without further purification. The conversion was 86%
based on 1H NMR analysis. Imines 7b and 10 were also isolated
as a mixture with the corresponding aldehyde.
2-(4-Chlorobenzylideneamino)-3-(1,4-dimethoxynaphthalen-2-
yl)propanenitrile 10. Brown oil. dH (250 MHz; CDCl3) 3.36 (1H,
dd, J = 13.4 Hz, J = 7.4 Hz, CH(H)), 3.50 (1H, dd, J = 13.4,
6.9 Hz, CH(H)), 3.88 (3H, s, OCH3), 3.94 (3H, s, OCH3), 4.96
(1H, dt, J = 7.2, 1.4 Hz, CHCN), 6.63 (1H, s, H-3), 7.38 (2H, d,
J = 8.5 Hz), 7.43–7.56 (2H, m, H-6, H-7), 7.67 (2H, d, J = 8.5 Hz),
8.00–8.04 (1H, m, H-8), 8.19–8.24 (1H, m, H-5), 8.29 (1H, d, J =
1.3 Hz, HC N). dC (63 MHz; CDCl3) 35.8 (CH2), 55.5 (OCH3),
59.2 (CHCN), 62.3 (OCH3), 106.0 (C-3), 117.9 (CN), 121.9 and
122.4 (C-5, C-8), 123.1 ( Cquat), 125.5 (C-6), 126.2 ( Cquat), 126.7
(C-7), 129.0 ( CH), 129.4 ( Cquat), 129.8 ( CH), 133.3 ( Cquat),
137.8 ( Cquat), 148.0 and 151.6 (2 ¥ C–OMe), 162.0 (CH N). IR
(ATR): n 1595, 1640 (C N), 2837, 2933 cm-1. MS (70 eV, m/z
(%)): 380 (18) [M + 2], 379 (12) [M + 1], 378 (52) [M], 202 (13),
201 (100) [M - ArCH NCHCN], 186 (27), 171 (12), 170 (21),
150 (12), 128 (19), 115 (16).
N -Benzylidene-2-(1,4-dimethoxynaphthalen-2-yl)ethanamine
7a. The crude reaction mixture contained 10–15% of benzalde-
hyde after washing with petroleum ether (to remove the non
reacted amine 5). Pale yellow oil. dH (250 MHz; CDCl3) 3.22
(2H, t, J = 7.3 Hz, CH2), 3.88 (3H, s, OCH3), 3.91 (3H, s, OCH3),
3.91–3.99 (2H, m, CH2N), 6.67 (1H, s, H-3), 7.39–7.54 (5H, m,
Ph), 7.69–7.73 (2H, m, H-6, H-7), 8.01–8.05 (1H, m, H-8), 8.17–
8.21 (2H, m, H-5; s, HC N). dC (63 MHz; CDCl3) 31.7 (CH2),
55.5 (OCH3), 62.2 (OCH3), 62.4 (CH2N), 106.2 (C-3), 121.7 and
122.2 (C-5, C-8), 124.8 (C-6), 125.5 ( Cquat), 126.4 (C-7), 127.7
(= Cquat), 128.0 ( CH), 128.55 ( CH), 128.59 ( Cquat), 130.6
(
CH), 136.1 ( Cquat), 147.2 and 151.5 (2 ¥ C–OMe), 161.5
(CH N). IR (ATR): n 1627, 1644 (C N), 3062 cm-1. MS (70
eV, m/z (%)): 320 (2) [M + 1], 319 (20) [M], 288 (100), 201 (49),
170 (26), 128 (21), 118 (60), 115 (20), 91 (92).
N -(4-Chlorobenzylidene)-2-(1,4- dimethoxynaphthalen-2-yl)-
ethanamine 7b. Pale yellow oil. dH (250 MHz; CDCl3) 3.21 (2H,
t, J = 7.3 Hz, CH2), 3.89 (3H, s, OCH3), 3.91 (3H, s, OCH3),
3.93–3.96 (2H, m, CH2N), 6.64 (1H, s, H-3), 7.35–7.38 (2H, m,
Ar), 7.50–7.53 (2H, m, H-6, H-9), 7.63–7.65 (2H, m, Ar), 8.01–
8.03 (1H, m, H-8), 8.15 (1H, s, HC N), 8.18–8.20 (1H, m, H-5).
dC (63 MHz; CDCl3) 31.7 (CH2), 55.5 (OCH3), 62.2 (OCH3), 62.3
(CH2N), 106.1 (C-3), 121.7 and 122.3 (C-5, C-8), 124.9 (C-6), 125.6
Reaction of imine 7a with CCl3COCl without Lewis acid
A solution of trichloroacetyl chloride (0.28 g, 1.54 mmol) in 1,2-
dichloroethane (1 ml) was added dropwise to a solution of imine
7a (0.44 g, 1.38 mmol) in 1,2-dichloroethane (5 ml). The mixture
was stirred at room temperature for 30 min and then heated to
reflux for 3 h. After cooling, the reaction mixture was poured
into water (20 ml), extracted with CH2Cl2 (3 ¥ 20 ml), dried
(MgSO4) and evaporated. The products were isolated by column
chromatography on silica gel.
(
Cquat), 126.5 (C-7), 127.6 ( Cquat), 128.9 ( CH), 129.2 ( CH),
130.9 ( Cquat), 134.6 ( Cquat), 136.5 ( Cquat), 147.3 and 151.5 (2 ¥
C–OMe), 160.1 (CH N). IR (ATR): n 1595, 1643 (C N), 2836,
2935, 3066 cm-1. MS (70 eV, m/z (%)): 355 (8) [M + 2], 353 (22)
[M], 324 (30) [M - OMe + 2], 323 (17) [M - OMe + 1], 322 (87)
[M - OMe], 202 (11), 201 (100), 186 (45), 171 (20), 170 (32), 154
(12), 152 (86), 128 (39), 127 (37), 125 (72), 115 (32), 89 (25).
