Synthesis of 3-substituted benzo[g]isoquinoline-5,10-diones: A convenient one-pot Sonogashira coupling/iminoannulation procedure

Article abstract of DOI:10.1016/j.tet.2011.01.074

A series of 3-substituted 5,10-dimethoxybenzo[g]isoquinolines were prepared by coupling of terminal alkynes with the tert-butylimine of 3-bromo-1,4-dimethoxy-2-naphthaldehyde in the presence of a Pd-catalyst and subsequent Cu-catalyzed cyclization of the intermediate 3-alkynyl-2- naphthylcarbaldehyde. A CAN-mediated oxidative demethylation yielded the corresponding 2-azaanthraquinones in excellent yields. Since this methodology proved to be limited to alkynes bearing aromatic groups, an alternative and more general Pd-catalyzed coupling procedure was developed, starting from 3-bromo-1,4-dimethoxy-2-naphthaldehyde. For more acidic terminal alkynes, like phenylacetylene, a combination of Pd(OAc)₂/P(t-Bu)₃/CuI (2/6/1) with potassium carbonate in DMF gave a complete conversion within 24 h. For less acidic acetylenes, 2 equiv of alkyne and caesium carbonate as a base were required in order to obtain complete conversion of the starting material within 24 h. These altered Sonogashira conditions also allowed the isolation of a benzo[f]indenone as an interesting side product in case Bu₄NCl was added to the reaction mixture. The 3-alkynyl-1,4-dimethoxy-2-naphthaldehyde acquired after completion of the Pd-catalyzed coupling could be cyclized by adding a solution of ethanolic ammonia and an extra equivalent of potassium carbonate to the reaction mixture. As such, this consecutive one-pot coupling/iminoannulation procedure was a convenient alternative to the Larock isoquinoline procedure, enabling the isolation of a series of 3-substituted 5,10-dimethoxybenzo[g]isoquinolines.

Full text of DOI:10.1016/j.tet.2011.01.074

Tetrahedron 67 (2011) 2269e2278
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 3-substituted benzo[g]isoquinoline-5,10-diones: a convenient
one-pot Sonogashira coupling/iminoannulation procedure
Sam Van Aeken a, Stefan Verbeeck b, Jurgen Deblander a, Bert U.W. Maes b,
,b,
Kourosch Abbaspour Tehrani a
*
a Laboratory of Organic Chemistry, Department of Applied Biological Sciences and Engineering, Faculty of Science and Bio-engineering Sciences, Vrije Universiteit Brussel,
Pleinlaan 2, B-1050 Brussels, Belgium
b Organic Synthesis, Department of Chemistry, Faculty of Sciences, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3-substituted 5,10-dimethoxybenzo[g]isoquinolines were prepared by coupling of terminal
alkynes with the tert-butylimine of 3-bromo-1,4-dimethoxy-2-naphthaldehyde in the presence of
Received 10 December 2010
Received in revised form 21 January 2011
Accepted 24 January 2011
a
Pd-catalyst and subsequent Cu-catalyzed cyclization of the intermediate 3-alkynyl-2-naph-
thylcarbaldehyde. CAN-mediated oxidative demethylation yielded the corresponding 2-azaan-
A
Available online 1 February 2011
thraquinones in excellent yields. Since this methodology proved to be limited to alkynes bearing aromatic
groups, an alternative and more general Pd-catalyzed coupling procedure was developed, starting from 3-
bromo-1,4-dimethoxy-2-naphthaldehyde. For more acidic terminal alkynes, like phenylacetylene,
a combination of Pd(OAc)2/P(t-Bu)3/CuI (2/6/1) with potassium carbonate in DMF gave a complete con-
version within 24 h. For less acidic acetylenes, 2 equiv of alkyne and caesium carbonate as a base were
required in order to obtain complete conversion of the starting material within 24 h. These altered So-
nogashira conditions also allowed the isolation of a benzo[f]indenone as an interesting side product in
case Bu4NCl was added to the reaction mixture. The 3-alkynyl-1,4-dimethoxy-2-naphthaldehyde acquired
after completion of the Pd-catalyzed coupling could be cyclized by adding a solution of ethanolic am-
monia and an extra equivalent of potassium carbonate to the reaction mixture. As such, this consecutive
one-pot coupling/iminoannulation procedure was a convenient alternative to the Larock isoquinoline
procedure, enabling the isolation of a series of 3-substituted 5,10-dimethoxybenzo[g]isoquinolines.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Benzo[g]isoquinoline-5,10-diones
Quinones
Sonogashira
Naphthalene
Iminoannulation
1. Introduction
2-azanaphthoquinone4 or the formation of the terminal hetero-
cyclic ring by cycloaddition of a heterodiene to a 1,4-naph-
Nowadays 2-azaanthraquinones receive increasing attention as
potential anticancer and antimicrobial antibiotics.1 Their cytotox-
icity is mainly based upon two mechanisms: first their DNA
intercalating properties, where they have the potential to stabilize
the topoisomerase IIeDNA or gyraseeDNA complex and thereby
effectively inhibiting the relaxation of supercoiled DNA2 and sec-
ond their ability to disrupt the cellular respiratory pathway by
interaction with NADH or NADPH dehydrogenases and the sub-
sequent generation of toxic super oxide anions.3 In the past
a number of synthetic routes have been developed to access this
interesting class of compounds. Most of the documented routes
make use of a DielseAlder protocol, be it the formation of the
heterocyclic ring by a cycloaddition of a polyoxygenated diene to a
thoquinone.5 Alternatively, a number of direct lithiation protocols
have also been reported.4,6 These generally involve the conden-
sation of a 3-lithiopyridine with a phthalic anhydride or a benza-
mide followed by the construction of the central 1,4-
benzoquinone ring. All these procedures however suffer from low
yields and a lack of regioselectivity. More recently, a facile entry to
a series of naturally and non naturally occurring 3-substituted 2-
azaanthraquinones has been established by reaction of 2-acylated-
3-phenoxymethyl-1,4-naphthoquinones with aqueous ammonium
hydroxide.7
We present a second, general and easy accessible synthetic
route towards a number of 3-substituted 2-azaanthraquinones 1
involving the construction of a 3-substituted 5,10-dimethox-
ybenzo[g]isoquinoline 2, followed by a cerium(IV) ammonium
nitrate (CAN) mediated oxidative demethylation as the key steps
(Scheme 1).
* Corresponding author. E-mail address: Kourosch.Abbaspourtehrani@ua.ac.be
(K. Abbaspour Tehrani).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.074

2270
S. Van Aeken et al. / Tetrahedron 67 (2011) 2269e2278
The reaction of 4 with sterically demanding acetylenes (Table 1,
entry 9) resulted in coupling, but no ring closed product was ob-
served. The presence of a free hydroxy group or a free amino group
(Table 1, entries 10 and 11) in the alkyne was not tolerated at all. In
the latter two cases only the debrominated starting material 6 was
isolated afterwards. The latter three findings were in accordance
with the earlier reported limitations of the Larock isoquinoline
synthesis.8a
Due to the basicity of the isoquinoline nitrogen the
3-substituted 5,10-dimethoxybenzo[g]isoquinolines 2 were iso-
lated as a mixture of protonated and non-protonated species after
workup with aqueous ammonium chloride. In an attempt to com-
pletely neutralize this mixture it was stirred with 100 equiv NaOH
in MeOH (0.1 M) under reflux. Surprisingly an unknown compound
was isolated, which was identified afterwards as 10,10-dimethoxy-
3-phenylbenzo[g]isoquinolin-5(10H)-one (10a) (Scheme 3). NOESY
analysis established a proximity correlation between H-1 and the
protons of the acetal thereby pinpointing its position at C-10. The
quantity of NaOH was crucial, since the addition of only 20 equiv of
NaOH and stirring for 20 h at room temperature left 9 unaltered.
The reaction was repeated in EtOH, adding 100 equiv of NaOH and
stirring it under reflux for 48 h. After workup only the mixed acetal
10b was isolated. Both acetals could be easily converted into the
corresponding quinone 1a in almost quantitative yield. The con-
version of these protonated 5,10-dimethoxybenzo[g]isoquinolines
into the corresponding quinones by treatment with excess base and
followed by an acidic workup is in fact a valuable metal-free al-
ternative for the CAN-oxidative demethylation, which is the stan-
dard procedure (vide infra).
Scheme 1. Retrosynthetic analysis: (a) oxidative demethylation. (b) Sonogashira
coupling and iminoannulation.
2. Results and discussion
2.1. Benzo[g]isoquinoline synthesis
Initially the Larock protocol8 was considered to be a valuable tool
for the construction of the 3-substituted 5,10-dimethoxybenzo[g]
isoquinolines 2. To use this versatile procedure a synthetic pathway
was envisaged, starting from 2-bromonaphthylcarbaldehyde 3a
(Y ¼ Br) (Scheme 2).9 Condensation of 3a with tert-butylamine in
the presence of anhydrous magnesium sulfate afforded the aldimine
4 in quantitative yield. Next, a PdCl2(PPh3)2/CuI catalyzed Sonoga-
shira coupling was carried out with a number of terminal acetylenes
in triethylamine at 70 ꢀC. When this coupling was complete, as in-
dicated by TLC, the solvent and precipitates were removed and DMF
and CuI wereadded tothe residue 5 in orderto induce the cyclization
of 5 at 100 ꢀC. This protocol worked fine for alkynes bearing aromatic
groups and 3-methoxyprop-1-yne (Table 1, entries 1e5) and in-
creasingly less for aliphatic alkynes (Table 1, entries 6e8), where the
conversion rates were significantly lower, with the formation of the
debrominated compounds 6 and 8 as the main products. The
observed yields for entries 1e5 are very satisfying in view of the fact
that no efficient Larock isoquinoline synthesis has been described
so far with completely substituted ortho-halobenzaldimines.8,10
Scheme 3. Reagents and conditions: (a) 100 equiv NaOH, ROH, reflux, 48 h; (b) ace-
tone/2 N HClaq, reflux, 3 h.
Scheme 2. Reagents and conditions: (a) 3 equiv t-BuNH2, CH2Cl2, MgSO4, rt, 16 h,
100%; (b) 1.1 equiv HC^CR, 4 mol % PdCl2(PPh3)2, 4 mol % CuI, Et3N, 70 ꢀC, 24 h, Ar
(Table 1); (c) 10 mol % CuI, DMF, 100 ꢀC, 4 h (Table 1).
