A new synthesis of benzo [f]|isoindole-4,9-diones by radical alkylation and bromomethylation of 1,4-naphthoquinones

Article abstract of DOI:10.1002/ejoc.200900562

Two synthetic routes towards substituted benzo[f]isoindole-4,9-diones have been developed. One strategy relies on the synthesis of N-trifluoroacetyl- protected 2-(l-aminoalkyl)-1,4-naphthoquinones starting from 1,4-naphthoquinone and N-trifluoroacetyl-a-a

Full text of DOI:10.1002/ejoc.200900562

FULL PAPER
DOI: 10.1002/ejoc.200900562
A New Synthesis of Benzo[f]isoindole-4,9-diones by Radical Alkylation and
Bromomethylation of 1,4-Naphthoquinones
Jurgen Deblander,[a] Sam Van Aeken,[a] Jan Jacobs,[b] Norbert De Kimpe,[b] and
Kourosch Abbaspour Tehrani*[a]
Keywords: Quinones / Radical reactions / Nitrogen heterocycles / Alkylation / Bromine
Two synthetic routes towards substituted benzo[f]isoindole-
4,9-diones have been developed. One strategy relies on the
synthesis of N-trifluoroacetyl-protected 2-(1-aminoalkyl)-1,4-
naphthoquinones starting from 1,4-naphthoquinone and N-
trifluoroacetyl-α-amino acids by a Kochi–Anderson oxidative
decarboxylation method. Furthermore, it was demonstrated
ones by bromomethylation and subsequent N-deprotection.
Further functionalization by N-alkylation and bromination
resulted in completely and asymmetrically substituted
benzo[f]isoindole-4,9-diones. The second synthesis is based
on a reductive amination of 3-(bromomethyl)-1,4-dimeth-
oxynaphthalene-2-carbaldehyde and subsequent oxidation.
that 2-(1-aminoalkyl)-1,4-naphthoquinones are suitable pre- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
cursors for the synthesis of 1-alkylbenzo[f]isoindole-4,9-di-
Germany, 2009)
An important example is the Reniera indole 5, which has
been isolated from the blue sponge Reniera sp. and exhibits
a pronounced antimicrobial activity.[4] Bhimamycin C (6)
and bhimamycin D (7), two related naphthoquinone-annu-
lated pyrroles, which have been isolated from a terrestrial
streptomycete,[5] are inhibitors of HIV-1 integrase,[6] display
bioactivities against human ovarian cancer cell lines[7] and
are EP4 receptor agonists in the treatment of pain.[8] Aza-
monosporascone (8) has been isolated from Monosporascus
cannonballus, a fungus responsible for crop losses of water
and musk melons.[9] 1,2,3-Triaryl-substituted benzo[f]iso-
indole-4,9-diones have also attracted attention as modula-
tors of the Pin 1 class of peptidyl-prolyl cis-trans isomerases
for the treatment of cancer.[10]
Introduction
Pyrroles and their derivatives are probably one of the
most important classes of heterocyclic nitrogen com-
pounds.[1] The electron-rich pyrrole moiety 1 can be found
extensively in natural and synthetic substances,[2] either as
a simple structural unit or as part of a more complex annu-
lated system, for example, as indoles 2 and isoindoles 3.
These two families, which are a result of the fusion of ben-
zene at the b or c bond of the pyrrole nucleus, respectively,
are characterized by a high aromaticity index[3] and an in-
creased stability in comparison with pyrrole.
Isoindole-4,7-diones 4, which can be considered as quin-
onoid derivatives of 3, are present in a number of natural
products and exhibit a wide range of biological activities.
[a] Laboratory of Organic Chemistry, Department of Applied Bio-
logical Sciences and Engineering, Faculty of Science and Bioen-
gineering Sciences, Vrije Universiteit Brussel,
Pleinlaan 2, 1050 Brussels, Belgium
Owing to the significant biological activity of benzo[f]-
isoindole-4,9-dione analogues 9, several pathways have been
developed for their synthesis. The majority of these reaction
strategies are based on a Huisgen-type cycloaddition of 1,3-
dipoles such as azomethine ylides,[11] isoquinolinium or
[b] Department of Organic Chemistry, Faculty of Bioscience Engi-
neering, Ghent University,
Coupure Links 653, 9000 Ghent, Belgium
E-mail: Kourosch.Abbaspour.Tehrani@vub.ac.be
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900562.
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Benzo[f]isoindolediones from Naphthoquinones
pyridinium[12] ylides and nitrile ylides[13] with 1,4-naphtho- the double substitution products 12 and not in the desired
quinone. The condensation reaction of 2,5-dimethylpyrrole 4,9-dimethoxy-2,3-dihydro-1H-benzo[f]isoindoles
11
or 1,2,5-trimethylpyrrole with phthalic anhydride leads to (Scheme 1).[20]
1,3-dimethyl- and 1,2,3-trimethylbenzo[f]isoindole-4,9-di-
Therefore it was decided to replace the bromide leaving
ones in 27–33% yields.[14] The Friedel–Crafts acylation of group by a group with moderate leaving-group ability. It
1-butyl-2,5-dimethyl-1H-pyrrole-3,4-dicarbonyl dichloride was thought that the double replacement of the bromide in
with benzene, toluene and xylenes also yielded benzo[f]iso- 10 by a phenoxy moiety would rule out the possibility of
indole-4,9-diones in 33–88% yields.[15] A photochemical cy- an SN1-like substitution and would favour the formation of
cloaddition reaction of benzonitrile benzylide with 1,4- 4,9-dimethoxy-2,3-dihydro-1H-benzo[f]isoindoles 14.[21]
naphthoquinones resulted in the formation of 1,3-diphenyl-
Thus, the reaction of 2,3-bis(bromomethyl)-1,4-dimeth-
2H-benzo[f]isoindole-4,9-diones.[16] Multiply substituted oxynaphthalene (10) with excess phenol in acetone in the
benzo[f]isoindole-4,9-diones have been synthesized by the presence of potassium carbonate at reflux gave the bis-
reaction of the rhodium complex of 3,4-bis(alkynoyl)pyr- (phenoxylated) naphthalene 13 in 52% yield (Scheme 2).
roles with acetylenes.[17] Other methods include the cy- Different reaction conditions were applied to achieve sub-
clocondensation of 2,3-diacetylenyl-1,4-naphthoquinones stitution of the phenoxy leaving group. The reaction of bis-
with hydrazine[18] and a particular rearrangement of 2- (phenoxylated) naphthalene 13 with 5 equiv. of tert-bu-
azaanthraquinones.[19]
tylamine at reflux in THF for 24 h was unsuccessful.
Although these listed approaches are of great impor- Changing the solvent to DMF or adding potassium carbon-
tance, very specifically substituted benzo[f]isoindole-4,9-di- ate was also unsuccessful, and the latter reaction performed
ones or symmetrically substituted 1,3-analogues can only in a sealed vessel under heating for 24 h also did not give
be synthesized by using elaborate synthetic pathways. Claes- any reaction. None of the reactions of compound 13 with
sens et al. were the first to present a more general and ef- tert-butylamine under different reaction conditions gave the
ficient method for the preparation of 2-alkyl-2H-benzo[f]- desired 2,3-dihydro-1H-benzo[f]isoindole 14.
isoindole-4,9-diones based on a ceric ammonium nitrate
Next, a desymmetrization strategy was developed to con-
mediated oxidation of 2,3-bis(aminoalkyl)-1,4-dimeth- struct the 2,3-dihydro-1H-benzo[f]isoindole 14 (Scheme 3).
oxynaphthalenes.[20] As a continuation of this research two By using a modified literature procedure,[22] 3-isopropoxy-
new syntheses of multiply substituted benzo[f]isoindole-4,9- methyl-1,4-dimethoxynaphthalene-2-carbaldehyde (16) was
diones have been developed.
prepared by substitution of both bromides of 2,3-bis(bromo-
methyl)-1,4-dimethoxynaphthalene (10) with sodium iso-
propoxide and subsequent oxidation of one isopropoxy-
methyl moiety to a formyl unit by using 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) in a dichloromethane/
water biphasic system. Substitution of the remaining iso-
propoxy group of compound 16 by bromide was achieved
by using 3 equiv. of bromotrimethylsilane in dichlorometh-
ane. With 3-(bromomethyl)-1,4-dimethoxynaphthalene-2-
carbaldehyde (17) in hand, a reductive amination reaction
was performed with tert-butylamine in the presence of so-
dium triacetoxyborohydride and triethylamine in 1,2-
dichloroethane at room temperature, which immediately re-
sulted in ring closure to yield 2,3-dihydro-1H-benzo[f]isoin-
dole 14. This compound proved to be unstable and was
therefore used immediately without purification. In the last
step, cerium(IV) ammonium nitrate (CAN) oxidation re-
sulted in the target benzo[f]isoindole-4,9-dione 18 in an
overall yield of 93% from compound 17. The presence of
triethylamine in the reductive amination step of compound
17 proved to be essential to avoid side-product formation.
By omitting triethylamine from the reductive amination
Results and Discussion
The previously published strategy originated from the
fact that the reaction of 2,3-bis(bromomethyl)-1,4-dimeth-
oxynaphthalene (10) with primary amines resulted in
Scheme 1.
Scheme 2.