2,2,2-Trichloro-1-(trans-4-chloro-6-methoxy-1-phenyl-3,4-dihy-
drobenzo[h]isoquinolin-2(1H)-yl)ethanone 14. Yield 0.225
g
(35%). Colorless crystals, mp 204.6 – 205.2 ◦C (from EtOAc–
Et2O). Rf = 0.57 (petroleum ether/EtOAc: 2/1). dH (250 MHz,
25 ◦C, ratio minor:major = 1 : 2.2; CDCl3) 3.51 (minor) and 3.91
(major) (1H, d, J = 15.0 Hz, C(H)H), 4.07 (3H, s, OCH3), 4.99
(1H, d, J = 15.0 Hz, C(H)H)), 5.24 (minor) and 5.39 (major) (1H,
br s, H-4), 6.82 (1H, s, H-5), 7.10–7.30 (5H, m, Ph), 7.40–7.65 (4H,
m, H-8, H-9, H-10, H-1), 8.27–8.38 (1H, m, H-7). dH (250 MHz,
50 ◦C; CDCl3) 3.20–3.95 (1H, br s, C(H)H), 4.08 (3H, s, OCH3),
5.00 (1H, d, J = 15.0 Hz, C(H)H)), 5.33 (1H, br s, H-4), 6.84 (1H,
s, H-5), 7.12–7.25 (5H, m, Ph), 7.40–7.51 (2H, m, H-8, H-9), 7.56
(1H, s, H-1), 7.62–7.66 (1H, m, H-10), 8.29–8.33 (1H, m, H-7). dC
(63 MHz, 25 ◦C; CDCl3) 46.8 (minor) and 47.0 (major) (C-3), 55.6
(minor) and 55.7 (major) (OCH3), 56.3 (major) and 57.5 (minor)
(C-1), 69.1 (minor) and 77.2 (major) (C-4), 86.8 (minor) and
N -(2,2-Dimethylpropylidene)- 2-(1,4-dimethoxynaphthalen-2-
yl)ethanamine 7c. Colorless oil. dH (250 MHz; CDCl3) 0.98 (9H,
s, (CH3)3C), 3.08 (2H, t, J = 7.3 Hz, CH2), 3.70 (2H, t, J = 7.3 Hz,
CH2), 3.89 (3H, s, OCH3), 3.95 (3H, s, OCH3), 6.64 (1H, s, H-3),
7.38 (1H, t, J = 1.1 Hz, HC N), 7.39–7.54 (2H, m, H-6, H-7),
7.99–8.03 (1H, m, H-5), 8.17–8.21 (1H, m, H-8). dC (63 MHz;
CDCl3) 26.8 ((CH3)3C), 31.9 (CH2), 35.9 ((CH3)3C), 55.6 (OCH3),
61.8 (CH2N), 62.1 (OCH3), 106.3 (C-3), 121.7 and 122.2 (C-5,
C-8), 124.7 and 126.4 (C-6, C-7), 125.5 ( Cquat), 127.7 ( Cquat),
128.6 ( Cquat), 147.3 and 151.4 (2 ¥ C–OMe), 172.6 (CH N). IR
(ATR): n 1595, 1664 (C N), 2836, 2950 cm-1. MS (70 eV, m/z
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93.0 (major) (CCl3), 103.6 (major) and 104.8 (minor) (C-5), 121.5
Cquat), 122.6 (major) and 123.3 (minor) ( CH), 122.8 ( Cquat),
124.3 ( CH), 126.3 ( CH), 127.7 ( CH), 128.3 ( CH), 128.4
CH), 128.7 ( CH), 130.7 (minor) and 131.1 (major) ( Cquat),
(CCl3C O), 176.9 (C O). IR (ATR): n 1595, 1708 (C O), 1676
(
(NC O), 2922 cm-1. MS (ESI): no molecular ion.
(
Reaction of imine 7d with acetyl chloride
138.0 (minor) and 139.5 (major) ( Cquat), 155.6 (C-6), 160.5
(C O). 13C NMR dC (125 MHz, 50 ◦C, CDCl3) 47.2 (C-3),
55.7 (OCH3), 57.5 (C-1), 93.2 (CCl3), 103.9 (C-5), 121.8 ( Cquat),
122.7 ( CH), 124.2 ( Cquat), 126.3 ( CH), 127.8 ( CH), 128.3
To a solution of imine 7d (0.45 g, 1.58 mmol) in 1,2-dichloroethane
(5 ml) a solution of acetyl chloride (0.14 g, 1.78 mmol) in 1,2-
dichloroethane (1 ml) was added dropwise and the mixture was
stirred at room temperature for 30 min and then heated to reflux
for 3 h. After cooling the mixture was poured into water (20 ml),
extracted with CH2Cl2 (3 ¥ 20 ml), dried (MgSO4) and evaporated.
The product was purified by column chromatography. Rf = 0.37
(petroleum ether/EtOAc : 1/2). Pale yellow oil. Yield 0.13 g (25%).
(
CH), 128.7 ( CH), 131.0 ( Cquat), 139.5 ( Cquat), 155.8 (C-6),
160.5 (C O). IR (ATR): n 1589, 1628, 1666 (C O), 2908, 2944,
3014, 3068 cm-1. MS (ESI): m/z (%) = 472 (15) [M + H+ + 4], 470
(26) [M + H+ + 2], 468 (23) [M + H+], 442 (27) [M - OCH2 + H+ +
4], 440 (100) [M - OCH2 + H+ + 2], 438 (86) [M - OCH2 + H+], 434
(30), 432 (32), 338 (43), 147 (30), 145 (68). Variable-temperature
1H NMR (250 MHz, CDCl3): 297 K (ratio 1 : 2.2), 313 K, 323 K;
13C NMR (125 MHz, CDCl3): 298 K, 323 K.
N-(2-(1,4-Dimethoxynaphthalen-2-yl)ethyl)-N-(2-methylprop-
1-enyl)acetamide (21). 1H NMR dH (250 MHz, CDCl3) 1.63 and
1.74 (2 ¥ 3H, 2¥d, J = 1.3 Hz, (CH3)2C), 1.99 (3H, s, CH3), 2.98–
3.05 (2H, m, CH2), 3.69–3.76 (2H, m, CH2N), 3.89 (3H, s, OCH3),
3.98 (3H, s, OCH3), 5.84 (1H, m, CH), 6.68 (1H, s, H-3), 7.40–
7.55 (2H, m, H-6 and H-7), 7.99–8.03 (1H, m, H-8), 8.18–8.22
(1H, m, H-5).13C NMR dC (63 MHz, CDCl3) 17.5 (CH3), 21.7
(CH3), 22.0 (CH3), 28.1 (CH2), 47.9 (CH2N), 55.6 (OCH3), 61.9
(OCH3), 105.5 (C-3), 121.6 ( CH), 122.2 ( CH), 124.3 ( CH),
124.8 ( CH), 125.5 ( Cquat), 126.4 ( CH), 126.9 ( Cquat), 128.5
2,2,2-Trichloro-N -(2-(1,4-dimethoxynaphthalen-2-yl)ethyl)-
acetamide 13a. Yield 0.05 g (9%). Colorless oil. Rf = 0.39
(petroleum ether/EtOAc : 2/1). dH (250 MHz, CDCl3) 3.05–3.11
(2H, m, CH2), 3.63–3.71 (2H, m, CH2N), 3.92 (3H, s, OCH3),
3.98 (3H, s, OCH3), 6.58 (1H, s, H-3), 7.44–7.58 (3H, m, H-6,
H-7, NH), 7.98–8.02 (1H, m, H-8), 8.20–8.25 (1H, m, H-5). dC
(63 MHz, CDCl3) 29.7 (CH2N), 42.7 (CH2), 55.7 (OCH3), 61.9
(OCH3), 92.5 (CCl3), 105.3 (C-3), 121.6 ( CH), 122.4 ( CH),
125.3 ( CH), 125.9 ( Cquat), 126.0 ( Cquat), 126.9 ( CH), 128.4
(
Cquat), 135.5 ( Cquat), 147.2 and 151.7 (2 ¥ C–OMe), 170.7
(C O). IR (ATR): n 1596, 1636 (C O), 2847, 2935 cm-1. MS
(ESI): m/z (%) = 329 (13) [M + H+ + 1], 328 (100) [M + H+].