The decomposition of the starting material 4, when alkynes
bearing aliphatic groups were used, was an indication of an in-
sufficiently fast transmetalation or deprotonation step. For this type
of terminal alkynes an optimization of the reaction conditions was
attempted (Table 2). Because of the moderate conversion of
cyclohexylacetylene with 4 (Table 2, entry 1), this reaction was
studied in more detail. With the formation of the copper acetylide
being not so efficient, some obvious changes to the reaction con-
ditions like increasing the quantity of CuI, raising the temperature
or doubling the quantity of the acetylene were first investigated
(Table 2, entries 2e4). Unfortunately, adding more CuI was not
tolerated as the conversion rate decreased steeply, whereas
changing the temperature did not lead to a significant improve-
ment in yield. Using an excess of acetylene proved beneficial for the
conversion, however the unreacted acetylene hampered the sub-
sequent cyclization, lowering the isolated yield of 2f. Changing the
catalytic system to Pd(OAc)2/P(t-Bu)3 further deteriorated the
conversion (Table 2, entry 5). As a last attempt a series of experi-
ments were conducted with DMF as a solvent and Pd(OAc)2 as
a precatalyst. Reactions where PPh3 was used as a ligand and
Table 1
Synthesis of benzo[g]isoquinolines by Pd-catalyzed coupling and Cu-catalyzed
cyclization of terminal alkynes
Entry
Alkyne
ReC^CH (R)
Ratioa (%)
Product (2)
Yieldb (%)
3aþ4
5þ7
6þ8
2
14
0
9
0
22
12
31
0
0
10
1
2
3
4
5
6
7
8
C6H5
0
0
0
0
7
13
82
40
0
98
86
100
91
93
65
6
2a
2b
2c
2d
2e
2f
2g
2h
2i
80
50
59
55
91
31
5
19
0
0
3-MeOC6H4
2-Mee4-MeOC6H3
4-MeC6H4
MeOCH2
cHex
CH(OEt)2
n-Bu
CMe2OMe
CH2NH2
29
90
0
9
10
11
100
80
2j
2k
CH2OH
0
0
a
The ratio was determined by 1H NMR analysis of the reaction mixture obtained
after the alkynylation (step b, Scheme 2).
b
Isolated yield (Scheme 2).

S. Van Aeken et al. / Tetrahedron 67 (2011) 2269e2278
2271
Table 2
Optimization of the Sonogashira coupling with N-[(3-bromo-1,4-dimethoxynaphthalen-2-yl)methylene]-2-methylpropan-2-amine 4
OMe
Br
OMe
R
X
X
OMe
3a X = O
4 X = Nt-Bu
OMe
5 X = Nt-Bu
7 X = O
OMe
Br
OMe
OMe
R
10 mol% CuI
DMF
R
Table 2
N
N
N
24 h
t-Bu
t-Bu
100 °C
OMe
OMe
Br
MeO
4
H
OMe
2
OH H
12
+
X
N
t-Bu
MeO
H
OH H
6 X = Nt-Bu
8 X = O
11
Entry
R (equiv)
Catalyst (mol %)
CuI (mol %)
Ligand (mol %)
Solvent
Base (equiv)
T (ꢀC)
Ratio (%)a
Yieldb 2 (%)
3þ4
13
73
8
5þ7
6þ8
22
0
1c
2
3
cHex (1.1)
cHex (1.1)
cHex (1.1)
cHex (2)
PdCl2(PPh3)2 (4)
PdCl2(PPh3)2 (4)
PdCl2(PPh3)2 (4)
PdCl2(PPh3)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
PdCl2(PPh3)2 (4)
Pd(OAc)2 (4)
PdCl2(PPh3)2 (4)
PdCl2(PPh3)2 (4)
PdCl2(PPh3)2 (4)
4
10
4
4
4
4
4
4
4
4
4
4
4
4
4
PPh3
PPh3
PPh3
PPh3
Et3N
Et3N
Et3N
Et3N
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
70
70
100
70
65
27
63
73
28
10
11
10
40
35
24
6
31
NAd
NAd
16
13
3
29
10
30
20
18
43
10
29
16
22
22
19
12
4
1
5
cHex (1.1)
cHex (1.1)
cHex (1.1)
cHex (1.1)
cHex (1.1)
cHex (1.1)
cHex (1.1)
cHex (1.1)
cHex (1.1)
CH(OEt)2 (1.1)
CH(OEt)2 (2)
P(t-Bu)3 (12)
PPh3 (12)
PPh3 (12)
P(t-Bu)3 (12)
P(t-Bu)3 (12)
P(t-Bu)3 (12)
PPh3
PPh3 (12)
PPh3
PPh3
Et3N
70
42
66
71
47
50
36
41
72
0
6e
7
Cs2CO3 (2)
DBU (2)
K2CO3 (1.1)
Cs2CO3 (1.1)
Na2CO3 (1.1)
Cs2CO3 (2)
DBU (10)
Et3N
100
100
100
100
100
100
100
70
NAd
0
0
8
9
10
11f
12
13g
14g
15h
0
4
NAd
58
53
0
78
78
12
Et3N
Et3N
70
70
3
76
PPh3
a
The ratio was determined by 1H NMR analysis of the reaction mixture obtained after the alkynylation reaction (step b, Scheme 2).
Isolated yield.
Compound 12f was observed additionally as a side product.
NA: no cyclization was attempted.
Compound 11 (1 mol %) was observed as a side product.
Compound 11 (18 mol % of) was observed as a side product.
After 24 h the reaction mixture was filtered over decalite, and the same amount of catalyst (Pd and Cu) and alkyne was added anew, after which the mixture was stirred at
b
c
d
e
f
g
70 ꢀC for an additional 24 h.
h
Other side products, that could not be identified, were present.
Cs2CO3 or DBU as a base performed poor (Table 2, entries 6 and 7).
A slight improvement was observed when PPh3 was replaced with
P(t-Bu)3. Of the three carbonate bases tested in combination with
P(t-Bu)3, Cs2CO3 gave the best result (Table 2, entries 8e10).
However, when the ring closing step was carried out by filtering the
reaction mixture over decalite, adding 10 mol % CuI and stirring for
several days at 100 ꢀC, no isoquinoline 2f was isolated. Investigation
by 1H NMR revealed that the N-tert-butylaldimine 4 was still intact.
Most likely the presence of P(t-Bu)3 combined with the absence of
an amine base plays a role in the inhibition of the CuI catalyzed
iminoannulation. Surprisingly, almost complete conversion could
be achieved when applying a double addition protocol that implied
adding the indicated quantities of catalyst and alkyne, monitoring
the reaction until it stalled, filtrating the reaction mixture over
decalite and once more adding the same quantity of catalyst to-
gether with a slight excess of alkyne in comparison to the non
used successfully to boost the coupling with 3,3-diethoxyprop-1-
yne (Table 2, entry 14).
Contrary to the coupling with cyclohexylacetylene (Table 2,
entry 4), doubling the amount of 3,3-diethoxyprop-1-yne to
2 equiv did not result in a better coupling and no cyclization was
observed either (Table 2, entry 15).
2.2. Sonogashira coupling/iminoannulation protocol
Since we were not completely pleased with the outcome of the
iminoannulation protocol with cyclohexylacetylene and 3,3-dieth-
oxyacetylene, an alternative approach was pursued. Instead of
carrying out a Sonogashira coupling on the tert-butylimine 4, the
Pd-catalyzed coupling was directly performed on 2-bromonaph-
thylaldehyde 3a (Table 3). First the coupling of 3a with phenyl-
acetylene was carried out under literature conditions.8a To our
surprise no reaction at all was observed (Table 3, entry 1). Since no
decomposition of the bromide 3a occurred, the lack of reactivity was
probably due to a sluggish oxidative addition step. This fact was
further supported when the reaction was carried out with 2-iodo-
1,4-dimethoxy-2-naphthaldehyde (3b) leading to the alkynylalde-
hyde 7a in good yield (Table 3, entry 2). We preferred to optimize the
reaction conditions for the bromide 3a instead. The solvent was
changed to DMF, while Pd(OAc)2 was used as a Pd source and
P(t-Bu)311 as a ligand. K2CO3 was chosen arbitrarily as a base. Taking
into account that the starting compound 3a has two substituents in
reacted aldimine
4
(conversion was estimated via HPLC
(l¼540 nm)) and following the reaction till completion (Table 2,
entry 13). In this case, ring closure did proceed smoothly, enabling
us to isolate the isoquinoline 2f in a good overall yield. The in-
termediate filtration before adding additional alkyne and catalyst
seemed vital, since omitting the filtration left the degree of coup-
ling unchanged. Accumulation of triethylammonium bromide salts
probably inhibits any further coupling. Removal of these salts by
filtration made it possible to reinitiate the catalytic cycle by adding
fresh catalyst and alkyne. The same double addition protocol was

2272
S. Van Aeken et al. / Tetrahedron 67 (2011) 2269e2278
Table 3
Optimization of the Sonogashira coupling with 3-bromo-1,4-dimethoxy-2-naphthaldehyde
Entry
Y
R (equiv)
Catalyst (mol %)
Ligand (mol %)
Base (equiv)
Ratioa (%)
Yieldc 7 (%)
3
7
8
13
14b
1d
2d
3f
Br
I
C6H5 (1.1)
C6H5 (1.1)
C6H5 (1.1)
C6H5 (1.1)
C6H5 (1.1)
C6H5 (1.1)
C6H5 (1.1)
C6H5 (1.1)
CH(OEt)2 (1.1)
cHex (1.1)
cHex (1.1)
cHex (1.1)
cHex (1.1)
cHex (2)
PdCl2(PPh3)2 (2)
PdCl2(PPh3)2 (2)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
PdCl2(PhCN)2 (4)
PdCl2(MeCN)2 (4)
Pd(dba)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
PPh3 (4)
PPh3 (4)
Et3N
Et3N
100
10
9
0
90
91
0
0
0
0
18
13
4
11
23
5
6
0
0
0
7
15
6
12
0
0
0
0
0
0
0
0
0
0
0
0
0
2
2
7
0
0
1
2
5
0
0
7a (0)
7a (69)
7a (58)
7a (81)
7a (0)
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
P(t-Bu)3 (12)
P(t-Bu)3 (12)
P(t-Bu)3 (12)
P(t-Bu)3 (12)
P(t-Bu)3 (12)
[(t-Bu)3PH]BF4 (12)
P(t-Bu)3 (12)
P(t-Bu)3 (12)
P(t-Bu)3 (12)
P(t-Bu)3 (12)
P(t-Bu)3 (12)
P(t-Bu)3 (12)
P(t-Bu)3 (12)
P(t-Bu)3 (12)
P(t-Bu)3 (12)
P(t-Bu)3 (12)
P(t-Bu)3 (12)
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
Cs2CO3 (1.2)
Na2CO3 (1.2)
Et(i-Pr)2N (1.2)
Cs2CO3 (1.2)
Cs2CO3 (2)
Cs2CO3 (4)
K2CO3 (1.2)
K2CO3 (1.2)
Cs2CO3 (1.2)
4e
5e
6e
7e
8e
9e
0
100
10
23
52
31
64
70
77
8
0
53
44
40
58
13
12
9
80
96
0
7
6
11
19
0
19
19
4
0
0
11
6
5
0
9
3
4
5
37
9
7a (1)
7a (36)
7a (ND)g
7g (31)
7f (51)
7f (67)
7f (8)
e
10
11e
12e
13e
14e
15h
16e
17i
4
7f (4)
91
82
74
66
24
91
7f (73)
7f (58)
7f (50)
7f (60)
7f (15)
7f (63)
cHex (1.1)
cHex (1.1)
cHex (1.1)
cHex (1.1)
C6H5 (2)
18j
19e
a
The ratio was determined by 1H NMR analysis of reaction mixture after a crude purification over a short silica column to remove all traces of salts, phosphine ligands and Pd
catalyst.
b
c
d
e
f
Tentative structure based on 1H NMR.
Isolated yield.
þ1 mol % CuI, Et3N, 50 ꢀC, 4 h.
þ2 mol % CuI, DMF, 100 ꢀC, 24 h.
þ1 mol % CuI, DMF, 100 ꢀC, 24 h.
g
h
i
ND: not determined.
þ2 mol % CuI, DMF, 100 ꢀC, 36 h.
þ2 mol % CuI, 10 mol % TBAB, DMF, 100 ꢀC, 24 h; additionally 7 mol % of 15 was isolated as a side product.
