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

Article abstract of DOI:10.1016/j.tet.2008.03.014

The synthesis of 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-dione hydrochlorides is reported starting from 1,4-dihydrobenz[g]isoquinoline-3(2H)-ones or ethyl (3-aminomethyl-1,4-dimethoxynaphth-2-yl)acetates. A third strategy relies on the synthesis of the title compounds via an N-protected 2-(3-bromomethyl-1,4-dimethoxynaphth-2-yl)ethylamine. The synthesized 1,2,3,4-tetrahydro-benz[g]isoquinoline-5,10-diones are a new class of quinones, which have not been reported yet.

Full text of DOI:10.1016/j.tet.2008.03.014

Tetrahedron 64 (2008) 5345–5353
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of N-substituted 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-diones
,
Jan Jacobs a, Jurgen Deblander b, Bart Kesteleyn a, Kourosch Abbaspour Tehrani b, Norbert De Kimpe a
*
a Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium
b Laboratory of Organic Chemistry, Department of Applied Biological Sciences and Engineering, Faculty of Sciences, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-dione hydrochlorides is reported starting
from 1,4-dihydrobenz[g]isoquinoline-3(2H)-ones or ethyl (3-aminomethyl-1,4-dimethoxynaphth-2-yl)-
acetates. A third strategy relies on the synthesis of the title compounds via an N-protected 2-(3-bromo-
methyl-1,4-dimethoxynaphth-2-yl)ethylamine. The synthesized 1,2,3,4-tetrahydro-benz[g]isoquinoline-
5,10-diones are a new class of quinones, which have not been reported yet.
Received 29 February 2008
Accepted 6 March 2008
Available online 18 March 2008
Keywords:
Ó 2008 Published by Elsevier Ltd.
Tetrahydroisoquinolines
Benz[g]isoquinoline-3,5,10(2H)-triones
Quinones
1. Introduction
instance, are known as antiepileptics, muscle relaxants, and insect
repellants.8
The 1,2,3,4-tetrahydroisoquinoline ring system is a structural
component of many biologically active natural products.1 There-
fore, tetrahydroisoquinolines have been used as a structural tem-
plate for the synthesis of naturally occurring potent antitumor
antibiotics such as saframycins 1 and lemonomycin 2.2 Methods
available for the construction of the 1,2,3,4-tetrahydroisoquinoline
skeleton include the Bischler–Napieralski reaction,3 the Pictet–
Spengler reaction,4 and the Pomeranz–Fritsch reaction,5 among
others.6 In view of their biological activity, especially the
2-substituted 1,2,3,4-tetrahydroisoquinolines have elicited con-
siderable interest.7 Compounds with general structure 3, for
Considering the interesting biological activities of 2-substituted
1,2,3,4-tetrahydroisoquinolines, the synthesis of 1,2,3,4-tetrahy-
drobenz[g]isoquinoline-5,10-diones 12 was envisaged as part of
our research on structural modifications of the natural product
pentalongin 4 toward SAR studies. Within our department, these
structural modifications resulted in the synthesis of 1-alkyl and
1-aryl 3,4-dehydropyranonaphthoquinones 5,9 3-alkyl 3,4-dehy-
dropyranonaphthoquinones 6,10 4-alkyl 3,4-dehydropyranonaph-
thoquinones 7, 1,3-dialkyl 3,4-dehydropyranonaphthoquinones
8,11 and 4-substituted pyranonaphthoquinones 9. The synthesis
of the S-analogue of pentalongin (10) also has been achieved.12
OMe
O
Me
O
HO
OH
O
O
O
H
H
N
H
N
Me
Me
(CH2)m
X
NH
H
N
Me
R3
H
N
MeO
MeO
(CH2)n
NHR
R1 R2
O
HO
X
O
3
(Y = O,S)
1 (Saframycins)
(R = H, alkyl, alkenyl,
carbonyl residue)
(R1 = H, CN, OH and R2 = H or R1,R2 = O)
(R3 = H, OH, OMe, OEt)
O
OH
NMe2
2 (Lemonomycin)
(n: 0 to 2, m: 1 to 3)
NH
O
(X =
or
)
O
O
O
* Corresponding author. Tel.: þ32 9 264 59 51; fax: þ32 9 264 62 43.
E-mail address: norbert.dekimpe@ugent.be (N. De Kimpe).
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.03.014

5346
J. Jacobs et al. / Tetrahedron 64 (2008) 5345–5353
The synthesis of direct N-analogues 11 of pentalongin 4 is currently
under progress in our department. By synthesizing these N-ana-
logues, an impetus was given by the pharmaceutical industry to
the synthesis of 2-substituted 1,2,3,4-tetrahydrobenz[g]isoquino-
line-5,10-diones 12 as more distant 2-aza analogues of the natural
product pentalongin 4.
the presence of a free electron pair on the amino group, which
can also provoke oxidation of the aminoalkyl moiety of compounds
17. Therefore, the oxidation was accomplished using silver(II) oxide
in the presence of nitric acid (6 M), which serves as a cooxidant.16 It
is believed that for this oxidation nitric acid serves as an intrinsic
protection of the amino group through its nitrate salt and prevents
the oxidation of the aminoalkyl moiety. In the case of cerium(IV)
ammonium nitrate, which is more of a weak acidic oxidant, there
is no possibility for this intrinsic protection. In order to liberate
the amine from the reaction mixture, treatment with an excess
of sodium hydrogen carbonate at the end of the reaction allowed
2-isopropyl-1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-dione 12a
to be isolated in a yield of 73%. However, this compound was found
to be only of limited stability as it turned into a black tarry material
due to spontaneous oxidation in the air over a couple of hours
at room temperature. From the black residue, two oxidation prod-
ucts were isolated and identified as 2-isopropylbenz[g]isoquino-
line-3,5,10(2H)-trione (19a) and the pyridinium salt 20a, which
were obtained in yields of 16% and 15%, respectively. To protect
the 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-diones 12 from
this spontaneous oxidation, the hydrochloride salts 18a–d were
prepared in 35–83% yield by precipitation from a solution of com-
pounds 12 in dry diethyl ether using dry hydrogen chloride gas
(Scheme 1). The stability of 1,2,3,4-tetrahydrobenz[g]isoquino-
line-5,10-diones 12 under an inert atmosphere (nitrogen or argon)
was not studied, since it is not relative to biological screening.
For the synthesis of N-tert-butyl and N-phenyl 1,2,3,4-tetrahy-
drobenz[g]isoquinoline-5,10-dione hydrochlorides 18e and 18f,
an alternative pathway was preferred since the starting materials
were available as the aminomethylnaphthylacetates 13a and 13b,
for which the cyclization to the corresponding 1,4-dihydrobenz[g]-
isoquinoline-3(2H)-ones 16 had already been proven to be very diffi-
cult or even impossible.14 Therefore, aminomethylnaphthylacetates
13 were first reduced by reaction with lithium aluminum hydride in
diethyl ether to afford the corresponding N-tert-butylaminomethyl
and the N-phenylaminomethylnaphth-2-yl alcohols 21a and 21b
in yields of 49% and 33%, respectively. The cyclization of compounds
21 was performed by reaction with 2 equiv of thionyl chloride in
boiling dichloromethane for 2 h and subsequent treatment with
2 MNaOHtogivethecorresponding5,10-dimethoxy-1,2,3,4-tetrahy-
drobenz[g]isoquinolines 17e and 17f in 88% and 93%, respectively.
Finally, oxidation of compound 17e using 4 equiv of silver(II) oxide
in a 5:3 mixture of 1,4-dioxane and nitric acid (6 M) and subsequent
protection as the hydrochloride salt gave N-tert-butyl-1,2,3,4-tetra-
hydrobenz[g]isoquinoline-5,10-dione hydrochloride 18e in 60%
yield. Similar treatment of the N-phenyl analogue 17f, however,
afforded only a complex reaction mixture (Scheme 2). Probably, the
presence of the N-phenyl group accelerated the oxidative aromatiza-
tion of the intermediate 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-
dione in the course of the oxidation reaction .
O
O
R1
O
O
O
O
R2
O
O
R3
O
R
4 (Pentalongin)
5 (R1 = alkyl, aryl; R2,R3 = H)
6 (R2 = alkyl; R1,R3 = H)
7 (R3 = alkyl; R1,R2 = H)
8 (R1,R2 = alkyl, R3 = H)
9 (R = Cl, OH)
O
O
O
O
R
N
R
S
N
O
O
O
O
10
11 (R = alkyl)
12 (R = alkyl)
Although several 2-substituted 1,2,3,4-tetrahydroisoquinolines
have been synthesized,13 the synthesis of 2-substituted 1,2,3,4-
tetrahydrobenz[g]isoquinoline-5,10-diones has not been reported.