(
Cquat), 147.1 and 152.3 (2 ¥ C–OMe), 162.1 (C O). IR (ATR):
n 1595, 1693 (C O), 2836, 2936, 3068, 3333 (NH) cm-1. MS (ESI):
m/z (%) = 379 (25) [M + H+ + 4], 378 (100) [M + H+ + 2], 376 (95)
[M + H+], 348 (15) [M - OCH3 + H+ + 4], 346 (43) [M - OCH3 +
H+ + 2], 344 (42) [M - OCH3 + H+], 232 (30), 199 (14), 183 (16).
Reaction of imines 10, 7a–c with acyl chlorides
Typical procedure. To a solution of imine 10 (1.06 g, 2.8 mmol)
in 1,2-dichloroethane (50 ml), KI (30 mg, 0.18 mmol) and
˚
molecular sieves (3 A) were added. Then a solution of acetyl
Preparation of 2,2,2-trichloro-N-(2-(1,4-dimethoxynaphthalen-2-
chloride (0.246 g, 3.08 mmol) in 1,2-dichloroethane (1 ml) was
added dropwise and after stirring the mixture at room temperature
for 30 min, anhydrous AlCl3 (0.38 g, 2.8 mmol) was added and
heating was applied to reflux for 3 h. After cooling, the mixture was
filtered, poured into water and extracted by CH2Cl2 (3 ¥ 20 ml).
The combined extracts were washed by brine, dried (MgSO4) and
evaporated. The product was isolated by column chromatography.
Yield 0.26 g (22%). Pale yellow crystals, mp 139.5–140.2 ◦C
(CH2Cl2–Et2O). Rf = 0.59 (petroleum ether/EtOAc : 1/2).
yl)ethyl)acetamide 13a
To a cooled (0 ◦C) solution of 5 (0.2 g, 0.86 mmol) in dry pyridine
(1 ml), trichloroacetyl chloride (0.16 g, 0.88 mmol) was added
dropwise. The reaction was stirred at room temperature for 2 h.
Then, the mixture was poured into 2 M HCl (5 ml), extracted with
CH2Cl2, dried (MgSO4) and evaporated. The product was isolated
by column chromatography (silica gel, petroleum ether/EtOAc :
2/1). Yield 185 mg (57%)
N-(4-Chlorobenzyl)-N-(1-cyano-2-(1,4-dimethoxynaphthalen-2-
yl)vinyl)acetamide (22). 1H NMR dH (250 MHz, CDCl3) 2.44
(3H, s, CH3), 3.88 (3H, s, OCH3), 3.98 (3H, s, OCH3), 4.23 (2H,
m, CH2Ar), 6.85 (1H, s, H-3), 7.37–7.54 (4H, m, H-6, H-7, Ar),
7.73–7.77 (2H, m, Ar), 8.03–8.07 (1H, m, H-8), 8.15–8.20 (1H,
m, H-5), 8.44 (1H, s, HC ).13C NMR dC (63 MHz, CDCl3) 14.5
(CH3C O), 26.1 (CH2Ar), 55.5 (OCH3), 62.3 (OCH3), 105.8 (C-
3), 121.9 ( CH), 122.2 ( CH), 124.9 ( CH), 125.7 ( Cquat),
126.4 ( CH), 126.6 ( Cquat), 128.6 ( Cquat), 129.0 ( CH), 129.4
Oxidation of 3,4-dihydrobenzo[h]isoquinoline by CAN
To a cooled (0 ◦C) solution of 14 (0.12 g, 0.25 mmol) in acetonitrile
(70 ml) was added dropwise a solution of CAN (0.46 g, 0.84 mmol)
in water (7 ml). The reaction was stirred at room temperature for
2 h. Then the mixture was poured into brine, extracted with ethyl
acetate, dried (MgSO4) and evaporated. The product was purified
by column chromatography. Yield 50 mg (62%).
4-Chloro-1-phenyl-2-(2,2,2-trichloroacetyl)-3,4-dihydrobenzo-
[h]isoquinolin-6(2H)-one 15. Orange crystals, mp 210.0–211.0 ◦C
(EtOAc). Rf = 0.27 (petroleum ether/EtOAc : 6/1). dH (250 MHz,
CDCl3) 3.68 (1H, m, C(H)H)), 4.94 (1H, d, J = 15.0 Hz, C(H)H)),
5.37 (1H, br s, H-4), 7.23 (1H, s, H-5), 7.32–7.60 (8H, m, Ph),
8.17–8.20 (1H, m, H-7). 13C NMR dC (63 MHz, DMSO-d6)
49.1 (C-3), 55.1 (C-4), 92.4 (CCl3), 127.5 ( CH), 128.3 ( CH),
128.9 ( CH), 129.1 ( CH), 130.6 ( CH), 131.9 ( Cquat), 132.3
(
(
CH), 134.0 ( Cquat), 134.8 ( Cquat), 136.9 ( Cquat), 147.0
Cquat), 149.0 ( Cquat), 151.4 (HC ), 151.7 ( Cquat), 158.2
(C O). IR (ATR): n 1560, 1596, 1613 (C O), 2836, 2937, 2967,
2993, 3065 cm-1. MS (ESI): m/z (%) = 423 (31) [M + H+ + 2], 421
(100) [M + H+].
2 - (2,2,2 - Trichloroacetyl) - 5,10 - dimethoxy - 1 - phenyl - 1,2,3,4-
tetrahydrobenzo[g]isoquinoline (12a). Scale of the reaction:
3.13 mmol imine 7a (1.0 g). Colorless crystals, mp 143.3–144.3 ◦C
(
Cquat), 134.9 ( CH), 136.9 ( Cquat), 143.9 ( Cquat), 159.8
544 | Org. Biomol. Chem., 2011, 9, 538–548
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◦
1
(Et2O). Rf = 0.5 (petroleum ether/EtOAc : 6/1). Yield 0.6 g (41%).