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J. Deblander, S. Van Aeken, J. Jacobs, N. De Kimpe, K. Abbaspour Tehrani
FULL PAPER
Scheme 3.
step, in addition to 2-tert-butylbenzo[f]isoindole-4,9-dione
As the key compounds 22 had to be prepared, preferably
(18), {3-[(tert-butylamino)methyl]-1,4-dimethoxy-2-naphth- in one step, starting from the cheap and readily available
yl}methyl acetate (19) was also formed in a 1.5:1 ratio after 1,4-naphthoquinone (23), radical alkylation using α-amino
CAN oxidation of the crude reaction mixture. Remarkably acids as radical precursors was chosen. Among the radical-
no oxidative demethylation of 19 occurred during the CAN mediated syntheses,[24] the Barton method, in which a radi-
treatment of this compound, which could be obtained in an cal is generated from a photosensitive thiohydroxamic ester,
analytically pure form by flash chromatography (Al2O3) seems to be the best method to date in terms of coupling
and preparative HPLC. The mechanism of the ring-closing efficiency, functional group compatibility and availability of
step probably involves a substitution of the bromide by tert- the radical precursors.[25,26]
butylamine followed by an intramolecular reductive amin-
The Barton decarboxylation procedure has already been
ation. Another possibility, in which a first equivalent of applied by Commandeur et al. in an unsuccessful attempt
tert-butylamine is used in a reductive amination step and a to generate 3-(aminoalkyl)-2-methylnaphthoquinones start-
second equivalent is consumed in a Michael-type substitu- ing from N-Boc-alanine and N-Boc-β-alanine.[27] An alter-
tion of the ortho-quinomethide formed by elimination of native radical decarboxylation method,[27,28] based on the
the benzylic bromide, is ruled out by the fact that no trace work of Kochi and Anderson,[29] resulted in the desired N-
of 2,3-bis(tert-butylaminomethyl)naphthalene was observed Boc-protected aminomethyl-functionalized quinone.
A
and that yields higher than 50% were obtained. A third major advantage of this strategy is the fact that no radical
alternative, a reductive amination followed by an intramo- precursors have to be prepared.
lecular substitution, may be rejected in light of the previous
Although the Kochi–Anderson method, which is a silver-
catalysed oxidative decarboxylation of acids by peroxydis-
mechanistic considerations.[20]
Although the N-substituted benzo[f]isoindole-4,9-dione ulfate, seemed to be a very interesting procedure by which
18 was successfully synthesized, the pathway followed was to prepare the key compounds 22, it was reported that this
too lengthy and did not satisfy the requirement concerning method was not suitable for the addition of N-Boc-pro-
the functionalization of C1 and/or C3. A new retrosynthetic tected chiral α-amino acids to menadione.[27]
strategy, using N-protected 2-(1-aminoalkyl)-1,4-naphtho-
In an effort to circumvent this problem we wondered if
quinones 22 as key intermediates, was proposed (Scheme 4). the choice of the N-protecting group and the use of 1,4-
Amines of the type 22 display interesting biological activi- naphthoquinone (23) instead of 2-methyl-1,4-naphtho-
ties, especially in the field of cancer research.[23]
quinone are decisive for the success of the radical addition
Scheme 4.
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Benzo[f]isoindolediones from Naphthoquinones
reaction. Based on the retrosynthetic analysis, it was de- isolated in 13% yield. The same coupling reaction of 1,4-
cided to use N-trifluoroacetyl-protected α-amino acids. The naphthoquinone with N-Fmoc-alanine resulted in a com-
trifluoroacetyl protecting group is highly stable under plex mixture, which was not further investigated.
strongly acidic conditions, whereas its moderate steric hin-
In a subsequent step, bromomethylation of 25a–g was
drance offers the advantages of easy attachment and re- accomplished by reaction with excess paraformaldehyde
moval.[30] The N-trifluoroacetyl-protected α-amino acids and a concentrated solution of 33% HBr in acetic acid over
were prepared by reaction of the corresponding α-amino 4 h to afford the asymmetrically bifunctionalized 1,4-naph-
acid with trifluoroacetic anhydride or with ethyl trifluo- thoquinones 27a–g in 80–92% yields (Scheme 6). Although
roacetate in combination with a base.[31]
benzyl ethers are robust and stable to a wide range of acidic
The radical addition was achieved by the reaction of 1,4- and basic conditions, the bromomethylation conditions
naphthoquinone (23) with 2.5 equiv. of the N-trifluoroace- proved to be too harsh for the benzyl ether 27e and led to
tyl-α-amino acid 24 and 0.3 equiv. of AgNO3 in 30% aque- a complex reaction mixture.
ous acetonitrile at 65 °C. The best results were obtained if
1.3 equiv. of the radical initiator ammonium persulfate were
added to the reaction mixture over 2 h. After stirring at
75 °C for 3 h, the reaction mixture was analysed by TLC or
HPLC, and an additional 0.3 equiv. of AgNO3 and
1.3 equiv. of ammonium persulfate were added (Scheme 5).
Scheme 6.
It was assumed that treatment of 3-(aminomethyl)-2-
(bromomethyl)-1,4-naphthoquinone 27 with a base would
result in the deprotection of the nitrogen atom and induce
subsequent ring closure towards the envisioned products.
The reactions of compounds 27a,b,d,g with an excess of
aqueous potassium hydroxide (5 ) in methanol/CH2Cl2 at
room temperature indeed resulted in benzo[f]isoindole-4,9-
diones 29a,b,d,g in 29–53% yields after flash chromatog-
Scheme 5.
raphy (Scheme 7). The intermediate 2,3-dihydrobenzo[f]iso-
Although the yields obtained after flash chromatography indoles 28 are not stable and are oxidized spontaneously
were rather moderate, this strategy allows the preparation by air oxygen to the corresponding benzo[f]isoindole-4,9-
of a wide range of 2-(aminomethyl)-1,4-naphthoquinones diones 29.[11b,20] Although the intramolecular ring closure,
25. It should be noted that after flash chromatography, 40– which is a 5-exo-tet reaction, is favoured, the reaction of
50% of the unconverted quinone 23 was also recovered. 27f (R = CH2OMe) with aqueous potassium hydroxide in
These results also indicate that the presence of an alkyl MeOH/CH2Cl2 did not result in the desired ring-closed
group generally has a small effect on the reactivity of the product; instead a complex mixture was obtained. Most
carbon radical. Only in one case, that is, the reaction of 1,4- likely, the intermediate 2,3-dihydrobenzo[f]isoindole, if
naphthoquinone (23) with N-trifluoroacetylglycine (24a), formed at all, undergoes elimination of MeOH under the
was a double addition product 26 observed in 10% yield by strongly basic conditions and thus triggers other degrada-
HPLC–MS. This clearly demonstrates that the steric hin- tion reactions.
drance, induced by the α-substituent of the amino acid,
In an attempt to synthesize peri-substituted benzo[f]iso-
plays an essential role in the outcome of the reaction. Be- indole-4,9-diones 32, the radical aminoalkylation of 5-
cause the retrosynthetic analysis in Scheme 4 necessitated methoxy-1,4-naphthoquinone (30) with N-trifluoroacetylal-
the use of a base-labile N-protecting group, the radical cou- anine was performed. One regioisomer (31) was formed and
pling of N-Fmoc-glycine to 1,4-naphthoquinone was also isolated in 42% yield after flash chromatography. Not com-
evaluated under the above-mentioned reaction conditions. pletely unexpectedly, the reaction of 31 with paraformalde-
After a cumbersome flash-chromatographic procedure, hyde and HBr resulted in double bromomethylation
Fmoc-protected 2-(aminomethyl)-1,4-naphthoquinone was (Scheme 8). It was not possible to effect a single bromo-
Eur. J. Org. Chem. 2009, 4882–4892
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J. Deblander, S. Van Aeken, J. Jacobs, N. De Kimpe, K. Abbaspour Tehrani
FULL PAPER
Scheme 7.
methylation because under the rather harsh conditions re- potassium carbonate at only 50 °C for 16 h, which led to
quired for the introduction of a bromomethyl group at the 34a in 74% yield. This optimized procedure was also used
3-position of 31, the 8-position of compound 31 also for the synthesis of the dialkylated 1-methyl-2-propyl-2H-
started to react. The correct regiochemistry of the aromatic benzo[f]isoindole-4,9-dione (34b) in 72% yield. Bromina-
bromomethyl and aminomethyl moiety in compound 32 tion of compounds 34b and 34a with 1 or 2 equiv. of bro-
was determined by NOESY. A cross-peak was observed be- mine in dichloromethane at room temperature for 1 h re-
tween the CH2 group at the 8-position and the CH3CH sulted in a complete substitution of the pyrrole unit
group at the 2-position. In the other possible regioisomer, (Scheme 9). The selective monobromination of 2-propyl-
that is, N-trifluoroacetyl-2-(1-aminoethyl)-3,5-bis(bromo- 2H-benzo[f]isoindole-4,9-dione (34a) with 1 equiv. of bro-
methyl)-8-methoxy-1,4-naphthoquinone, a cross-peak be- mine was not possible under these reaction conditions. The
tween the OCH3 group and the CH3CH group at the 2- brominated benzo[f]isoindole-4,9-diones 35a,b were ob-
position would have to appear, which was not the case. By tained in 100% yield and may be interesting substrates for
extension, the structure of compound 31 was assigned as transition-metal-catalysed coupling reactions.
N-trifluoroacetyl-2-(1-aminoethyl)-5-methoxy-1,4-naphtho-
quinone. Unfortunately, the final potassium hydroxide in-
duced ring closure only led to inseparable reaction mixtures.
Scheme 9.
Scheme 8.
