Synthesis of 4-amino substituted 1,8-naphthalimide derivatives using palladium-mediated amination

Article abstract of DOI:10.1016/j.dyepig.2014.05.006

Successful amination of 4-bromo-1,8-naphthalimides with 'lengthy' imide N-functionality has been achieved using a general palladium mediated approach (conventional thermal protocols were sub-optimal). Only readily available Pd/ligand combinations were considered and the resulting Buchwald-Hartwig procedure using Pd₂(dba)₃, Xantphos and Cs ₂CO₃ is high yielding, relatively mild (40-80 °C, 24 h, yields 50-90%), requires only a modest excess of amine (3.0 equiv) and works equally well with other imide N-substituents. As such, the protocol complements existing methods but is superior for more complex substrates. Herein we compare this Pd mediated approach to the methods most commonly used and further demonstrate its utility by synthesising a number of new, highly fluorescent, 4-aminonaphthalimides.

Full text of DOI:10.1016/j.dyepig.2014.05.006

Accepted Manuscript
Synthesis of 4-Amino Substituted 1,8-Naphthalimide Derivatives Using Palladium-
mediated Amination
Cassandra L. Fleming , Trent D. Ashton , Frederick M. Pfeffer
PII:
S0143-7208(14)00186-7
10.1016/j.dyepig.2014.05.006
DYPI 4378
DOI:
Reference:
To appear in: Dyes and Pigments
Received Date: 25 February 2014
Revised Date: 4 May 2014
Accepted Date: 6 May 2014
Please cite this article as: Fleming CL, Ashton TD, Pfeffer FM, Synthesis of 4-Amino Substituted 1,8-
Naphthalimide Derivatives Using Palladium-mediated Amination, Dyes and Pigments (2014), doi:
10.1016/j.dyepig.2014.05.006.
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ACCEPTED MANUSCRIPT
Buchwald-Hartwig Amination
This work
X = Br, Pd, 40 °C
R1 = 'lengthy/large'
R1
Mild reaction conditions
Modest excess of amine (3 equiv)
High yields (70−90%)
R1
SNAr
O
N
O
O
N
O
H
X = Br or Cl ≥ 100 °C
N
Large excess of amine (≥ 10 equiv)
Poor conversion of starting materials
R2
R3
X
S Ar
N
N
R2
R3
X = NO2, 21 °C, DMF
Poor mass recovery
Low isolated yields

ACCEPTED MANUSCRIPT
Synthesis of 4-Amino Substituted 1,8-Naphthalimide Derivatives Using Palladium-
mediated Amination
Cassandra L. Fleming, Trent D. Ashton and Frederick M. Pfeffer*
Research Centre for Chemistry and Biotechnology, School of Life and Environmental
Sciences, Deakin University, Waurn Ponds, Victoria, 3216, Australia
*Corresponding author. Tel: +61 3 5227 1439, Email: fred.pfeffer@deakin.edu.au
Graphical Abstract
Abstract
Successful amination of 4-bromo-1,8-naphthalimides with ‘lengthy’ imide N-functionality
has been achieved using a general palladium mediated approach (conventional thermal
protocols were sub-optimal). Only readily available Pd/ligand combinations were considered
and the resulting Buchwald-Hartwig procedure using Pd (dba) , Xantphos and Cs CO is
2
3
2
3
high yielding, relatively mild (40–80 °C, 24 h, yields 70–90%), requires only a modest excess
of amine (3.0 equiv) and works equally well with other imide N-substituents. As such, the
protocol complements existing methods but is superior for more complex substrates. Herein
we compare this Pd mediated approach to the methods most commonly used and further
demonstrate its utility by synthesising a number of new, highly fluorescent, 4-
aminonaphthalimides.
Keywords: synthesis, 4-aminonaphthalimides, Buchwald-Hartwig, amination
1
. Introduction
1

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Historically, 4-amino-1,8-naphthalimides have been widely employed as components of
fluorescent dyes [1]. More recently, these fluorophores have been used in a number of more
specialist applications including; cellular imaging [2], DNA intercalation [3] and
supramolecular chemistry [4]. With these more sophisticated end uses, higher levels of
structural complexity is required. Therefore, more advanced and practical methodology for
the synthesis of substituted naphthalimides is necessary. Established methods employed for
the synthesis of 4-amino-1,8-naphthalimide derivatives involve nucleophilic aromatic
substitution by either (i) heating (≥ 100 °C) 4-halo-naphthalimides with the desired amine [5]
or (ii) treating 4-nitro-naphthalimide with the amine in DMF at 21 °C (Figure 1) [6]. While
the use of copper catalysts to aid the transformation has been known for some time (Ullmann
condensation) [7], it is only recently that a handful of examples of palladium mediated
coupling of anilines have also emerged to access highly specific 4-arylamino-1,8-
naphthalimide derivatives [8]. Herein, we describe a general, high yielding, Buchwald-
Hartwig cross coupling protocol for the synthesis of 4-amino-1,8-naphthalimde derivatives
using Pd (dba) and Xantphos—one of the most readily available (and affordable) Pd source
2
3
and ligand combinations known.
Figure 1. Comparison of methodology for synthesis of 4-amino-1,8-naphthalimide
derivatives. Top: existing S Ar approaches,[9–11] Bottom: Buchwald-Hartwig amination.
N
2
. Results and Discussion
Substitution reactions of N-ethyl-4-bromo-1,8-naphthalimide (1) are usually accomplished
using nucleophilic aromatic substitution (S Ar) [9–11]. For example, nucleophilic
N
substitution of 4-bromonaphthalimide 1 with morpholine (5.0 equiv.) afforded the 4-amino
derivative 3 (83%) after heating by microwave irradiation at 100 °C for 4 hours (Scheme 1).
2

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Unfortunately it is our experience that this method gives poor yields with longer/larger N-
alkyl imide substituents. Indeed, when a solution of N-heptyl naphthalimide 2, morpholine
(
5.0 equiv) and Et N in EtOH was heated by microwave irradiation at 100 °C for 4 hours
3
poor conversion of starting materials was observed and only 40% of the desired 4-amino-1,8-
naphthalimide derivative 4 was isolated (Scheme 1). While exceptions exist in the literature
[
12], protocols for the synthesis of related imides generally require the use of high boiling
solvents (eg. 1,4-dioxane or 2-methoxyethanol), high temperatures (≥ 100 °C) [5] and a large
excess of amine (≥ 10 equiv) [13]. Such reaction conditions are not always practical.
Scheme 1. Nucleophilic aromatic substitution of 4-bromo naphthalimide derivatives with
morpholine highlighting the lower yields obtained when longer N-substituents are present.
When the N-imide substituent contained additional functionality such as an ester (for
example, imide 7 formed in 92% yield by the condensation of commercially available 1,8-
naphthalic anhydride 5 with methyl 6-aminohexanoate hydrochloride), the S Ar reaction
N
again gave low yields (Scheme 2). Indeed, only 45% of the desired 4-amino-1,8-
naphthalimide 9 was isolated after heating 4-bromo naphthalimide 7 with morpholine (5.0
equiv) at 100 °C in EtOH using microwave irradiation. A conventional thermal method was
also trialed but again little conversion was noted (< 25% after 24 h). In addition to isolating
the desired 4-amino-1,8-naphthalimide derivative 9, amidation of the methyl ester was also
observed (10, Scheme 2, X = Br, see Supporting Information Figure S11 and S12).
Scheme 2. Synthesis of 4-amino derivative 9 by nucleophilic aromatic substitution: X = Br,
morpholine (5.0 equiv), Et N, EtOH, MW 100 °C, 4 h (≤ 45%); X = NO , morpholine, DMF,
3
2
2
1 °C, 24 h (≤ 20%).
3