1/2). Yield 0.155 g (35%). H NMR dH (250 MHz, 24 C, ratio
minor/major : 1/3, CDCl3) 2.23 (major) and 2.36 (minor) (3H,
s, CH3), 2.91–3.26 (2H, m, H-4), 3.51–3.78 (2H, m, H-3), 3.84
(major) and 3.86 (minor) (3H, s, OCH3), 3.91 (major and minor)
(3H, s, OCH3), 6.51 (minor) and 7.35 (major) (1H, br s, H-1), 7.08–
7.13 (2H, m, CHAr), 7.18–7.28 (2H, m, CHAr), 7.51–7.59 (2H, m,
H-7, H-8), 8.04–8.13 (2H, m, H-6, H-9).13C NMR dC (125 MHz,
24 ◦C, CDCl3) 21.4 (minor) and 22.9 (major) (C-4), 21.8 (major)
and 22.0 (minor) (CH3), 39.0 (minor) and 41.0 (major) (C-3), 50.0
(major) and 54.9 (minor) (C-1), 61.6 and 62.3 (major, 2¥OCH3),
61.8 and 62.6 (minor, 2¥OCH3), 122.2 and 122.7 (major, CH),
122.5 and 122.6 (minor, CH), 123.9 (major) and 124.4 (minor)
◦
1H NMR dH (250 MHz, 24 C, CDCl3) 3.11–3.36 (2H, m, H-4),
3.49–3.62 (1H, m, NC(H)H), 3.79 and 3.93 (6H, 2¥s, 2¥OCH3),
4.52–4.58 (1H, m, NC(H)H), 7.14–7.17 (2H, m, Ph), 7.25–7.29
(3H, m, Ph), 7.33 (1H, s, H-1), 7.47–7.59 (2H, m, H-7, H-8), 8.02–
8.13 (2H, m, H-6, H-9).13C NMR dC (63 MHz, 24 ◦C, CDCl3)
23.3 (C-4), 41.0 (C-3), 54.6 (C-1), 61.2 (OCH3), 62.1 (OCH3),
93.4 (CCl3), 122.2 ( CH), 122.7 ( CH), 123.2 ( Cquat), 124.3
(
(
(
Cquat), 125.9 ( CH), 126.4 ( Cquat), 127.2 ( Cquat), 127.89
CH), 127.95 ( CH), 128.0 ( Cquat), 128.6 ( CH), 140.4
Cquat), 149.3 and 149.7 (2¥C–OMe), 160.0 (C O). IR (ATR):
n 1670 (C O), 2840, 2936 cm-1. MS (ESI): m/z (%) = 468 (16) [M
+ H+ + 4], 466 (53) [M + H+ + 2], 464 (54) [M + H+], 428 (10) [M
- Cl], 405 (21), 404 (100), 225 (26), 200 (22). HRMS (ESI): m/z
calcd for C23H20Cl3NO3 + H+: 464.0582; found 464.0563. HMBC
and HMQC were recorded for the correct assignment of the NMR
signals.
(
Cquat), 125.5 ( Cquat), 126.0 and 126.4 (major, CH), 126.1 and
126.6 (minor, CH), 127.0 (minor) and 127.4 (major) ( Cquat),
127.9 ( CH), 128.2 (major) and 128.6 (minor) ( Cquat), 128.4
and 128.8 ( CH), 133.0 (major) and 133.5 (minor) ( Cquat), 139.1
(minor) and 140.2 (major) ( Cquat), 148.1 and 149.7 (minor, 2 ¥
C–OMe), 149.1 and 149.5 (major, 2 ¥ C–OMe), 169.7 (major)
and 170.1 (minor) (C O). IR (ATR): n 1637 (C O), 2838, 2936
cm-1. MS (ESI): m/z (%) = 398 (9) [M + H+ + 2], 396 (25) [M
+ H+], 300 (13), 293 (15), 292 (100). HRMS (ESI): m/z calcd for
C23H22ClNO3 + H+: 396.1361; found 396.1343.
2-(2,2,2-Trichloroacetyl)-5,10-dimethoxy-1-(4-chlorophenyl)-
1,2,3,4-tetrahydrobenzo[g]isoquinoline (12b). Scale of the reac-
tion: 1.2 mmol imine 7b (0.41 g). Colorless crystals, mp 166.0–
◦
166.7 C (Et2O). Rf = 0.5 (petroleum ether/EtOAc : 6/1). Yield
◦
1
0.21 g (36%). H NMR dH (250 MHz, 22 C, CDCl3) 3.13–3.35
(2H, m, H-4), 3.43–3.56 (1H, m, NC(H)H), 3.81 and 3.93 (6H, 2¥s,
2¥OCH3), 4.53–4.59 (1H, m, NC(H)H), 7.08–7.12 (2H, m, Ar),
7.23–7.27 (3H, m, Ar, H-1), 7.49–7.60 (2H, m, H-7, H-8), 8.01–8.13
(2H, m, H-6, H-9).13C NMR dC (63 MHz, 23 ◦C, CDCl3) 23.2 (C-
4), 41.0 (C-3), 54.0 (C-1), 61.2 (OCH3), 62.1 (OCH3), 93.1 (CCl3),
122.2 ( CH), 122.7 ( CH), 123.0 ( Cquat), 123.7 ( Cquat),
126.1 ( CH), 126.6 ( CH), 127.2 ( Cquat), 128.2 ( Cquat), 128.8
2-Acetyl-5,10-dimethoxy-1-tert-butyl-1,2,3,4-tetrahydrobenzo-
[g]isoquinoline (12e). Scale of the reaction: 1.1 mmol imine 7c
(0.33 g). Colorless crystals, mp 147.5–147.7 ◦C (Et2O-pentane).
Rf = 0.35 (petroleum ether/EtOAc : 1/2). Yield 0.155 g (41%).