Conclusions
To functionalize the pyrrole unit of benzo[f]isoindole-
4,9-dione 29a (R = H), the N-alkylation of 29a was per-
N-Trifluoroacetyl-protected 2-(1-aminoalkyl)-1,4-naph-
formed by treatment of the isoindole in the presence of po- thoquinones have been synthesized for the first time by a
tassium carbonate with bromopropane in DMF at 90 °C procedure based on the Kochi–Anderson oxidative decar-
for 15 h in accordance with a literature method.[32] After boxylation method starting from 1,4-naphthoquinone and
flash chromatography of the very impure reaction mixture, N-trifluoroacetyl-α-amino acids. Furthermore, it has been
2-propyl-2H-benzo[f]isoindole-4,9-dione (34a) was ob- demonstrated that 2-(1-aminoalkyl)-1,4-naphthoquinones
tained in 43% yield. The reaction conditions were opti- are suitable precursors for the synthesis of 1-alkylbenzo[f]-
mized by using an excess of potassium hydroxide instead of isoindole-4,9-diones by a bromomethylation and subse-
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Benzo[f]isoindolediones from Naphthoquinones
Synthesis of 1,4-Dimethoxy-2,3-bis(phenoxymethyl)naphthalene
(13): A solution of 2,3-bis(bromomethyl)-1,4-dimethoxynaphtha-
lene (10; 1.00 g, 2.7 mmol) in acetone (10 mL) was added to a solu-
tion containing phenol (1.25 g, 13.5 mmol) and potassium carbon-
ate (1.85 g, 13.5 mmol) in acetone (10 mL). The reaction mixture
was heated at reflux for 18 h. The solvent was evaporated in vacuo,
and the residue was redissolved in dichloromethane. The organic
solution was washed with water and brine and dried (MgSO4).
Evaporation of the solvent yielded 1,4-dimethoxy-2,3-bis(phenoxy-
methyl)naphthalene (13), which was purified by recrystallization
(petroleum ether/ethyl acetate) to give off-white crystals (0.56 g,
quent N-deprotection. Further functionalization by N-alky-
lation and bromination resulted in completely and asym-
metrically substituted benzo[f]isoindole-4,9-diones.
Experimental
General Experimental Methods: GC–MS analyses were performed
by using an Interscience GC 8000 series gas chromatograph with
a ECTM-5 column (length: 30 m, internal diameter: 0.32 mm, film
thickness: 0.25 µm). Products were injected into a split injector
(250 °C); the inert carrier gas was helium. Mass spectra were mea-
sured with a Fisons MD 800 instrument by using electron impact
(70 eV) as the ionization method. HRMS data were obtained with
a QTof Micro mass spectrometer (positive ion mode). Under stan-
dard measurement conditions the sample was dissolved in CH3CN/
H2O (1:1) containing 0.1% formic acid. High-resolution 1H
(250 MHz) and 13C NMR (63 MHz) spectra were recorded in
CDCl3, [D6]DMSO, CD3OD, CD3CN or CD2Cl2 with a Bruker
Avance DRX 250 spectrometer. Chemical shifts are reported in
ppm downfield from TMS. 13C NMR assignments were made by
analysis of DEPT, HMQC, HMBC, 2D COSY and 2D NOESY
spectra. Infrared spectra were recorded with an Avatar 370 FT-IR
apparatus (Thermo Nicolet). Unless otherwise stated, the IR spec-
tra were recorded by using attenuated total reflection technology.
Flash chromatography was performed by using Merck silica (dia-
meter: 40–63 µm). TLC analysis was performed on glass-backed
1
52%). M.p. 124.3 °C. H NMR (300 MHz, CDCl3): δ = 3.98 (s, 6
H, 2 MeO), 5.37 (s, 4 H, 2 CH2), 6.93–7.02 (m, 6 H, 6 CHar), 7.24–
7.30 (m, 4 H, 4 CHar), 7.56–7.61 (m, 2 H, 2 CHar), 8.14–8.19 (m,
2 H, 2 CHar) ppm. 13C NMR (75 MHz, CDCl3): δ = 62.06 (2
MeO), 63.97 (2 CH2), 114.93 (4 CHar), 121.09 (2 CHar), 123.10 (2
CHar), 125.39 (2 Cquat), 127.12 (2 CHar), 129.36 (2 Cquat), 152.61
(2 Cquat), 158.92 (2 Cquat) ppm. IR (ATR): ν
= 1355 cm–1. MS
˜
max
(ES+): m/z (%) = 307 (100) [M – PhO]+.
Synthesis of 2-tert-Butyl-2H-benzo[f]isoindole-4,9-dione (18)
Synthesis of 2,3-Bis(isopropoxymethyl)-1,4-dimethoxynaphthalene
(15): 2-Propanol (0.707 g, 12 mmol) was added dropwise to a solu-
tion of 2,3-bis(bromomethyl)-1,4-dimethoxynaphthalene (10; 2 g,
5.35 mmol) and sodium hydride (0.334 g, 13.9 mmol) in tetra-
hydrofuran (12 mL). The mixture was stirred at room temperature
for 3 h and then quenched with water. The ethyl acetate extract was
washed with water and brine and dried (MgSO4). After evaporation
in vacuo, a yellow oil (1.84 g, 99%) was obtained, which was used
without purification in the next step. An analytically pure sample
was obtained by silica gel column chromatography (EtOAc/cyclo-
plates (Merck) coated with 0.2 mm silica with UV indicator 60F254
.
Preparative HPLC was performed by using a Gilson HPLC instru-
ment (332 PUMP) and a Gilson UV detector (UV/Vis-156) with a
reversed-phase Discovery BIO wide-pore C18 column (length:
25 cm, internal diameter: 21.2 mm, particle size: 10 µm) using a
MeCN/H2O gradient containing 0.1% trifluoroacetic acid. Melting
points (m.p.) were determined with a melting point apparatus with
a temperature gradient of 1 °C/min and are not corrected.
1
hexane, 1:9; Rf = 0.28). H NMR (250 MHz, CDCl3): δ = 1.28 (d,
J = 6.1 Hz, 12 H, 4 CH3), 3.81 (sept, J = 6 Hz, 2 H, 2 CH), 3.98
(s, 6 H, 2 OMe), 4.82 (s, 4 H, 2 CH2), 7.47–7.55 (m, 2 H, 2 CHar),
8.09 (dd, J = 3.3, 6.4 Hz, 2 H, 2 CHar) ppm. 13C NMR (63 MHz,
CDCl3): δ = 22.3 (4 CH3), 61.7 (2 CH2), 63.5 (2 OMe), 71.8 (2
CH), 122.8 (2 CHar), 126.4 (2 CHar), 127.1 (2 Cquat), 129.0 (2
General Method for the Synthesis of N-Trifluoroacetyl-Protected
Amino Acids 24a–f: Triethylamine (3.1 mL, 22 mmol) was added to
a suspension of α-amino acid (22 mmol) in methanol (11 mL). Af-
ter stirring for about 5 min, ethyl trifluoroacetate (3.3 mL,
28 mmol) was added, and the resulting mixture was stirred at room
temperature for about 16 h. The solvent was removed under re-
duced pressure, and the resulting residue was dissolved in water
(50 mL), acidified with concentrated aqueous hydrochloric acid
(4 mL) and stirred for 15 min. The mixture was then extracted with
ethyl acetate (2ϫ30 mL), and the organic layers were combined.
The combined organic layers were washed with brine, dried
(MgSO4), and the solvent was removed under reduced pressure to
provide a solid, which was washed with hexane and dried to pro-
vide the desired N-trifluoroacetyl amino acid 24a–f.
C
quat), 152.0 (2 Cquat) ppm. IR (ATR): ν
= 1353, 1122, 1076,
˜
max
1046, 1019, 772 cm–1. MS (EI, 70 eV): m/z (%) = 332 (48) [M]+,
272 (57), 257 (31), 214 (47), 229 (100), 215 (99), 186 (57), 171 (56),
143 (31), 128 (48), 115 (50). HRMS (ESI): calcd. for C20H28O4 +
H+ 333.2060; found 333.2089.
Synthesis of 3-(Isopropoxymethyl)-1,4-dimethoxynaphthalene-2-
carbaldehyde (16): 2,3-Dichloro-4,5-dicyano-1,4-naphthoquinone
(DDQ; 1.336 g, 5.89 mmol) was added to a solution of 2,3-bis(isop-
ropoxymethyl)-1,4-dimethoxynaphthalene (15; 1.836 g, 5.35 mmol)
in dichloromethane/water (10:1; 75 mL). The reaction was moni-
tored to completion by TLC. After completion, the reaction mix-
ture was washed with a saturated sodium hydrogen carbonate solu-
tion and brine, and afterwards dried with MgSO4 and concentrated
in vacuo. Purification with silica gel column chromatography
(EtOAc/cyclohexane, 1:9; Rf = 0.15) gave a colourless oil (0.848 g,
Spectroscopic data have been reported for N-trifluoroacetylglycine
(24a),[31c,31e,33] N-trifluoroacetylalanine (24b),[31a,31f] N-trifluoro-
acetylvaline (24c),[33,34] N-trifluoroacetylphenylalanine (24d),[33,35]
N-trifluoroacetyl-O-benzylserine (24e)[31d] and N-trifluoroacetyl-
proline (24g).[31b] Spectroscopic data for N-trifluoroacetyl-O-meth-
1
55%). H NMR (500 MHz, CDCl3): δ = 1.25 (d, J = 6.1 Hz, 6 H,
2 CH3), 3.82 (sept, J = 6.1 Hz, 1 H, CH), 3.98 and 4.05 (2 s, 2ϫ3
H, 2 OMe), 4.98 (s, 2 H, CH2), 7.57–7.67 (m, 2 H, 2 CHar), 8.14
and 8.21 (2 d, J = 8.3 Hz, 2ϫ1 H, CHar), 10.70 (s, 1 H, CHO)
1
ylserine (24f): Yield: 94%. H NMR (250 MHz, [D6]DMSO): δ =
3.25 (s, 3 H, OMe), 3.66 [dd, J = 10.2, 4.5 Hz, 1 H, CH(H)], 3.70
[dd, J = 10.2, 7.3 Hz, 1 H, CH(H)], 4.51 (td, J = 7.5, 4.5 Hz, 1 H, ppm. 13C NMR (126 MHz, CDCl3): δ = 22.1 (2 CH3), 60.6 (CH2),
CH), 9.80 (br. d, J = 7.7 Hz, 1 H, NH), 13.1 (br. s, 1 H, OH) ppm.