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Moneva et. al. described the successful amination of 4-nitro-N-phenyl substituted 1,8-
naphthalimide derivatives using N-allylamines in DMF at 21 °C (Scheme 2, X = NO ) [6].
2
Unfortunately, in our hands, the use of the 4-nitro-1,8-naphthalimide derivative 8 also gave
poor conversion and low isolated yields (≤ 20%). Only when the temperature was increased
to 80 °C were all starting materials consumed. Nevertheless, even with full consumption of
starting material, poor mass recovery and low isolated yields (≤ 20%) resulted. In addition,
another undesired side reaction occurred, which gave small amounts of the 4-dimethylamino
product 11 (Scheme 2, see Supporting Information, Figure S13 and S14) [14].
An alternate methodology involving palladium-catalysed Buchwald-Hartwig cross-
coupling was pursued. While a handful of examples exist in which a palladium mediated
approach for coupling of specific aromatic amines, anilines and carbazoles with 4-bromo-1,8-
naphthalimide derivatives have been reported [8], the reaction conditions vary considerably
with each substrate. As such, a more general protocol was sought that would be practical for
a range of anilines and amines (both 1° and 2°).
A plethora of possible palladium sources and phosphine ligand combinations are available
for Buchwald-Hartwig cross-coupling reactions [15–19] and while many are very high
yielding they require either an expensive catalyst/ligand combination or the synthesis of a
specialist ligand [20]. As our aim was to develop a protocol that would be more cost
effective and user friendly only a selection of common Pd catalysts and readily available
ligands were trialled (Table 1). In the initial reaction Pd(OAc) (2 mol%), PPh (4 mol%), 4-
2
3
t
bromo-1,8-naphthalimide 7, morpholine and NaO Bu were heated in toluene for 24 h at 40 °C
Table 1, Entry 1). Whilst the yield for this reaction was poor (5%), formation of the desired
(
compound occurred at low temperature (40 °C) and the previously discussed side products
associated with high reaction temperatures were not observed. After screening a small
number of palladium and ligand combinations (Entries 1–9), it became clear that (with the
4

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exception of dppf, Entry 7) bulky bidentate bisphosphines, such as (S)-BINAP and Xantphos
were the ligands of choice (35% and 40% yields, Entries 8 and 9 respectively).
Table 1. Optimisation for the Pd-mediated amination of 4-bromonaphthalimide 7 with
α
morpholine.
Entry
Pd-source
Pd(OAc)2
Pd(OAc)2
mol%
Ligand
PPh3
TrixiPhos
RuPhos
DavePhos
CyJohnPhos
JohnPos
mol%
Base
equiv Yield (%)
t
1
2
3
4
5
6
7
8
9
2
2
2
2
2
2
2
2
2
3
3
4
4
4
4
4
4
4
4
4
4
4
4
4
4
12
12
4
4
4
NaO Bu
2
2
2
2
2
2
2
2
2
2
2
2
2
3
2
3
5
N/R
16
10
12
6
10
35
40
18
24
50
47
10
24
90
t
NaO Bu
t
Pd (dba) ·CHCl
NaO Bu
2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
t
Pd (dba) ·CHCl
NaO Bu
2
3
t
Pd (dba) ·CHCl
NaO Bu
2
3
t
Pd (dba) ·CHCl
NaO Bu
2
3
t
Pd (dba) ·CHCl
dppf
NaO Bu
2
3
t
Pd (dba) ·CHCl
Xantphos
(S)-BINAP
Xantphos
(S)-BINAP
Xantphos
(S)-BINAP
Xantphos
Xantphos
Xantphos
NaO Bu
2
3
t
Pd (dba) ·CHCl
NaO Bu
2
3
t
1
1
1
1
1
1
1
0
1
2
3
4
5
6
Pd (dba) ·CHCl
NaO Bu
2
3
t
Pd (dba) ·CHCl
NaO Bu
2
3
t
Pd (dba) ·CHCl
NaO Bu
2
3
t
Pd (dba) ·CHCl
NaO Bu
2
3
t
Pd (dba) ·CHCl
NaO Bu
2
3
Pd (dba) ·CHCl
4
4
Cs CO3
2
3
2
Pd (dba) ·CHCl
Cs CO3
2
3
2
α
Reagents and Conditions: 4-Bromo-1,8-naphthalimide (7) (0.25 mmol), morpholine (0.74 mmol), Pd, ligand,
base (0.49 mmol or 0.74 mmol), PhMe (5 mL), 40 °C, 24 h.
Further investigation into the effect of the palladium/ligand (Pd/L) ratio was conducted
using (S)-BINAP and Xantphos as the ligands. Lower yields were observed when a Pd/L
ratio of 1:2 was used (Table 1, Entries 10 and 11) instead of 1:1 (Entries 8 and 9). However,
t
the 2:1 combination of Pd (dba) ·CHCl (4 mol%) and Xantphos (4 mol%) with NaO Bu
2
3
3
gave the desired adduct in 50% isolated yield (Entry 12). Even though (S)-BINAP proved to
be as effective as Xantphos (Entry 13), in our hands, Xantphos was removed more easily than
(S)-BINAP during chromatographic purification and was therefore chosen for further studies.
The use of Cs CO is reported to provide a cleaner reaction profile in Buchwald-Hartwig
2
3
t
reactions [16] and when Cs CO (2 equiv) was used in place of NaO Bu (2 equiv) in the
2
3
amination of bromonaphthalimide 7 (Entry 15) the reaction mixture indeed contained fewer
by-products according to TLC analysis, however, the isolated yield of product was
5

ACCEPTED MANUSCRIPT
significantly lower (24%). Nevertheless, when 3 equivalents of Cs CO was used, the
2
3
reaction proceeded smoothly and the desired 4-morpholino naphthalimide 9 was isolated in
0% (Entry 16), which corresponds to an overall yield of 83% over two steps from naphthalic
9
anhydride 5. This compares favourably to the 43% overall yield in the previously reported
two step synthesis of 4-morpholino naphthalimide 9 using (i) S Ar reaction of morpholine
N
with the naphthalic anhydride 5, followed by (ii) nucleophilic acyl substitution to install the
imide moiety [21].
To demonstrate the versatility of these reaction conditions, the amination of simple N-
ethyl, N-heptyl, N-hydroxyethyl and N-benzyl naphthalimides as the aryl bromide partner
with morpholine was pursued (Table 2). The palladium-mediated amination performed very
well with isolated yields ranging from 60–90%. The reactions were repeated using the
conventional S Ar approach and in most cases the yields obtained using the new Pd-
N
mediated approach were higher than those obtained when nucleophilic substitution
methodology was employed (Table 2). As mentioned earlier the most notable differences
arose when the imide functionality was lengthy (Table 2, Entries 2-3).
Table 2. Nucleophilic substitution versus Pd-mediated amination of 4-bromonaphthalimide
α
derivatives.
Entry Product
Yield (%)
Pd-Mediated
SNAr
83
1
2
3
4
5
3
4
90
75
90
40
9
45
β
14
15
60
60
69
54
α
Reagents and Conditions: S Ar Method: 4-Bromo-1,8-naphthalimide derivative, morpholine (5 equiv), Et N (4
N
3
equiv), EtOH, MW 100 °C, 4 h; Pd-Mediated Coupling: 4-Bromo-1,8-naphthalimide derivative, morpholine (3
equiv), Pd (dba) ·CHCl (4 mol%), Xantphos (4 mol%), Cs CO (4 equiv), PhMe, 40 or 80 °C, 24 h.
2
3
3
2
3
β
Reaction was conducted at 60 °C for 48 h.
6