1H NMR dH (250 MHz, 25 ◦C, ratio minor/major : 1/3, CDCl3)
1.01 (major) and 1.04 (minor) (9H, s, (CH3)3C), 2.18 (major) and
2.34 (minor) (3H, s, CH3), 3.07–3.20 (1H, m, C(H)H), 3.30–3.46
(1H, m, C(H)H), 3.58–3.70 (1H, m, NC(H)H), 3.82–4.00 (1H,
m, NC(H)H), 3.88 (minor) and 3.89 (major) (3H, s, OCH3), 3.91
(major) and 3.92 (minor) (3H, s, OCH3), 5.22 (minor) and 6.18
(major) (1H, s, H-1), 7.48–7.54 (2H, m, H-7, H-8), 8.04–8.13 (2H,
m, H-6, H-9).13C NMR dC (63 MHz, 25 ◦C, CDCl3) 20.8 (minor)
and 21.8 (major) (C-4), 22.6 (minor) and 22.7 (major) (CH3),
28.8 (major) and 28.9 (minor) ((CH3)3C), 38.2 (minor) and 42.8
(major) (C-3), 39.1 (major) and 39.7 (minor) ((CH3)3C), 54.2 (C-1),
59.9 and 61.3 (minor, 2¥OCH3), 61.7 and 62.3 (major, 2¥OCH3),
122.0 and 122.9 (major, CH), 122.2 and 122.8 (minor, CH),
124.1 (major) and 124.2 (minor) ( Cquat), 125.7 ( CH), 126.1
(major) and 126.2 (minor) ( CH), 126.5 ( Cquat), 127.5 ( Cquat),
127.8 ( Cquat), 148.8 and 149.3 (2 ¥ C–OMe), 170.5 (minor) and
171.1 (major) (C O). IR (ATR): n 1639 (C O), 2839, 2870, 2955
cm-1. MS (ESI): no molecular ion was observed. Anal. calcd. for
C21H27NO3: C, 73.87; H, 7.97; N, 4.10. Found: C, 73.91; H, 8.00;
(
CH), 129.3 ( CH), 133.8 ( Cquat), 139.1 ( Cquat), 149.2 and
149.8 (2 ¥ C–OMe), 160.0 (C O). IR (ATR): n 1669 (C O),
2841, 2945, 2990 cm-1. MS (ESI): m/z (%) = 502 (38) [M + H+ +
4], 501 (46) [M + 4], 500 (73) [M + H+ + 2], 499 (100) [M + 2], 498
(57) [M + H+], 497 (86) [M], 464 (50) [M - Cl + 2], 462 (57) [M
- Cl]. HRMS (ESI): m/z calcd for C23H19Cl4NO3 + H+: 498.0192;
found 498.0169.
2-(2,2,2-Trichloroacetyl)-5,10-dimethoxy-1-tert-butyl-1,2,3,4-
tetrahydrobenzo[g]isoquinoline (12c). Scale of the reaction:
1.6 mmol imine 7c (0.49 g). Colorless crystals, mp 177.5–178.3 ◦C
(Et2O). Rf = 0.58 (petroleum ether/EtOAc : 6/1). Yield 0.255
g (35%). H NMR dH (250 MHz, 22 ◦C, CDCl3) 1.07 (9H, s,
1
C(CH3)3), 3.07–3.18 (1H, m, C(H)H), 3.29–3.44 (1H, m, C(H)H),
3.91 and 3.94 (6H, 2¥s, 2¥OCH3), 4.00–4.16 (1H, m, NC(H)H),
4.66–4.77 (1H, m, NC(H)H), 6.06 (1H, s, H-1), 7.49–7.54 (2H, m,
H-7, H-8), 8.03–8.12 (2H, m, H-6, H-9).13C NMR dC (63 MHz,
24 ◦C, CDCl3) 21.9 (C-4), 28.8 (C(CH3)3), 39.2 (C(CH3)3), 42.1
(C-3), 57.7 (C-1), 61.0 (OCH3), 62.4 (OCH3), 93.9 (CCl3), 121.9
1
N, 4.03. Variable temperature H NMR (250 MHz, CDCl3): 297
K, 321 K. 1H NMR (250 MHz, DMSO-d6): 297 K, 308 K, 318 K,
328 K, 338 K, 348 K. Signals became broader, but the ratio did
not change substantially.
(
(
CH), 122.9 ( CH), 123.1 ( Cquat), 124.8 ( Cquat), 125.8
CH), 126.3 ( CH), 127.5 ( Cquat), 127.8 ( Cquat), 149.2 and
149.3 (2 ¥ C–OMe), 160.4 (C O). IR (ATR): n 1663 (C O),
2838, 2935, 2950, 2967, 2990 cm-1. MS (ESI): m/z (%) = 448 (16)
[M + H+ + 4], 446 (49) [M + H+ + 2], 444 (47) [M + H+], 272 (36),
242 (9), 224 (100). HRMS (ESI): m/z calcd for C21H24Cl3NO3 +
H+: 444.0895; found 444.0912.
Oxidation of N-acyltetrahydro[g]isoquinolines 12
Typical procedure. To a mixture of 12a (0.075 g, 0.16 mmol) and
silver(II) oxide (0.08 g, 0.64 mmol) in 1,4-dioxane (5 ml) was added
dropwise 6 M HNO3 (0.7 ml), and the reaction was kept for 16 h at
50 ◦C. The reaction mixture was poured into a saturated solution
of NaHCO3 and extracted with Et2O (3 ¥ 20 ml). The combined
ether extracts were dried (MgSO4) and concentrated. The product
was isolated by column chromatography. Rf = 0.70 (petroleum
2-Acetyl-5,10-dimethoxy-1-(4-chlorophenyl)-1,2,3,4-tetrahydro-
benzo[g]isoquinoline (12d). Scale of the reaction: 1.1 mmol imine
7b (0.40 g). Colorless oil. Rf = 0.34 (petroleum ether/EtOAc :
This journal is
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ether/EtOAc : 2/1). Yellow crystals, mp 170.0–218.0 ◦C (Et2O,
decomposition). Yield 0.052 g (74%).
and evaporated. The product 24b and unreacted compound
12b were separated by column chromathography. Rf = 0.68
(petroleum ether/EtOAc : 1/1). Yield 0.005 g (10%, according
to conversion). 1-(4-Chlorophenyl)benzo[g]isoquinoline-5,10-dione
(24b). Pale yellow crystals, mp 230.2–232.0 ◦C (CH2Cl2–Et2O,
2-(2,2,2-Trichloroacetyl)-1-phenyl-1,2,3,4-tetrahydrobenzo[g]-
isoquinoline-5,10-dione (23a). 1H NMR dH (250 MHz, 24 ◦C,
CDCl3) 2.94–3.00 (2H, m, H-4), 3.33–3.47 (1H, m, NC(H)H),
4.57–4.64 (1H, m, NC(H)H), 7.00 (1H, s, H-1), 7.31–7.37 (5H,
m, Ph), 7.71–7.80 (2H, m, H-7, H-8), 8.01–8.05 (1H, m, H-6),
8.12–8.16 (1H, m, H-9).13C NMR dC (63 MHz, 25 ◦C, CDCl3)
23.4 (C-4), 39.7 (C-3), 53.7 (C-1), 92.8 (CCl3), 126.4 ( CH),
126.8 ( CH), 128.2 ( CH), 128.6 ( CH), 128.9 ( CH), 131.70
1
decomposition). H NMR dH (250 MHz, CDCl3) 7.47 (4H, s,
C6H4Cl), 7.82–7.86 (2H, m, H-6 and H-9), 8.15–8.20 (2H, m, d,
J = 4.9 Hz, H-4 and H-8, overlap), 8.29–8.33 (1H, m, H-7), 9.08
(1H, d, J = 4.9 Hz, H-3). IR (ATR): n 1593, 1668 (C O), 1679
(C O), 2849, 2917, 2955 cm-1. MS (ESI): m/z (%) = 322 (33) [M
+ H+ + 2], 321 (20) [M + H+ + 1], 320 (100) [M + H+].