13C NMR (63 MHz, [D6]DMSO): δ = 52.7 (CH), 58.1 (OMe), 70.0
(CH2), 115.8 (q, J = 288.0 Hz, CF3), 156.5 (q, J = 36.6 Hz,
63.6 (OMe), 64.9 (OMe), 72.1 (CH), 123.1 (CHar), 123.4 (CHar),
124.9 (Cquat), 125.7 (Cquat), 127.2 (CHar), 128.8 (Cquat), 129.5
(CHar), 131.6 (Cquat), 151.9 (Cquat), 158.5 (Cquat), 191.6 (CHO)
COCF ), 169.7 (COOH) ppm. IR (ATR): ν = 3218, 1743, 1698,
ppm. IR (ATR): ν
= 1688, 1350, 1051, 959, 776 cm–1. MS (EI,
max
˜
˜
3
1561, 1158, 1118, 1044, 898, 807, 668 cm–1.
70 eV): m/z (%) = 288 (18) [M]+, 245 (86), 230 (61), 215 (53), 213
Eur. J. Org. Chem. 2009, 4882–4892
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4887

J. Deblander, S. Van Aeken, J. Jacobs, N. De Kimpe, K. Abbaspour Tehrani
FULL PAPER
(58), 199 (46), 189 (40), 186 (100), 143 (42), 127 (79), 114 (89).
C17H20O4 (288.34): calcd. C 70.81, H 6.99; found C 68.59, H 7.22.
HPLC to remove traces of 18. 1H NMR (250 MHz, CDCl3): δ =
1.27 [s, 9 H, C(CH3)3], 2.10 [s, 3 H, C(O)CH3], 3.95 and 4.00 (2 s,
2ϫ3 H, 2 OMe), 4.09 (br. s, 2 H, CH2N), 5.50 (s, 2 H, CH2O),
Synthesis of 3-(Bromomethyl)-1,4-dimethoxynaphthalene-2-carbal-
dehyde (17): Bromotrimethylsilane (2.20 g, 14.35 mmol) was added
dropwise to a solution of 3-(isopropoxymethyl)-1,4-dimethoxy-
naphthalene-2-carbaldehyde (16; 1.038 g, 4.8 mmol) in dichloro-
methane (50 mL). The reaction mixture was stirred at room tem-
perature overnight and then washed with a saturated sodium hydro-
gen carbonate solution and dried (MgSO4). Concentration in vacuo
gave a white solid (1.812 g, 80%), which was used without further
purification. An analytically pure sample was obtained by silica gel
column chromatography (EtOAc/cyclohexane, 1:6; Rf = 0.30). M.p.
105–106 °C. It was impossible to obtain a suitable mass spectrum
because the analyses of the compound by EI (GC/MS) and by ESI
(positive and negative) gave no signal. 1H NMR (250 MHz,
CDCl3): δ = 3.98 and 4.01 (2 s, 2ϫ3 H, 2 OMe), 5.20 (s, 2 H,
CH2), 7.52–7.66 (m, 2 H, 2 CHar), 8.04 (dd, J = 0.5, 7.7 Hz, 1 H,
+
7.50–7.60 (m, 2 H, 2 CHar), 8.03–8.14 (m, 2 H, 2 CHar) ppm (NH2
signal was not visible). 13C NMR (63 MHz, CDCl3): δ = 8.97
[C(CH3)3], 20.3 [C(O)CH3], 28.9 [C(CH3)3], 37.4 (CH2N), 58.2
(CH2O), 62.1 (OCH3), 62.7 (OCH3), 121.8 (CHar), 122.2 (CHar),
123.4 (Cquat), 125.8 (Cquat), 126.3 (2 CHar), 151.1 and 152.5 (2
OMe), 170.1 [C(O)CH3] ppm (CF3, COO– and two Cquat signals
could not be distinguished). IR (ATR): νmax = 719, 775, 968, 1019,
˜
1197, 1224, 1357, 1685, 1736 cm–1. MS (ES+): m/z (%) = 346 (100)
[M + H]+, 304 (20), 286 (52), 273 (38).
General Procedure for the Preparation of N-Trifluoroacetyl-Pro-
tected 2-(1-Aminoalkyl)-1,4-naphthoquinones 25 and 31: N-Trifluo-
roacetyl-protected amino acid 24 (2.5 equiv.) and silver nitrate
(0.3 equiv.) were added to a stirred solution of 1,4-naphthoquinone
23 or 29 (6 mmol) in 30% aq. CH3CN. The mixture was heated to
CHar), 8.14 (dd, J = 0.5, 8.1 Hz, 1 H, CHar), 10.63 (s, 1 H, CHO) 65 °C, and a solution of ammonium persulfate (1.3 equiv.) in 30%
ppm. 13C NMR (63 MHz, CDCl3): δ = 22.8 (CH2), 60.7 (OMe), aq. CH3CN was added dropwise over 2 h. Subsequently, the mix-
63.7 (OMe), 120.6 (Cquat), 121.4 (CHar), 121.5 (CHar), 123.8
(Cquat), 125.9 (CHar), 126.9 (Cquat), 127.9 (CHar), 129.7 (Cquat),
ture was stirred at 75 °C for 3 h. After TLC or HPLC analysis,
an additional amount of silver nitrate (0.3 equiv.) and ammonium
persulfate (1.3 equiv.) in 30% aq. CH3CN were added dropwise
over 2 h. After being stirred at 75 °C for an additional 3 h, the
reaction mixture was cooled to room temperature and extracted
with dichloromethane. The organic extracts were washed with
brine, dried (MgSO4) and the solvents evaporated in vacuo. The
crude product was purified by flash chromatography on silica gel.
149.9 (Cquat), 159.2 (Cquat), 189.3 (CHO) ppm. IR (ATR): ν
=
˜
max
1679, 1404, 1351, 1047, 956, 777, 724 cm–1. C14H13BrO3 (309.16):
calcd. C 54.39, H 4.24; found C 54.58, H 4.27.
Synthesis of 2-tert-Butyl-4,9-dimethoxy-2,3-dihydro-1H-benzo[f]iso-
indole (14): Triethylamine (0.0462 g, 0.46 mmol), sodium triacetox-
yborohydride (0.067 g, 0.32 mmol) and tert-butylamine (0.0166 g,
0.23 mmol) were added successively to a solution of 3-(bro-
momethyl)-1,4-dimethoxynaphthalene-2-carbaldehyde (17; 0.070 g,
0.23 mmol) in 1,2-dichloroethane (3 mL). The reaction mixture was
stirred under argon at room temperature and monitored to comple-
tion by HPLC. After 6 h, the reaction mixture was quenched with
a saturated sodium hydrogen carbonate solution, extracted with
ethyl acetate and dried (MgSO4). After filtration and removal of
the solvent in vacuo, a black solid was obtained, which was used
as such in the subsequent reaction step because the compound
proved to be unstable. Any attempt to purify the compound by
column chromatography or by crystallization only led to further
degradation. 1H NMR (250 MHz, CDCl3): δ = 1.37 [s, 9 H,
C(CH3)3], 3.96 (s, 6 H, OMe), 4.47 (s, 4 H, 2 CH2), 7.46–7.50 (m,
2 H, 2 CHar), 8.09 (dd, J = 3.3, 6.3 Hz, 2 H, 2 CHar) ppm. 13C
NMR (63 MHz, CDCl3): δ = 25.6 (3 CH3), 43.5 (Cquat), 49.8 (2
CH2), 61.2 (2 OMe), 122.0 (2 CHar), 125.8 (2 CHar), 128.7 (2 Cquat),
146.2 (2 Cquat), 175.4 (2 Cquat) ppm. MS (EI, 70 eV): m/z = 286 [M
+ 1]+.
N-Trifluoroacetyl-2-(aminomethyl)-1,4-naphthoquinone (25a): Yield:
49%. Rf = 0.18 (EtOAc/cyclohexane, 1:4). M.p. 146.2–147.1 °C. 1H
NMR (250 MHz, CDCl3): δ = 4.48 (d, J = 6.3 Hz, 2 H, CH2), 6.93
(s, 1 H, 3-H), 7.03 (br. s, 1 H, NH), 7.73–7.84 (m, 2 H, 6-H and 7-
H), 8.05–8.16 (m, 2 H, 5-H and 8-H) ppm. 13C NMR (63 MHz,
CDCl3): δ = 39.2 (CH2), 115.7 (q, J = 287.7 Hz, CF3), 126.5 and
126.6 (C-5 and C-8), 131.7 and 132.0 (Cquat), 134.1 and 134.5 (C-
6 and C-7), 135.9 (C-3), 143.8 (Cquat), 157.2 (q, J = 37.1 Hz,
COCF ), 184.4 (C=O), 185.1 (C=O) ppm. IR (ATR): ν = 3316,
˜
3
1709, 1660, 1536, 1300, 1157, 995, 922, 777 cm–1. MS (ES): m/z (%)
= 284 (100) [M + H]+. HRMS (ESI): calcd. for C13H8F3NO3 + H+
284.0529; found 284.0522; ∆ = 2.4 ppm.