þ2 mol % CuI, 10 mol % TBAB, DMF/H2O (10/1), 100 ꢀC, 24 h; additionally 8 mol % of 15 was isolated as a side product.
j
ortho position of the bromide and is further deactivated by two
methoxy groups, the electron rich, monoligated Pd0P(t-Bu)3 would
probably undergo an easier oxidative addition. This was confirmed
by the experimental results (Table 3, entry 3). A further improve-
ment of the conversionwas established byadding 2 mol % CuI, giving
an almost quantitative coupling and a good isolated yield (Table 3,
entry 4). If the catalyst precursor was changed to bis(benzonitrile)
palladium(II) dichloride (PdCl2(PhCN)2), bis(acetonitrile)palladium
(II) dichloride (PdCl2(MeCN)2) or to bis(dibenzylideneacetone)pal-
ladium(0) (Pd(dba)2) a steep deterioration of the conversion was
observed (Table 3, entries 5e7) with most noticeably a partial de-
composition of the naphthylbromide 3a and the formation of
a benzo[f]indenoneside product 13f (vide infra). When replacing the
phosphine ligand with the air stable [(t-Bu)3PH]BF4 salt the degree
of conversion was inferior in comparison to P(t-Bu)3 (Table 3,
entry 8).
The initial reaction conditions with Pd(OAc)2/P(t-Bu)3 as catalyst
gave excellent results with phenylacetylene, but when introducing
more demanding acetylenes, like 3,3-diethoxyprop-1-yne and
cyclohexylacetylene (Table 3, entries 9 and 10) the degree of cou-
pling dropped. To attain a more general and higher yielding pro-
cedure, a further optimization of the reaction conditions was
attempted. The conversions with K2CO3, Cs2CO3, Na2CO3 and
i-Pr2NEt were compared (Table 3, entries 10e13), with Cs2CO3 giving
the best results. Next, the amount of added alkyne (Table 3, entry 14)
was doubled. This resulted in complete conversion. Further tests
were performed with Cs2CO3 combined with 1.1 equiv of alkyne, like
prolonging the reaction time and adding 2 or 4 equivof base (Table 3,
entries 15 and 16), but this did not lead to any significant improve-
ment in coupling. Cs2CO3 probablygave better results in comparison
with K2CO3 and Na2CO3 due to its superior solubility in organic
solvents. A further enhancement of the reaction might be obtained
by adding a phase transfer (PT) catalyst.12 A first experiment con-
ducted under PT conditions (Table 3, entry 17) consisted in adding
10 mol % tetrabutylammonium bromide (TBAB) to the reaction
mixture. This did not result in any improvement in the degree of
coupling. Since it was reported in literature13 that an alkali metal
base (K2CO3) requires the addition of 10 v/v% water to the solvent to
perform optimally under PT conditions, the reaction was repeated
with addition of 10 v/v% of water (Table 3, entry 18). Instead of an
improved coupling, we noticed an increased formation of 13f, which
was observed in earlier experiments (Table 3, entries 5e17) but was
only marginally present. Under the new PT conditions 13f was the
major product after workup. A structural elucidation was based on
LCeMS, 1H NMR, 13C NMR and ATR-IR measurements. The com-
pound had a molecular mass of 322, equal to the o-alkynylnaph-
thylaldehyde 7c, but lacked an aldehyde proton (1H NMR), although
a carbonyl group was present according to IR (1684 cmꢁ1). 1H NMR
further revealed the presence of the cyclohexyl group and of a fifth
aromatic proton (
d
7.43, d, J¼1.3 Hz). IR absorption peaks at
2922 cmꢁ1 and 2849 cmꢁ1 indicated a double bond, corroborating
that a benzo[f]indenone might be formed. The analytical data of
compound 13f were compared to those of indenones reported in
literature thus further supporting the proposed structure.14
The observation that terminal alkynes were able to annulate
with o-bromonaphthaldehydes was remarkable, since only the

S. Van Aeken et al. / Tetrahedron 67 (2011) 2269e2278
2273
preparation of 2,3-disubstituted-1-indenones by a Pd catalyzed
annulation of internal alkynes was reported in literature by Larock
and Doty.15 Since Larock employed conditions (5 mol % Pd(OAc)2, 1
or 4 equiv of Na2CO3, 1 equiv of n-Bu4NCl, N,N-dimethylacetamide,
100 ꢀC) that were partially similar to our conditions, it was assumed
that both annulation processes proceeded via an identical catalytic
cycle with following steps: the oxidative addition of the in situ
procedure went quite well, furnishing the isoquinolines 2 in
moderate to good yields after chromatography.
generated Pd0 to the aryl bromide followed by arylpalladium
p-
complexation to the alkyne and a consecutive carbopalladation
with formation of a Z-alkenylpalladium(II) intermediate. A second
oxidative insertion into the formyl CeH bond would create a PdIV
species. The regeneration of Pd0 occurs by a HBr elimination and
a reductive elimination generating the indenone 13f (Scheme 4).
For comparison, the optimal coupling conditions for cyclo-
hexylacetylene (Table 3, entry 14) were repeated with phenyl-
acetylene (Table 3, entry 19). The yield of 7a was less compared to
initial employed coupling procedure (Table 3, entry 1), but more
remarkably 9 mol % (1H NMR) of the corresponding benzo[f]
indenone 13a was formed as well, but could not be isolated.
Scheme 6. Reagents and conditions: (a) (1) 2 equiv HC^CR,
4 mol % Pd(OAc)2,
0.12 equiv P(t-Bu)3, 2 mol % CuI, 1.2 equiv Cs2CO3, DMF, 100 ꢀC, 24 h; (2) 1 equiv K2CO3,
NH4OHaq, 100 ꢀC, 2 h; (b) 2 N HClaq, Et2O, rt, 2 h.
2.4. Oxidation
The acquired 3-substituted 5,10-dimethoxybenzo[g]isoquino-
lines
2 were oxidized with cerium(IV) ammonium nitrate
(CAN)17 and furnished the corresponding 3-substituted 2-azaan-
thraquinones 1 in almost quantitative yield (Scheme 7). Even
mixtures of protonated and non-protonated 5,10-dimethoxybenzo
[g]isoquinolines 2 could be oxidized. The 2-azaanthraquinones
1 were isolated solely as the non-protonated species after flash
chromatography.
Scheme 7. Reagents and conditions: (a) 3 equiv CAN, CH3CN/H2O (2/1), 0 ꢀC, 1 h.
Scheme 4. Plausible catalytic cycle for benzo[f]indenone formation (ligands have been
omitted for clarity).
3. Conclusions
2.3. One-pot coupling/cyclization procedure
In conclusion, a convenient procedure based on the Larock
isoquinoline synthesis was developed to construct a series of
3-substituted benzo[g]isoquinoline-5,10-diones 1. The protocol
worked satisfactorily for terminal alkynes bearing aromatic groups
and for 3-methoxypropyne. For alkynes, bearing aliphatic groups,
an alternative procedure starting from an ortho-bromonaph-
thaldehyde 3a and consisting of a consecutive one-pot Sonogashira
coupling and an iminoannulation was pursued. As a key step the
coupling of an ortho-bromonaphthaldehyde 3a with cyclo-
hexylacetylene was investigated thoroughly, revealing the forma-
tion of benzo[f]indenone 13 as an interesting side product in case
Bu4NCl was added to the reaction mixture. In all cases the
3-substituted 5,10-dimethoxybenzo[g]isoquinolines 2 were easily
CAN oxidized into the desired 2-azaanthraquinones 1.
Ring closure of the acquired alkynylnaphthylaldehydes 7 could
be accomplished by treating them with an aqueous ammonia
solution.16 This was demonstrated by refluxing 7a in the presence
of K2CO3 in an ethanol/aqueous ammonia solution for 2 h, where
after the isoquinoline 2a was isolated in good yield (Scheme 5).
Scheme 5. Reagents and conditions: (a) 1.5 equiv K2CO3, 27% NH4OHaq, EtOH, reflux,
2 h.
The similar polarities of the coupled product 7a, the aldehyde 3a
and the other side products (8, 14, 15) made their purification by
column chromatography a difficult task. The isoquinoline 2a on the
other hand exhibited a quite different retention time in comparison
to the o-alkynylnaphthylaldehyde 7a, which facilitated its isolation
as a pure compound, despite the sometimes significant adsorption
of the product 2a on silica or on Al2O3. Further improvement to the
synthetic procedure was made by directly adding an aqueous am-
monia solution to the reaction mixture obtained after the coupling
reaction and stirring it at 100 ꢀC for 2 h (Scheme 6). This one-pot
4. Experimental section
4.1. General experimental methods
1H NMR spectra were recorded on a Bruker Avance DRX 250
spectrometer at 250 MHz, Bruker Avance II 500 spectrometer at
500 MHz with an internal standard TMS. J values are given in hertz.
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
(d
¼77). 13C NMR

2274
S. Van Aeken et al. / Tetrahedron 67 (2011) 2269e2278
assignments were made using DEPT spectra. Melting points were
via preparative RP-HPLC. Mp 107.7e108.4 ꢀC. 1H NMR (250 MHz,
CDCl3): dH 4.17 (3H, s, C5eOCH3), 4.32 (3H, s, C10eOCH3), 7.53e7.64
(3H, m, H-30, H-40, H-50), 7.68 (1H, ddd, J 1.3, 6.6 and 8.6, H-7), 7.77
(1H, ddd, J 1.3, 6.6 and 8.6, H-8), 8.03 (2H, d, J 6.8, H-20, H-60), 8.36
(1H, d, J 8.5, H-6), 8.41 (1H, d, J 8.4, H-9), 8.50 (1H, s, H-4), 10.27 (1H,
s, H-1), 16.07 (1H, s, NH). 13C NMR (63 MHz, CDCl3): dC 63.9 (C5-
OCH3), 65.9 (C10eOCH3), 115.1 (C-4), 117.3 (C-4a), 122.9 (C-6), 123.8
(C-9), 125.5 (C-10a), 126.9 (C-5a), 127.5 (C-7), 127.6 (C-20, C-60),
129.5 (C-30, C-40), 130.1 (C-8), 130.2 (C-40), 131.2 (C-9a), 134.0 (C-10),
143.2 (C-3), 148.1 (C-5), 148.7 (C-1), 154 (C-10). IR (ATR): vmax 670,
775, 966, 1071, 1297, 1367, 1456, 1605 cmꢁ1. MS (ESþ) m/z (%): 316
(MþHþ, 100). HRMS (ESI): calcd for C21H17NO2þHþ: 316.3726;
found 316.3712.
€
determined on a Buchi melting point apparatus B-540 and are
uncorrected. GCeMS analyses were performed using an Inter-
science GC 8000 series gas chromatograph with a ECÔ-5 column
(length: 30 m, internal diameter: 0.32 mm, film thickness:
0.25 m
m). 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 spec-
trometer. Infrared spectra were recorded with an Avatar 370 FT-IR
apparatus (Thermo Nicolet), using the attenuated total reflection
technology (ATR). Column chromatography was performed using
Merck silica (diameter 40e63 mm). Preparative HPLC was carried
out with an Agilent 1100 series equipped with a Discovery BIO wide
PoreÒ RP C18 column (25 cmꢂ4.6 mmꢂ5
m
m) using a MeCN/H2O
4.3.2. 5,10-Dimethoxy-3-(3-methoxyphenyl)benzo[g]isoquinoline
(2b). Purified over a silica column (cHexane/EtOAc, 9/1) and af-
terwards stirred in a MeOH/NaOH solution for 24 h, affording 2b in
50% yield as a yellow powder. Mp 149.7e150.1 ꢀC. 1H NMR
gradient containing 0.1% TFA. TLC-analysis was performed on glass
backed plates (Merck) coated with 0.2 mm silica 60 F254
.