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In order to further evaluate the scope of the Buchwald-Hartwig cross-coupling reaction, a
variety of aryl and alkyl amines (including alkylamines, anilines, benzylamines and
heterocyclic arylamine derivatives) were trialled. Using the optimized reaction conditions
described above, a family of 4-amino substituted naphthalimides (including 13 previously
unreported compounds) were synthesised in good to high yields (Scheme 3).
Scheme 3. Pd-mediated coupling of 4-bromo naphthalimide 7 with various amino substrates.
The coupling reactions of electron deficient anilines and aliphatic amines were the most
successful (compounds 16–19, 21, 25–26 and 28); when sterically hindered aliphatic amines
were used (including; tert-butylamine and diisopropylamine) the desired products were not
formed, possibly due to a slower rate of ligand exchange [22].
As most compounds synthesised herein are new and 4-aminonaphthalimide derivatives are
widely used as fluorescent agents a selection were evaluated photophysically (Table 3). High
quantum yields (ɸ up to 0.90) and large Stokes shifts (ranging from 67–135 nm) consistent
with the 4-aminonaphthalimide class of compounds were recorded [23].
Table 3. Photophysical properties of selected 4-amino naphthalimide derivatives in CHCl3
and DMSO.
λAbs
nm) (nm)
λEm
Stokes
Shift
116
135
84
96
67
85
75
Compound Solvent
CHCl
a
a
ɸ
(
9
3
386
399
426
442
411
425
421
439
427
449
502
534
510
538
478
510
496
521
502
528
0.55
0.02
0.15
<0.01
N/A
0.17
0.81
0.47
0.90
0.60
DMSO
CHCl
DMSO
CHCl
DMSO
CHCl
DMSO
CHCl
DMSO
1
7
0
1
5
3
b
2
2
2
3
3
82
75
79
3
a
Wavelengths of maximum absorbance (λAbs
)
and emission intensity (λEm).
b
A high level of scattering interfered with the emission spectrum.
7

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Consistent with previous reports [7a,8a,24] the maximum wavelength for both absorption
and emission was sensitive to the polarity of the solvent used (Table 3) and larger Stokes
shifts and a decrease in fluorescence quantum yields were observed in the more polar solvent,
DMSO.
3
. Conclusion
A convenient, high yielding, Pd-mediated amination methodology to access 4-amino-1,8-
naphthalimide derivatives has been developed. The protocol requires only Pd (dba) and
2
3
Xantphos (both readily available) and while it complements existing S Ar methods the new
N
procedure gives high yields when longer/larger N-imide substituents are present. These
reaction conditions have proven to be applicable to the coupling of a variety of anilines as
well as unencumbered primary and secondary amines (13 new compounds have been
synthesised) and should find use in situations where the conventional approaches are
unsatisfactory.
4
. Experimental
4
.1. Materials and Instrumentation
All general reagents and solvents were purchased from commercial sources and used as
supplied. Column chromatography was performed using 230–400 Mesh silica gel. All NMR
1
13
spectra ( H and C) were collected on a JEOL Eclipse JNM-Ex 270 MHz, 400 MHz FT-
NMR or Bruker Avance 500SB spectrometer as specified. Melting points are uncorrected and
were determined using a Bibby Stuart Scientific SMP3 melting point apparatus. High
Resolution Mass Spectra (HRMS) analysis were conducted and recorded on an HRMS-ESI-
TOF. Those reactions that employed microwave irradiation were conducted using a CEM
Discover S-Class Microwave reactor, operating at a frequency of 50/60 Hz and continuous
irradiation power from 0 to 200 W. Reaction mixture temperatures were monitored by an
8

ACCEPTED MANUSCRIPT
external infrared sensor. All reactions were conducted in either 10 mL or 35 mL microwave
®
vials sealed with a Teflon crimp cap. UV-visible absorption spectra were collected using a
Cary 300 Bio UV-Vis spectrophotometer. Emission spectra were collected with a Cary
Eclipse Spectrofluorimeter. All samples were placed in a 1 cm quartz cuvette either for UV or
fluorescence measurements. Absolute quantum yields were collected using a 150 mm
QuantaPhi integrating sphere and the Symphony II LN cooled CCD detector. Quantum
2
yields were calculated using the supplied Fluorescence (Horiba JY) software and are the
average of three replicates.
4
4
.2. Synthesis and characterisation
.2.1. General Procedure 1: Nucleophilic Aromatic Substitution (S Ar) Reactions.
N
In a 10 mL microwave vial, a solution of 4-bromo naphthalimide, morpholine (5 equiv)
and Et N (4 equiv) in EtOH was heated using microwave irradiation at 100 °C for 4 h. Excess
3
solvent was removed in vacuo and the resulting residue was purified by flash column
chromatography.
4
.2.2. General Procedure 2: Buchwald-Hartwig Amination Reactions.
To a solution of 4-bromo naphthalimide dissolved in toluene (5 mL), Pd (dba) ·CHCl (4
2
3
3
mol%), Xantphos (4 mol%), amine (3 equiv) and Cs CO (3 equiv) were added sequentially.
2
3
The resulting mixture was stirred for 24 h at the temperature stated. After 24 h an appropriate
quantity of SiO was added, the solvent was removed in vacuo and the resulting residue dry
2
loaded and purified by flash column chromatography.
4
.2.3. 6-Bromo-2-ethylbenzo[de]isoquinoline-1,3-dione (1).
Compound 1 was synthesised according to the method previously described in the
1
literature [10]. Yield 88%, white solid, mp 157–159 °C (lit. 160–162 °C) [10]; H NMR (270
MHz, CDCl ): δ 1.34 (t, J = 7.3 Hz, 3H), 4.25 (q, J = 6.9 Hz, 2H), 7.86 (t, J = 8.5 Hz, 1H),
3
9

ACCEPTED MANUSCRIPT
8
1
1
.05 (d, J = 7.9 Hz, 1H), 8.43 (d, J = 7.9, 1H), 8.58 (d, J = 8.5 Hz, 1H), 8.67 (d, J = 7.2 Hz,
1
3
H); C NMR (100 MHz, CDCl ): δ 13.4, 35.7, 122.4, 123.3, 128.2, 129.1, 130.3, 130.7,
3
31.2, 131.3, 132.1, 133.3, 163.51, 163.54.
4
.2.4. 6-Bromo-2-heptyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (2).
In a 10 mL microwave vial, a solution of 4-bromo-1,8-naphthalic anhydride 5 (500 mg,
.80 mmol) and N-heptylamine (207 mg, 1.80 mmol) in EtOH (5 mL) was heated using
1
microwave irradiation at 100 °C for 1 h. The solution was then poured into H O to precipitate
2
out a solid, which was collected by filtration, washing thoroughly with H O and dried to
2
1
afford the title compound (515 mg, 77%) as a beige solid; mp 69–70 °C; H NMR (270 MHz,
CDCl ): δ 0.86 (t, J = 6.9 Hz, 3H), 1.32 (m, 8H), 1.70 (m, 2H), 4.15 (t, J = 7.9 Hz, 2H), 7.84
3
(t, J = 7.3 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 8.41 (d, J = 7.9 Hz, 1H), 8.56 (d, J = 8.6 Hz,
1
3
1
3
1
3
H), 8.65 (d, J = 7.2 Hz, 1H); C NMR (125 MHz, CDCl ): δ 14.1, 22.6, 27.1, 28.1, 29.0,
3
1.8, 40.6, 122.3, 123.2, 128.1, 129.0, 130.2, 130.7, 131.1, 131.2, 132.0, 133.2, 163.62,
+
79
20
63.64; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H BrNO 374.0750; Found
1
9
2
74.0765.
4
.2.5. 2-Ethyl-6-morpholino-1H-benzo[de]isoquinoline-1,3(2H)-dione (3).
General Procedure 1: A solution of compound 1 (100 mg, 0.33 mmol), morpholine (143
mg, 1.65 mmol) and Et N (133 mg, 1.32 mmol) in EtOH (3 mL) was reacted according to the
3
general procedure. Purification by flash column chromatography (2% MeOH in CH Cl )
2
2
afforded the title compound (84 mg, 83%, R = 0.22) as a bright yellow solid; General
f
Procedure 2: Compound 1 (50 mg, 0.16 mmol), Pd (dba) ·CHCl (7 mg, 0.007 mmol),
2
3
3
Xantphos (4 mg, 0.007 mmol), morpholine (43 mg, 0.49 mmol) and Cs CO (160 mg, 0.49
2
3
mmol) were heated at 40 °C. Purification by flash column chromatography (2% MeOH in 1:1
EtOAc/Pet Spirits) afforded the title compound (46 mg, 90%, R = 0.48) as a bright yellow
f
1
0