N-Trifluoroacetyl-2-(1-aminoethyl)-1,4-naphthoquinone (25b): Yield:
45%. Rf = 0.23 (EtOAc/cyclohexane, 1:4). M.p. 167.8–168.7 °C. 1H
NMR (250 MHz, CDCl3): δ = 1.60 (d, J = 7.1 Hz, CH3), 5.11 [dq
(pseudo-quint), J = 7.2 Hz, 1 H, CH], 6.87 (s, 1 H, 3-H), 7.26 (br.
s, 1 H, NH + CHCl3), 7.75–7.82 (m, 2 H, 6-H and 7-H), 8.07–8.13
(m, 2 H, 5-H and 8-H) ppm. 13C NMR (63 MHz, [D6]DMSO): δ
Synthesis of 2-tert-Butyl-2H-benzo[f]isoindole-4,9-dione (18): The = 19.0 (CH3), 43.4 (CHN), 115.7 (q, J = 288.4 Hz, CF3), 125.6 and
above-obtained crude product 14 (0.064 g, 0.22 mmol) was dis-
126.2 (C-5 and C-8), 131.3 and 131.6 (Cquat), 133.0 (C-3), 134.3 (C-
solved in a mixture of acetonitrile/water (2:1; 3 mL) and cooled to
6 and C-7), 150.2 (Cquat), 155.5 (q, J = 36.8 Hz, COCF3), 183.4
0 °C, after which cerium(IV) ammonium nitrate (0.369 g, (C=O), 184.5 (C=O) ppm. IR (ATR): ν = 3298, 1696, 1661, 1593,
˜
0.067 mmol) was added. The reaction mixture was stirred for 1 h
and then quenched with water, extracted with ethyl acetate and
dried (MgSO4). After filtration and removal of the solvent in
vacuo, the residue was purified by flash chromatography on alu-
minium oxide (EtOAc/petroleum ether, 1:4; Rf = 0.10) to provide
a yellow powder (0.052 g, 93%). M.p. 172–173 °C. The NMR spec-
troscopic data of 18 were in accordance with data reported in the
literature.[20]
1549, 1334, 1167, 987, 782 cm–1. MS (ES): m/z (%) = 298 (100) [M
+ H]+. HRMS (ESI): calcd. for C14H10F3NO3 + H+ 298.0685;
found 298.0679; ∆ = 2.0 ppm.
N-Trifluoroacetyl-2-[(1-amino-2-methyl)propyl]-1,4-naphthoquinone
(25c): Yield: 27%. Rf = 0.39 (EtOAc/cyclohexane, 1:3). M.p. 129.8–
130.7 °C. Over a period of 12 h this compound started to decom-
1
pose in CDCl3. H NMR (250 MHz, CDCl3): δ = 1.06 and 0.93 [2
d, J = 6.7 Hz, 2 ϫ 3 H, CH(CH3)2], 2.22–2.31 [m, 1 H, CH-
(CH3)2], 4.59 [dd (pseudo-t), J = 9.3 Hz, 1 H, HCN], 6.85 (s, 1 H,
3-H), 7.43–7.47 (br. s, 1 H, NH), 7.77–7.82 (m, 2 H, 6-H and 7-
H), 8.06–8.12 (m, 2 H, 5-H and 8-H) ppm. 13C NMR (63 MHz,
CDCl3): δ = 19.2 (CH3), 20.1 (CH3), 31.8 [CH(CH3)2], 58.8
(CHNH), 115.7 (q, J = 288.1 Hz, CF3), 126.4 and 126.8 (C-5 and
{3-[(tert-Butylamino)methyl]-1,4-dimethoxynaphthalen-2-yl}methyl
Acetate (Trifluoroacetate Salt) (19): This compound was obtained
by rinsing the aluminium oxide of the above-mentioned chromato-
graphic separation with CH2Cl2/MeOH (98:2). These combined
washings were concentrated in vacuo and purified by preparative
4888
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4882–4892

Benzo[f]isoindolediones from Naphthoquinones
C-8), 131.7 and 132.0 (Cquat), 134.1 and 134.5 (C-6 and C-7), 137.0
(ATR): ν = 2984, 1689, 1661, 1593, 1448, 1186, 1150, 965, 778,
˜
(C-3), 145.9 (Cquat), 156.9 (q, J = 37.2 Hz, COCF3), 184.4 (C=O), 760, 703 cm–1. MS (ES): m/z (%) = 324 (100) [M + H]+. HRMS
185.5 (C=O) ppm. IR (ATR): ν = 3315, 2965, 1698, 1659, 1592, (ESI): calcd. for C16H12F3NO3 + H+ 324.0847; found 324.0834; ∆
˜
1550, 1204, 1151, 929, 779, 718, 699 cm–1. MS (ES): m/z (%) =
326 (100) [M + H]+, 284 (47), 213 (55). HRMS (ESI): calcd. for
C16H14F3NO3 + H+ 326.0999; found 326.0997; ∆ = 0.6 ppm.
= 4.5 ppm.
N-Trifluoroacetyl-2-(1-aminoethyl)-5-methoxy-1,4-naphthoquinone
(31): Yield: 42%. Rf = 0.25 (EtOAc/cyclohexane, 2:3). M.p. 170.5–
1
171.5 °C. H NMR (250 MHz, CDCl3): δ = 1.58 (d, J = 7.0 Hz, 3
N-Trifluoroacetyl-2-(1-amino-2-phenylethyl)-1,4-naphthoquinone
(25d): Yield: 32%. Rf = 0.13 (EtOAc/cyclohexane, 1:6). M.p. 178.0–
179.2 °C. 1H NMR (250 MHz, CDCl3): δ = 3.18 [dd, J = 9.9,
7.6 Hz, 1 H, CH(H)], 3.22 [dd, J = 9.9, 7.6 Hz, 1 H, CH(H)], 5.20
[dt (pseudo-q), J = 7.7 Hz, 1 H, CH], 6.59 (s, 1 H, 3-H), 7.11–7.20
(m, 2 H, CHar), 7.23–7.30 (m, 3 H, CHar), 7.45 (br. d, J = 8.8 Hz,
1 H, NH), 7.75–7.84 (m, 2 H, 6-H and 7-H), 8.01–8.08 (m, 1 H, 8-H
or 5-H), 8.09–8.17 (m, 1 H, 5-H or 8-H) ppm. 13C NMR (63 MHz,
CDCl3): δ = 40.5 (CH2), 53.4 (CH), 115.6 (q, J = 287.8 Hz, CF3),
126.4, 126.8 and 127.5 (Cquat), 129 (C-5 and C-8), 131.7 and 132.0
(Cquat), 134.2 and 134.5 (C-6 and C-7), 135.5 (Cquat), 136.3 (C-3),
145.6 (Cquat), 156.5 (q, J = 37.6 Hz, COCF3), 184.2 (C=O), 185.4
H, CH3), 4.03 (s, 3 H, OCH3), 5.05 [dq (pseudo-quint), J = 7.4 Hz,
1 H, CHN], 6.80 (s, 1 H, 3-H), 7.30–7.37 (m, 1 H, 7-H), 7.45 (br.
d, J = 8.0 Hz, 1 H, NH), 7.70–7.74 (m, 2 H, 6-H and 8-H) ppm.
13C NMR (63 MHz, CDCl3): δ = 20.9 (CH3), 48.5 (NCH), 56.7
(OCH3), 115.8 (q, J = 288.0 Hz, CF3), 118.3 (C-7), 119.3 (C-6 or
C-8), 119.9 (Cquat), 133.4 (C-3), 134.1 (Cquat), 135.8 (C-6 or C-8),
149.1 (Cquat), 156.5 (q, J = 37.4 Hz, CO), 160.3 (COMe), 184.6
(C=O), 184.9 (C=O) ppm. IR (ATR): ν = 3292, 1723, 1650, 1587,
˜
1308, 1213, 1182, 1142, 946, 725 cm–1. MS (ES): m/z (%) = 328
(100) [M + H]+. HRMS (ESI): calcd. for C15H12F3NO4 + H+
328.0791; found 328.0803; ∆ = 3.7 ppm.
(C=O) ppm. IR (ATR): ν = 3290, 1701, 1658, 1593, 1562, 1168,
˜
General Procedure for the Preparation of N-Trifluoroacetyl-Pro-
tected 2-(1-Aminoalkyl)-3-(bromomethyl)naphthalene-1,4-diones
(27): Paraformaldehyde (50 mmol, 1.5 g) and a solution of 33%
HBr in acetic acid (10 mL) were added to a stirred mixture of N-
trifluoroacetyl-protected 2-(1-aminoalkyl)naphthalene-1,4-diones
25 (1 mmol) in acetic acid (5 mL). The mixture was stirred at room
temperature for 4 h, then water (20 mL) was added, and the aque-
ous solution was extracted with dichloromethane. The organic ex-
tracts were washed with water, dried (MgSO4) and the solvents
evaporated in vacuo. Flash chromatography on silica gel gave the
desired compound 27.
967, 913, 775 cm–1. MS (ES): m/z (%) = 374 (50) [M + H]+, 261
(100). HRMS (ESI): calcd. for C20H14F3NO3 + H+ 374.1004; found
374.0979; ∆ = 5.0 ppm.
N-Trifluoroacetyl-2-[1-amino-2-(benzyloxy)ethyl]-1,4-naphthoquin-
one (25e): Yield: 46%. Rf = 0.31 (EtOAc/cyclohexane, 1:4). M.p.
1
103–104 °C. H NMR (250 MHz, CDCl3): δ = 3.77 [dd, J = 10.0,
4.5 Hz, 1 H, CH(H)], 3.79 [dd, J = 10.0, 4.5 Hz, 1 H, CH(H)], 4.50
(s, 2 H, CCH2), 5.29 (dt, J = 8.0, 4.4 Hz, 1 H, CH), 6.81 (s, 1 H,
3-H), 7.17–7.27 (m, 5 H, CHar), 7.30–7.35 (br. s, 1 H, NH), 7.73–
7.77 (m, 2 H, 6-H and 7-H), 8.04–8.07 (m, 2 H, 5-H and 8-H) ppm.