Depending on the type of substrate, the target compounds could
be prepared in three different ways. First, by reduction of the
lactam function of 1,4-dihydrobenz[g]isoquinoline-3(2H)-ones 16
and subsequent oxidative O-demethylation of the dimethoxynaph-
thalene moiety. In the case of aminomethylnaphthylacetates 13, re-
duction of the ester function followed by thionyl chloride mediated
intramolecular ring closure and subsequent oxidation should give
the targeted 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-diones 12.
The third strategy consists of the synthesis of 1,4-dimethoxynaph-
thalene 15, containing an N-protected aminoethyl group at C-3 and
a leaving group LG at the C-2-methylene group. An intramolecular
substitution, an optional N-alkylation, and a subsequent oxidation
should afford the desired target compounds 12.
2. Results and discussion
The reduction of N-substituted 1,4-dihydrobenz[g]isoquinoline-
3(2H)-ones 1614 with an excess of lithium aluminum hydride in
diethyl ether gave the corresponding 5,10-dimethoxy-1,2,3,4-tetra-
hydrobenz[g]isoquinolines 17 in 32–72% yield. Although cerium(IV)
ammonium nitrate has been used to convert tetrahydroisoquino-
lines in the corresponding quinones,15 the oxidative demethylation
of dimethoxynaphthalenes 17 with cerium(IV) ammonium nitrate
afforded only complex reaction mixtures. This is probably due to
R
MeO HN
OMe
O
R
O
R
O
N
N
OEt
OMe
OMe
O
13
16
12
OMe
OMe
LG
NHPG
NH
OMe
OMe
LG = Leaving group
PG = Protecting group
15
14

J. Jacobs et al. / Tetrahedron 64 (2008) 5345–5353
5347
OMe
OMe
R
O
R
4 equiv. LiAlH4
Et2O, rt, 16 h
N
N
OMe
OMe
16
17a : R = i-Pr (72%)
17b : R = n-Bu (32%)
17c : R = i-Bu (54%)
17d : R = sec-Bu (35%)
(R = i-Pr, n-Bu, i-Bu, sec-Bu)
4 equiv. AgO
dioxane, 6 M HNO3
50 °C, 16 h
O
O
R
N
R
N
HClg, Et2O
.
HCl
O
O
18a : R = i-Pr (35%)
18b : R = n-Bu (80%)
18c : R = i-Bu (73%)
18d : R = sec-Bu (83%)
12a-d (12a isolated in 73%)
(1) O2 (air), rt, 2 h
(R = i-Pr)
(2) HClg, EtOH
O
O
O
N
N
+
Cl
O
O
19a (16%)
20a (25%)
Scheme 1.
In an alternative approach, 5,10-dimethoxy-1,2,3,4-tetrahydro-
benz[g]isoquinoline was used as the key intermediate, which can
be synthesized starting from (1,4-dimethoxynaphth-2-yl)acetoni-
trile 22.17 In a first attempt, the nitrile function was treated with
LiAlH4 in refluxing tetrahydrofuran (THF) in order to obtain the
corresponding amine 23.18 Although the reducing agent was used
in excess, only partial reduction was observed. Based on this result
and on the fact that the reduction with LiAlH4 always led to a very
impure reaction mixture, the reduction was repeated by reaction
with an excess of BH3$THF (2.4 equiv) in refluxing THF. Full conver-
sion was achieved after 6 h and subsequent acid–base workup
afforded the desired 2-(1,4-dimethoxynaphth-2-yl)ethylamine 23
in 74% yield. Treatment of amine 23 with ethyl trifluoroacetate in
THF at room temperature gave the pure N-protected trifluoroacet-
amide 24 in 99% yield. This type of N-protecting group was selected
because of its high stability under strong acidic conditions, while
the moderate sterical hindrance of the trifluoroacetyl blocking
group offers the advantages of easy attachment and removal.19 Bro-
momethylation of 24 was accomplished by reaction with excess
paraformaldehyde and a concentrated solution of 33% HBr in acetic
acid during 8 h to afford the unsymmetrical bifunctionalized
1,4-dimethoxynaphtalene 25 in 54% yield. It is interesting to note
that an increase in reaction time induced a number of side reac-
tions, which led to a complex reaction mixture. The desired key
intermediate, 5,10-dimethoxy-1,2,3,4-tetrahydrobenz[g]isoquino-
line 26, was finally obtained as a trifluoroacetate salt in 75% yield
by deprotection of 25 with potassium hydroxide (5 M) in methanol
at room temperature, followed by an intramolecular substitution
and subsequent purification by preparative HPLC. Oxidationofcom-
pound 26 using silver(II) oxide and nitric acid(6 M) and protection as
the hydrochloride salt followed by a purification with preparative
HPLC afforded the N-unsubstituted 1,2,3,4-tetrahydrobenz[g]isoqui-
noline-5,10-dione trifluoroacetic acid salt 18g in 59% yield. If this
oxidation was performed on small scale (ꢀ0.15 mmol), only a trace
amount of a side product, probably the fully oxidized benz[g]isoqui-
noline-5,10-dione 27 (based on m/z 210 in ES-MS), was detected.
However, when the reaction was performed on a more extended
scale, the putative benz[g]isoquinoline-5,10-dione 27 became the
major compound of the reaction mixture. This is probably due to
the fact that the large scale workup is more time-consuming, in-
creasing the possibility of spontaneous oxidation of the amino moi-
ety, before the compound can be protected as a hydrochloride salt.
N-Alkylation of 5,10-dimethoxy-1,2,3,4-tetrahydrobenz[g]iso-
quinoline 26 with n-propylbromide and sodium carbonate in
refluxing EtOH or in refluxing 1,2-dichloroethane in the presence
of triethylamine only led to the unaltered starting material. Similar
R
MeO HN
OMe
OMe
R
2.2 equiv. LiAlH4
Et2O, rt, 16 h
O
N
H
OEt
OH
OMe
13a : R = t-Bu
13b : R = Ph
21a : R = t-Bu (49%)
21b : R = Ph (33%)
(1) 2 equiv. SOCl2
CH2Cl2, , 2 h
(2) 2 M NaOH, , 16 h
(1) 4 equiv. AgO
dioxane, 6 M HNO3
50 °C, 16 h
O
OMe
R
N
R
N
(2) HClg, Et2O
.
HCl
O
OMe
18e : R = t-Bu (60%)
18f : R = Ph (0%)
17e : R = t-Bu (88%)
17f : R = Ph (93%)
Scheme 2.

5348
J. Jacobs et al. / Tetrahedron 64 (2008) 5345–5353
OMe
OMe
(1) 2.4 equiv. BH3.THF
THF, N2, , 6 h
CN
(2) 0.5 M HCl, , 1 h
NH2
OMe
OMe
22
23 (74%)
1.1 equiv. CF3COOEt
THF, rt, 4 h
OMe
OMe
(CH2O)n
33% HBr/HOAc
O
Br
O
CH3COOH, rt, 8 h
CF3
N
H
CF3
N
H
OMe
OMe
24 (99%)
25 (54%)
(1) 10 equiv. KOH (5 M)
MeOH, rt, 20 h
(2) Prep. HPLC (CH3CN,
H2O, 0.1% TFA)
(1) 4 equiv. AgO
O
O
O
O
OMe
dioxane, 6 M HNO3
50 °C, 16 h
N
NH
NH
+
(2) HClg, Et2O
(3) Prep. HPLC (CH3CN,
H2O, 0.1% TFA)
.CF3COOH
.CF3COOH
.CF3COOH
OMe
27 (trace)
18g (59%)
26 (75%)
1.25 equiv. ethyl chloroformate
toluene, 4 M NaOH,
0 °C to rt, 12 h
(1) 4 equiv. AgO
dioxane, 6 M HNO3
50 °C, 16h
O
OMe
O
OMe
Me
Me
3 equiv. LiAlH4
THF, , 36 h
N
N
OEt
N
(2) HClg, Et2O
(3) Prep. HPLC (CH3CN,
H2O, 0.1% TFA)
.CF3COOH
O
OMe
28 (95%)
OMe
30 (62%)
29 (63%)
Scheme 3.