ACCEPTED MANUSCRIPT
1
solid; mp 191–193 °C; H NMR (270 MHz, CDCl ): δ 1.29 (t, J = 6.9 Hz, 3H), 3.24 (app. t,
3
Japp. = 4.6 Hz, 4H), 4.00 (app. t, Japp. = 4.6 Hz, 4H), 4.20 (q, J = 7.3 Hz, 2H), 7.19 (d, J = 7.9
Hz, 1H), 7.66 (t, J = 7.2 Hz, 1H), 8.38 (dd, J = 7.6, 0.7 Hz, 1H), 8.48 (d, J = 7.9 Hz, 1H),
1
3
8
1
.54 (dd, J = 6.3, 1.0 Hz, 1H); C NMR (67.5 MHz, CDCl ): δ 13.5, 35.4, 53.5, 67.0, 115.0,
3
17.3, 123.4, 125.9, 126.2, 129.9, 130.0, 131.1, 132.4, 155.6, 163.8, 164.2; HRMS (ESI-
+
TOF) m/z: [M+H] Calcd for C H N O 311.1390; Found 311.1393.
1
8
18
2
3
4
.2.6. 2-Heptyl-6-morpholino-1H-benzo[de]isoquinoline-1,3(2H)-dione (4).
General Procedure 1: A solution of compound 2 (100 mg, 0.27 mmol), morpholine (116
mg, 1.34 mmol) and Et N (107 mg, 1.07 mmol) in EtOH (3 mL) was reacted according to the
3
general procedure. Purification by flash column chromatography (2% MeOH in 1:1
EtOAc/Pet Spirits) afforded the title compound (41 mg, 40%, R = 0.53) as a yellow oil that
f
solidified upon standing; General Procedure 2: Compound 2 (70 mg, 0.19 mmol),
Pd (dba) ·CHCl (7 mg, 0.007 mmol), Xantphos (4 mg, 0.007 mmol), morpholine (49 mg,
2
3
3
0
.56 mmol) and Cs CO (212 mg, 0.56 mmol) were heated at 40 °C. Purification by flash
2 3
column chromatography (2% MeOH in 1:1 EtOAc/Pet Spirits) afforded the title compound
1
(
53 mg, 75%, R = 0.53) as a yellow oil that solidified upon standing; H NMR (270 MHz,
f
CDCl ): δ 0.86 (t, J = 6.9 Hz, 3H), 1.32 (m, 8H), 1.70 (m, 2H), 3.25 (app. t, J = 4.6 Hz,
3
app.
4
H), 4.01 (app. t, Japp. = 4.6 Hz, 4H), 4.13 (t, J = 7.6 Hz, 2H), 7.20 (d, J = 7.9 Hz, 1H), 7.68
(dd, J = 8.4, 7.3 Hz, 1H), 8.39 (dd, J = 8.5, 1.3 Hz, 1H), 8.51 (d, J = 8.2 Hz, 1H), 8.56 (dd, J
1
3
=
6.3, 1.0 Hz, 1H); C NMR (67.5 MHz, CDCl ): δ 14.2, 22.7, 27.2, 28.2, 29.1, 31.9, 40.4,
3
5
3.5, 67.1, 115.0, 117.4, 123.5, 125.9, 126.2, 129.9, 130.0, 131.2, 132.5, 155.6, 164.0, 164.4;
+
HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N O 381.2173; Found 381.2185.
2
3
28
2
3
4
.2.7. Methyl 6-(6-bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)hexanoate (7).
1
1

ACCEPTED MANUSCRIPT
In a 35 mL microwave vial, a solution of 4-bromo-1,8-naphthalic anhydride 5 (1.00 g,
3
.61 mmol), methyl 6-aminohexanoate hydrochloride [25] (656 mg, 3.61 mmol) and Et N
3
(365 mg, 3.61 mmol) in EtOH (5 mL) was heated using microwave irradiation at 100 °C for
4
5 mins. The resulting mixture was transferred into a separatory funnel and diluted with H O
2
(30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed
with 0.1 M HCl (10 mL), sat. NaHCO (10 mL) and brine (10 mL), then dried (MgSO ),
3
4
filtered and the solvent was removed in vacuo to afford the title compound (1.34 g, 92%) as a
1
pale yellow oil that solidified upon standing; H NMR (400 MHz, CDCl ): δ 1.44 (m, 2H),
3
1
.71 (m, 4H), 2.32 (t, J = 7.7 Hz, 2H), 3.64 (s, 3H), 4.13 (t, J = 7.7 Hz, 2H), 7.80 (t, J = 7.5
Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.60 (d,
1
3
J = 7.2 Hz, 1H); C NMR (67.5 MHz, CDCl ): δ 24.7, 26.7, 27.8, 34.0, 40.4, 51.6, 122.3,
3
1
23.1, 128.1, 129.0, 130.3, 130.7, 131.1, 131.3, 132.1, 133.3, 163.59, 163.61, 174.1; HRMS
+
79
(
ESI-TOF) m/z: [M+H] Calcd for C H BrNO 404.0492; Found 404.0493;
19 18 4
Characterisation data matched that in the literature [26].
4
.2.8. Methyl 6-(6-nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)hexanoate (8).
In a 35 mL microwave vial, a solution of 4-nitro-1,8-naphthalic anhydride 6 (500 mg, 2.06
mmol), methyl 6-aminohexanoate hydrochloride (374 mg, 2.06 mmol) and Et N (208 mg,
3
2
.06 mmol) in EtOH (5 mL) was heated using microwave irradiation at 100 °C for 45 mins.
The resulting mixture was transferred into a separatory funnel and diluted with H O (20 mL)
2
and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with 0.1
M HCl (10 mL), sat. NaHCO (10 mL) and brine (10 mL), then dried (MgSO ), filtered and
3
4
the solvent was removed in vacuo to afford the title compound (637 mg, 84%) as a pale
1
yellow oil that solidified upon standing; H NMR (270 MHz, CDCl ): δ 1.44 (m, 2H), 1.70
3
(m, 4H), 2.34 (t, J = 7.3 Hz, 2H), 3.63 (s, 3H), 4.14 (t, J = 7.3 Hz, 2H), 7.95 (t, J = 6.9 Hz,
1
H), 8.36 (d, J = 7.9 Hz, 1H), 8.64 (d, J = 7.9 Hz, 1H), 8.68 (d, J = 7.2 Hz, 1H), 8.78 (d, J =
1
2

ACCEPTED MANUSCRIPT
1
3
7
.9 Hz, 1H); C NMR (67.5 MHz, CDCl ): δ 24.6, 26.6, 27.7, 33.9, 40.6, 51.6, 123.0, 123.7,
3
1
24.0, 127.0, 129.1, 129.4, 129.9, 130.0, 132.5, 149.6, 162.5, 163.3, 174.1; HRMS (ESI-
+
TOF) m/z: [M+H] Calcd for C H N O 371.1238; Found 371.1235.
1
9
18
2
6
4
.2.9. Methyl 6-(6-morpholino-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)hexanoate (9).
General Procedure 1: A solution of compound 7 (85 mg, 0.21 mmol), morpholine (91 mg,
1
.05 mmol) and Et N (85 mg, 0.84 mmol) in EtOH (3 mL) was reacted according to the
3
general procedure. Purification by flash column chromatography (2% MeOH in 1:1
EtOAc/Pet Spirits) afforded the title compound (38 mg, 45%, R = 0.52) as a yellow oil that
f
solidified upon standing; General Procedure 2: Compound 7 (200 mg, 0.49 mmol),
Pd (dba) ·CHCl (21 mg, 0.02 mmol), Xantphos (12 mg, 0.02 mmol), morpholine (129 mg,
2
3
3
1
.48 mmol) and Cs CO (483 mg, 1.48 mmol) were heated at 40 °C. Purification by flash
2 3
column chromatography (2% MeOH in 1:1 EtOAc/Pet Spirits) afforded the title compound
1
(
182 mg, 90%, R = 0.52) as a yellow oil that solidified upon standing; H NMR (270 MHz,
f
CDCl ): δ 1.40 (m, 2H), 1.66 (m, 4H), 2.28 (t, J = 7.3 Hz, 2H), 3.21 (app. t, J = 4.6 Hz,
3
app.
4
H), 3.61 (s, 3H), 3.97 (app. t, Japp. = 4.7 Hz, 4H), 4.10 (t, J = 7.6 Hz, 2H), 7.17 (d, J = 8.1
Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 8.36 (dd, J = 7.3, 1.2 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H),
1
3
8
5
1
4
.51 (dd, J = 6.1, 1.2 Hz, 1H); C NMR (67.5 MHz, CDCl ): δ 24.7, 26.7, 27.8, 34.0, 40.1,
3
1.5, 53.5, 67.0, 115.0, 117.2, 123.3, 125.9. 126.1, 129.9, 130.1, 131.2, 132.5, 155.6, 163.9,
+
64.4, 174.1; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N O 411.1915; Found
2
3
26
2
5
11.1925; Characterisation data matched that in the literature [21].
4
.2.10. 6-Bromo-2-(2-hydroxyethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (12).
In a 10 mL microwave vial, a solution of 4-bromo-1,8-naphthalic anhydride 5 (1 g, 3.16
mmol) and ethanolamine (220 mg, 3.16 mmol) in EtOH (5 mL) was heated using microwave
irradiation at 100 °C for 45 min. The solution was then poured into H O to precipitate out a
2
1
3