13C NMR (63 MHz, CDCl3): δ = 49.7 (CH), 69.0 [CH(CH2)], 73.3
(CH2), 115.6 (q, J = 287.7 Hz, CF3), 126.3, 126.7 and 128.2 (Cquat),
127.9 and 128.6 (C-5 and C-8), 131.8 and 131.9 (Cquat), 134.0 and
134.3 (C-6 and C-7), 135.7 (C-3), 136.8 (Cquat), 145.2 (Cquat), 156.7
(q, J = 37.7 Hz, COCF3), 184.3 (C=O), 184.5 (C=O) ppm. IR
N-Trifluoroacetyl-2-(aminomethyl)-3-(bromomethyl)-1,4-naphtho-
quinone (27a): Yield: 86 %. Rf = 0.22 (EtOAc/cyclohexane, 1:6).
M.p. 116–117 °C. 1H NMR (250 MHz, CDCl3): δ = 4.59 (d, J =
6.4 Hz, 2 H, CH2N), 4.77 (s, 2 H, CH2Br), 7.22–7.28 (m, 1 H, NH
+ CHCl3), 7.77–7.81 (m, 2 H, 6-H and 7-H), 8.06–8.10 (m, 1 H, 8-
H or 5-H), 8.12–8.16 (m, 1 H, 5-H or 8-H) ppm. 13C NMR
(63 MHz, CDCl3): δ = 20.2 (CH2Br), 36.3 (CH2N), 115.6 (q, J =
287.6 Hz, CF3), 126.5 and 127.1 (C-5 and C-8), 131.4 and 131.6
(Cquat), 134.4 and 134.7 (C-6 and C-7), 140.5 (Cquat), 144.6 (Cquat),
157.4 (q, J = 37.6 Hz, COCF3), 182.2 (C=O), 185.3 (C=O) ppm.
(ATR): ν = 3280, 1698, 1661, 1560, 1206, 1168, 113, 1083,
˜
780 cm–1. No suitable MS could be recorded by EI or ESI (positive
or negative). C21H16F3NO4 (403.36): calcd. C 62.53, H 4.00, N
3.47; found C 62.76, H 4.04, N 3.43.
N-Trifluoroacetyl-2-(1-amino-2-methoxyethyl)-1,4-naphthoquinone
(25f): Yield: 47%. Rf = 0.24 (EtOAc/cyclohexane, 1:3). M.p. 143.7–
44.6 °C. 1H NMR (250 MHz, CDCl3): δ = 3.36 (s, 3 H, OCH3),
3.72 (d, J = 4.4 Hz, 2 H, CH2), 5.31 (dt, J = 7.7, 4.4 Hz, 1 H, CH),
6.82 (s, 1 H, 3-H), 7.31 (br. d, J = 7.4 Hz, 1 H, NH), 7.76–7.79 (m,
2 H, 6-H and 7-H), 8.07–8.14 (m, 2 H, 5-H and 8-H) ppm. 13C
NMR (63 MHz, CDCl3): δ = 49.4 (CH), 59.2 (OCH3), 71.8 (CH2),
115.6 (q, J = 286.0 Hz, CF3), 126.4 and 126.7 (C-5 and C-8), 131.9
and 132.0 (Cquat), 134.1 and 134.3 (C-6 and C-7), 135.7 (C-3), 145.1
(Cquat), 156.7 (q, J = 36.2 Hz, CO), 184.3 (C=O), 184.6 (C=O)
IR (ATR): ν = 3303, 1695, 1661, 1291, 1179, 1154, 984, 732 cm–1.
˜
MS (ES): m/z (%) = 376/378 (15) [M + H]+, 296 (100). HRMS
(ESI): calcd. for C14H9BrF3NO3 + H+ 375.9791; found 375.9783;
∆ = 2.1 ppm.
N-Trifluoroacetyl-2-(1-aminoethyl)-3-(bromomethyl)-1,4-naphtho-
quinone (27b): Yield: 82 %. Rf = 0.31 (EtOAc/cyclohexane, 1:6).
1
M.p. 142.5–143.5 °C. H NMR (250 MHz, CDCl3): δ = 1.67 (d, J
= 7.0 Hz, CH3), 4.75 and 4.59 (2 d, J = 9.9 Hz, 2ϫ1 H, CH2Br),
5.41 [dq (pseudo-quint), J = 7.2 Hz, 1 H, CH], 7.64–7.71 (br. s, 1
H, NH), 7.75–7.80 (m, 2 H, 6-H and 7-H), 8.05–8.13 (m, 2 H, 5-
H and 8-H) ppm. 13C NMR (63 MHz, CDCl3): δ = 19.5 (CH3),
20.2 (CH2Br), 45.3 (CHN), 115.7 (q, J = 287.6 Hz, CF3), 126.6 and
127.0 (C-5 and C-8), 131.3 and 131.9 (Cquat), 134.4 and 134.6 (C-
6 and C-7), 142.7 and 144.1 (Cquat), 156.6 (q, J = 37.4 Hz, COCF3),
ppm. IR (ATR): ν = 3247, 3083, 1717, 1662, 1562, 1185, 1152,
˜
1089, 923, 782, 700 cm–1. HRMS (ESI): calcd. for C15H12F3NO4 +
H+ 328.0797; found 328.0810; ∆ = 3.9 ppm.
N-Trifluoroacetyl-2-(2-pyrrolidinyl)-1,4-naphthoquinone (25g):
Yield: 33 %. Rf = 0.32 (EtOAc/cyclohexane, 1:3). M.p. 115.5–
116.3 °C. 1H NMR (250 MHz, CDCl3): δ = 1.87–2.13 (m, 3 H,
NCHCH2CH2), 2.36–2.51 (m, 1 H, NCHCH2CH2), 3.76–3.96 (m,
2 H, NCH2), 5.33 (dd, J = 8.7, 3.6 Hz, 1 H, CH), 6.53 (s, 1 H, 3-
H), 7.72–7.81 (m, 2 H, 6-H and 7-H), 8.03–8.14 (m, 2 H, 5-H and
182.0 (C=O), 182.4 (C=O) ppm. IR (ATR): ν = 3438, 1721, 1667,
˜
1525, 1329, 1292, 1168, 1151, 938, 726 cm–1. HRMS (ESI): calcd.
for C15H11BrF3NO3 + H+ 389.9947; found 389.9944; ∆ = 0.7 ppm.
N-Trifluoroacetyl-2-(1-amino-2-methylpropyl)-3-(bromomethyl)-1,4-
8-H) ppm. 13C NMR (63 MHz, CDCl3): δ = 24.3 (NCH2CH2), 30.8 naphthoquinone (27c): Yield: 83%. Rf = 0.17 (EtOAc/cyclohexane,
(NCHCH2), 47.6 (NCH2), 57.6 (NCH), 116.1 (q, J = 287.6 Hz,
1
1:3). M.p. 165.5–166.4 °C. H NMR (250 MHz, CDCl3): δ = 0.96
CF3), 126.2 and 126.6 (C-5 and C-8), 131.9 (Cquat), 132.1 (C-3), (d, J = 6.8 Hz, 3 H, CH3), 1.14 (d, J = 6.5 Hz, 3 H, CH3), 2.40–
132.8 (Cquat), 134.0 and 134.1 (C-6 and C-7), 148.3 (Cquat), 155.5
(q, J = 37.3 Hz, COCF3), 184.2 (C=O), 184.7 (C=O) ppm. IR
2.55 [m, 1 H, CH(CH3)2], 4.71 and 4.69 (2 d, J = 10.0 Hz, 2ϫ1 H,
CH2Br), 4.85 [dd (pseudo-t), J = 9.8 Hz, 1 H, CHN], 7.37 (br. d,
Eur. J. Org. Chem. 2009, 4882–4892
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4889

J. Deblander, S. Van Aeken, J. Jacobs, N. De Kimpe, K. Abbaspour Tehrani
FULL PAPER
J = 9.2 Hz, 1 H, NH), 7.75–7.84 (m, 2 H, 6-H and 7-H), 8.05–8.10
4.56 (2 d, J = 10.0 Hz, 2ϫ1 H, C3CH2Br), 5.02 and 5.00 (2 d, J =
10.0 Hz, 2ϫ1 H, C8CH2Br), 5.36 (dq, J = 9.0, J = 7.0 Hz, 1 H,
(m, 1 H, 8-H or 5-H), 8.13–8.18 (m, 1 H, 5-H or 8-H) ppm. 13C
NMR (63 MHz, CDCl3): δ = 19.6 and 20.1 [CH(CH3)2], 20.5 NCH), 7.32 (d, J = 8.9 Hz, 1 H, 6-H), 7.64 (d, J = 8.8 Hz, 1 H,
(CH2Br), 31.9 [CH(CH3)2], 56.0 (NCH), 115.7 (q, J = 287.9 Hz, NH), 7.75 (d, J = 8.9 Hz, 1 H, 7-H) ppm. 13C NMR (63 MHz,
CF3), 126.6 and 127.1 (C-5 and C-8), 131.6 and 131.7 (Cquat), 134.3
and 134.7 (C-6 and C-7), 143.5 and 144.2 (Cquat), 157.0 (q, J =
CDCl3): δ = 19.5 (CH3), 20.4 (CH2Br), 32.1 (CH2Br), 45.2 (NCH),
56.7 (OCH3), 116.7 (q, J = 287.7 Hz, CF3), 118.3 (C-6), 121.2 and
37.4 Hz, COCF ), 182.0 (C=O), 185.8 (C=O) ppm. IR (ATR): ν = 130.3 (Cquat), 132.0 (C-8), 139.6 (C-7), 144.2 and 145.7 (Cquat),
˜
3
3212, 2968, 1671, 1684, 1592, 1556, 1292, 1189, 1138, 726 cm–1.