alkylation reactions with a stronger base, like sodium hydride or
potassium hydride, in combinationwith methyl iodide inTHFat room
temperature did not lead to the desired 2-methyl-5,10-dimethoxy-
1,2,3,4-tetrahydrobenz[g]isoquinoline 29. Based on these results,
the direct N-alkylation approach was abandoned and a reductive
alkylation method was tested. After deprotection of the quaternary
ammonium salt 26, the corresponding secondary amine was
treated with ethylchloroformate and sodium hydroxide (4 M) in
toluene at 0 ꢁC. After 2 h stirring at room temperature, the corre-
sponding carbamate 28 was obtained in 95% yield. Reduction of
the carbamate 28 with an excess of lithium aluminum hydride in
refluxing THF during 36 h resulted in the synthesis of N-methyl
5,10-dimethoxy-1,2,3,4-tetrahydrobenz[g]isoquinoline 29 in 63%
yield. In a second approach, N-methylation was performed by re-
ductive methylation using sodium cyanoborohydride and parafor-
maldehyde to obtain compound 29 in 55% yield. Finally, the
synthesis of N-methyl-1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-
dione trifluoroacetic acid salt 30 was achieved in 62% yield by
oxidation of compound 29 using 4 equiv of silver(II) oxide in com-
bination with nitric acid (6 M) and subsequent protection as the hy-
drochloride salt and purification by preparative HPLC (Scheme 3).
acetates 13 for the synthesis of the target compounds required
an extra thionyl chloride mediated ring closure to the correspond-
ing 5,10-dimethoxy-1,2,3,4-tetrahydrobenz[g]isoquinolines 17. The
synthesis of N-unsubstituted 1,2,3,4-tetrahydrobenz[g]isoquino-
line-5,10-dione trifluoroacetic acid salt 18g could be achieved after
oxidation of the 5,10-dimethoxy-1,2,3,4-tetrahydrobenz[g]isoqui-
nolinium trifluoroacetate (26) with silver(II) oxide in nitric acid.
Reductive N-alkylation of compound 26 made it also possible to
synthesize the N-methyl 1,2,3,4-tetrahydrobenz[g]isoquinoline-
5,10-dione trifluoroacetic acid salt 30.
4. Experimental section
4.1. General experimental methods
Spectroscopic data were recorded as follows: 1H NMR spectra
were recorded at 250 MHz, 270 MHz, 300 MHz, or 500 MHz and
13C NMR spectra were recorded at 63 MHz, 68 MHz, 75 MHz, or
126 MHz. Peak assignments were performed with the aid of the
DEPT technique, 2D-COSY, and HETCOR spectra. Melting points
(mps) were determined on a Bu¨chi B540 Melting Point Apparatus
with a temperature gradient of 1 ꢁC/min. The reported melting
points are not corrected. Mass spectra were recorded using a direct
inlet system (70 eV) with a VL detector (ES, 4000 V). Elemental
analyses were executed with Perkin Elmer Series II CHNS/O Ana-
lyzer 2400. Flash chromatography was carried out using a glass
column with silica gel (particle size 0.035–0.07 mm, pore diameter
ca. 6 nm). Solvent systems were determined via initial TLC analysis.
Infrared spectra were recorded with an Avatar 370 FTIR apparatus
3. Conclusions
The synthesis of N-substituted 1,2,3,4-tetrahydrobenz[g]isoqui-
noline-5,10-dione hydrochlorides 18 succeeded through reduction
of 1,4-dihydrobenz[g]isoquinoline-3(2H)-ones 16 with lithium alu-
minum hydride and subsequent oxidation with silver(II) oxide in
nitric acid. The use of (3-aminomethyl-1,4-dimethoxynaphth-2-yl)-

J. Jacobs et al. / Tetrahedron 64 (2008) 5345–5353
5349
(Thermo Nicolet). Unless otherwise stated, the IR spectra were
recorded using the attenuated total reflection technology. Prepara-
tive RP-HPLC was performed using a Gilson apparatus with a re-
verse phase C-18 column (Discovery Wide Pore, 25 cmꢂ21.2 mm,
10 mm). The mobile phase (water/acetonitrile) contained 0.1% TFA.
The standard gradient consisted of a 20 min run from 3% to 97%
acetonitrile at a flow of 20 ml/min with UV detection at 215 nm.
GC–MS analyses were performed using an Interscience, GC 8000
series gas chromatograph with an ECÔ-5 column (length: 30 m, in-
ternal diameter: 0.32 mm, film thickness: 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.
8.01–8.06 (2H, m, H-6 and H-9). 13C NMR (75 MHz, CDCl3): d 21.2
(2ꢂCH3), 24.6, 25.9, 50.7, 52.4, 60.9, 61.3, 67.1, 122.0 (2ꢂCHar),
125.3, 125.4, 125.5, 125.9, 127.0, 127.3, 148.1, 149.4. IR (NaCl): n
max
1594, 1456, 1356, 1061 cmꢃ1. MS (ES) m/z (%): 300 (MþHþ, 100).
Anal. Calcd for C19H25NO2: C 76.22, H 8.42, N 4.68; found: C 76.10,
H 8.31, N 4.58.
4.2.5. 2-sec-Butyl-5,10-dimethoxy-1,2,3,4-tetrahydrobenz[g]-
isoquinoline (17d)
Flash chromatography on silica gel with ethyl acetate/hexane
(1:1) as eluent gave 17d as a brown oil. 1H NMR (300 MHz,
CDCl3): d 0.97 (3H, t, J¼7.4 Hz, CH2CH3), 1.12 (3H, d, J¼6.6 Hz,
CHCH3), 1.39–1.49 and 1.69–1.78 (2H, m, CH2CH3), 2.70–2.78 (1H,
m, NCH), 2.80 (2H, t, J¼6.2 Hz, CH2-3), 3.06 (2H, t, J¼6.2 Hz, CH2-
4), 3.87 (3H, s, MeO), 3.89 (3H, s, MeO), 3.94 (2H, d, J¼5.8 Hz,
CH2-1), 7.40–7.46 (2H, m, H-7 and H-8), 7.99–8.05 (2H, m, H-6
and H-9). 13C NMR (75 MHz, CDCl3): d 11.5, 13.8, 25.3, 26.2, 45.3,
47.4, 60.7, 60.8, 61.2, 121.9 (2ꢂCHar), 125.2, 125.3, 125.4, 126.3,
4.2. Synthesis of 5,10-dimethoxy-1,2,3,4-tetrahydro-
benz[g]isoquinolines 10 starting from 1,4-dihydrobenz[g]-
isoquinoline-3(2H)-ones 16
4.2.1. General procedure
126.9, 127.1, 148.1, 149.4. IR (NaCl):
n
1594, 1456, 1356,
max
To a cooled solution (0 ꢁC) of 1,4-dihydrobenz[g]isoquinoline-
3(2H)-ones 16 (1.7 mmol) in dry diethyl ether (10 ml) was added
lithium aluminum hydride (6.8 mmol, 0.26 g) portionwise and the
mixture was stirred at room temperature for 16 h in a flask fitted
with a calcium chloride tube. The reaction was quenched by careful
addition of water (5 ml) and the reaction mixture was filtered over
CeliteÒ, rinsing the filter cake several times with diethyl ether. The
organic phase was separated, dried (MgSO4), and evaporated in
vacuo followed by flash chromatography on silica gel.
1079 cmꢃ1. MS (ES) m/z (%): 300 (MþHþ, 100). Anal. Calcd for
C19H25NO2: C 76.22, H 8.42, N 4.68; found: C 76.14, H 8.51, N 4.54.
4.3. Synthesis of 2-isopropyl-1,2,3,4-tetrahydrobenz[g]-
isoquinoline-5,10-dione (12a)
To a solution of 2-isopropyl-5,10-dimethoxy-1,2,3,4-tetrahydro-
benz[g]isoquinoline (17a) (0.7 mmol, 200 mg) in 1,4-dioxane (5 ml)
was added first silver(II) oxide (2.8 mmol, 347 mg) and then 6 M
HNO3 (3 ml) was added dropwise. The suspension was stirred for
16 h at 50 ꢁC. A saturated solution of sodium hydrogen carbonate
was added until basic pH and the aqueous solution was extracted
four times with diethyl ether. The combined organic extracts
were washed with brine, dried (MgSO4), and evaporated in vacuo.