ACCEPTED MANUSCRIPT
solid, which was collected by filtration, washing thoroughly with H O and dried to afford the
2
1
title compound (1.026 g, 89%) as a beige solid; mp 202–204 °C; H NMR (270 MHz,
CDCl ): δ 2.23 (t, J = 5.5 Hz, 1H), 3.99 (q, J = 5.5 Hz, 2H), 4.46 (t, J = 5.5 Hz, 2H), 7.87 (dd,
3
J = 8.6, 8.2 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 8.44 (d, J = 7.9 Hz, 1H), 8.61 (dd, J = 7.6, 1.0
1
3
Hz, 1H), 8.68 (dd, J = 6.3, 1.0 Hz, 1H); C NMR (100 MHz, CDCl ): δ 43.0, 61.6, 122.0,
3
1
22.9, 128.2, 129.2, 130.7, 130.8, 131.3, 131.7, 132.5, 133.7, 164.6; HRMS (ESI-TOS) m/z:
+
79
[
M+H] Calcd for C H BrNO 319.9917; Found 319.9916; Characterisation data matched
14 10 3
that in the literature [27].
4
.2.11. 4-Bromo-N-(benzyl)-1,8-naphthalimide (13).
In a 10 mL microwave vial, a solution of 4-bromo-1,8-naphthalic anhydride 5 (150 mg,
.54 mmol) and benzylamine (58 mg, 0.54 mmol) in EtOH (3 mL) was heated using
0
microwave irradiation at 100 °C for 45 min. The solution was then poured into H O to
2
precipitate out a solid, which was collected by filtration, washing thoroughly with H O and
2
dried to afford the title compound (160 mg, 81%) as a beige solid; mp 173–174 °C (lit. 174
1
°
C) [26]; H NMR (270 MHz, CDCl ): δ 5.36 (s, 2H), 2.27 (m, 3H), 7.53 (d, J = 2.2 Hz, 2H),
3
7
.81 (dd, J = 8.3, 7.3 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 8.40 (d, J = 7.9 Hz, 1H), 8.54 (dd, J
1
3
=
7.3, 1.0 Hz, 1H), 8.64 (dd, J = 6.3, 1.0 Hz, 1H); C NMR (100 MHz, CDCl ): δ 43.8,
3
1
1
22.3, 123.1, 127.7, 128.2, 128.6, 129.1 (2C), 130.5, 130.7, 131.2, 131.5, 132.4, 133.5, 137.1,
+
79
63.7; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H BrNO 366.0124; Found 366.0112;
19
12
2
Characterisation data matched that in the literature [28].
4
.2.12. 2-(2-Hydroxyethyl)-6-morpholino-1H-benzo[de]isoquinoline-1,3(2H)-dione (14).
General Procedure 1: A solution of compound 12 (100 mg, 0.31 mmol), morpholine (135
mg, 1.56 mmol) and Et N (125 mg, 1.25 mmol) in EtOH (3 mL) was reacted according to the
3
general procedure. Purification by flash column chromatography (2% MeOH in 1:1
1
4

ACCEPTED MANUSCRIPT
EtOAc/Pet. Spirits) afforded the title compound (59 mg, 60%, R = 0.16) as a bright yellow
f
solid; General Procedure 2: Compound 12 (100 mg, 0.31 mmol), Pd (dba) ·CHCl (10 mg,
2
3
3
0
.01 mmol), Xantphos (6 mg, 0.01 mmol), morpholine (82 mg, 0.94 mmol) and Cs CO (305
2 3
mg, 0.94 mmol) were heated at 60 °C for 48 h. Purification by flash column chromatography
(
2% MeOH in 1:1 EtOAc/Pet Spirits) afforded the title compound (60 mg, 60%, R = 0.16) as
f
1
a bright yellow solid; mp 166–168 °C; H NMR (270 MHz, CDCl ): δ 2.18 (br s, 1H), 3.28
3
(app. t, Japp. = 4.3 Hz, 4H), 3.97 (t, J = 5.2 Hz, 2H), 4.03 (app. t, Japp. = 4.6 Hz, 4H), 4.46 (t, J
=
5.2 Hz, 2H), 7.24 (d, J = 2.9 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 8.44 (d, J = 8.6 Hz, 1H),
1
3
8
5
1
.54 (d, J = 7.9 Hz, 1H), 8.60 (d, J = 7.2 Hz, 1H); C NMR (67.5 MHz, CDCl ): δ 42.9,
3
3.5, 62.2, 67.0, 115.1, 116.9, 123.1, 126.0, 126.2, 130.1, 130.5, 131.6, 133.0, 156.0, 165.0,
+
65.4; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N O 327.1339; Found 327.1354.
1
8
18
2
4
4
.2.13. 2-Benzyl-6-morpholino-1H-benzo[de]isoquinoline-1,3(2H)-dione (15).
General Procedure 1: A solution of compound 13 (53 mg, 0.15 mmol), morpholine (63
mg, 0.73 mmol) and Et N (58 mg, 0.58 mmol) in EtOH (2 mL) was reacted according to the
3
general procedure. Purification by flash column chromatography (2% MeOH in 1:1
EtOAc/Pet. Spirits) afforded the title compound (29 mg, 54%, R = 0.44) as a bright yellow
f
solid; General Procedure 2: Compound 13 (87 mg, 0.24 mmol), Pd (dba) ·CHCl (10 mg,
2
3
3
0
.01 mmol), Xantphos (6 mg, 0.01 mmol), morpholine (63 mg, 0.71 mmol) and Cs CO (233
2 3
mg, 0.71 mmol) were heated at 40 °C. Purification by flash column chromatography (2%
MeOH in 1:1 EtOAc/Pet Spirits) afforded the title compound (60 mg, 69%, R = 0.44) as a
f
1
yellow oil that solidified upon standing; mp 170–172 °C; H NMR (270 MHz, CDCl ): δ 3.24
3
(app. t, Japp. = 4.6 Hz, 4H), 4.00 (app. t, Japp. = 4.6 Hz, 4H), 5.36 (s, 2H), 7.25 (m, 4H), 7.52
(d, J = 6.9 Hz, 2H), 7.68 (t, J = 7.6 Hz, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.53 (d, J = 8.2 Hz,
1
3
1
H), 8.58 (d, J = 7.3 Hz, 1H); C NMR (100 MHz, CDCl ): δ 43.5, 53.5, 67.0, 115.1, 117.2,
3
1
5