0
4.2. Preparation of N-[(3-bromo-1,4-dimethoxynaphthalen-
(250 MHz, CDCl3): dH 3.95 (3H, s, C3 eOCH3), 4.15 (3H, s, C5eOCH3),
2-yl)methylene]-2-methyl-propan-2-amine (4)
4.23 (3H, s, C10eOCH3), 6.99 (1H, dd, J 1.9 and 8.1, H-40), 7.44 (1H, t, J
7.9, H-50), 7.54 (1H, dd, J 6.7 and 8.5, H-7), 7.60 (1H, dd, J 7.0 and 7.9,
H-8), 7.79 (1H, d, J 7.7, H-60), 7.85 (1H, s, CHar), 8.31 (1H, d, J 8.7, H-6),
8.35 (1H, d, J 8.6, H-9), 8.40 (1H, s, H-20), 9.88 (1H, s, H-1). 13C NMR
(126 MHz, CDCl3): dC 54.4 (OCH3), 62.4 (OCH3), 63.6 (OCH3), 109.2
(CHar), 111.3 (CHar), 113.5 (CHar), 117.8 (Cq), 118.4 (CHar), 121.5 (CHar),
122.1 (CHar), 124.8 (Cq), 124.9 (CHar), 125.1 (Cq), 126.4 (CHar), 127.3
(Cq), 128.8 (CHar), 140.2 (Cq), 146.9 (Cq), 147.7 (Cq), 148.9 (CHar),
149.9 (Cq), 159.2 (Cq). IR (ATR): vmax 699, 765, 865, 966, 1070, 1367,
1453, 1595 cmꢁ1. MS (ESþ) m/z (%): 346 (MþHþ, 100). HRMS (ESI):
calcd for C22H19NO3þHþ: 346.3986; found 346.3971.
3-Bromo-1,4-dimethoxy-2-naphthaldehyde (3a)9 (2.28 g,
7.7 mmol) was dissolved in dry CH2Cl2 (20 mL). tert-Butylamine
(1.69 g, 23.2 mmol) and anhydrous MgSO4 (3 g) were added and the
reaction mixture was stirred for 20 h at room temperature. After
completion, the reaction mixture was filtrated and afterwards
concentrated in vacuo. The imine was isolated as a yellowish-white
solid (0.8 g, 100%). No further purification was required. Mp
67e68 ꢀC. 1H NMR (250 MHz, CDCl3): dH 1.41 (9H, s, C(CH3)3), 3.93
(3H, s, OCH3), 3.98 (3H, s, OCH3), 7.56 (1H, dd, J 2.5 and 7.2, CHar),
7.56 (1H, dd, J 3.9 and 5.8, CHar), 8.07e8.16 (2H, m, CHar), 8.51 (1H, s,
CH]N). 13C NMR (63 MHz, CDCl3): dC 29.5 (C(CH3)3), 58.7 (C(CH3)3),
61.4 (OCH3), 63.4 (OCH3), 100.2 (Cq), 113.0 (Cq), 122.5 (CHar), 123.1
(CHar), 126.8 (CHar), 127.5 (CHar), 128.5 (Cq), 129.1 (Cq), 150.0
(CeOMe), 151.5 (CeOMe), 153.3 (C]N). IR (ATR): nmax 763, 1007,
1079, 1347, 1454, 2966 cmꢁ1. MS (70 eV, m/z (%)): 351 (17), 349 (17),
294 (82), 292 (79), 279 (82), 277 (85), 240 (51), 198 (100), 113 (47).
HRMS (ESI): calcd for C17H20BrNO2þHþ: 350.0750; found 350.0731.
4.3.3. 5,10-Dimethoxy-3-(4-methoxy-2-methylphenyl)benzo[g]iso-
quinoline (2c). Purified over a silica column (cHexane/EtOAc, 9/1)
and afterwards stirred in MeOH/NaOH solution for 24 h, affording
2c in 59% yield as a yellow powder. Mp 155.8e157.3 ꢀC. 1H NMR
0
(250 MHz, CDCl3): dH 2.50 (3H, s, CH3), 3.86 (3H, s, C4 eOCH3), 4.10
(3H, s, C5eOCH3), 4.24 (3H, s, C10eOCH3), 6.88e6.89 (2H, m, H-50,
H-60), 7.25e7.60 (3H, m, H-7, H-8, H-30), 8.04 (1H, s, H-4), 8.30 (1H,
d, J 4.3, H-6), 8.35 (1H, d, J 4.3, H-9), 9.85 (1H, s, H-1). 13C NMR
(125 MHz, CDCl3): dC 21.0 (CH3), 55.3 (OCH3), 63.4 (OCH3), 64.6
(OCH3), 111.4 (CHar), 113.5 (CHar), 116.3 (CHar), 118.3 (Cq), 122.5
(CHar), 123.1 (CHar), 125.6 (Cq), 125.8 (CHar), 125.9 (Cq), 127.4 (CHar),
128.2 (Cq), 131.5 (CHar), 133.5 (Cq), 137.8 (Cq), 147.5 (Cq), 149.2 (CHar),
147.5 (Cq), 149.2 (CHar), 150.9 (Cq), 151.0 (Cq), 159.5 (Cq). IR (ATR):
vmax 689, 772, 811, 860, 965, 1070, 1254, 1286, 1286, 1367,
1607 cmꢁ1. MS (ESþ) m/z (%): 360 (MþHþ, 100). HRMS (ESI): calcd
for C23H21NO3þHþ: 360.4251; found 360.4268.
4.3. Palladium/copper catalyzed formation of 3-substituted
5,10-dimethoxybenzo[g]isoquinolines from terminal
acetylenes
The synthesis of 5,10-dimethoxy-3-phenylbenzo[g]isoquinoline
(2a) is representative.
The imine 4 (0.8 g, 2.29 mmol), phenylacetylene (0.256 g,
2.51 mmol), Pd(PPh3)2Cl2 (0.064 g, 0.09 mmol) and CuI (0.017 g
0.09 mmol) were placed in a pressure tube and dissolved in Et3N
(11 mL). The vial was flushed with argon, closed with a screw-top
and heated in an oil bath to 70 ꢀC for 24 h. After completion, the
precipitate was filtered over decalite and rinsed with Et2O. The
filtrate was subsequently concentrated in vacuo. The residue was
redissolved in DMF (11 mL) and CuI (0.044 g, 0.23 mmol) was
added. The reaction mixture (poured in an argon flushed pressure
tube) was heated to 100 ꢀC for 4 h. After completion the mixture
was cooled, diluted with Et2O, washed with aqueous NH4Cl, dried
over MgSO4 and filtered. The solvent was removed in vacuo and the
crude residue was purified by column chromatography (PE/EtOAc,
9/1). The isolated solid was either treated with NaOH in MeOH
(50 equiv NaOH, 0.1 M solution, 24 h) or further purified via pre-
parative RP-HPLC.
4.3.4. 5,10-Dimethoxy-3-p-tolylbenzo[g]isoquinoline (2d). Purified
over a silica column (cHexane/EtOAc, 9/1) and isolated with 55%
yield as an orange powder. Mp 135e137 ꢀC. 1H NMR (250 MHz,
CDCl3): dH 2.44 (3H, s, CH3), 4.15 (3H, s, C5eOCH3), 4.23 (3H, s,
C10eOCH3), 7.53 (1H, ddd, J 1.4, 6.6 and 8.2, H-7), 7.60 (1H, ddd, J 1.4,
6.6 and 8.3, H-8), 7.35 (2H, d, J 7.5, H-30, H-50), 8.12 (2H, d, J 8.2, H-20,
H-60), 8.31 (1H, dd, J 1.7 and 5.7, H-6), 8.34 (1H, dd, J 1.7, and 8.0, H-
9), 8.37 (1H, d, J 1, H-4), 9.87 (1H, d, J 1, H-1). 13C NMR (125 MHz,
CDCl3): dC 21.33 (CH3), 63.4 (C5eOCH3), 64.7 (C10eOCH3), 109.4 (C-
4), 118.7 (C-4a), 122.5 (C-6), 123.1 (C-9), 125.6 (Cq-10a), 125.8 (C-7),
126.2 (C-5a), 126.9 (C-30, C-50), 127.4 (C-8), 128.2 (C-40), 129.6 (C-20,
C-60), 136.8 (C-9a), 138.5 (C-10), 147.7 (C-3), 149.0 (C-5), 149.9 (C-1),
150.9 (C-10). IR (ATR): vmax 757, 769, 827, 1072, 1369, 1605 cmꢁ1. MS
(ESþ) m/z (%): 330 (MþHþ, 100). HRMS (ESI): calcd for
C22H19NO2þHþ: 330.3992; found 330.3979.
4.3.1. 5,10-Dimethoxy-3-phenylbenzo[g]isoquinoline (2a) (HCl salt).
Purified over a silica column (cHexane/EtOAc, 9/1) or Al2O3
(cHexane/EtOAc, 12/1) and obtained in 80% yield as a yellow
powder. An analytically pure sample was obtained by purification
4.3.5. 5,10-Dimethoxy-3-(methoxymethyl)benzo[g]isoquinoline
(2e). This compound was isolated as an orange powder in 91% yield

S. Van Aeken et al. / Tetrahedron 67 (2011) 2269e2278
2275
after purification over a silica gel column (gradient: cHexane/EtOAc,
9/1 over cHexane/EtOAc, 4/1 to EtOAc). Mp 102.0e103.5 ꢀC. 1H NMR
(500 MHz, CDCl3): dH 3.60 (3H, s, CH2OCH3), 4.12 (3H, s, C5eOCH3),
4.20 (3H, s, C10eOCH3), 4.79 (2H, s, CH2), 7.55 (1H, dt, J 1.0 and 7.5,
H-7), 7.61 (1H, dt, J 1.0 and 7.6, H-8), 8.04 (1H, s, H-4), 8.22 (1H, d, J
9.0, H-6), 8.35 (1H, d, J 8.5, H-9), 9.76 (1H, s, H-1). 13C NMR (63 MHz,
CDCl3): dC 58.9 (CH2OCH3), 63.4 (OCH3), 64.6 (OCH3), 75.7 (CH2),
111.4 (CHar), 119.0 (Cq), 119.0 (Cq), 122.6 (CHar), 123.1 (CHar), 125.6
(Cq),125.9 (CHar),127.4 (CHar),128.2 (Cq),131.9 (Cq),149.0 (Cq),149.9
(CHar), 150.9 (Cq). IR (ATR): vmax 741, 769, 968, 1065, 1364, 1621,
2981 cmꢁ1. MS (ESþ) m/z (%): 284 (MþHþ, 100). HRMS (ESI): calcd
for C17H17NO3þHþ: 284.3292; found 284.3304.
(%): 296 (MþHþ, 100), 328 (73). HRMS (ESI): calcd for
C19H21NO2þHþ: 296.1645; found 296.1659.