Flash chromatography on silica gel with 1% methanol in chloroform
as eluent gave 12a (130 mg, 73%) as a brown oil (purityz95% by 1H
NMR). This compound was stable enough to run NMR spectra
(spectral data: see below). However, compound 12a was found to
decompose rapidly as it turned black after a couple of hours. The
black residue was dissolved in a solution of ethanol, which had
been presaturated with hydrogen chloride gas (1 ml). Dry diethyl
ether was added, which caused the precipitation of a brown pow-
der. The precipitate was obtained by filtration and it was identified
as pyridinium salt 20a (50 mg, 25%), mp 140–150 ꢁC. Evaporation of
the mother liquor and flash chromatography on silica gel using
ethyl acetate/hexane (1:4) as eluent gave 2-isopropylbenz[g]isoqui-
noline-3,5,10(2H)-trione 19a (30 mg, 16%) as a yellow powder. The
spectral data (1H NMR, 13C NMR, IR, MS) of 2-isopropylbenz[g]iso-
quinoline-3,5,10(2H)-trione 19a were identical with the data
reported in the literature by us.14
4.2.2. 2-Isopropyl-5,10-dimethoxy-1,2,3,4-tetrahydrobenz[g]-
isoquinoline (17a)
Flash chromatography on silica gel with 2% methanol in chloro-
form as eluent gave 17a as a brown oil. 1H NMR (270 MHz, CDCl3):
d 1.20 (6H, d, J¼6.6 Hz, 2ꢂCH3), 2.81 (2H, t, J¼5.9 Hz, CH2-3), 3.00
(1H, septet, J¼6.6 Hz, NCH), 3.09 (2H, t, J¼5.9 Hz, CH2-4), 3.87
(3H, s, MeO), 3.90 (3H, s, MeO), 3.94 (2H, s, CH2-1), 7.41–7.47 (2H,
m, H-7 and H-8), 7.99–8.05 (H-6 and H-9). 13C NMR (68 MHz,
CDCl3): d 18.4, 24.9, 45.6, 47.4, 60.9, 61.3, 122.0 (2ꢂCHar, ]Cquat),
125.0, 125.3, 125.4, 126.9, 127.2, 148.2, 149.5. IR (NaCl): nmax 1590,
1450, 1350, 1075 cmꢃ1. MS (70 eV) m/z (%): 285 (Mþ, 33), 270
(100), 254 (54), 240 (36), 199 (26). Anal. Calcd for C18H23NO2: C
75.76, H 8.12, N 4.91; found: C 76.08, H 8.01, N 4.68.
4.2.3. 2-n-Butyl-5,10-dimethoxy-1,2,3,4-tetrahydrobenz[g]-
isoquinoline (17b)
Flash chromatography on silica gel with ethyl acetate/hexane
(gradient of 9:1 to 1:1) as eluent gave 17b as a brown oil. 1H NMR
(300 MHz, CDCl3): d 0.97 (3H, t, J¼7.3 Hz, CH3), 1.40 (2H, sextet,
J¼7.3 Hz, CH2CH3), 1.60–1.70 (2H, m, NCH2CH2), 2.59 (2H, t,
J¼7.7 Hz, NCH2), 2.77 (2H, t, J¼6.1 Hz, CH2-3), 3.10 (2H, t, J¼6.1 Hz,
CH2-4), 3.87 (2H, s, CH2-1), 3.88 (3H, s, MeO), 3.90 (3H, s, MeO),
7.44–7.49 (2H, m, H-7 and H-8), 8.01–8.08 (2H, m, H-6 and H-9).
13C NMR (75 MHz, CDCl3): d 14.1, 20.9, 24.5, 29.4, 50.4, 51.9, 58.5,
60.8, 61.2, 122.0 (2ꢂCHar), 122.2, 124.9, 125.3, 125.4, 126.9, 127.2,
4.3.1. 2-Isopropyl-1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-
dione (12a)
1H NMR (270 MHz, CDCl3): d 1.14 (6H, d, J¼6.6 Hz, 2ꢂCH3), 2.72
(4H, m, CH2-3 and CH2-4), 3.98 (1H, septet, J¼6.6 Hz, NCH), 3.61
(2H, m, CH2-1), 7.67–7.72 (2H, m, H-7 and H-8), 8.04–8.08 (2H, m,
H-6 and H-9). 13C NMR (68 MHz, CDCl3): d 18.2, 24.5, 44.3, 45.6,
54.2, 126.1, 126.2, 131.9, 132.0, 133.5 (2ꢂCHar), 142.99 (2ꢂ]Cquat),
183.7, 184.0.
148.0, 149.4. IR (NaCl): n
1594, 1456, 1356, 1026 cmꢃ1. MS (ES)
max
m/z (%): 300 (MþHþ, 100). Anal. Calcd for C19H25NO2: C 76.22, H
8.42, N 4.68; found: C 76.36, H 8.27, N 4.79.
4.2.4. 2-Isobutyl-5,10-dimethoxy-1,2,3,4-tetrahydro-
benz[g]isoquinoline (17c)
4.3.2. 2-Isopropyl-5,10-dioxo-5,10-dihydrobenz[g]isoquinolinium
chloride (20a)
Flash chromatography on silica gel with ethyl acetate/hexane
(3:7) as eluent gave 17c as a brown oil. 1H NMR (300 MHz,
1H NMR (270 MHz, CD3OD): d 1.83 (6H, d, J¼6.6 Hz, 2ꢂCH3), 5.31
(1H, septet, J¼6.6 Hz, CH), 8.04–8.07 (2H, m, H-7 and H-8), 8.39–
8.44 (2H, m, H-6 and H-9), 8.77 (1H, d, J¼6.3 Hz, H-4), 9.51 (1H,
d, J¼6.3 Hz, H-3), 9.85 (1H, s, H-1). 13C NMR (68 MHz, CD3OD):
d 23.1, 68.3, 126.2, 128.2, 128.7, 132.8, 134.2, 135.7, 136.9 (2ꢂCHar),
CDCl3):
d
0.98 (6H, d, J¼6.6 Hz, 2ꢂCH3), 1.91–2.05 (1H, m,
CH(CH3)2), 2.34 (2H, d, J¼7.4 Hz, NCH2), 2.71 (2H, t, J¼6.0 Hz, CH2-
3), 3.07 (2H, t, J¼6.0 Hz, CH2-4), 3.80 (2H, s, CH2-1), 3.87 (3H,
s, MeO), 3.88 (3H, s, MeO), 7.41–7.46 (2H, m, H-7 and H-8),

5350
J. Jacobs et al. / Tetrahedron 64 (2008) 5345–5353
145.3, 145.4, 148.0, 180.0, 180.3. IR (KBr): nmax 1680, 1580 cmꢃ1. MS
(70 eV) m/z (%): 252 (MþꢃCl, 15), 209 (100), 181 (42), 153 (51).
H-6 and H-9). 13C NMR (68 MHz, CDCl3): d 25.8, 25.9, 43.8, 44.6,
54.4, 60.8, 61.2, 125.2, 125.3, 126.4, 126.9, 127.2, 128.3, 130.9, 148.3,
149.3. IR (NaCl): n
1455, 1354, 1085 cmꢃ1. MS (70 eV) m/z (%):
max
4.4. Synthesis of N-tert-butyl- and N-phenyl-2-(3-amino-
methyl-1,4-dimethoxynaphth-2-yl)ethanol 21a and 21b
299 (Mþ, 20), 284 (100), 57 (40). Anal. Calcd for C19H25NO2: C
76.22, H 8.42, N 4.68; found: C 76.07, H 8.56, N 4.55.
4.4.1. General procedure
4.5.3. 2-Phenyl-5,10-dimethoxy-1,2,3,4-tetrahydrobenz[g]-
isoquinoline (17f)
To a cooled (0 ꢁC) solution of ethyl (3-aminomethyl-1,4-dimeth-
oxynaphth-2-yl)acetates 13 (0.56 mmol) in dry diethyl ether (5 ml)
was added lithium aluminum hydride (1.23 mmol, 47 mg) and
the reaction mixture was kept stirring at room temperature for
16 h in a flask fitted with a calcium chloride tube. The reaction
was quenched by careful addition of a few drops of water. Potas-
sium carbonate (1 g) was added and the mixture was stirred for
30 min in a stoppered flask, filtered, and evaporated in vacuo.