ACCEPTED MANUSCRIPT
1
1
23.4, 125.9, 126.2, 127.5, 128.5, 129.0, 130.0, 130.3, 131.5, 132.8, 137.6, 155.8, 164.1,
+
64.5; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N O 373.1547; Found 373.1565.
23
20
2
3
4
.2.14. Methyl 6-(1,3-dioxo-6-(phenylamino)-1H-benzo[de]isoquinolin-2(3H)-yl)hexanoate
(16).
Following general procedure 2, compound 7 (200 mg, 0.49 mmol), Pd (dba) ·CHCl (21
2
3
3
mg, 0.02 mmol), Xantphos (12 mg, 0.02 mmol), aniline (138 mg, 1.48 mmol) and Cs CO
2
3
(483 mg, 1.48 mmol) were heated at 40 °C. Purification by flash column chromatography
(
2% MeOH in 1:1 EtOAc/Pet Spirits) afforded the title compound (169 mg, 82%, R = 0.57)
f
1
as an orange oil that solidified upon standing; H NMR (270 MHz, CDCl ): δ 1.45 (m, 2H),
3
1
.70 (m, 4H), 2.32 (t, J = 7.6 Hz, 2H), 3.64 (s, 3H), 4.15 (t, J = 7.6 Hz, 2H), 6.81 (s, 1H),
.20 (t, J = 7.6 Hz, 1H), 7.29 (m, 3H), 7.43 (t, J = 8.2 Hz, 2H), 7.69 (t, J = 7.6 Hz, 1H), 8.29
7
1
3
(
d, J = 8.2 Hz, 1H), 8.40 (d, J = 8.2 Hz, 1H), 8.61 (d, J = 6.9 Hz, 1H); C NMR (67.5 MHz,
CDCl ): δ 24.8, 26.7, 27.9, 34.1, 40.1, 51.5, 109.1, 113.5, 122.0, 122.5, 123.4, 125.0, 125.6,
3
1
26.4, 130.0, 131.5, 133.6, 140.0, 146.7, 164.0, 164.6, 174.2; HRMS (ESI-TOF) m/z:
+
[
M+H] Calcd for C H N O 417.1809; Found 417.1825.
2
5
24
2
4
4
.2.15. Methyl 6-(6-((3-fluorophenyl)amino)-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)hexanoate (17).
Following general procedure 2, compound 7 (200 mg, 0.49 mmol), Pd (dba) ·CHCl (21
2
3
3
mg, 0.02 mmol), Xantphos (12 mg, 0.02 mmol), 3-fluoroaniline (165 mg, 1.48 mmol) and
Cs CO (483 mg, 1.48 mmol) were heated at 80 °C. Purification by flash column
2
3
chromatography (2% MeOH in 1:1 EtOAc/Pet Spirits) afforded the title compound (174 mg,
1
8
2
1
1%, R = 0.63) as an orange solid; mp 116–118 °C; H NMR (270 MHz, CDCl ): δ 1.42 (m,
f
3
H), 1.69 (m, 4H), 2.30 (t, J = 7.6 Hz, 2H), 3.63 (s, 3H), 4.13 (t, J = 7.6 Hz, 2H), 6.84 (m,
H), 6.94 (s, 1H), 7.00 (m, 2H), 7.35 (m, 2H), 7.66 (t, J = 7.7 Hz, 1H), 8.29 (d, J = 7.6 Hz,
1
6

ACCEPTED MANUSCRIPT
1
3
1
2
1
1
H), 8.40 (d, J = 8.2 Hz, 1H), 8.56 (d, J = 6.3 Hz, 1H); C NMR (125 MHz, CDCl ): δ 24.7,
3
6.6, 27.8, 34.0, 40.0, 51.5, 108.5 (d, J = 23.8 Hz), 110.4, 111.0 (d, J = 21.3 Hz), 114.4,
17.0 (d, J = 2.7 Hz), 122.5, 123.2, 125.8, 126.7, 129.8, 131.0 (d, J = 9.6 Hz), 131.5, 133.2,
42.2 (d, J = 10.0 Hz), 145.6, 163.4 (d, J = 245.2 Hz), 163.8, 164.4, 174.2; HRMS (ESI-
+
TOF) m/z: [M+H] Calcd for C H FN O 435.1715; Found 435.1729.
2
5
23
2
4
4
.2.16. Methyl 6-(1,3-dioxo-6-((3-(trifluoromethyl)phenyl)amino)-1H-benzo[de]isoquinolin-
(3H)-yl)hexanoate (18).
2
Following general procedure 2, compound 7 (100 mg, 0.25 mmol), Pd (dba) ·CHCl (11
2
3
3
mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), 3-(trifluoromethyl)aniline (120 mg, 0.74
mmol) and Cs CO (242 mg, 0.74 mmol) were heated at 80 °C. Purification by flash column
2
3
chromatography (2% MeOH in 1:1 EtOAc/Pet Spirits) afforded the title compound (73 mg,
1
6
2
1
8
2
1
1
4
2%, R = 0.68) as an orange solid; mp 119–121 °C; H NMR (400 MHz, CDCl ): δ 1.44 (m,
f
3
H), 1.71 (m, 4H), 2.32 (t, J = 7.3 Hz, 2H), 3.65 (s, 3H), 4.15 (t, J = 7.8 Hz, 2H), 6.92 (s,
H), 7.39 (t, J = 8.3 Hz, 2H), 7.50 (m, 3H), 7.71 (t, J = 8.3 Hz, 1H), 8.32 (d, J = 8.3 Hz, 1H),
1
3
.43 (d, J = 8.3 Hz, 1H), 8.61 (d, J = 7.3 Hz, 1H); C NMR (125 MHz, CDCl ): δ 24.7, 26.6,
3
7.8, 34.0, 40.1, 51.5, 110.5, 114.9, 118.0 (q, J = 3.7 Hz), 120.7 (q, J = 3.7 Hz), 122.7, 123.4,
23.7 (q, J = 270.0 Hz), 124.3, 126.6, 129.8, 130.4, 131.6, 132.0 (q, J = 32.4 Hz), 133.1,
+
41.2, 145.3, 163.7, 164.3, 174.2; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H F N O
2
6
23
3
2
4
85.1683; Found 485.1685.
4
.2.17. Methyl 6-(6-((3-cyanophenyl)amino)-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)hexanoate (19).
Following general procedure 2, compound 7 (100 mg, 0.25 mmol), Pd (dba) ·CHCl (11
2
3
3
mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), 3-aminobenzonitrile (88 mg, 0.74 mmol) and
Cs CO (242 mg, 0.74 mmol) were heated at 80 °C. Purification by flash column
2
3
1
7

ACCEPTED MANUSCRIPT
chromatography (2% MeOH in 1:1 EtOAc/Pet Spirits) afforded the desired compound (80
1
mg, 74%, R = 0.38) as a bright yellow solid; mp 178–179 °C; H NMR (500 MHz, CDCl ): δ
f
3
1
.41 (m, 2H), 1.68 (m, 4H), 2.29 (t, J = 7.6 Hz, 2H), 3.63 (s, 3H), 4.11 (t, J = 7.3 Hz, 2H),
.21 (s, 1H), 7.37 (d, J = 7.9 Hz, 2H), 7.50 (m, 3H), 7.66 (t, J = 9.0 Hz, 1H), 8.33 (d, J = 7.6
7
1
3
Hz, 1H), 8.40 (d, J = 8.2 Hz, 1H), 8.55 (dd, J = 6.6, 0.6 Hz, 1H); C NMR (125 MHz,
CDCl ): δ 24.7, 26.7, 27.8, 34.0, 40.1, 51.5, 111.5, 113.9, 115.8, 118.3, 123.1, 123.4, 123.5,
3
1
24.8, 126.2, 126.6, 127.1, 129.8, 130.8, 131.7, 132.9, 141.9, 144.6, 163.7, 164.2, 174.1;
+
HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N O 442.1761; Found 442.1765.
2
6
23
3
4
4
.2.18. Methyl 6-(1,3-dioxo-6-(pyrazin-2-ylamino)-1H-benzo[de]isoquinolin-2(3H)-
yl)hexanoate (20).
Following general procedure 2, compound 7 (100 mg, 0.25 mmol), Pd (dba) ·CHCl (11
2
3
3
mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), aminopyrazine (71 mg, 0.74 mmol) and
Cs CO (242 mg, 0.74 mmol) were heated at 40 °C. Purification by flash column
2
3
chromatography (2% MeOH in 1:1 EtOAc/Pet Spirits) afforded the title compound (62 mg,
1
6
0%, R = 0.30) as a yellow oil; H NMR (270 MHz, CDCl ): δ 1.45 (m, 2H), 1.70 (m, 4H),
f
3
2
.33 (t, J = 7.6 Hz, 2H), 3.65 (s, 3H), 4.17 (t, J = 7.6 Hz, 2H), 7.29 (brs, 1H), 7.78 (t, J = 7.9
Hz, 2H), 8.20 (m, 2H), 8.27 (m, 1H), 8.33 (d, J = 7.6 Hz, 1H), 8.49 (d, J = 1.3 Hz, 1H), 8.58
1
3
(
d, J = 8.3 Hz, 1H), 8.65 (dd, J = 6.3, 1.0 Hz, 1H); C NMR (125 MHz, CDCl ): δ 24.7,
3
2
1
6.6, 27.8, 34.0, 40.1, 51.5, 115.3, 117.3, 123.4, 124.0, 126.5, 126.7, 129.5, 131.5, 132.6,
+
34.6, 137.3, 141.3, 142.2, 151.2, 163.6, 164.2, 174.2; HRMS (ESI-TOF) m/z: [M+H] Calcd
for C H N O 419.1714; Found 419.1732.
2
3
22
4
4
4
.2.19. Methyl 6-(6-(benzylamino)-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)hexanoate
(21).
1
8