4.3.9. 5,10-Dimethoxybenzo[g]isoquinoline-3-carbaldehyde (2l) (HCl
salt). This compound was prepared by stirring 2g in a biphasic
Et2O/2 N HClaq solution at ambient temperature for 2 h. Neutrali-
zation of the aqueous phase with 2 N NaOH, extraction with Et2O
and combination of the organic phases gave after drying over
MgSO4 and removal of the volatiles 2l as a yellow powder. An an-
alytically pure sample was obtained by preparative RP-HPLC. Mp
167.5e167.7 ꢀC. Yellow powder. 1H NMR (250 MHz, CDCl3): dH 4.18
(3H, s, C5eOCH3), 4.23 (3H, s, C10eOCH3), 7.63e7.73 (2H, m, H-7, H-
8), 8.35e8.43 (2H, m, H-6, H-9), 8.73 (1H, d, J 0.9, H-4), 9.86 (1H, d, J
0.8, H-1), 10.31 (1H, s, CHO). 13C NMR (63 MHz, CDCl3): dC 64.3
(C5eOCH3), 64.8 (C10eOCH3), 118.3 (C-4), 120.2 (C-4a), 123 (C-6),
123.3 (C-9), 124.3 (C-10a), 127.6 (C-7), 128.0 (C-5a), 128.1 (C-8),
128.7 (C-9a), 144.8 (C-3), 150.5 (C-5), 150.9 (C-1), 151.1 (C-10), 193.0
(CHO). IR (ATR): vmax 690, 741, 965, 1067, 1364,1694, 2828 cmꢁ1. MS
(ESþ) m/z (%): 268 (MþHþ, 100). HRMS (ESI): calcd for
C16H13NO3þHþ: 268.2867; found 268.2881.
4.3.6. 3-Cyclohexyl-5,10-dimethoxybenzo[g]isoquinoline
(2f). Purified over a silica column (cHexane/EtOAc, 9/1) and after-
wards stirred in MeOH/NaOH solution for 24 h, affording 2f in 31%
yield as a yellow powder. Mp 124e125 ꢀC. 1H NMR (500 MHz,
CDCl3): dH 1.34e1.41 (1H, m, CH), 1.47e1.55 (2H, m, CH2), 1.64e1.72
(2H, m, CH2), 1.78e1.82 (1H, m, CH), 1.92e1.94 (2H, m, CH2),
2.12e2.15 (2H, m, CH2), 2.88e2.93 (1H, m, H-10), 4.10 (3H, s,
C5eOCH3), 4.20 (3H, s, C10eOCH3), 7.50 (1H, dd, J 7.3 and 7.3, H-7),
7.57 (1H, dd, J 7.3 and 7.3, H-8), 7.77 (1H, s, H-4), 8.27 (1H, d, J 8.5, H-
6), 8.32 (1H, d, J 8.5, H-9), 9.75 (1H, s, H-1). 13C NMR (125 MHz,
CDCl3): dC 26.25 (CH2), 26.74 (2ꢂCH2), 33.03 (2ꢂCH2), 46.26 (C-10),
63.06 (C5eOCH3), 64.49 (C10eOCH3),109.3 (C-40),118.7 (C-4a),122.4
(C-6), 123.1 (C-9), 125.1 (C-10a), 125.4 (C-7), 126.2 (C-5a), 127.1 (C-
8), 128.0 (C-9a), 147.0 (C-3), 149.4 (C-1), 150.8 (C-5), 157.9 (C-10). IR
(ATR): vmax 703, 772, 969, 1063, 1294, 1367, 1450, 1613, 2847,
2923 cmꢁ1. MS (ESþ) m/z (%): 322 (MþHþ, 100). HRMS (ESI): calcd
for C21H23NO2þHþ: 322.4202; found 322.4218.
4.3.10. 1,4-Dimethoxy-3-(3-methoxy-3-methylbut-1-ynyl)-2-naph-
thaldehyde (7i). An analytically pure sample was obtained via
preparative RP-HPLC, isolating 7i as a black viscous liquid. 1H NMR
(250 MHz, CDCl3): dH 1.65 (6H, s, CH3), 3.54 (3H, s, OCH3), 4.05 (3H,
s, OCH3), 4.10 (3H, s, OCH3), 7.61 (1H, ddd, J 1.4, 6.8 and 8.2, CHar),
7.68 (1H, ddd, J 1.4, 6.8 and 8.3, CHar), 8.16 (1H, d, J 8.4, CHar), 8.25
(1H, d, J 8.4, CHar), 10.7 (1H, s, CHO). 13C NMR (63 MHz, CDCl3): dC
28.23 (2ꢂCH3), 52.08 (OCH3), 61.70 (OCH3), 64.53 (OCH3), 71.35
(Cq), 102.2 (Cq), 111.1 (Cq), 122.9 (CHar), 124.0 (CHar), 128.0 (CHar),
128.8 (Cq), 129.7 (CHar), 131.6 (Cq), 156.0 (CeOMe), 156.6 (CeOMe),
195.1 (CHO). IR (ATR): vmax 775, 965, 1061, 1350, 1690, 2934,
2982 cmꢁ1. MS (ESþ) m/z (%): 299 (MþHþ, 100), 281 (41), 281 (100).
HRMS (ESI): calcd for C19H20O4þHþ: 313.1434; found 313.1452.
4.3.7. 3-(Diethoxymethyl)-5,10-dimethoxybenzo[g]isoquinoline
(2g). Isolated after purification over a short Al2O3 column (Petro-
leum ether/EtOAc, 9/1) as
a red powder in 5% yield. Mp
108.3e109.2 ꢀC. 1H NMR (250 MHz, CDCl3): dH 1.33 (6H, d, J 7.1,
2ꢂCH3), 3.77 (4H, qd J 7.0 and 9.2, 2ꢂCH2), 4.13 (3H, s, C5eOCH3),
4.20 (3H, s, C10eOCH3), 5.72 (1H, s, H-10), 7.49e7.67 (2H, m, H-7, H-
8), 8.26 (1H, d, J 0.4, H-4), 8.32 (1H, d, J 8.9, H-6), 8.35 (1H, d, J 8.6, H-
9), 9.79 (1H, s, H-1). 13C NMR (63 MHz, CDCl3): dC 15.3 (2ꢂCH3), 62.4
(2ꢂCH2), 63.5 (C5eOCH3), 64.6 (C10eOCH3), 102.7 (C-10), 111.5 (C-4),
119.4 (C-4a), 122.6 (C-6), 123.1 (C-9), 125.4 (C-10a), 125.9 (C-9a),
126.1 (C-7), 127.4 (C-8), 128.2 (C-4a), 148.1 (C-3), 149.0 (C-5), 149.9
(C-1), 150.1 (C-10). IR (ATR): vmax 770, 968, 1059, 1369, 1439, 1452,
1610 cmꢁ1. MS (ESþ) m/z (%): 342 (MþHþ, 100). HRMS (ESI): calcd
for C20H23NO4þHþ: 342.4083; found 342.4068.
4.4. 2-[(tert-Butylimino)methyl]-3-(cyclohexylethynyl)-4-
methoxynaphthalen-1-ol (12f)
This compound was isolated impure via flash chromatography
on silica gel of the reaction mixture from entry 1 in Table 2 (gra-
dient: PE/EtOAc, 12/1 to 9/1). 1H NMR (250 MHz, CDCl3): dH 1.49
(9H, s, C(CH3)3), 1.92e2.00 (2H, m, CH2), 2.72e2.85 (1H, m, CH),
3.96 (3H, s, OCH3), 7.44 (1H, ddd, J 1.2, 7.1 and 8.0, CHar), 7.60 (1H,
ddd, J 1.4, 6.4 and 8.8, CHar), 7.89 (1H, d, J¼8.1, CHar), 8.42 (1H, d,
J¼8.9, CHar), 8.46 (1H, br s, HC]N), 13.5 (1H, br s, OH). The other
cyclohexyl protons could not be discerned due to other impurities.
MS (ESþ) m/z (%): 365 (22), 364 (MþHþ, 100), 363 (19).
4.3.8. 3-Butyl-5,10-dimethoxybenzo[g]isoquinoline (2h). Isolated as
an equimolar mixture of the isoquinoline 2h and the iso-
quinolinium chloride 2h$HCl after Al2O3 flash chromatography
(gradient: Petroleum ether/EtOAc, 20/1 over Petroleum ether/
EtOAc, 12/1 to Petroleum ether/EtOAc, 9/1). The compounds were
treated with a solution of NaOH (50 equiv) in MeOH and the mix-
ture was stirred for 24 h, affording 2h with 50% yield (still 15%
present as the hydrochloride). Mp 54e58 ꢀC. Yellow powder.
Spectral data for 2h were obtained from an equimolar mixture of
2h and 2h$HCl. 1H NMR (250 MHz, CDCl3): dH 0.99 (3H, t, J 7.3, H-40),
1.47 (2H, pseudo sextet, J 7.4, H-30), 1.80 (2H, pseudo quintet, J 7.6,
H-20), 3.00 (2H, t, J 7.7, H-10), 4.11 (3H, s, OCH3), 4.20 (3H, s, OCH3),
7.51 (1H, dd, J 1.4 and 7.6, H-7), 7.58 (1H, dd, J 1.4 and 7.8, H-8), 7.79
(1H, s, H-4), 8.26e8.43 (2H, m, H-6, H-9), 9.74 (1H, s, H-1). 13C NMR
(63 MHz, CDCl3): dC 14.02 (CH3), 22.55 (CH2), 31.96 (CH2), 38.05
(CH2), 63.13 (OCH3), 64.55 (OCH3), 101.5 (Cq), 111.1 (Cq), 122.4 (CHar),
123.1 (CHar), 125.1 (CHar), 125.5 (CHar), 127.2 (CHar), 128.1 (CHar),
136.7 (Cq),138.8 (Cq), 146.8 (CeOMe), 150.8 (CeOMe). IR (ATR): vmax
771, 870, 977,1068,1368,1453,1614, 2855, 2953 cmꢁ1. MS (ESþ) m/z
4.5. 3-Bromo-2-[(tert-butylimino)methyl]-4-methoxynaphtha-
len-1-ol (11)
This compound was isolated via flash chromatography on silica
gel of the reaction mixture from entry 11 in Table 2 (gradient: PE/
EtOAc, 12/1 to 9/1). Mp 73.0e73.5 ꢀC, yellow powder. 1H NMR
(250 MHz, CDCl3): dH 1.50 (9H, s, C(CH3)3), 3.88 (6H, s, OCH3), 7.41
(1H, ddd, J 1.3, 7.0 and 8.1, CHar), 7.62 (1H, ddd, J 1.3, 7.0 and 8.2,
CHar), 7.85 (1H, dd, J 0.6 and 8.2, CHar), 8.42 (1H, s, HC]N), 8.46 (1H,
d, J 5.2, CHar), 13.8 (1H, s, OH). 13C NMR (63 MHz, CDCl3): dC 29.83 (C
(CH3)3), 54.58 (C(CH3)3), 60.83 (OCH3), 105.9 (Cq), 113.4 (Cq), 122.1
(CHar), 126.0 (CHar), 126.4 (CHar), 130.8 (Cq), 131.2 (CHar), 132.6 (Cq),
141.7 (Cq), 156.8 (CH), 177.5 (HC]N). IR (ATR): vmax 701, 769, 1228,
1324, 1599, 1624 cmꢁ1. MS (ESþ) m/z (%): 338 (MþHþ, 100), 336
(MþHþ, 100), 282 (30), 280 (30). HRMS (ESI): calcd for
C16H18BrNO2þHþ: 337.2310; found 337.2294.