Flash chromatography on silica gel with ethyl acetate/hexane
(1:1) as eluent gave 17f as a brown oil. 1H NMR (270 MHz,
CDCl3): d 3.15 (2H, t, J¼5.9 Hz, CH2-3), 3.56 (2H, t, J¼5.9 Hz, CH2-
4), 3.86 (3H, s, MeO), 3.91 (3H, s, MeO), 4.60 (2H, s, CH2-1), 6.80–
6.85 (1H, m, CHar), 7.02–7.06 (2H, m, 2ꢂCHar), 7.25–7.32 (2H, m,
2ꢂCHar), 7.43–7.48 (2H, m, H-7 and H-8), 8.02–8.07 (2H, m, H-6
and H-9). 13C NMR (68 MHz, CDCl3): d 23.8, 46.4, 46.5, 61.2, 61.4,
115.6 (2ꢂCHar), 118.9, 122.0 (2ꢂCHar), 124.8, 125.1, 125.5, 126.7,
4.4.2. 2-[3-((tert-Butylamino)methyl)-1,4-dimethoxynaphth-2-
yl]ethanol (21a)
127.0, 127.4, 129.2, 148.3, 149.3, 150.6. IR (NaCl): n
1597, 1497,
max
1451, 1356, 1074 cmꢃ1. MS (70 eV) m/z (%): 319 (Mþ, 5), 288 (5),
91 (100). Anal. Calcd for C21H21NO2: C 78.97, H 6.63, N 4.39; found:
C 78.66, H 6.40, N 4.02.
Recrystallization form ethyl acetate/hexane (1:1) gave 21a as
a white powder, mp 137–138 ꢁC. 1H NMR (270 MHz, CDCl3): d 1.29
(9H, s, 3ꢂCH3), 3.13 (2H, t, J¼5.3 Hz, CH2), 3.92 (3H, s, MeO), 3.94–
3.95 (4H, m, CH2OH and NCH2), 3.97 (3H, s, MeO), 7.49–7.55 (2H,
m, H-6 and H-7), 8.03–8.08 (2H, m, H-5 and H-8). 13C NMR
(68 MHz, CDCl3): d 28.3, 30.5, 37.3, 51.5, 61.4, 62.3, 63.2, 122.5
(2ꢂCHar), 125.7, 126.1, 127.5, 128.1, 128.5, 130.4, 150.8, 151.1. IR
4.6. Synthesis of N-substituted 1,2,3,4-tetrahydrobenz[g]-
isoquinoline-5,10-dione hydrochlorides 18
4.6.1. General procedure
(KBr): n
3220, 3060, 1585, 1490, 1455, 1355, 1100, 1065 cmꢃ1
.
To a solution of 5,10-dimethoxy-1,2,3,4-tetrahydrobenz[g]iso-
quinolines 17 (1.4 mmol) in 1,4-dioxane (5 ml) was added first
silver(II) oxide (5.6 mmol, 0.69 g) followed by the addition of 6 M
HNO3 (3 ml) dropwise. The suspension was stirred for 16 h at
50 ꢁC. A saturated solution of sodium hydrogen carbonate was
added until basic pH and the aqueous phase was extracted four
times with small portions of diethyl ether. The combined organic
extracts were washed with brine, dried (MgSO4), and concentrated
in vacuo to 10 ml. A saturated solution of dry hydrogen chloride gas
in dry diethyl ether was added dropwise until the precipitation of
the hydrochloride salt 18 was completed.
max
MS (70 eV) m/z (%): 317 (Mþ, 9), 302 (26), 287 (60), 272 (10), 260
(14), 245 (79), 229 (45), 214 (100). Anal. Calcd for C19H27NO3: C
71.89, H 8.57, N 4.41; found: C 71.97, H 8.30, N 4.29.
4.4.3. 2-[3-((Phenylamino)methyl)-1,4-dimethoxynaphth-2-
yl]ethanol (21b)
Flash chromatography on silica gel using ethyl acetate/hexane
(1:4) as eluent gave 21b as a white powder. An analytical sample
was obtained by recrystallization from diethyl ether to give 21b
as white crystals, mp 143–144 ꢁC. 1H NMR (270 MHz, CDCl3):
d 3.08 (2H, t, J¼6.1 Hz, CH2), 3.87–3.91 (8H, m, CH2OH and
2ꢂMeO), 4.42 (2H, s, NCH2), 6.73–6.78 (3H, m, 3ꢂCHar), 7.18–7.24
(2H, m, 2ꢂCHar), 7.48–7.54 (2H, m, H-6 and H-7), 8.01–8.10 (2H,
m, H-5 and H-8). 13C NMR (68 MHz, CDCl3): d 30.3, 40.3, 43.1,
61.7, 63.3, 113.4 (2ꢂCHar), 118.0, 122.3, 122.8, 126.0, 126.5, 127.4,
127.9, 128.1, 128.4, 129.3 (2ꢂCHar), 148.3, 151.1, 151.6. IR (KBr):
nmax 3416, 3290, 1614, 1598, 1507, 1352, 1155, 1067 cmꢃ1. MS
(70 eV) m/z (%): 337 (Mþ, 51), 319 (22), 288 (28), 245 (60), 244
(100). Anal. Calcd for C21H23NO3: C 74.75, H 6.87, N 4.15; found: C
74.64, H 7.01, N 4.03.
4.6.2. 2-Isopropyl-1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-dione
hydrochloride (18a)
The salt was obtained by filtration and it was recrystallized from
dichloromethane/diethyl ether (1:1) to give 18a as brown crystals,
mp 176.5–177 ꢁC. 1H NMR (270 MHz, CDCl3): d 1.54 (3H, d,
J¼5.5 Hz, CH3), 1.60 (3H, d, J¼5.5 Hz, CH3), 2.84–3.01 (1H, m, CH2-
4), 3.06–3.21 (1H, dꢂd, J¼1.2, 17.5 Hz, CH2-4), 3.45–3.87 (4H, m,
NCH, CH2-3, and CH2-1), 4.33–4.45 (1H, dꢂd, J¼1.0, 17.5 Hz, CH2-
1), 7.76–7.80 (2H, m, H-7 and H-8), 8.07–8.14 (2H, m, H-6 and H-9),
13.14 (1H, br s, NH). 13C NMR (68 MHz, D2O): d 16.7, 17.4, 22.0, 44.8,
45.9, 59.7, 127.4, 127.7, 132.2, 132.4, 135.8, 135.9, 137.5, 142.6, 184.6,
185.2. IR (KBr): nmax 3400, 1660, 1650, 1585, 1330, 1290 cmꢃ1. MS
(ES) m/z (%): 256.3 ([MꢃHCl]þHþ,100). Anal. Calcd for C16H18ClNO2:
C 65.86, H 6.22, N 4.80; found: C 65.68, H 5.90, N 4.64.
4.5. Synthesis of 2-tert-butyl- and 2-phenyl-5,10-dimethoxy-
1,2,3,4-tetrahydrobenz[g]isoquinoline 17e and 17f
4.5.1. General procedure
A solution of (3-aminomethylnaphth-2-yl)alcohol 21 (1.3 mmol)
and thionyl chloride (2.6 mmol, 0.31 g) in dichloromethane (10 ml)
was heated under reflux for 2 h. NaOH (2 M, 20 ml) was added and
the vigorously stirred biphasic system was heated under reflux for
16 h. The organic phase was separated and the aqueous phase was
extracted twice with dichloromethane. The combined organic
extracts were dried (MgSO4) and evaporated in vacuo.
4.6.3. 2-n-Butyl-1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-dione
hydrochloride (18b)
Recrystallization from diethyl ether/dichloromethane (1:1) gave
18b as green crystals, mp 177.5–178.1 ꢁC. 1H NMR (300 MHz,
CDCl3): d 1.02 (3H, t, J¼7.4 Hz, CH3), 1.47 (2H, sextet, J¼7.4 Hz,
CH2CH3), 1.98–2.09 (2H, m, NCH2CH2), 2.91–3.21 (4H, m, NCH2
and CH2-4), 3.45–3.55 (1H, m, CH2-1), 3.70–3.78 (2H, m, CH2-3),
4.52–4.58 (1H, dꢂd, J¼1.2 Hz, 18.0 Hz, CH2-1), 7.78–7.82 (2H, m,
H-7 and H-8), 8.08–8.14 (H-6 and H-9), 13.43 (1H, br s, NH). 13C
NMR (75 MHz, CDCl3): d 13.6, 20.2, 20.4, 25.6, 47.2, 48.1, 57.1,
126.5, 126.9, 131.4, 131.6, 134.3, 134.5, 135.2, 142.8, 182.1, 182.3. IR
(KBr): nmax 3401, 1666, 1649, 1592, 1335, 1297 cmꢃ1. MS (ES) m/z
(%): 270.2 ([MꢃHCl]þHþ, 100). Anal. Calcd for C17H20ClNO2: C
66.77, H 6.59, N 4.58; found: C 66.53, H 6.73, N 4.75.