ACCEPTED MANUSCRIPT
Following general procedure 2, compound 7 (100 mg, 0.25 mmol), Pd (dba) ·CHCl (11
2
3
3
mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), benzylamine (79 mg, 0.74 mmol) and Cs CO3
2
(242 mg, 0.74 mmol) were heated at 80 °C. Purification by flash column chromatography
(
2% MeOH in 1:1 EtOAc/Pet Spirits) afforded the title compound (104 mg, 98%, R = 0.47)
f
1
as a yellow solid; mp 108–110 °C; H NMR (270 MHz, CDCl ): δ 1.43 (m, 2H), 1.70 (m,
3
4
5
7
H), 2.30 (t, J = 7.6 Hz, 2H), 3.63 (s, 3H), 4.12 (t, J = 7.6 Hz, 2H), 4.59 (d, J = 4.9 Hz, 2H),
.73 (br s, 1H), 6.71 (d, J = 8.6 Hz, 1H), 7.36 (m, 5H), 7.58 (t, J = 7.6 Hz, 1H), 8.12 (d, J =
1
3
.9 Hz, 1H), 8.39 (d, J = 8.2 Hz, 1H), 8.54 (d, J = 7.3 Hz, 1H); C NMR (100 MHz, CDCl ):
3
δ 24.8, 26.8, 27.9, 34.1, 40.0, 48.1, 51.5, 105.1, 111.1, 120.4, 123.3, 125.0, 126.0, 127.8,
1
28.2, 129.2, 129.8, 131.2, 134.4, 137.1, 149.1, 164.1, 164.7, 174.2; HRMS (ESI-TOF) m/z:
+
[
M+H] Calcd for C H N O 431.1965; Found 431.1965.
2
6
26
2
4
4
.2.20. Methyl 6-(1,3-dioxo-6-((pyridin-3-ylmethyl)amino)-1H-benzo[de]isoquinolin-2(3H)-
yl)hexanoate (22).
Following general procedure 2, compound 7 (100 mg, 0.25 mmol), Pd (dba) ·CHCl (11
2
3
3
mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), 3-picolylamine (81 mg, 0.74 mmol) and
Cs CO (242 mg, 0.74 mmol) were heated at 80 °C. Purification by flash column
2
3
chromatography (2% MeOH in 1:1 EtOAc/Pet Spirits) afforded the title compound (59 mg,
1
5
1
4
7
5%, R = 0.34) as a bright yellow solid; mp 155–156 °C; H NMR (400 MHz, CDCl ): δ
f
3
.43 (m, 2H), 1.68 (m, 4H), 2.31 (t, J = 7.8 Hz, 2H), 3.64 (s, 3H), 4.14 (t, J = 7.3 Hz, 2H),
.66 (d, J = 5.3 Hz, 2H), 5.67 (t, J = 4.9 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 7.32 (m, 1H),
.63 (t, J = 7.8 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 8.42 (d, J = 8.3
1
3
Hz, 1H), 8.59 (m, 1H), 8.79 (s, 1H); C NMR (125 MHz, CDCl ): δ 24.7, 26.7, 27.8, 34.0,
3
4
1
0.0, 45.5, 51.5, 105.1, 111.6, 120.4, 123.3, 123.9, 125.2, 125.8, 129.7, 131.3, 132.8, 134.1,
+
35.3, 148.5, 149.2, 149.6, 164.0, 164.5, 174.2; HRMS (ESI-TOF) m/z: [M+H] Calcd for
C H N O 432.1918; Found 432.1938.
25
25
3
4
1
9

ACCEPTED MANUSCRIPT
4
.2.21. Methyl 6-(1,3-dioxo-6-(pyren-1-ylamino)-1H-benzo[de]isoquinolin-2(3H)-
yl)hexanoate (23).
Following general procedure 2, compound 7 (100 mg, 0.25 mmol), Pd (dba) ·CHCl (11
2
3
3
mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), 1-aminopyrene (161 mg, 0.74 mmol) and
Cs CO (242 mg, 0.74 mmol) were reacted according to general procedure 1 at 40 °C.
2
3
Purification by flash column chromatography (CH Cl ) afforded the title compound (67 mg,
2
2
1
5
2
0%, R = 0.15) as dark red oil; H NMR (270 MHz, CDCl ): δ 1.44 (m, 2H), 1.72 (m, 4H),
f 3
.31 (t, J = 7.6 Hz, 2H), 3.64 (s, 3H), 4.15 (t, J = 7.6 Hz, 2H), 6.72 (d, J = 8.3 Hz, 1H), 7.40
(s, 1H). 7.76 (t, J = 8.7 Hz, 1H), 8.01 (m, 3H), 8.08 (m, 3H), 8.23 (m, 4H), 8.52 (d, J = 7.7
1
3
Hz, 1H), 8.65 (d, J = 6.6 Hz, 1H); C NMR (67.5 MHz, CDCl ): δ 24.8, 26.7, 27.9, 34.1,
3
4
1
0.1, 51.6, 108.8, 112.8, 121.2, 121.5, 123.4, 123.9, 124.8, 125.6, 125.8, 126.5, 126.6, 127.3,
27.6, 128.5, 130.0, 130.1, 131.1, 131.4, 131.6, 132.7, 133.8, 148.7, 164.0, 164.7, 174.3;
+
HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N O 541.2122; Found 541.2122.
3
5
28
2
4
4
.2.22. Methyl 6-(1,3-dioxo-6-(quinolin-3-ylamino)-1H-benzo[de]isoquinolin-2(3H)-
yl)hexanoate (24).
Following general procedure 2, compound 7 (100 mg, 0.247 mmol), Pd (dba) ·CHCl (11
2
3
3
mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), 3-aminoquinoline (107 mg, 0.741 mmol) and
Cs CO (242 mg, 0.741 mmol) were heated at 40 °C. Purification by flash column
2
3
chromatography (2% MeOH in 4:3 EtOAc/Pet Spirits) afforded the title compound (57 mg,
1
5
0%, R = 0.40) as a yellow oil; H NMR (270 MHz, CDCl ): δ 1.44 (m, 2H), 1.72 (m, 4H),
f
3
2
.32 (t, J = 7.2 Hz, 2H), 3.64 (s, 3H), 4.16 (t, J = 7.6 Hz, 2H), 7.10 (s, 1H), 7.40 (d, J = 8.3
Hz, 1H), 7.57 (m, 1H), 7.68 (m, 1H), 7.76 (t, J = 7.3 Hz, 1H), 8.00 (d, J = 2.3 Hz, 1H), 8.11
d, J = 8.6 Hz, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.64 (dd, J = 6.3, 1.0
(
1
3
Hz, 1H), 8.95 (d, J = 2.6 Hz, 1H); C NMR (67.5 MHz, CDCl ): δ 24.8, 26.7, 27.9, 34.1,
3
4
0.2, 51.6, 110.2, 115.1, 122.7, 123.5, 125.0, 126.2, 126.7, 127.1, 127.9, 128.5, 128.8, 129.2,
2
0