2276
S. Van Aeken et al. / Tetrahedron 67 (2011) 2269e2278
4.6. Synthesis of 3-substituted 5,10-dimethoxybenzo[g]-
isoquinolines 2 via the double addition protocol
5.64 (1H, s, CH), 7.60e7.73 (2H, m, CHar), 8.17 (1H, d, J 8.4, CHar),
8.26 (1H, J 8.5, CHar). 13C NMR (63 MHz, CDCl3): dC 15.18 (2ꢂCH3),
61.16 (2ꢂCH2), 62.04 (OCH3), 64.59 (OCH3), 78.46 (Cq), 92.02 (CH),
95.31 (Cq), 110.1 (Cq), 123.0 (CHar), 124.0 (CHar), 128.2 (CHar), 129.1
(Cq), 129.8 (CHar), 131.5 (Cq), 156.7 (CeOCH3), 156.8 (CeOCH3), 189.9
(CHO). IR (ATR): vmax 720, 775, 979, 1061, 1339, 1351, 1687, 2936,
2971 cmꢁ1. MS (ESþ) m/z (%): 343 (MþHþ, 20), 315 (100), 297 (35).
HRMS (ESI): calcd for C20H22O5þHþ: 343.3931; found 343.3945.
4.6.1. 3-(Diethoxymethyl)-5,10-dimethoxybenzo[g]isoquinoline
(2g). The imine 4 (0.8 g, 2.29 mmol), 3,3-diethoxy-1-propyne
(0.324 g, 2.51 mmol), PdCl2(PPh3)2 (0.064 g, 0.09 mmol) and CuI
(0.017 g, 0.09 mmol) were placed in a pressure tube and dissolved
in Et3N (11 mL). The vial was flushed with argon, closed with
a screw-top and heated in an oil bath to 70 ꢀC. The reaction mixture
was stirred and monitored with HPLC until the conversion stalled
(after approximately 8 h). The reaction mixture was subsequently
filtered over decalite and rinsed with Et3N. The collected filtrate
was placed in a pressure tube, PdCl2(PPh3)2 (0.032 g), CuI (0.08 g)
and 3,3-diethoxypropyne (0.162 g) were added anew in quantities
depending on the earlier degree of conversion (estimated via HPLC
at w50%), the reaction vessel was flushed with argon, closed and
heated at 70 ꢀC for another 8 h. After completion, the reaction
mixture was filtered over decalite and rinsed with Et2O. The filtrate
was subsequently concentrated in vacuo. The residue was dissolved
in DMF (11 mL) and CuI (0.044 g, 0.23 mmol) was added. The re-
action mixture (poured in an argon flushed pressure tube) was
heated to 100 ꢀC for 4 h. After completion the mixture was cooled,
diluted with Et2O, washed with aqueous NH4Cl, dried over MgSO4
and filtered. The solvent was removed in vacuo and the crude
residue was purified by Al2O3 gel column chromatography (PE/
EtOAc, 9/1), isolating 2g (0.414 g, 53%) as a red powder.
4.7.3. 3-(Cyclohexylethynyl)-1,4-dimethoxy-2-naphthaldehyde
(7f). The aldehyde 3a (0.077 g, 0.26 mmol) was dissolved in DMF
(1 mL) in a pressure tube. Pd(OAc)2 (0.0023 g, 0.01 mmol), CuI
(0.001 g, 0.005 mmol), Cs2CO3 (0.102 g, 0.31 mmol), P(t-Bu)3
(0.012 g, 0.03 mmol) and cyclohexylacetylene (0.056 g, 0.52 mmol)
were added subsequently. The reaction vessel was purged with
argon, closed with a screw top and placed in a 100 ꢀC oil bath while
the reaction mixture was stirred for 24 h. Afterwards, the reaction
mixture was cooled to room temperature and quenched with 10 mL
of aqueous NH4Cl. Extraction with Et2O (3ꢂ10 mL), drying of the
combined organic phases and in vacuo concentration resulted in
a brown residue that was further purified by column chromatog-
raphy on silica gel (PE/EtOAc, 9/1). Compound 7f was isolated as
a red viscous liquid (0.062 g, 73%). 1H NMR (250 MHz, CDCl3): dH
1.37e2.00 (10H, m, (CH2)5), 2.79 (1H, ddd, J 3.8, 8.9 and 12.7, CH
(CH2)), 4.03 (3H, s, OCH3), 4.09 (3H, s, OCH3), 7.58 (1H, ddd, J 1.4, 6.8
and 8.2, CHar), 7.66 (1H, ddd, J 1.5, 6.8 and 8.2, CHar), 8.15 (1H, dd, J
1.3 and 8.3, CHar), 8.25 (1H, dd, J 1.4 and 8.4, CHar), 10.7 (1H, s, CHO).
13C NMR (63 MHz, CDCl3): dC 24.87 (2ꢂCH2), 25.91 (CH2), 30.24
(CH), 32.47 (2ꢂCH2), 61.51 (OCH3), 64.21 (OCH3), 73.54 (Cq), 106.3
(Cq), 112.9 (Cq), 122.6 (CHar), 124.1 (Cq), 124.1 (CHar), 127.5 (CHar),
128.5 (Cq), 129.5 (CHar), 131.6 (Cq), 155.5 (CeOMe), 155.8 (CeOMe),
191.1 (CHO). IR (ATR): vmax 728, 776, 908, 1076, 1283, 1350, 1449,
1565, 1694, 2852, 2929 cmꢁ1. MS (ESþ) m/z (%): 323 (MþHþ, 100).
HRMS (ESI): calcd for C21H22O3þHþ: 323.4050; found 323.4033.
4.6.2. 3-Cyclohexyl-5,10-dimethoxybenzo[g]isoquinoline (2f). The pro-
cedure to synthesize 2f was identical to that of 2g (vide supra). 2f was
isolated as a yellow powder after flash chromatography (PE/EtOAc,
9/1) in 58% yield.
4.7. Sonogashira coupling of aldehyde 3a with alkynes
The synthesis of 1,4-dimethoxy-3-(phenylethynyl)-2-naph-
thaldehyde (7a) is representative.
4.7.4. 2-Cyclohexyl-4,9-dimethoxy-1H-cyclopenta[b]naphthalen-1-
one (13f). This compound was isolated from the reaction mixture
obtained in entry 18 in Table 3.
The aldehyde 3a (0.148 g, 0.5 mmol) was dissolved in DMF
(3 mL) in a pressure tube. Pd(OAc)2 (0.005 g, 0.02 mmol), CuI
(0.004 g, 0.02 mmol), K2CO3 (0.083 g, 0.6 mmol), P(t-Bu)3 (0.012 g,
0.06 mmol) and phenylacetylene (0.061 g, 0.6 mmol) were added
subsequently, after which the pressure tube was purged with ar-
gon, closed with a screw top and placed in a 100 ꢀC oil bath for 24 h
while being stirred. Afterwards, the reaction mixture was cooled to
room temperature and quenched with 10 mL of aqueous NH4Cl.
Extraction with Et2O (3ꢂ10 mL), drying (MgSO4) of the combined
organic phases and in vacuo concentration resulted in a brown
residue that was further purified by silica column chromatography
(PE/EtOAc, 9/1). Compound 7a was isolated as a red powder
(0.128 g, 81%).
Yellow viscous liquid. 1H NMR (250 MHz, CDCl3): dH 1.25e2.27
(10H, m, (CH2)5), 2.38e2.47 (1H, m, CH), 4.02 (3H, s, OCH3), 4.27
(3H, s, OCH3), 7.43 (1H, d, J 1.3, CH), 7.43 (1H, dt, J 1.3 and 7.6, CHar),
7.54 (1H, dt, J 1.3 and 7.6, CHar), 7.96 (1H, dd, J 1.0 and 8.3, CHar), 8.21
(1H, dd, J 0.9 and 8.1, CHar). 13C NMR (125 MHz, CDCl3): dC 24.78
(CH2), 25.75 (CH2), 26.36 (CH2), 29.50 (CH), 32.15 (CH2), 32.29
(CH2), 62.71 (OCH3), 62.84 (OCH3), 119.3 (Cq), 122.8 (CHar), 125.6
(CHar), 126.8 (CHar), 131.0 (Cq), 132.8 (Cq), 137.2 (CHar), 144.3 (Cq),
145.9 (Cq), 148.7 (CeOMe), 151.9 (CeOMe), 193.2 (C]O). IR (ATR):
vmax 770,1034,1341,1448,1685, 2849, 2922 cmꢁ1. MS (ESþ) m/z (%):
323 (MþHþ, 100). HRMS (ESI): calcd for C21H22O3þHþ: 323.1642;
found 323.1629.
4.7.1. 1,4-Dimethoxy-3-(phenylethynyl)-2-naphthaldehyde (7a). Mp
96e97 ꢀC. Red solid. 1H NMR (250 MHz, CDCl3): dH 4.08 (1H, s,
OCH3), 4.19 (1H, s, OCH3), 7.35e7.45 (2H, m, CHar), 7.73e7.45 (5H, m,
CHar), 8.19e8.29 (2H, m, CHar), 10.8 (1H, s, CHO). 13C NMR (63 MHz,
CDCl3): dC 61.9 (OCH3), 64.6 (OCH3), 83.1 (Cq), 100.2 (Cq), 111.4 (Cq),
122.9 (CHar), 123.2 (Cq), 124.0 (CHar), 128.0 (CHar), 128.5 (2ꢂCHar),
128.8 (CHar), 128.9 (Cq), 129.7 (CHar), 131.6 (2ꢂCHar), 156.0
(CeOMe), 156.7 (CeOMe), 190.2 (CHO). IR (ATR): vmax 2935, 1694,
1348, 1023, 778, 756, 692 cmꢁ1. MS (ESþ) m/z (%): 317 (MþHþ, 100).
HRMS (ESI): calcd for C21H16O3þHþ: 317.3573; found 317.3562.
4.8. A sequential one-pot cyclization and ammonia
annulation procedure
The synthesis of 3-cyclohexyl-5,10-dimethoxybenzo[g]iso-
quinoline (2f) is representative.
The aldehyde 3a (0.077 g, 0.26 mmol) was dissolved in DMF
(1 mL) in a pressure tube. Pd(OAc)2 (0.0023 g, 0.01 mmol), CuI
(0.001 g, 0.005 mmol), Cs2CO3 (0.102 g, 0.31 mmol), P(t-Bu)3
(0.012 g, 0.03 mmol) and cyclohexylacetylene (0.056 g, 0.52 mmol)
were added subsequently. The reaction vessel was purged with
argon, closed with a screw cap and placed in a 100 ꢀC oil bath while
the reaction mixture was stirred for 24 h. Afterwards 1 mL of a 28%
aqueous NH4OH solution was added together with K2CO3 (0.036 g,
0.26 mmol) and the mixture was heated to 100 ꢀC for 2 h. Upon
completion the reaction mixture was diluted with water (20 mL)
4.7.2. 3-(3,3-Diethoxyprop-1-ynyl)-1,4-dimethoxynaphthalene-2-
carbaldehyde (7g). Compound 7g was purified via Al2O3 gel column
chromatography (cHexane/EtOAc, 9/1) and isolated as a yellow,
viscous liquid with a yield of 31%. 1H NMR (250 MHz, CDCl3): dH 1.31
(6H, t, J 7.1, 2ꢂCH3), 3.77 (2H, q, J 7.1, CH2), 3.90 (2H, q, J 7.1, CH2),

S. Van Aeken et al. / Tetrahedron 67 (2011) 2269e2278
2277
and extracted with Et2O (3ꢂ10 mL). The combined organic phases
were dried over MgSO4, concentrated in vacuo and purified via
silica gel column chromatography (PE/EtOAc, 9/1), resulting in
a yellow powder 2f (0.058 g, 70%).