4.5.2. 2-tert-Butyl-5,10-dimethoxy-1,2,3,4-tetrahydrobenz[g]-
isoquinoline (17e)
Flash chromatography on silica gel using ethyl acetate/hexane
(1:1) as eluent gave 17e as a dark brown oil. 1H NMR (270 MHz,
CDCl3): d 1.24 (9H, s, 3ꢂCH3), 2.84 (2H, t, J¼5.9 Hz, CH2-3), 3.08
(2H, t, J¼5.9 Hz, CH2-4), 3.88 (3H, s, MeO), 3.90 (3H, s, MeO), 4.00
(2H, s, CH2-1), 7.42–7.47 (2H, m, H-7 and H-8), 7.99–8.05 (2H, m,

J. Jacobs et al. / Tetrahedron 64 (2008) 5345–5353
5351
4.6.4. 2-Isobutyl-1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-dione
hydrochloride (18c)
s, MeO), 6.54 (1H, s, CHar), 7.33–7.48 (2H, m, H-6 and H-7), 7.95 (1H,
dꢂm, J¼8.1 Hz, H-5 or H-8), 8.13 (1H, dꢂm, J¼7.9 Hz, H-5 or H-8).
13C NMR (63 MHz, CDCl3): d 33.5, 42.0, 54.7, 61.0, 104.5, 120.7,
121.3, 123.9, 124.6, 125.5, 126.4, 127.6, 146.4, 150.8. IR (ATR): nmax
2931, 2839, 1594, 1459, 1369, 1090 cmꢃ1. MS (ES) m/z (%): 232
(MþHþ, 40), 215 (90), 200 (100). HRMS (ESI) m/z calcd for
Recrystallization from diethyl ether/dichloromethane (1:1) gave
18c as yellow-brown crystals, mp 178.9–179.6 ꢁC. 1H NMR
(300 MHz, CDCl3): d 1.20 (3H, d, J¼6.8 Hz, CH3), 1.25 (3H, d,
J¼6.8 Hz, CH3), 2.32–2.40 (1H, m, CH), 2.94–3.09 (4H, m, NCH2
and CH2-4), 3.51–3.63 (1H, m, CH2-1), 3.71–3.84 (2H, m, CH2-3),
4.58 (1H, dꢂd, J¼1.1, 17.3 Hz, CH2-1), 7.77–7.80 (2H, m, H-7 and
H-8), 8.08–8.14 (2H, m, H-6 and H-9), 13.06 (1H, br s, NH). 13C
NMR (75 MHz, CDCl3): d 20.5 (2ꢂCH3), 21.4, 25.1, 44.6, 49.4, 64.8,
127.3, 127.5, 133.0, 133.1, 135.4, 135.5, 136.6, 142.1, 183.3, 183.6. IR
(KBr): nmax 3394, 1662, 1648, 1592, 1337, 1299 cmꢃ1. MS (ES) m/z
(%): 270.2 ([MꢃHCl]þHþ, 100). Anal. Calcd for C17H20ClNO2: C
66.77, H 6.59, N 4.58; found: C 66.95, H 6.46, N 4.40.
C
14H17NO2þH: 232.1338; found: 232.1364.
4.8. Synthesis of N-[2-(1,4-dimethoxynaphth-2-yl)-ethyl]-
2,2,2-trifluoroacetamide (24)
Ethyl trifluoroacetate (0.72 mmol, 102 mg) was added dropwise
to
a solution of 2-(1,4-dimethoxynaphth-2-yl)ethylamine 23
(0.65 mmol, 150 mg) in tetrahydrofuran (8 ml). The reaction mix-
ture was stirred for 4 h at room temperature. Evaporation of the
solvent under vacuum gave 24 as a white solid in a 99% yield, mp
112.5–114 ꢁC. For the subsequent bromomethylation, the product
was used without further purification. An optional purification by
flash chromatography on silica gel using ethyl acetate/cyclohexane
(1:3) as eluent can be performed.
4.6.5. 2-sec-Butyl-1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-dione
hydrochloride (18d)
Recrystallization from diethyl ether/dichloromethane (1:1) gave
18d as pink crystals, mp 170.5–170.8 ꢁC. Mixture of two diastereo-
mers (ratio 1:1). 1H NMR (300 MHz, CDCl3): d 1.09 (3H, 2ꢂt,
J¼7.4 Hz, CH2–CH3), 1.48 and 1.55 (3H, d, J¼6.6 Hz, CH3), 1.56–1.80
(2H, m, CH2CH3), 2.90–3.02 (1H, m, NCH), 3.13 (1H, m, CH2-4),
3.37–3.50 (1H, m, CH2-4), 3.58–3.68 (2H, m, CH2-3), 3.79–3.87
(1H, m, CH2-1), 4.37 (1H, dꢂd, J¼1.5, 17.0 Hz, CH2-1), 7.76–7.79
(2H, m, H-7 and H-8), 8.10–8.11 (2H, m, H-6 and H-9), 13.08 (1H,
br s, NH). 13C NMR (75 MHz, CDCl3): d 10.8, 10.9, 12.2, 13.6, 20.9,
23.0, 24.3, 42.3, 43.5, 44.6, 45.4, 63.7, 63.8, 126.5, 126.9, 131.5,
4.8.1. N-[2-(1,4-Dimethoxynaphth-2-yl)-ethyl]-2,2,2-
trifluoroacetamide (24)
1H NMR (250 MHz, CDCl3): d 3.04 (2H, t, J¼6.6 Hz, CH2CH2N),
3.64 (2H, q, J¼5.9 Hz, CH2N), 3.91 (3H, s, MeO), 3.97 (3H, s, MeO),
6.54 (1H, s, CH), 7.28 (1H, br s, NH), 7.45–7.59 (2H, m, H-6 and H-
7), 8.01 (1H, dꢂm, J¼7.9 Hz, H-5 or H-8), 8.23 (1H, dꢂm,
J¼8.4 Hz, H-5 or H-8). 13C NMR (63 MHz, CDCl3): d 29.1, 40.7, 55.0,
61.3, 104.6, 115.2 (q, J¼287.9 Hz, CF3), 121.0, 121.9, 124.8, 125.3,
125.4, 126.3, 127.7, 146.5, 151.9, 156.8 (q, J¼36.8 Hz, CO). IR (ATR):
131.7, 134.2, 134.5, 135.7, 141.8, 182.1, 182.5. IR (KBr): n
3303,
max
1662, 1647, 1592, 1336, 1298 cmꢃ1
. MS (ES) m/z (%): 270.2
([MꢃHCl]þHþ, 100). Anal. Calcd for C17H20ClNO2: C 66.77, H 6.59,
N 4.58; found: C 66.62, H 6.41, N 4.70.
n
3289, 2946, 1703, 1365, 1153, 1095 cmꢃ1. MS (EI, 70 eV) m/z
max
4.6.6. 2-tert-Butyl-1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-dione
hydrochloride (18e)
(%): 328 (Mþþ1, 36), 327 (Mþ, 86), 280 (13), 214 (58), 201 (65),
200 (43), 199 (100), 186 (57), 184 (43), 171 (61), 170 (41), 159 (18),
141 (31), 78 (16), 69 (23). HRMS (ESI) m/z calcd for C16H16F3NO3þH:
328.1161; found: 328.1226.
Recrystallization from diethyl ether/dichloromethane (1:1) gave
18e as brown crystals, mp 180 ꢁC. 1H NMR (270 MHz, D2O): d 1.46
(9H, s, 3ꢂCH3), 2.76–2.92 (1H, m, CH2-4), 3.05–3.15 (2H, m, CH2-
3), 3.95 (1H, dꢂdꢂd, J¼11.8, 6.5, 1.3 Hz, CH2-4), 4.17 (1H, dꢂd,
J¼17.8, 1.8 Hz, CH2-1), 4.40 (1H, d, J¼17.8 Hz, CH2-1), 7.79–7.83
(2H, m, H-7 and H-8), 8.00–8.05 (2H, m, H-6 and H-9), 12.90 (1H,
br s, NH). 13C NMR (68 MHz, CDCl3): d 21.6, 24.3, 42.9, 43.1, 64.7,
126.6, 126.8, 131.8 (2ꢂCquat), 134.4, 134.6, 136.2, 141.8, 182.4, 182.7.
IR (KBr): nmax 3407, 1656, 1616, 1381, 1335, 1298 cmꢃ1. MS (ES)
m/z (%): 270.2 ([MꢃHCl]þHþ, 100). Anal. Calcd for C17H20ClNO2: C
66.77, H 6.59, N 4.58; found: C 66.82, H 6.58, N 4.18.