MS (ES): m/z (%) = 418/420 (30) [M + H]+, 338 (100). HRMS
(ESI): calcd. for C17H15BrF3NO3 + H+ 418.0260; found 418.0255;
∆ = 1.2 ppm.
156.6 (q, J = 37.5 Hz, COCF3), 183.9 (C=O), 184.7 (C=O) ppm.
IR (ATR): ν = 3270, 1698, 1653, 1560, 1259, 1186, 1158, 1035, 881,
˜
727 cm–1. No suitable MS could be recorded by EI or ESI (positive
or negative).
General Procedure for the Synthesis of Benzo[f]isoindole-4,9-diones
29: A 5  KOH solution (10 equiv.) was added to a solution of
N-trifluoroacetyl-protected 2-(1-aminoalkyl)-3-(bromomethyl)-1,4-
naphthoquinone 27 (100 mg) in methanol/dichloromethane (1:1,
20 mL) at 0 °C under N2. The cooling bath was removed, and the
mixture was stirred at room temperature for 20 h. In the next step,
the solvent was removed under vacuum, and water (15 mL) was
added to the residue. After extraction with dichloromethane (1ϫ)
and ethyl acetate (1ϫ), the combined organic layers were dried
(MgSO4) and the solvents evaporated in vacuo. Purification by
flash chromatography on silica gel afforded benzo[f]isoindole-4,9-
diones 29.
N-Trifluoroacetyl-2-(1-amino-2-phenylethyl)-3-(bromomethyl)-1,4-
naphthoquinone (27d): Yield: 92%. Rf = 0.26 (EtOAc/cyclohexane,
1:6). M.p. 203.4–204.2 °C. H NMR (250 MHz, CDCl3): δ = 3.27
1
[dd, J = 14.2, 6.6 Hz, 1 H, CCH(H)], 3.30 [dd, J = 14.2, 7.9 Hz, 1
H, CCH(H)], 4.52 and 4.53 (2 d, J = 10.3 Hz, 2ϫ1 H, CH2Br),
5.48 [dt (pseudo-q), J = 8.0 Hz, 1 H, CH], 7.22–7.35 (m, 5 H, CHar
+ CHCl3), 7.58 (br. d, J = 9.2 Hz, 1 H, NH), 7.78–7.85 (m, 2 H,
6-H and 7-H), 8.11–8.17 (m, 2 H, 5-H and 8-H) ppm. 13C NMR
(63 MHz, CDCl3): δ = 20.2 (CH2Br), 39.6 (CHCH2), 51.3 (CH),
115.6 (q, J = 287.7 Hz, CF3), 126.7, 127.1 and 127.5 (Cquat), 128.9
and 129.2 (C-5 and C-8), 131.4 and 131.8 (Cquat), 134.5 and 134.8
(C-6 and C-7), 135.9 (Cquat), 143.0 and 143.5 (Cquat), 156.7 (q, J =
37.5 Hz, COCF ), 181.9 (C=O), 185.9 (C=O) ppm. IR (ATR): ν =
˜
3
2H-Benzo[f]isoindole-4,9-dione (29a): Yield: 53%. The NMR spec-
troscopic data were in accordance with the data reported in the
literature.[36]
3322, 1716, 1653, 1665, 1295, 1181, 1153, 727, 698 cm–1. HRMS
(ESI): calcd. for C21H15BrF3NO3 + H+ 466.0260; found 466.0269;
∆ = 2.0 ppm.
1-Methyl-2H-benzo[f]isoindole-4,9-dione (29b): Yield: 42%. Rf =
0.24 (EtOAc/cyclohexane, 3:2). M.p. 241.2–241.8 °C. 1H NMR
(250 MHz, CD3OD): δ = 2.60 (s, 3 H, CH3), 7.42 (s, 1 H, 3-H),
7.71–7.75 (m, 2 H, 6-H and 7-H), 8.14–8.18 (m, 2 H, 5-H and 8-
H) ppm (NH was not visible). 13C NMR (63 MHz, [D6]DMSO): δ
= 12.3 (CH3), 116.8 (Cquat), 121.4 (C-3), 121.6 (Cquat), 126.2 (C-5
and C-8), 132.9 and 133.1 (C-6 and C-7), 135.1 and 135.6 (Cquat),
N-Trifluoroacetyl-2-(1-amino-2-methoxyethyl)-3-(bromomethyl)-1,4-
naphthoquinone (27f): Yield: 80%. Rf = 0.31 (EtOAc/cyclohexane,
1:3). M.p. 157–158 °C. 1H NMR (250 MHz, CDCl3): δ = 3.41 (s, 3
H, OCH3), 3.69 [dd, J = 9.9, 6.0 Hz, 1 H, CH(H)OMe], 3.94 [dd,
J = 9.9, 7.9 Hz, 1 H, CH(H)OMe], 4.69 and 4.67 (2 d, J = 9.9 Hz,
2ϫ1 H, CH2Br), 5.57 (ddd, J = 8.3, 8.3, 6.2 Hz, 1 H, CH), 7.68
(br. d, J = 8.6 Hz, 1 H, NH), 7.78–7.82 (m, 2 H, 6-H and 7-H),
8.08–8.11 (m, 1 H, 8-H or 5-H), 8.14–8.17 (m, 1 H, 5-H or 8-H)
ppm. 13C NMR (63 MHz, CDCl3): δ = 18.0 (CH2Br), 46.8 (CH),
56.7 (OCH3), 69.8 (CH2O), 113.3 (q, J = 287.7 Hz, CF3), 124.4 and
124.7 (C-5 and C-8), 139.0 and 129.4 (Cquat), 132.1 and 132.4 (C-
6 and C-7), 138.7 and 142.6 (Cquat), 154.7 (q, J = 37.7 Hz, COCF3),
136.8 [C(CH )], 179.3 (C=O), 179.8 (C=O) ppm. IR (ATR): ν =
˜
3
3225, 2399, 1641, 1532, 1336, 932, 713 cm–1. MS (ES): m/z (%) =
212 (100) [M + H]+. HRMS (ESI): calcd. for C13H9NO2 + H+
212.0706; found 212.0702; ∆ = 1.9 ppm.
1-Benzyl-2H-benzo[f]isoindole-4,9-dione (29d): Yield: 44%. Rf =
1
0.16 (EtOAc/cyclohexane, 1:3). H NMR (500 MHz, CD2Cl2): δ =
179.5 (C=O), 183.4 (C=O) ppm. IR (ATR): ν = 3229, 3060, 1702,
˜
4.51 (s, 2 H, CH2), 7.26–7.36 (m, 5 H, CHar), 7.39 (s, 1 H, CHN),
7.70–7.75 (m, 2 H, 6-H and 7-H), 8.21–8.26 (m, 2 H, 5-H and 8-
H), 8.84 (br. s, 1 H, NH) ppm. 13C NMR (126 MHz, CD2Cl2): δ
= 33.3 (CH2), 120.5 (CH), 127.0 and 127.1 and 127.5 (Car), 129.3
and 129.4 (C-5 and C-8), 133.1 and 133.3 (C-6 and C-7), 136.0,
136.6 and 137.5 (Cquat), 138.8 (Cquat), 180.7 (C=O), 181.2 (C=O)
1671, 1631, 1550, 1291, 1185, 1147, 1119, 1080, 921, 725, 669 cm–1.
No suitable MS could be recorded by EI or ESI (positive or nega-
tive).
N-Trifluoroacetyl-2-(2-pyrrolidinyl)-3-(bromomethyl)-1,4-naphtho-
quinone (27g): Yield: 84 %. Rf = 0.25 (EtOAc/cyclohexane, 1:9).
1
ppm. IR (ATR): ν = 3213, 1643, 1528, 1359, 1242, 930, 710 cm–1.
M.p. 152.1–152.6 °C. H NMR (250 MHz, CDCl3): δ = 2.02–2.37
˜
MS (ES): m/z (%) = 288 (100) [M + H]+. HRMS (ESI): calcd. for
C19H13NO2 + H+ 288.1019; found 288.1012; ∆ = 2.4 ppm.
(m, 3 H, CHCH2CH2N), 2.45–2.55 (m, 1 H, CHCH2CH2N), 3.97–
4.19 (m, 2 H, NCH2), 4.84 and 4.62 (2 d, J = 9.9 Hz, 2ϫ1 H,
CH2Br), 5.15 (t, J = 8.3 Hz, 1 H, CH), 7.70–7.78 (m, 2 H, 6-H and
7-H), 7.99–8.05 (m, 1 H, 8-H or 5-H), 8.08–8.14 (m, 1 H, 5-H or
8-H) ppm. 13C NMR (63 MHz, CDCl3): δ = 20.7 (NCH2CH2), 26.0
(CH2Br), 29.6 (CHCH2), 48.1 (NCH2), 58.3 (CH), 116.0 (q, J =
287.2 Hz, CF3), 126.5 and 126.7 (C-5 and C-8), 131.4 and 132.2
(Cquat), 134.1 (C-6 and C-7), 144.0 and 145.0 (Cquat), 155.4 (q, J =
Synthesis of 2,3-Dihydro-1H-benzo[f]pyrrolo[2,1-a]isoindole-6,11-di-
one (29g): A 5  aqueous KOH solution (10 equiv.) was added to
a solution of N-trifluoroacetyl-2-(2-pyrrolidinyl)-3-(bromomethyl)-
1,4-naphthoquinone (27g; 100 mg, 0.241 mmol) in methanol/
dichloromethane (1:1; 20 mL) at 0 °C under N2. The cooling bath
was removed, and the mixture was heated at reflux for 7 h. In the
next step, the solvent was removed under vacuum, and water
(15 mL) was added to the residue. After extraction with dichloro-
methane and ethyl acetate, the combined organic layers were dried
(MgSO4) and the solvents evaporated in vacuo. Purification by
flash chromatography on silica gel afforded the benzo[f]isoindole-
4,9-dione 29g in 29% yield. Rf = 0.21 (EtOAc/cyclohexane, 1:1).