Compounds 2g (0.036 g, 41%) and 2h (0.036 g, 50%) were con-
structed according to the above described procedure. After purifi-
cation by Al2O3 flash chromatography (gradient PE/EtOAc, 20/1
over PE/EtOAc, 12/1 to PE/EtOAc, 9/1) 2h was treated with a NaOH
(50 equiv) solution in MeOH (0.02 M) and stirred for 24 h at room
temperature prior to NMR analysis. Compound 2g was purified by
Al2O3 flash chromatography (PE/EtOAc, 9/1).
9/1 to PE/EtOAc 4/1). Compound 1a was isolated as a yellow pow-
der (0.088 g, 98%).
4.9.1. 3-Phenylbenzo[g]isoquinoline-5,10-dione (1a). Mp 203.7e
204.0 ꢀC (lit.,7 199.7e201.6 ꢀC). Yellow powder. The spectral data
are, within the experimental error, in accordance with the litera-
ture.7 1H NMR (500 MHz, CDCl3): dH 7.50e7.57 (3H, m, CHar), 7.85
(1H, dꢂpseudo t, J 1.5 and 7.5, CHar), 7.88 (1H, dꢂpseudo t, J 1.5 and
7.5, CHar), 8.21 (2H, d, J 7.0, CHar), 8.34 (1H, dd, J 1.5 and 6.8, CHar),
8.36 (1H, dd, J 1.0 and 6.0, CHar), 8.50 (1H, s, CHar), 9.61 (1H, s, CHar).
13C NMR (126 MHz, CDCl3): dC 115.3 (C-4), 124.6 (Cq), 127.3 (CHar),
127.4 (CHar), 127.6 (2ꢂCHar), 129.0 (CHar), 129.2 (CHar), 130.7 (CHar),
133.2 (Cq), 133.4 (Cq), 134.4 (CHar), 135.0 (CHar), 137.7 (Cq), 139.3
(Cq), 150.1 (C-1), 162.9 (C-3), 182.3 (C]O), 182.8 (C]O). IR (ATR):
vmax 711, 925, 1285, 1580, 1674 cmꢁ1. MS (ESþ) m/z (%): 286 (MþHþ,
100).
4.8.1. Synthesis of 10,10-dimethoxy-3-phenylbenzo[g]isoquinolin-5
(10H)-one (10a). To a solution of 9 (0.07 g, 0.2 mmol) in MeOH
(4 mL), NaOH (0.48 g, 16 mmol) was added. The reaction mixture
was stirred at 80 ꢀC for 30 h, where after it was diluted with water
(20 mL) and extracted with Et2O (2ꢂ10 mL). The organic phases
were combined, dried over MgSO4 and the volatiles were removed
in vacuo. The isolated residue was purified over a short silica
column (PE/EtOAc, 12/1 to PE/EtOAc, 9/1) to give a yellow powder
(58 mg, 89%). Mp 92.5e93.7 ꢀC. 1H NMR (250 MHz, CDCl3): dH 3.06
(6H, s, 2ꢂOCH3), 7.52e7.56 (3H, m, H-30, H-40, H-50), 7.63 (1H, ddd,
J 7.5, 7.5 and 1.2, H-8), 7.82 (1H, ddd, J 7.5, 7.5 and 1.2, H-7), 7.92
(1H, dd, J 0.9 and 7.9, H-9), 8.14e8.23 (2H, m, H-20, H-60), 8.33 (1H,
dd, J 1.0 and 7.8, H-6), 8.5 (1H, s, H-4), 9.2 (1H, s, H-1). 13C NMR
(63 MHz, CDCl3): dC 52.1 (2ꢂOCH3), 97.0 (C-10), 115.5 (C-4), 127.1
(C-20,C-60,C-9), 127.5 (C-6), 129.0 (C-30, C-50), 129.8 (C-40), 129.9 (C-
8), 130.9 (C-4a), 132.8 (C-9a), 135.0 (C-7), 138.1 (C-10), 182.4 (C]O),
139.4 (C-10a), 139.6 (C-5a), 150.3 (C-1), 158.8 (C-3). IR (ATR): vmax
693, 710, 1064, 1291, 1383, 1596, 1676 cmꢁ1. MS (ESþ) m/z (%): 332
(MþHþ, 100). HRMS (ESI): calcd for C21H17NO3þHþ: 332.3720;
found 332.3738.
4.9.2. 3-(3-Methoxyphenyl)benzo[g]isoquinoline-5,10-dione
(1b). Isolated with 80% yield after purification over a short silica
column (PE/EtOAc, 4/1) to remove traces of CAN. Mp
191.4e192.1 ꢀC. Yellow powder. 1H NMR (500 MHz, CDCl3): dH
3.94 (3H, s, OCH3), 7.07 (1H, dd, J 1.5 and 8.0, CHar), 7.46 (1H,
pseudo t, J 8.0, CHar), 7.77e7.79 (2H, m, CHar), 7.86 (1H, dꢂpseudo
t, J 1.5 and 7.3, H-7), 7.89 (1H, dꢂpseudo t, J 1.3 and 7.4 Hz, H-8),
8.35 (1H, dd, J 1.0 and 7.0, H-6), 8.37 (1H, dd, J 1.5 and 6.8, H-9),
8.50 (1H, s, H-4), 9.62 (1H, s, H-1). 13C NMR (63 MHz, CDCl3): dC
53.21 (OCH3), 110.1 (CHar), 113.2 (CHar), 114.7 (CHar), 117.7 (CHar),
122.4 (Cq), 125.0 (CHar), 125.2 (CHar), 127.8 (CHar), 130.9 (Cq), 131.0
(Cq), 132.2 (CHar),133.7 (CHar), 136.7 (Cq), 136.9 (Cq), 147.6 (CHar),
158.0 (Cq), 160.2 (Cq), 180.0 (C]O), 180.5 (C]O). IR (ATR): vmax
679, 712, 1294, 1322, 1582, 1673 cmꢁ1. MS (ESþ) m/z (%): 316
(MþHþ, 100). HRMS (ESI): calcd for C20H13NO3þHþ: 316.3295;
found 316.3287.
4.8.2. Synthesis of 10-ethoxy-10-methoxy-3-phenylbenzo[g]iso-
quinolin-5(10H)-one (10b). To a solution of 9 (0.035 g, 0.1 mmol)
in EtOH (4 mL), NaOH (0.48 g, 16 mmol) was added. The reaction
mixture was stirred at 80 ꢀC for 30 h, where after it was diluted
with water and extracted with Et2O. The combined organic
extracts were dried over MgSO4 and concentrated in vacuo. The
isolated residue was purified over a short silica column (PE/EtOAc,
9/1) to give a yellow powder (26 mg, 76%). Mp 117.9e120.9 ꢀC. 1H
NMR (250 MHz, CDCl3): dH 1.66 (3H, t, J 7.0, CH3), 4.16 (3H, s,
OCH3), 4.38 (2H, q, J 7.0, CH2), 7.43e7.64 (5H, m, CHar), 8.19e8.24
(2H, m, CHar), 8.29e8.37 (2H, m, CHar), 8.41 (1H, d, J 1.1, H-4), 9.88
(1H, d, J 1.1, H-1). 13C NMR (63 MHz, CDCl3): dC 16.01 (CH3), 63.43
(OCH3), 73.34 (OCH2CH3), 109.9 (CHar), 119.1 (Cq), 122.5 (CHar),
123.4 (CHar), 125.8 (CHar), 126.1 (CHar), 127.0 (2ꢂCHar), 127.2 (Cq),
127.4 (CHar), 128.2 (Cq), 128.5 (CHar), 128.8 (2ꢂCHar), 139.7 (Cq),
147.6 (Cq), 148.9 (Cq), 150.1 (Cq), 150.2 (Cq), C]O was not visible.
IR (ATR): vmax 700, 768, 1070, 1354, 1375, 1608 cmꢁ1. MS (ESþ) m/z
(%): 346 (MþHþ). HRMS (ESI): calcd for C22H19NO3þHþ: 346.1438;
found 346.1419.
4.9.3. 3-(4-Methoxy-2-methylphenyl)benzo[g]isoquinoline-5,10-di-
one (1c). Isolated with 95% yield after purification over a short
silica column (PE/EtOAc, 4/1) to remove traces of CAN. Mp
197.5e198.5 ꢀC. Yellow powder. 1H NMR (250 MHz, CDCl3): dH 2.49
(3H, s, CH3), 3.87 (3H, s, OCH3), 6.86 (1H, s, H-3), 7.84e7.89 (2H, m,
H-7, H-8), 8.18 (1H, s, H-4), 8.27e8.38 (2H, m, H-6, H-9), 9.61 (1H,
s, H-1). 13C NMR (63 MHz, CDCl3): dC 21.1 (CH3), 29.7 (C-20), 55.3
(OCH3), 111.7 (C-30), 116.8 (C-50), 127.3 (C-7), 127.4 (C-8), 131.6 (C-4,
C-6), 133.2 (Cq), 133.3 (Cq), 134.4 (C-6), 135.0 (C-9), 138.3 (Cq), 138.6
(Cq), 149.4 (C-1), 160.6 (2ꢂCq), 165.7 (C-40), 182.4 (C]O), 182.9 (C]
O). IR (ATR): vmax 711, 923, 1117, 1249, 1293, 1328, 1578, 1671 cmꢁ1
.
MS (ESþ) m/z (%): 330 (MþHþ, 40), 238 (40), 200 (65). HRMS (ESI):
calcd for C21H15NO3þHþ: 330.3561; found 330.3555.
4.9.4. 3-p-Tolylbenzo[g]isoquinoline-5,10-dione (1d). Isolated with
98% yield after purification over a short silica column (PE/EtOAc,
4/1) to remove traces of CAN. Mp 190.8e191.2 ꢀC (lit.,7
192e193 ꢀC). Yellow powder. The spectral data are, within the
experimental error, in accordance with the literature.7 1H NMR
(500 MHz, CDCl3): dH 2.36 (3H, s, CH3), 7.26 (2H, d, J 7.8, H-20, H-
60), 7.76 (1H, pseudo t, J 7.7, H-7), 7.80 (1H, pseudo t, J 7.7, H-8),
8.01 (2H, d, J 8.0, H-30, H-50), 8.24 (1H, d, J 7.5, H-6), 8.26 (1H, d, J
7.3, H-9), 8.38 (1H, s, H-4), 9.50 (1H, s, H-1). 13C NMR (126 MHz,
CDCl3): dC 20.5 (CH3), 114.1 (CHar), 123.4 (Cq), 126.3 (CHar), 126.4
(CHar), 126.5 (CHar), 126.5 (CHar), 128.9 (2ꢂCHar), 132.2 (Cq), 132.3
(Cq), 133.4 (CHar), 133.8 (Cq), 134.0 (CHar), 138.2 (Cq), 140.3 (Cq),
148.9 (CHar), 161.7 (CHar), 181.2 (CO), 181.8 (CO). IR (ATR): vmax
704, 717, 742, 820, 924, 1298, 1584, 1668 cmꢁ1. MS (ESþ) m/z (%):
300 (MþHþ, 100).
4.9. Oxidative demethylation of 5,10-dimethoxybenzo[g]-
isoquinolines with CAN
The synthesis of 3-phenylbenzo[g]isoquinoline-5,10-dione (1a)
is representative.