4.9. Synthesis of N-[2-(3-bromomethyl-1,4-dimethoxy-
naphth-2-yl)-ethyl]-2,2,2-trifluoroacetamide (25)
To a stirred mixture of N-[2-(1,4-dimethoxynaphth-2-yl)-ethyl]-
2,2,2-trifluoroacetamide 24 (0.3 mmol, 100 mg) and acetic acid
(1 ml) were added paraformaldehyde (16.7 mmol, 500 mg) and
a solution of 33% HBr in acetic acid (3 ml). The mixture was stirred
for 8 h at room temperature and then water (10 ml) was added and
the aqueous solution was extracted with diethyl ether (2ꢂ25 ml).
The organic extracts were washed with water, dried (MgSO4), and
evaporated in vacuo. Flash chromatography on silica gel with 15%
ethyl acetate in cyclohexane as eluent gave 25 (70 mg, 54%) as
a light brown powder, mp 89–90 ꢁC.
4.7. Synthesis of 2-(1,4-dimethoxynaphth-2-yl)ethyl-
amine (23)
To a solution of (1,4-dimethoxynaphth-2-yl)acetonitrile 22
(2.2 mmol, 500 mg) in anhydrous tetrahydrofuran (15 ml) under
Schlenk conditions was added
a 1 M solution of BH3$THF
(5.28 mmol, 5.28 ml). After refluxing for 6 h under N2, the reaction
mixture was cooled to 0 ꢁC and quenched by the addition of meth-
anol (5 ml) for 30 min. The solvents were then removed under
reduced pressure. Now the residue was dissolved in a 0.75 M
HCl solution (25 ml) and the mixture was boiled for 1 h. After wash-
ing with diethyl ether (3ꢂ10 ml), the mixture was rendered
alkaline by a 2 M NaOH solution and extracted with dichlorome-
thane (3ꢂ25 ml). The combined extracts were dried (MgSO4) and
evaporated in vacuo to afford the amine 23 as a brown oil in 74%
yield.
4.9.1. N-[2-(3-Bromomethyl-1,4-dimethoxynaphth-2-yl)-ethyl]-
2,2,2-trifluoroacetamide (25)
1H NMR (250 MHz, CDCl3): d 3.15 (2H, t, J¼6.8 Hz, CH2CH2N),
3.61 (2H, q, J¼6 Hz, CH2N), 3.89 (3H, s, MeO), 4.00 (3H, s, MeO),
4.75 (2H, s, CH2Br), 7.39 (1H, br s, NH), 7.43–7.54 (2H, m, H-6 and
H-7), 7.94–8.05 (2H, m, H-5 and H-8). 13C NMR (63 MHz, CDCl3):
d 24.2, 24.6, 40.0, 61.0, 61.6, 114.8 (q, J¼287.8 Hz, CF3), 122.1, 121.4,
125.0 (2ꢂCquat), 125.7, 126.4, 127.0, 127.8, 149.9, 151.1, 156.5 (q,
J¼36.8 Hz, CO). IR (ATR): n
3276, 2948, 1692, 1555, 1453, 1357,
max
1153, 1023 cmꢃ1. MS (EI, 70 eV) m/z (%): 421 (Mþþ2, 16), 419 (Mþ,
16), 340 (100), 293 (50), 277 (12), 227 (68), 212 (52), 200 (37),
199 (40), 197 (37), 196 (33), 185 (25), 171 (21), 141 (60), 128 (57),
115 (72), 105 (14), 76 (20), 69 (32). HRMS (ESI) m/z calcd for
4.7.1. 2-(1,4-Dimethoxynaphth-2-yl)ethylamine (23)
1H NMR (250 MHz, CDCl3): d 1.51 (2H, br s, NH2), 2.84–2.89 (2H,
m, CH2CH2N), 2.90–3.09 (2H, m, CH2N), 3.80 (3H, s, MeO), 3.89 (3H,
C17H17BrF3NO3þH: 420.0422; found: 420.0396.

5352
J. Jacobs et al. / Tetrahedron 64 (2008) 5345–5353
4.10. Synthesis of 5,10-dimethoxy-1,2,3,4-tetrahydro-
benz[g]isoquinolinium trifluoroacetate (26)
The reaction mixture was stirred for 12 h at room temperature.
On completion, the reaction mixture was extracted with dichloro-
methane (2ꢂ20 ml) and the combined organic extracts were dried
over MgSO4. Evaporation of the solvent afforded carbamate 28
(186 mg, 95%) as a light brown liquid, which was characterized
and then used without any purification.
To a solution of the carbamate 28 (0.6 mmol, 186 mg) in anhy-
drous THF (5 ml) was added lithium aluminum hydride (1.8 mmol,
68 mg) portionwise, and the reaction mixture was refluxed for
36 h and then cooled to room temperature. A 3 M NaOH solution
(1 ml) was added and stirring was continued for further 30 min.
The solid was removed by filtration and the organic phase was dried
over MgSO4. The solvent was evaporated in vacuo followed by flash
chromatography on silica gel.
To a solution of N-[2-(3-bromomethyl-1,4-dimethoxynaphth-
2-yl)-ethyl]-2,2,2-trifluoroacetamide 25 (0.24 mmol, 100 mg) in
methanol (3 ml) was added a 5 M KOH (0.5 ml) at 0 ꢁC under N2.
The cooling bath was removed and the mixture was stirred at
room temperature for 20 h. In a next step, methanol was removed
under vacuum and water (5 ml) was added to the residue. After
extraction with dichloromethane (3ꢂ10 ml), the combined organic
layers were dried (MgSO4) and evaporated in vacuo. Purification
by preparative HPLC gave 26 (64 mg, 75%) as a yellow powder,
mp 159.1–159.9 ꢁC.
4.10.1. 5,10-Dimethoxy-1,2,3,4-tetrahydrobenz[g]isoquinolinium
trifluoroacetate (26)
Method B. To a suspension of 5,10-dimethoxy-1,2,3,4-tetrahydro-
benz[g]isoquinolinium trifluoroacetate (26) (0.62 mmol, 221 mg)
in dichloromethane (15 ml) was added 0.5 M NaOH (2 ml). After
separation, the organic phase was dried and evaporated under re-
duced pressure. To the remaining product, dissolved in acetonitrile
(10 ml), was added 37% aqueous formaldehyde (7.44 mmol, 0.6 ml)
followed by NaBH3CN (0.74 mmol, 47 mg). After 30 min, acetic
acid was added until neutral pH and the mixture was stirred for
16 h. The solvent was removed under reduced pressure and the
crude residue was dissolved in 2 M NaOH (10 ml). The mixture
was extracted with dichloromethane (3ꢂ15 ml). The organic layer
was washed with brine, dried over MgSO4, and concentrated in
vacuo.
1H NMR (250 MHz, CD3OD): d 3.27–3.34 (2H, m, CH2-4), 3.57 (2H,
t, J¼6.4 Hz, CH2-3), 3.93 (3H, s, MeO), 3.95 (3H, s, MeO), 4.56 (2H, s,
CH2-1), 7.56–7.61 (2H, m, H-7 and H-8), 8.07–8.12 (2H, m, H-6 and
H-9). 13C NMR (63 MHz, CD3OD): d 21.4, 42.1, 42.5, 61.9, 62.3, 118.6,
122.2, 123.2, 123.3, 127.6, 127.9, 128.6, 129.5, 150.5, 151.2. IR (ATR):
n
3003, 2847, 1775, 1651, 1592, 1358, 1146, 1074 cmꢃ1. MS (ES)
max
m/z (%): 244 ([MꢃHOCOCF3]þHþ, 100), 212 (30). HRMS (ESI) m/z
calcd for C15H17NO2þH: 244.1338; found: 244.1300.
4.11. Synthesis of 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-
dione trifluoroacetic acid salt (18g)
A suspension of 5,10-dimethoxy-1,2,3,4-tetrahydrobenz[g]iso-
quinolinium trifluoroacetate (26) (0.165 mmol, 59 mg) in dichloro-
methane (10 ml) was treated with 0.5 M NaOH (1 ml). After
separation, the organic phase was dried and evaporated under re-
duced pressure. To the remaining product, dissolved in 1,4-dioxane
(2 ml), was added first silver(II) oxide (0.66 mmol, 81 mg) followed
by the addition of 6 M HNO3 (0.5 ml) dropwise. The suspension was
stirred for 16 h at 50 ꢁC. A saturated solution of sodium hydrogen
carbonate was added until basic pH and the aqueous phase was
extracted four times with small portions of diethyl ether. The com-
bined organic extracts were washed with brine, dried (MgSO4), and
concentrated in vacuo to 5 ml. A saturated solution of dry hydrogen
chloride gas in dry diethyl ether was added dropwise until the
precipitation of the hydrochloride salt 18g was completed. Extra
purification by preparative HPLC gave 18g (32 mg, 59%) as a yellow
powder, mp 136.6–137.6 ꢁC.