(
(
Cquat), 131.73 ( Cquat), 134.0 ( CH), 134.1 ( CH), 138.1
Cquat), 142.0 ( Cquat), 143.3 ( Cquat), 159.5 (C O), 182.0
Reactions with nucleophiles: MeOH/NaOH
(C O), 183.6 (C O). IR (ATR): n 1595, 1633 (C O), 1654
(C O), 1663 (C O), 2850, 2919, 2950 cm-1. MS (ESI): m/z (%)
(with a lot of ‘noise’) = 438 (15) [M + H+ + 4], 436 (80) [M + H+
+ 2], 434 (87) [M + H+], 273 (100), 242 (29), 224 (90).
To a solution of compound 12a (0.33 g, 0.71 mmol) in methanol
(5 ml) a solution of NaOH (0.1 g, 2.5 mmol) in water (1 ml) was
added and the mixture was refluxed for 30 min. Methanol was
evaporated and the residue was extracted with CH2Cl2 (3 ¥ 10 ml).
The combined extracts were dried (MgSO4) and evaporated. The
product was isolated by column chromatography. Yield 0.19 g
(71%).
2-(2,2,2-Trichloroacetyl)-1-(4-chlorophenyl)-1,2,3,4-tetrahydro-
benzo[g]isoquinoline-5,10-dione (23b). Scale of the reaction:
0.22 mmol 12b (110 mg). Yellow crystals, mp 223.3–
225.9 ◦C (CH2Cl2–Et2O, decomposition). Rf = 0.77 (petroleum
ether/EtOAc : 2/1). Yield 0.094 g (91%). 1H NMR dH (250 MHz,
25 ◦C, CDCl3) 2.94–2.99 (2H, m, H-4), 3.29–3.41 (1H, m,
NC(H)H), 4.59–4.66 (1H, m, NC(H)H), 6.93 (1H, s, H-1), 7.32
(4H, s, Ar), 7.71–7.80 (2H, m, H-7, H-8), 8.01–8.05 (1H, m, H-6),
8.12–8.16 (1H, m, H-9).13C NMR dC (63 MHz, 25 ◦C, CDCl3)
23.3 (C-4), 39.7 (C-3), 53.1 (C-1), 92.7 (CCl3), 126.5 ( CH),
126.8 ( CH), 129.2 ( CH), 129.5 ( CH), 131.6 ( Cquat), 134.1
Methyl 3,4-dihydro-5,10-dimethoxy-1-phenylbenzo[g]isoquino-
line-2(1H)-carboxylate (25). Colorless crystals, mp 139.9–
◦
1
140.6 C (Et2O). Rf = 0.57 (petroleum ether/EtOAc : 2/1). H
◦
NMR dH (250 MHz, 22 C, CDCl3) 2.81–2.93 (1H, m, C(H)H),
3.04–3.21 (1H, m, C(H)H), 3.40–3.50 (1H, m, NC(H)H), 3.74 and
3.79 and 3.82 and 3.84 (3H, 4¥s, CO2CH3), 3.89 (6H, s, OCH3),
3.89–4.01 (1H, m, NC(H)H), 6.82 and 6.95 (1H, 2¥ br s, H-1),
7.18–7.26 (5H, m, Ph), 7.49–7.56 (2H, m, H-7 and H-8), 8.04–8.13
(
(
CH), 134.2 ( CH), 134.6 ( Cquat), 136.7 ( Cquat), 141.5
Cquat), 143.5 ( Cquat), 159.5 (C O), 181.9 (C O), 183.5
(2H, m, H-6 and H-9). H NMR dH (250 MHz, 50 ◦C, CDCl3)
1
(C O). IR (ATR): n 1593, 1639 (C O), 1662 (C O), 2896,
2.78–2.90 (1H, m, C(H)H), 3.06–3.19 (1H, m, C(H)H), 3.40–3.51
(1H, m, NC(H)H), 3.78 and 3.80 (3H, 2¥s, CO2CH3), 3.89 (6H, s,
OCH3), 3.80–3.95 (1H, m, NC(H)H), 6.90 (1H, br s, H-1), 7.15–
7.24 (5H, m, Ph), 7.43–7.53 (2H, m, H-7 and H-8), 8.03–8.11 (2H,
m, H-6 and H-9).13C NMR dC (63 MHz, 24 ◦C, CDCl3) 21.9 and
22.3 (C-4), 38.7 and 38.8 (C-3), 52.8 and 52.9 and 62.1 and 62.2
(CO2CH3), 53.1 and 53.2 (C-1), 61.5 (OCH3), 122.16 and 122.26
2939, 3065 cm-1. MS (ESI): m/z (%) = no molecular ion.
2-(2,2,2-Trichloroacetyl)-1-tert-butyl-1,2,3,4-tetrahydrobenzo-
[g]isoquinoline-5,10-dione (23c). Scale of the reaction: 0.24 mmol
12c (106 mg). Yellow crystals, mp 216.7–218.8 ◦C (CH2Cl2–Et2O,
decomposition). Rf = 0.81 (petroleum ether/EtOAc : 2/1). Yield
0.08 g (81%). 1H NMR dH (250 MHz, 24 ◦C, CDCl3) 1.12 (9H, s,
C(CH3)3), 2.80–3.04 (2H, m, H-4), 3.70–3.83 (1H, m, NC(H)H),
4.77–4.87 (1H, m, NC(H)H), 5.87 (1H, s, H-1), 7.71–7.80 (2H, m,
H-7, H-8), 8.05–8.14 (2H, m, H-6, H-9).13C NMR dC (63 MHz,
25 ◦C, CDCl3) 22.8 (C-4), 29.5 (C(CH3)3), 37.9 (C(CH3)3), 41.6
(C-3), 56.0 (C-1), 93.3 (CCl3), 126.1 ( CH), 126.9 ( CH),
131.5 ( Cquat), 132.2 ( Cquat), 133.7 ( CH), 134.0 ( CH),
142.4 ( Cquat), 144.4 ( Cquat), 159.7 (C O), 182.8 (C O), 183.6
(C O). IR (ATR): n 1595, 1628 (C O), 1664 (C O), 2873, 2954,
2976 cm-1. MS (ESI): m/z (%) = 418 (26) [M + H+ + 4], 416 (96)
[M + H+ + 2], 414 (100) [M + H+], 379 (9) [M - Cl + 1], 378 (32)
[M - Cl], 324 (18) [M - Cl–C4H9 + 2], 322 (32) [M - Cl– C4H9].