To a solution of 1a (0.1 g, 0.32 mmol) in a mixture of CH3CN/H2O
(2/1) (3 mL) was added CAN (0.53 g, 0.96 mmol) at 0 ꢀC. The
mixture was stirred for 1 h at 0 ꢀC and the solution was quenched
with water (20 mL) and extracted with EtOAc (3ꢂ10 mL). The
combined organic phases were dried over MgSO4, and the residue
collected after removal of the volatiles was further purified by
means of silica gel column chromatography (gradient: PE/EtOAc,
4.9.5. 3-(Methoxymethyl)benzo[g]isoquinoline-5,10-dione
(1e). Isolated with 98% yield after purification over a short silica

2278
S. Van Aeken et al. / Tetrahedron 67 (2011) 2269e2278
column (PE/EtOAc, 4/1) to remove traces of CAN. Mp
114.6e116.6 ꢀC. Yellow powder. 1H NMR (250 MHz, CDCl3): dH 3.57
(3H, s, OCH3), 4.76 (2H, s, CH2) 7.84e7.91 (2H, m, H-7, H-8), 8.21 (1H,
s, H-4), 8.30e8.36 (2H, m, H-6, H-9), 9.50 (1H, s, H-1). 13C NMR
(63 MHz, CDCl3): dC 59.2 (OCH3), 75.1 (CH2), 116.3 (CHar), 125.3
(CHar), 127.3 (CHar), 127.4 (CHar), 133.1 (Cq), 133.2 (Cq), 134.5
(2ꢂCHar), 135.0 (2ꢂCHar), 139.1 (Cq), 149.4 (CHar), 165.8 (Cq), 182.4
(C]O), 182.6 (C]O). IR (ATR): vmax 707, 927, 1106, 1121, 1295, 1586,
1677 cmꢁ1. MS (ESþ) m/z (%): 254 (MþHþ, 100). HRMS (ESI): calcd
for C15H11NO3þHþ: 254.2601; found 254.2620.
238 (MþHþ, 100). HRMS (ESI): calcd for C14H7NO3þHþ: 238.0499;
found 238.0514.
Acknowledgements
We gratefully acknowledge the Research FoundationdFlanders
(FWO-Vlaanderen) and the IWT for financial support of this research.
Supplementary data
Copies of 1H NMR and 13C NMR spectra for compounds 1aeg, 1l,
2aeh, 2l, 4, 7a, 7f, 7g, 7i, 10a, 10b, 11 and 13f are included in the
Supplementary data. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2011.01.074. These data include MOL files and InChiKeys of the
most important compounds described in this article.
4.9.6. 3-Cyclohexylbenzo[g]isoquinoline-5,10-dione
(1f). Isolated
with 98% yield after purification over a short silica column (PE/
EtOAc, 4/1) to remove traces of CAN. Mp 157.6e159.2 ꢀC. Yellow
powder. 1H NMR (500 MHz, CDCl3): dH 1.26e1.81 (6H, m, (CH2)3),
1.90e1.93 (2H, m, CH2), 2.02e2.04 (2H, m, CH2), 2.92e2.99 (1H, m,
H-10), 7.84 (1H, dꢂpseudo t, J 1.1 and 5.9, H-7), 7.86 (1H, dꢂpseudo
t, J 1.3 and 7.6, H-8) 7.93 (1H, s, H-4), 8.32 (1H, dd, J 1.2 and 8.6, H-6),
8.32 (1H, dd, J 1.2 and 8.6, H-9), 9.48 (1H, s, H-1). 13C NMR (63 MHz,
CDCl3): dC 25.9 (C-40), 26.3 (C-30 and C-50), 32.6 (C-20 and C-60), 47.3
(C-10), 116.3 (C-4), 124.4 (Cq), 127.3 (2ꢂCHar), 133.2 (2ꢂCq), 134.4
(CHar), 134.9 (CHar), 138.9 (Cq), 149.4 (C-1), 173.7 (C-3), 182.5 (C]O),
183.1 (C]O). IR (ATR): vmax 712, 928, 1309, 1327, 1584, 1679,
2920 cmꢁ1. MS (ESþ) m/z (%): 292 (MþHþ, 100). HRMS (ESI): calcd
for C19H17NO2þHþ: 292.3512; found 292.3498.
References and notes
1. (a) Koyama, J.; Morita, I.; Kobayashi, N.; Osakai, T.; Usuki, Y.; Taniguchi, M.
Bioorg. Med. Chem. Lett. 2005, 15, 1079e1082; (b) Gomez-Monterrey, I.; Cam-
piglia, P.; Grieco, P.; Vittoria Diurno, M.; Bolognese, A.; La Colla, P.; Novellino, E.
Bioorg. Med. Chem. 2003, 11, 3769e3775.
€
€
2. (a) Bruckhardt, G.; Walter, A.; Triebel, H.; Storl, K.; Simon, H.; Storl, J.; Opitz, A.;
Roemer, E.; Zimmer, C. Biochemistry 1998, 37, 4703e4711; (b) Hazlehurst, L. A.;
Krapcho, A. P.; Hacker, M. P. Cancer Lett. 1995, 91, 115e124.
3. (a) Tarasiuk, J.; Mazerski, J.; Tkaczyk-Gobis, K.; Borowski, E. Eur. J. Med. Chem.
2005, 40, 321e328; (b) Koyama, J.; Morita, I.; Kobayashi, N.; Osaki, T.; Hotta, H.;
Takayasu, J.; Nishino, H.; Tokuda, H. Cancer Lett. 2004, 212, 1e6.
4. (a) Potts, K. T.; Bhattacharjee, D.; Walsh, E. B. J. Org. Chem. 1986, 51, 2011e2021;
(b) Valderrama, J. A.; Colonelli, P.; Vasquez, D.; Gonzalez, M. F.; Rodríguez, J. A.;
4.9.7. 3-(Diethoxymethyl)benzo[g]isoquinoline-5,10-dione
(1g). Isolated with 98% yield after purification over a short Al2O3
column (PE/EtOAc, 9/1) to remove traces of CAN. Mp
118.8e119.8 ꢀC. Brown powder. 1H NMR (500 MHz, CDCl3): dH 1.29
(6H, t, J 7.0, 2ꢂCH3), 3.66e3.78 (4H, m, 2ꢂCH2), 5.62 (1H, s, CH),
7.87 (1H, d pseudo t, J 1.5 and 7.0, H-7), 7.88 (1H, dꢂpseudo t, J 1.5
and 7.0, H-8), 8.33 (1H, dd, J 2.0 and 5.0, H-6), 8.35 (1H, dd, J 2.0
and 5.0, H-9), 8.37 (1H, s, H-4), 9.54 (1H, s, H-1). 13C NMR
(63 MHz, CDCl3): dC 15.2 (2ꢂCH3), 62.5 (2ꢂCH2), 101.8 (CH), 116.9
(CHar), 126.0 (Cq), 127.3 (CHar), 127.5 (CHar), 133.1 (Cq), 133.2 (Cq),
134.6 (CHar), 135.0 (CHar), 139.2 (Cq), 149.3 (CHar), 164.7 (Cq), 182.3
(C]O), 182.5 (C]O). IR (ATR): vmax 706, 924, 1288, 1584,
1676 cmꢁ1. MS (ESþ) m/z (%): 312 (MþHþ, 100), 307 (45), 266
(38), 238 (37). HRMS (ESI): calcd for C18H17NO4þHþ: 312.3393;
found 312.3379.
ꢀ
ꢀ
Theoduloz, C. Bioorg. Med. Chem. 2008, 16, 10172e10181.
5. Opitz, A.; Roemer, E.; Haas, W.; Gorls, H.; Werner, W.; Grafe, U. Tetrahedron
2000, 56, 5147e5155.
€
€
6. (a) Sartori, G.; Casnati, G.; Bigi, F.; Robles, P. Tetrahedron Lett. 1987, 28,
1533e1536; (b) Wanatabe, M.; Shinoda, E.; Shimizu, Y.; Furukawa, S. Tetrahe-
ꢀ
dron 1987, 43, 5281e5286; (c) Rebstock, A.-S.; Mongin, F.; Trecourt, F.;
ꢀ
Queguiner, G. Org. Biomol. Chem. 2004, 2, 291e295.
7. (a) Kesteleyn, B.; Nguyen Van, T.; De Kimpe, N. Tetrahedron 1999, 55,
2092e2102; (b) Nguyen Van, T.; Verniest, G.; Claessens, S.; De Kimpe, N.
Tetrahedron 2005, 61, 2295e2300.
8. (a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002, 67, 86e94; (b) Roy, S.; Roy, S.;
Neuenswander, B.; Hill, D.; Larock, R. C. J. Comb. Chem. 2009, 11, 1061e1065.
9. (a) Mondal, S.; Nogami, T.; Asao, N.; Yamamoto, Y. J. Org. Chem. 2003, 68,
9496e9498; (b) Syper, L.; M1ochowski, J. Synthesis 1983, 747e752.
10. Magnus, P.; Matthews, K. S.; Lynch, V. Org. Lett. 2003, 5, 2181e2184.
11. (a) Paul, F.; Patt, J.; Hartwig, J. F. Organometallics 1995, 14, 3030e3039; (b) Van
der Heiden, M.; Plenio, H. Chem. Commun. 2007, 972e974.
12. (a) Jeffery, T. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI:
Greenwich, 1996; Vol. 5, pp 153e260; (b) Jeffery, T.; Galland, J.-C. Tetrahedron
Lett. 1994, 35, 4103e4106; (c) Jeffery, T. Tetrahedron 1996, 52, 10113e10130;
Jeffery, T. Tetrahedron Lett. 1994, 35, 3051e3954; (d) Chow, H.-F.; Wan, C.-W.;
Low, K.-H.; Yeung, Y.-Y. J. Org. Chem. 2001, 66, 1910e1913; (e) Nguefack, J.-F.;
Bolitt, V.; Sinou, D. Tetrahedron Lett. 1996, 37, 5527e5530.
13. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009e3066.
14. Liebeskind, L. S.; South, M. S. J. Org. Chem. 1980, 45, 5426e5429.
15. Larock, R. C.; Doty, M. J. J. Org. Chem. 1993, 58, 4579e4583.
4.9.8. 5,10-Dioxobenzo[g]isoquinoline-3-carbaldehyde (1l). Isolated
with 98% yield after purification over a short silica column (PE/
EtOAc, 4/1) to remove traces of CAN. Mp 173.0e173.8 ꢀC. Brown
powder. 1H NMR (250 MHz, CDCl3): dH 7.90e7.94 (2H, m, H-7, H-
8), 8.36e8.40 (2H, m, H-6, H-9), 8.71 (1H, s, H-4), 9.72 (1H, s, H-
1), 10.3 (1H, s, CHO). 13C NMR (63 MHz, CDCl3): dC 117.7 (C-4),
127.6 (CHar), 127.7 (CHar), 133.0 (Cq), 135.1 (CHar), 135.5 (CHar),
150.4 (C-1), 181.5 (C]O), 181.9 (C]O), 191.9 (CHO). IR (ATR): vmax
708, 764, 927, 1196, 1286, 1581, 1676, 1719 cmꢁ1. MS (ESþ) m/z (%):
16. (a) Chandra, A.; Singh, B.; Upadhyay, S.; Singh, R. M. Tetrahedron 2008, 64,
11608e11685; (b) Alfonsi, M.; Dell’Acqua, M.; Facoetti, D.; Arcadi, A.; Abbiati,
G.; Rossi, E. Eur. J. Org. Chem. 2009, 2852e2862.
17. For examples of oxidative demethylations with CAN see: Sridharan, V.;
ꢀ
Menendez, J. C. Chem. Rev. 2010, 110, 3805e3849.