4.12.1. 5,10-Dimethoxy-3,4-dihydro-1H-benz[g]isoquinoline-2-
carboxylic acid ethyl ester (28)
1H NMR (250 MHz, CDCl3): d 1.32 (3H, t, J¼7.1 Hz, OCH2CH3),
3.06 (2H, t, J¼6.0 Hz, CH2-4), 3.73 (2H, t, J¼6.0 Hz, CH2-3), 3.89
(3H, s, MeO), 3.93 (3H, s, MeO), 4.22 (2H, q, J¼7.1 Hz, OCH2CH3),
4.83 (2H, s, CH2-1), 7.46–7.52 (2H, m, H-7 and H-8), 8.04–8.09
(2H, m, H-6 and H-9). 13C NMR (63 MHz, CDCl3): d 12.8, 21.5, 39.2,
39.5, 59.4, 59.5, 120.0, 120.1, 120.2, 122.8, 123.7, 123.9, 125.1, 125.4,
146.2, 147.3, 153.8. IR (ATR): nmax 2936, 2840, 2250, 1693, 1594,
1428, 1355, 1233, 1061 cmꢃ1. MS (ES) m/z (%): 316 (MþHþ, 100),
284 (90), 256 (30), 227 (40), 185 (20). HRMS (ESI) m/z calcd for
C18H21NO4þH: 316.1549; found: 316.1548.
4.12.2. 2-Methyl-5,10-dimethoxy-1,2,3,4-tetrahydrobenz[g]-
isoquinoline (29)
Flash chromatography on silica gel with 3% methanol in
dichloromethane as eluent gave 29 as a brown-yellow powder,
mp 100.5–101.5 ꢁC. 1H NMR (270 MHz, CDCl3): d 2.54 (3H, s,
NCH3), 2.73 (2H, t, J¼6.0 Hz, CH2-3), 3.12 (2H, t, J¼6.0 Hz, CH2-4),
3.79 (2H, s, CH2-1), 3.88 (3H, s, MeO), 3.89 (3H, s, MeO), 7.43–7.47
(2H, m, H-7 and H-8), 8.00–8.05 (H-6 and H-9). 13C NMR
(63 MHz, CDCl3): d 24.6, 46.4, 52.5, 53.6, 60.9, 61.3, 122.0 (2ꢂCHar),
124.3, 125.3, 125.4, 125.5, 127.0, 127.3, 147.9, 149.5. IR (ATR): nmax
2933, 2837, 2781, 1592, 1456, 1352, 1053 cmꢃ1. MS (ES) m/z (%):
258 (MþHþ, 100). HRMS (ESI) m/z calcd for C16H19NO2þH:
258.1494; found: 258.1505.
4.11.1. 1,2,3,4-Tetrahydrobenz[g]isoquinoline-5,10-dione
trifluoroacetic acid salt (18g)
1H NMR (500 MHz, D2O): d 3.01 (2H, m, CH2-4), 3.59 (2H, t,
J¼6.2 Hz, CH2-3), 3.77 (1H, s, NH), 4.32 (2H, s, CH2-1), 7.92–7.93
(2H, m, H-7 and H-8), 8.13–8.16 (2H, m, H-6 and H-9). 13C NMR
(63 MHz, D2O): d 20.1, 40.3, 40.6, 127.1, 127.4, 132.0, 132.2, 135.5,
135.6, 137.1, 142.4, 184.6, 185.1. IR (ATR): n
3009, 2817, 1661,
max
1593, 1294, 1122 cmꢃ1. MS (ES) m/z (%): 214 ([MꢃHOCOCF3]þHþ,
100), 185 (10). HRMS (ESI) m/z calcd for C13H11NO2þH: 214.0868;
found: 214.0903.
4.13. Synthesis of N-methyl-1,2,3,4-tetrahydrobenz[g]-
4.12. Synthesis of 2-methyl-5,10-dimethoxy-1,2,3,4-
isoquinoline-5,10-dione trifluoroacetic acid salt (30)
tetrahydrobenz[g]isoquinoline (29)
To a solution of 2-methyl-5,10-dimethoxy-1,2,3,4-tetrahydro-
benz[g]isoquinoline (29) (0.2 mmol) in 1,4-dioxane (2 ml) was
added first silver(II) oxide (0.78 mmol, 96 mg) followed by the
dropwise addition of 6 M HNO3 (0.6 ml). The suspension was stirred
for 16 h at 50 ꢁC. A saturated solution of sodium hydrogen carbonate
was added until basic pH and the aqueous phase was extracted four
times with small portions of diethyl ether. The combined organic
extracts were washed with brine, dried (MgSO4), and concentrated
Method A. A suspension of 5,10-dimethoxy-1,2,3,4-tetrahydro-
benz[g]isoquinolinium trifluoroacetate (26) (0.62 mmol, 221 mg)
in dichloromethane (15 ml) was treated with 0.5 M NaOH (2 ml).
After separation, the organic phase was dried (MgSO4) and evapo-
rated under reduced pressure. To the remaining product, dissolved
in toluene (30 ml) and cooled to 0 ꢁC, were simultaneously added
ethylchloroformate (0.78 mmol, 84 mg) and 4 M NaOH (0.1 ml).

J. Jacobs et al. / Tetrahedron 64 (2008) 5345–5353
5353
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references cited therein; (b) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102,
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3. For a study on the mechanism, see: (a) Fodor, G.; Nagubandi, S. Tetrahedron
1980, 36, 1279–1300; (b) Berger, U.; Dannhardt, G.; Wiegrebe, W. Arch. Pharm.
1983, 316, 182–189.
in vacuo to 5 ml. A saturated solution of dry hydrogen chloride gas
in dry diethyl ether was added dropwise until precipitation of the
hydrochloride salt was completed. Extra purification by preparative
HPLC gave 30 (44 mg, 62%) as a brown-yellow powder.
4. For recent reviews, see: (a) Yuon, S. W. Org. Prep. Proced. Int. 2006, 38, 505–591;
(b) Larghi, E. L.; Kaufman, T. S. Synthesis 2006, 187–220.
4.13.1. 2-Methyl-1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-dione
trifluoroacetic acid salt (30)
5. (a) Birch, A. J.; Jackson, A. H.; Shannon, P. V. R. J. Chem. Soc., Perkin Trans. 1 1974,
2190–2194; (b) Brown, E. V. J. Org. Chem. 1977, 42, 3208–3209.
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7. Speckamp, W. H.; Hiemstra, H. Tetrahedron 1985, 41, 4367–4416.
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1179.
10. (a) Aldersley, M. F.; Dean, F. M.; Hamzah, A. S. Tetrahedron Lett. 1986, 27, 255–
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V.; Florent, I.; Deprez, B. P.; Deprez-Poulain, R. F. J. Med. Chem. 2007, 50, 1322–
1334.
1H NMR (500 MHz, D2O): d 2.92–2.96 (1H, m, CH2-3 or CH2-4),
3.05–3.09 (1H, m, CH2-3 or CH2-4), 3.14 (3H, s, NCH3), 3.35–3.40 (1H,
m, CH2-3 or CH2-4), 3.80–3.83 (1H, m, CH2-3 or CH2-4), 4.09 (1H, d,
J¼17.9 Hz, CH2-1), 4.55 (1H, d, J¼17.9 Hz, CH2-1), 7.79–7.80 (2H,
m, H-7 and H-8), 7.94–7.95 (2H, m, H-6 and H-9). 13C NMR
(126 MHz, D2O): d 20.9, 43.2, 49.1, 50.3, 115.8 (q, J¼291.2 Hz, CF3),
127.0, 127.3, 131.7, 131.8, 135.5 (2ꢂCHar), 136.5, 141.7, 163.3 (q,
J¼35.8 Hz, CO), 183.9, 184.5. IR (ATR): n
2578, 1775, 1661, 1593,
max
1400, 1294, 1130 cmꢃ1. MS (ES) m/z (%): 228 ([MꢃHOCOCF3]þHþ,
100). HRMS (ESI) m/z calcd for C14H13NO2þH: 228.1025; found:
228.0985.
Acknowledgements
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The authors are indebted to the ‘Fonds voor Wetenschappelijk
OnderzoekdVlaanderen’ for financial support of this research.
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´
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