36.9 Hz, COCF ), 182.1 (C=O), 183.4 (C=O) ppm. IR (ATR): ν =
˜
3
1680, 1663, 1589, 1295, 1456, 1445, 1295, 1239, 1176, 1143, 954,
799, 758, 727, 710 cm–1. HRMS (ESI): calcd. for C17H13BrF3NO3
+ H+ 416.0104; found 416.0109; ∆ = 1.2 ppm.
N-Trifluoroacetyl-2-(1-aminoethyl)-3,8-bis(bromomethyl)-5-meth-
oxy-1,4-naphthoquinone (32): Yield: 69%. Rf = 0.19 (EtOAc/cyclo-
hexane, 3:7). M.p. 112.9–113.9 °C. 1H NMR (250 MHz, CDCl3): δ M.p. 219.2–219.7 °C. 1H NMR (250 MHz, CDCl3): δ = 2.67 (quint,
= 1.64 (d, J = 7.0 Hz, 3 H, CH3), 4.04 (s, 3 H, OCH3), 4.72 and
J = 7.1 Hz, 2 H, NCH2CH2), 3.21 (t, J = 7.3 Hz, 2 H, NCCH2),
4890
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4882–4892

Benzo[f]isoindolediones from Naphthoquinones
4.10 (t, J = 7.2 Hz, 2 H, NCH2), 7.36 (s, 1 H, 5-H), 7.65–7.72 (m, CH2CH3), 4.18 (t, J = 7.6 Hz, 2 H, NCH2), 7.70–7.76 (m, 2 H, 6-
2 H, 8-H and 9-H), 8.21–8.26 (m, 2 H, 7-H and 10-H) ppm. 13C H and 7-H), 8.24–8.31 (m, 2 H, 5-H and 8-H) ppm. 13C NMR
NMR (63 MHz, CDCl3): δ = 24.9 (NCH2CH2), 27.4 (NCCH2),
47.1 (NCH2), 114.0 (Cquat), 117.7 (CH), 126.7 and 126.9 (C-7 and 108.6 (2 Cquat), 120.6 (2 Cquat), 127.0 (C-5 and C-8), 133.4 (C-6
C-10), 132.7 and 132.9 (C-8 and C-9), 135.6, 136.7 and 143.9 and C-7), 135.0 (2 Cquat), 178.1 (2 C=O) ppm. IR (ATR): ν = 2923,
(63 MHz, CDCl3): δ = 11.0 (CH3), 23.0 (CH2CH3), 48.8 (NCH2),
˜
(Cquat), 180.3 (C=O), 180.6 (C=O) ppm. IR (ATR): ν = 3119, 2959, 1656, 1593, 1491, 1356, 1230, 996, 715 cm–1. HRMS (ESI): calcd.
˜
1652, 1528, 1222, 988, 719 cm–1. MS (ES): m/z (%) = 238 (100) [M
+ H]+. HRMS (ESI): calcd. for C15H11NO2 + H+ 238.08630; found
238.08639; ∆ = 3.8 ppm.
for C15H11Br2NO2 + H+ 395.9229; found 395.9248; ∆ = 4.8 ppm.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra of compounds 14–19, 24e, 25a–g,
27a–d,f,g, 29a,b,d,g, 31, 32, 34a,b and 35a,b.
N-Alkylation. Synthesis of 2-Propyl-2H-benzo[f]isoindole-4,9-dione
(34a) and 1-Methyl-2-propyl-2H-benzo[f]isoindole-4,9-dione (34b):
Synthesis of 34a as an example. Compound 29a (50 mg, 0.25 mmol)
was added to a suspension of KOH (70 mg, 1.25 mmol) in DMF
(5 mL) . After stirring the solution for 1 h, 1-bromopropane
(43 mg, 0.35 mmol) was added. The reaction mixture was then
heated and stirred at 50 °C overnight. The resulting suspension was
poured into water and extracted with dichloromethane. The com-
bined organic layers were washed with water, dried with anhydrous
MgSO4 and filtered, and the solvent was removed in vacuo. The
crude product was purified by column chromatography on silica
gel (EtOAc/cyclohexane, 1:3; Rf = 0.16) to obtain 44 mg (74%) of
34a.
Acknowledgments
This work was financially supported by the Fund for Scientific Re-
search – Flanders (FWO – Vlaanderen).
[1] W. Ando, U. Bergsträßer, D. StC. Black, H. Heydt, B. König,
G. Maas, F. Mathey, M. Regitz, J. Schatz, N. Tokithoh, K.-P.
Zeller in Science of Synthesis (Ed.: G. Maas), Georg Thieme,
Stuttgart, New York, 2001.
[2] a) A. Sato, L. McNulty, K. Cox, S. Kim, A. Scott, K. Daniell,
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1998, 54, 4151–4202.
2-Propyl-2H-benzo[f]isoindole-4,9-dione (34a): The NMR spectro-
scopic data were in accordance with data reported in the litera-
ture.[20]
1-Methyl-2-propyl-2H-benzo[f]isoindole-4,9-dione (34b): Yield:
72%. Rf = 0.24 (EtOAc/cyclohexane, 3:2). M.p. 172.4–173.4 °C. 1H
NMR (250 MHz, [D6]DMSO): δ = 0.85 (t, J = 7.3 Hz, 3 H,
CH2CH3), 1.72 (sext, J = 7.3 Hz, 2 H, CH2CH3), 2.58 (s, 3 H,
CH3), 3.94 (t, J = 7.3 Hz, 2 H, NCH2), 7.67 (s, 1 H, 3-H), 7.73–
7.77 (m, 2 H, 6-H and 7-H), 8.04–8.09 (m, 2 H, 5-H and 8-H) ppm.
13C NMR (63 MHz, [D6]DMSO): δ = 10.6 (CH3), 10.7 (CH2CH3),
23.0 (CH2CH3), 47.9 (NCH2), 117.2 and 120.4 (Cquat), 125.1 (CH),
126.1 and 126.2 (C-5 and C-8), 133.0 and 133.2 (C-6 and C-7),
134.8 and 135.5 (Cquat), 137.0 [C(CH3)], 178.9 (C=O), 179.6 (C=O)
[3] C. W. Bird, Tetrahedron 1992, 48, 335–340.
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ppm. IR (ATR): ν = 1645, 1538, 1261, 1224, 953, 711 cm–1. MS
˜
(ES): m/z (%) = 254 (100) [M + H]+. HRMS (ESI): calcd. for
C16H15NO2 + H+ 254.1103; found 254.1113; ∆ = 3.9 ppm.
Bromination. Synthesis of 1-Bromo-3-methyl-2-propyl-2H-benzo[f]-
isoindole-4,9-dione (35b) and 1,3-Dibromo-2-propyl-2H-benzo[f]iso-
indole-4,9-dione (35a): Synthesis of 35b as an example. A solution
of bromine (33 mg, 0.21 mmol) in dichloromethane (5 mL) was
added dropwise to 34b (51 mg, 0.2 mmol) in dichloromethane
(5 mL). The reaction mixture was stirred at room temperature for
1 h. Evaporation of the solvent under vacuum gave 35b (66 mg) in
100% yield.
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J. A. S. Cavaleiro, Tetrahedron Lett. 2007, 48, 8904–8908; b)
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1-Bromo-3-methyl-2-propyl-2H-benzo[f]isoindole-4,9-dione
(35b):
1
Yield: 100%. M.p. 133–134 °C. H NMR (250 MHz, CDCl3): δ =
1.01 (t, J = 7.4 Hz, 3 H, CH2CH3), 1.78 (sext, J = 7.6 Hz, 2 H,
CH2CH3), 2.73 (s, 3 H, CH3), 3.98 (t, J = 7.3 Hz, 2 H, NCH2),
7.65–7.71 (m, 2 H, 6-H and 7-H), 8.19–8.27 (m, 2 H, 5-H and 8-
H) ppm. 13C NMR (63 MHz, CDCl3): δ = 11.1 (CH3), 11.9
(CH2CH3), 23.2 (CH2CH3), 46.7 (NCH2), 107.6 (Cquat), 118.8 and
119.3 (Cquat), 126.6 and 126.7 (C-5 and C-8), 133.0 (C-6 and C-7),
135.4 and 135.6 (Cquat), 137.6 (Cquat), 179.0 (C=O), 180.2 (C=O)
ppm. IR (ATR): ν = 1649, 1510, 1248, 1227, 1062, 968, 712 cm–1.
˜
HRMS (ESI): calcd. for C16H14BrNO2 + H+ 332.0281; found
332.0282; ∆ = 0.3 ppm.
1,3-Dibromo-2-propyl-2H-benzo[f]isoindole-4,9-dione (35a): Yield:
100%. M.p. 127.5–128.5 °C. 1H NMR (250 MHz, CDCl3): δ = 1.04
(t, J = 7.4 Hz, 3 H, CH2CH3), 1.85 (sext, J = 7.6 Hz, 2 H,
Eur. J. Org. Chem. 2009, 4882–4892
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4891

J. Deblander, S. Van Aeken, J. Jacobs, N. De Kimpe, K. Abbaspour Tehrani
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Received: May 20, 2009
Published Online: August 24, 2009
4892
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4882–4892