HRMS (ESI): m/z calcd for C19H18Cl3NO3 + H+: 414.0425; found
414.0446.
(
CH), 122.6 and 122.7 ( CH), 124.6 ( Cquat), 125.7 ( CH),
126.1 ( CH), 126.3 ( Cquat), 127.2 and 127.3 ( CH), 128.3
CH), 141.5 and 141.6 ( Cquat), 148.4 and 148.8 (C–OMe),
(
149.4 and 149.5 (C–OMe), 156.1 and 156.6 (C O). IR (ATR):
n 1684 (C O), 2840, 2932, 2994 cm-1. MS (ESI): m/z (%) = 378
(100) [M + H+], 303 (15), 224 (7). Anal. Calcd for C23H23NO4: C,
73.19; H, 6.14; N, 3.71. Found: C, 72.78; H, 6.02; N, 3.58.
Variable-temperature 1H NMR (250 MHz, CDCl3): 298 K,
303 K, 308 K, 313 K, 318 K, 323 K. HMQC was used for the
assignment of the NMR signals.
Methyl trans-4-chloro-6-methoxy-1-phenyl-3,4-dihydrobenzo-
[h]isoquinolin-2(1H)-carboxylate (16). The same reaction
conditions were used as described above. Yield 0.015 g (51%) Rf =
1
0.55 (petroleum ether/EtOAc : 2/1). H NMR dH (250 MHz,
Transformations of the N-trichloroacetyl group
25 ◦C, ratio minor/major = 1/1.7, CDCl3) 3.53–3.61 (1H, m,
CH(H)), 3.81 (major) and 3.94 (minor) (3H, 2¥s, OCH3), 4.05
(3H, s, OCH3), 4.47 (major) and 4.65 (minor) (1H, 2¥d, J =
15.0 Hz, CH(H)), 5.23–5.29 (1H, m, H-4), 6.76 (major) and 6.79
(minor) (1H, 2¥s, H-5), 6.96 (minor) and 7.13 (major) (1H, 2¥s,
H-1), 7.12–7.26 (5H, m, Ph), 7.32–7.59 (3H, m, H-8, H-9, H-10),
Cleavage under acidic conditions. To a solution of compound
12b (0.105 g, 0.26 mmol) in methanol (5 ml) 12 M HCl (1 ml)
was added and the mixture was refluxed for 8 h. The mixture
was rendered alkaline by 5% aqueous NaOH and extracted with
ether (3 ¥ 10 ml). The combined extracts were dried (MgSO4)
546 | Org. Biomol. Chem., 2011, 9, 538–548
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8.24–8.29 (1H, m, H-7). No 13C NMR could be recorded because
of decomposition of this compound during the measurement.
Oxidation of compounds 25 and 27 with silver(II) oxide
An analogous procedure was used as described for the oxidation
of 12.
Cleavage under basic conditions
Methyl
3,4-dihydro-5,10-dioxo-1-phenylbenzo[g]isoquinolin-
To a solution of compound 12b (0.095 g, 0.19 mmol) in acetonitrile
(5 ml) a solution of NaOH (0.04 g, 0.1 mmol) in water (1 ml) was
added and the mixture was refluxed for 2 h. The mixture was
poured into water (20 ml) and extracted with CH2Cl2 (3 ¥ 10 ml).
The combined extracts were dried (MgSO4) and evaporated. The
product was used for the oxidation without purification. Pale
yellow oil. Crude yield 0.06 g (89%). 1-(4-Chlorophenyl)-1,2,3,4-
2(1H,5H,10H)-carboxylate (26). Scale of the reaction:
0.2 mmol 25 (100 mg). Rf = 0.47 (petroleum ether/EtOAc :
2/1). Yellow crystals, mp 196.5–197.2 ◦C (Et2O). Yield 0.08 g
(87%). H NMR dH (250 MHz, 25 ◦C, CDCl3) 2.78–3.07 (3H,
1
m, NCH(H)CH2), 3.75 and 3.83 (3H, 2¥s, CO2CH3), 4.10–4.32
(1H, m, NC(H)H), 6.45 and 6.59 (1H, 2¥ br s, H-1), 7.26–7.31
(5H, m, Ph), 7.67–7.76 (2H, m, H-7 and H-8), 7.98–8.02 (1H, m,
1
tetrahydro-5,10-dimethoxybenzo[g]isoquinoline (32). H NMR dH
H-6), 8.11–8.14 (1H, m, H-9). H NMR dH (250 MHz, 50 ◦C,
1
(250 MHz, CDCl3) 2.08 (1H, br s, NH), 2.99–3.05 (4H, m, H-4, H-
3), 3.58 (3H, s, OCH3), 3.94 (3H, s, OCH3), 5.55 (1H, s, H-1), 7.07–
7.26 (4H, m, Ar), 7.41–7.53 (2H, m, H-7, H-8), 7.92–7.96 (1H, m,
H-6), 8.08–8.11 (1H, m, H-9).13C NMR dC (63 MHz, CDCl3)
23.9 (C-4), 37.5 (C-3), 55.3 (C-1), 61.0 (OCH3), 61.4 (OCH3),
122.1 ( CH), 122.4 ( CH), 125.4 ( CH), 125.8 ( CH), 126.8
CDCl3) 2.84–2.92 (2H, m, CH2), 3.00–3.12 (1H, m, NC(H)H)),
3.78 (3H, s, CO2CH3), 4.16–4.24 (1H, m, NC(H)H)), 6.51 (1H,
br s, H-1), 7.25–7.30 (5H, m, Ph), 7.64–7.73 (2H, m, H-7 and
H-8), 7.98–8.01 (1H, m, H-6), 8.09–8.13 (1H, m, H-9). 1H NMR
dH (250 MHz, -30 ◦C, CDCl3) 2.72–3.15 (3H, m, NCH(H)CH2),
3.75 and 3.77 and 3.86 and 3.87 (3H, 4¥s, CO2CH3), 4.18–4.37
(1H, m, NC(H)H), 6.47 and 6.60 (1H, 2¥ br s, H-1), 7.29–7.42
(5H, m, Ph), 7.76–7.79 (2H, m, H-7 and H-8), 8.00–8.02 (1H,
m, H-6), 8.14–8.17 (1H, m, H-9). 13C NMR dC (63 MHz, 25 C,
CDCl3) 22.7 and 23.0 (C-4), 35.1 and 35.5 (C-3), 52.6 (CO2CH3),
52.9 (C-1), 126.3 ( CH), 126.6 ( CH), 128.0 ( CH, br), 128.6
(
(
Cquat), 1126.9 ( Cquat), 127.8 ( Cquat), 128.3 ( CH), 129.1
Cquat), 129.4 ( CH), 132.7 ( Cquat), 143.2 ( Cquat), 148.9 and
149.6 (2 ¥ C–OMe). IR (ATR): n 1589, 2838, 2932, 3070, 3329
(NH) cm-1. MS (ESI): m/z (%) = 356 (26) [M + H+ + 2], 355 (18)
[M + H+ + 1], 354 (100) [M + H+]. HRMS (ESI): m/z calcd for
C21H20ClNO2 + H+: 354.1255; found 354.1237.