ACCEPTED MANUSCRIPT
1
30.0, 131.8, 133.2, 134.3, 145.1, 145.6, 146.6, 163.8, 164.4, 174.2; HRMS (ESI-TOF) m/z:
+
[
M+H] Calcd for C H N O 468.1918; Found 468.1938.
2
8
25
3
4
4
.2.23. Methyl 6-(1,3-dioxo-6-(propylamino)-1H-benzo[de]isoquinolin-2(3H)-yl)hexanoate
(25).
Following general procedure 2, compound 7 (100 mg, 0.25 mmol), Pd (dba) ·CHCl (11
2
3
3
mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), n-propylamine (44 mg, 0.74 mmol) and
Cs CO (242 mg, 0.74 mmol) were heated at 40 °C. Purification by flash column
2
3
chromatography (2% MeOH in 1:1 EtOAc/Pet Spirits) afforded the title compound (88 mg,
1
9
3%, R = 0.36) as a yellow solid; mp 134–137 °C; H NMR (270 MHz, CDCl ): δ 1.10 (t, J
f
3
=
7.2 Hz, 3H), 1.44 (m, 2H), 1.69 (m, 4H), 1.84 (m, 2H), 2.31 (t, J = 7.6 Hz, 2H), 3.37 (q, J =
5
.3 Hz, 2H), 3.63 (s, 3H), 4.14 (t, J = 7.3 Hz, 2H), 5.26 (brs, 1H), 6.71 (d, J = 8.6 Hz, 1H),
.60 (t, J = 7.6 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 8.44 (d, J = 8.3 Hz, 1H), 8.56 (d, J = 6.6
7
1
3
Hz, 1H); C NMR (100 MHz, CDCl ): δ 11.7, 22.4, 24.8, 26.8, 27.9, 34.1, 40.0, 45.5, 51.5,
3
1
04.5, 110.4, 120.2, 123.3, 124.8, 125.8, 129.9, 131.2, 134.6, 149.5, 164.2, 164.8, 174.2;
+
HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N O 383.1965; Found 383.1883.
2
2
26
2
4
4
.2.24. Methyl 6-(6-(heptylamino)-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)hexanoate
26).
Following general procedure 2, compound 7 (100 mg, 0.25 mmol), Pd (dba) ·CHCl (11
(
2
3
3
mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), n-heptylamine (86 mg, 0.74 mmol) and
Cs CO (242 mg, 0.74 mmol) were heated at 40 °C. Purification by flash column
2
3
chromatography (2% MeOH in 1:1 EtOAc/Pet Spirits) afforded the title compound (101 mg,
1
9
3%, R = 0.63) as a bright yellow solid; mp 94–96 °C; H NMR (270 MHz, CDCl ): δ 0.88
f
3
(
t, J = 6.7 Hz, 3H), 1.27 (m, 6H), 1.42 (m, 5H), 1.71 (m, 5H), 2.31 (t, J = 7.3 Hz, 2H), 3.37
q, J = 7.2 Hz, 2H), 3.63 (s, 3H), 4.13 (t, J = 7.2 Hz, 2H), 5.27 (t, J = 4.9 Hz, 1H), 6.69 (d, J
(
2
1

ACCEPTED MANUSCRIPT
=
8.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 8.43 (d, J = 8.6 Hz, 1H),
1
3
8
2
1
.54 (d, J = 6.6, 0.6 Hz, 1H); C NMR (125 MHz, CDCl ): δ 14.1, 22.6, 24.7, 26.7, 27.1,
3
7.8, 29.0, 29.04, 31.7, 34.0, 39.9, 43.7, 51.5, 104.3, 110.2, 120.2, 123.2, 124.6, 125.8, 129.8,
+
31.1, 134.5, 149.4, 164.1, 164.7, 174.2; HRMS (ESI-TOS) m/z: [M+H] Calcd for
C H N O 439.2591; Found 439.2577.
26
34
2
4
4
.2.25. Methyl 6-(1,3-dioxo-6-(pyrrolidin-1-yl)-1H-benzo[de]isoquinolin-2(3H)-yl)hexanoate
27).
Following general procedure 2, compound 7 (200 mg, 0.49 mmol), Pd (dba) ·CHCl (21
(
2
3
3
mg, 0.02 mmol), Xantphos (12 mg, 0.02 mmol), pyrrolidine (105 mg, 1.48 mmol) and
Cs CO (483 mg, 1.48 mmol) were heated at 40 °C. Purification by flash column
2
3
chromatography (2% MeOH in 1:1 EtOAc/Pet Spirits) afforded the title compound (103 mg,
1
5
2
3%, R = 0.50) as an orange oil; H NMR (400 MHz, CDCl ): δ 1.44 (m, 2H), 1.71 (m, 4H),
f
3
.08 (m, 4H), 2.32 (t, J = 7.8 Hz, 2H), 3.64 (s, 3H), 3.76 (t, J = 6.3 Hz 4H), 4.15 (t, J = 7.8
Hz, 2H), 6.78 (d, J = 8.8 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.54 (t, J
1
3
=
4.9 Hz, 2H); C NMR (125 MHz, CDCl ): δ 24.7, 26.1, 26.7, 27.8, 34.0, 39.9, 51.5, 53.2,
3
1
08.5, 110.8, 122.62, 122.64, 123.0, 131.0, 131.2, 131.9, 133.4, 152.7, 164.1, 164.9, 174.2;
+
HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N O 395.1965; Found 395.1970.
2
3
26
2
4
4
.2.26. Methyl 6-(6-(benzyl(methyl)amino)-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-
yl)hexanoate (28).
Following general procedure 2, compound 7 (100 mg, 0.25 mmol), Pd (dba) ·CHCl (11
2
3
3
mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), N-methylbenzylamine (90 mg, 0.74 mmol)
and Cs CO (242 mg, 0.74 mmol) were heated at 80 °C. Purification by flash column
2
3
chromatography (2% MeOH in 1:1 EtOAc/Pet Spirits) afforded the title compound (88 mg,
1
8
1%, R = 0.55) as a yellow solid; mp 105–106 °C; H NMR (270 MHz, CDCl ): δ 1.46 (m,
f
3
2
2

ACCEPTED MANUSCRIPT
2
H), 1.69 (m, 4H), 2.32 (t, J = 7.9 Hz, 2H), 2.95 (s, 3H), 3.64 (s, 3H), 4.15 (t, J = 7.6 Hz,
2
H), 4.53 (s, 2H), 7.17 (d, J = 8.3 Hz, 1H), 7.36 (m, 5H), 7.61 (t, J = 6.4 Hz, 1H), 8.47 (d, J
1
3
=
8.3 Hz, 2H), 8.56 (dd, J = 5.9, 1.3 Hz, 1H), 8.56 (d, J = 6.2 Hz, 1H); C NMR (67.5 MHz,
CDCl ): δ 24.8, 26.7, 27.9, 34.1, 40.1, 40.2, 51.6, 61.5, 114.9, 115.7, 123.3, 125.5, 125.8,
3
1
27.7, 128.9, 130.2, 130.6, 131.2, 132.6, 137.2, 156.4, 164.1, 164.6, 174.2; HRMS (ESI-
+
TOF) m/z: [M+H] Calcd for C H N O 445.2122; Found 445.2139.
2
7
28
2
4
Acknowledgements
CLF thanks the Research Centre for Chemistry and Biotechnology for a top up scholarship
and Dr Egan Doeven for assistance with photophysical measurements. The authors would
like to acknowledge the Australian Research Council for equipment support related to this
project (LE120100213).
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