◦
(
CH), 131.7 ( Cquat), 133.76 ( Cquat), 133.85 ( CH), 139.3
and 139.5 ( Cquat), 142.5 and 143.0 ( Cquat), 143.9 and 144.2
Cquat), 155.2 (C O), 182.2 (C O), 183.9 (C O). IR (ATR): n
Reactions with nucleophiles: n-propylamine
(
1595, 1633 (C O), 1661 (C O), 1689 (C O), 2884, 2954, 3007
cm-1. MS (ESI): m/z (%) = 348 (100) [M + H+], 272 (10), 224 (10).
Variable-temperature 1H NMR (250 MHz, CDCl3): 224 K, 234
K, 244 K; 245 K, 255 K, 265 K, 274 K, 284 K, 293 K, 303 K, 313
K, 323 K.
To compound 12c (0.1 g, 0.22 mmol), excess propylamine (1 ml)
was added and the mixture was refluxed for 21 h. Then the mixture
was evaporated, water (15 ml) was added and the organic material
was extracted with CH2Cl2 (3 ¥ 10 ml). The combined extracts
were dried (MgSO4) and evaporated. The product and unreacted
compound 12c were separated by column chromatography. Rf =
0.42 (petroleum ether/EtOAc : 1/1). Yield 0.06 g (81%, taking
into account a conversion of 80%).
2 - (1 - tert - Butyl - 3,4 - dihydro - 5,10 - dioxobenzo[g]isoquinolin-
2(1H,5H,10H)-yl)-2-oxo-N-propylacetamide (31). Scale of the
reaction: 0.15 mmol 27 (60 mg). Rf = 0.40 (petroleum ether/EtOAc
1
: 1/1). Yellow oil. Yield 0.035 g (63%). H NMR dH (250 MHz,
2-(1-tert-Butyl-3,4-dihydro-5,10-dimethoxybenzo[g]isoquinolin-
◦
24 C, CDCl3) 0.89–0.98 (3H, m, CH3), 1.06 and 1.07 (9H, 2¥s,
2(1H)-yl)-2-oxo-N-propylacetamide
(27). 1H
NMR
dH
C(CH3)3), 1.54–1.63 (2H, m, CH2), 2.76–3.09 (2H, m, H-4), 3.22–
3.33 (2H, m, CH2N), 3.33–3.86 (1H, 2¥m, NC(H)H), 4.58–5.02
(1H, 2¥m, NC(H)H), 5.86 and 6.66 (1H, 2¥s, H-1), 7.19 and 7.31
(1H, 2¥br s, NH), 7.70–7.78 (2H, m, H-7, H-8), 8.07–8.13 (2H,
m, H-6, H-9).13C NMR dC (63 MHz, 25 ◦C, CDCl3) 10.1 and
11.3 (CH3), 20.8 and 21.4 and 22.5 and 22.9 (C-4, CH2), 29.2
and 29.4 (C(CH3)3), 37.9 and 38.1 (C(CH3)3), 37.3 and 40.1 and
41.15 and 41.22 (C-3, CH2N), 54.0 and 56.1 (C-1), 126.1 and 126.2
(250 MHz, 24 ◦C, CDCl3) 0.96–1.00 (3H, m, CH3), 1.01
and 1.05 (9H, 2¥s, C(CH3)3), 1.53–1.65 (2H, m, CH2), 3.05–3.50
(4H, m, H-4, CH2N), 3.71–3.80 (1H, m, NC(H)H), 3.89 and 4.00
(6H, 2¥s, OCH3), 4.26–4.50 (1H, m, NC(H)H), 6.09 and 6.84 (1H,
2¥s, H-1), 7.21 and 7.41 (1H, 2¥br s, NH), 7.48–7.52 (2H, m, H-7,
H-8), 8.05–8.08 (2H, m, H-6, H-9).13C NMR dC (63 MHz, 25 ◦C,
CDCl3) 10.1 and 11.3 (CH3), 20.6 and 21.0 and 22.43 and 22.46
(C-4, CH2), 28.6 and 28.7 (C(CH3)3), 39.0 and 39.5 (C(CH3)3),
40.2 and 41.1 and 41.2 and 41.7 (C-3, CH2N), 55.5 and 57.8 (C-1),
61.3 (OCH3), 62.1 and 62.5 (OCH3), 122.0 ( CH), 122.8 and
123.0 ( CH), 123.5 and 123.9 ( Cquat), 125.4 and 125.5 ( Cquat),
125.6 and 125.7 ( CH), 126.09 and 126.11 ( CH), 127.2 and
127.3 ( Cquat), 127.9 ( Cquat), 148.9 and 149.0 (C–OMe), 149.2
(C–OMe), 161.96 and 162.06 (C O), 163.2 (C O). IR (ATR):
n 1614 (C O), 1676 (C O), 2875, 2920, 2961, 3307 (NH) cm-1.
MS (ESI): m/z (%) = 414 (18) [M + H+ + 1], 413 (100) [M + H+],
355 (10) [M - C4H10]. HRMS (ESI): m/z calcd for C24H32N2O4 +
H+: 413.2435; found 413.2443.
(
CH), 126.8 and 126.9 ( CH), 131.6 ( Cquat), 132.2 ( Cquat),
133.6 ( CH), 133.9 ( CH), 143.0 and 143.2 ( Cquat), 144.5 and
144.7 ( Cquat), 160.9 and 161.4 (C O), 162.2 (C O), 182.7 and
183.0 (C O), 183.6 and 183.8 (C O). IR (ATR): n 1629 (C O),
1662 (C O), 2875, 2931, 2963, 3312 (NH) cm-1. MS (ESI): m/z
(%) = 384 (21) [M + H+ + 1], 383 (100) [M + H+], 228 (22). HRMS
(ESI): m/z calcd for C22H26N2O4 + H+: 383.1965; found 383.1941.
Acknowledgements
Variable-temperature 1H NMR (250 MHz, CDCl3): 298 K, 303
K, 308 K, 313 K, 318 K. No coalescence was observed.
We gratefully acknowledge the Research Foundation – Flanders
(FWO-Vlaanderen) and the Vrije Universiteit Brussel (HOA) for
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financial support of this research. We thank Philippe Franck (UA)
for the help with UPLC analyses.
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