A simple two-step sequence for the synthesis of novel 4-aryl-4,5-dihydro- 6H-[1,3]dioxolo[4,5-h]pyrrolo[1,2-a][1]benzazepin-6-ones from 6-amino-3,4-methylenedioxyacetophenone

Article abstract of DOI:10.1002/ejoc.200800493

Herein is provided an efficient and two-step short procedure for the synthesis of novel 6H-[1,3]dioxolobenzo[4,5-h]pyrrolo[1,2-a][1]benzazepin-6-one derivatives promoted by commercial phosphoric acid. In a parallel approach some pyrrolyl chalcones were isolated that proved to behave as intermediates for the title compounds. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800493

FULL PAPER
DOI: 10.1002/ejoc.200800493
A Simple Two-Step Sequence for the Synthesis of Novel 4-Aryl-4,5-dihydro-
6H-[1,3]dioxolo[4,5-h]pyrrolo[1,2-a][1]benzazepin-6-ones from 6-Amino-3,4-
methylenedioxyacetophenone
Rodrigo Abonia,*[a] Paola Cuervo,[a] Braulio Insuasty,[a] Jairo Quiroga,[a]
Manuel Nogueras,[b] and Justo Cobo[b]
Keywords: Phosphoric acid / Michael addition / Chalcones / Cyclization / Heterocycles
Herein is provided an efficient and two-step short procedure
for the synthesis of novel 6H-[1,3]dioxolobenzo[4,5-h]pyr-
pyrrolyl chalcones were isolated that proved to behave as
intermediates for the title compounds.
rolo[1,2-a][1]benzazepin-6-one derivatives promoted by (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
commercial phosphoric acid. In a parallel approach some
Germany, 2008)
action, showed moderate activities in several in vitro assays
for adrenergic, dopaminergic and serotoninergic recep-
tors.[2a] Fluorinated compound 5 was synthesized by a 1,3-
dipolar cycloaddition domino sequence because of its po-
tential biological activity.[2b] Compounds 6 were prepared
for screening as novel and selective peripheral-type benzodi-
azepine receptor (PBR) ligands and to evaluate their ability
Introduction
The biological activity of compounds containing a modi-
fied azepine ring towards different diseases has been inten-
sively studied, both in vitro and in vivo.[1] Within this con-
text, compounds containing the benzo-pyrrolo-fused azepin
framework have gained significant attention in recent years
because of the possibility of finding it as part of naturally
occurring materials or constructing it by synthetic ap-
proaches. In both cases such structures exhibit interesting
biological activities.[2] Pyrrolo-benzazepines can exist in the
three isomeric forms 1, 2 or 3 (see Scheme 1).
Scheme 1. General structures for the three possible benzo-pyrrolo-
fused azepin systems.
Biological or synthetic modifications of any of the three
rings will originate diverse derivatives of the structures 1, 2
and 3 in varied and interesting fashions. Scheme 2 shows
some examples of such compounds. For example, com-
pounds 4, obtained through an asymmetric 1,3-dipolar re-
[a] Departamento de Química, Universidad del Valle,
A.A. 25360, Cali, Colombia
Fax: +57-2-3393248
E-mail: abonia@quimica.univalle.edu.co
[b] Departamento de Química Inorgánica y Orgánica, Universidad
de Jaén,
23071 Jaén, Spain
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Scheme 2. Some pyrrolobenzazepine derivatives of chemical and
practical interest.
4684
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4684–4689

Novel Benzo-Pyrrolo-Fused Azepin Frameworks
to modulate steroid biosynthesis in rats.[2c] Structures 7 and
Following this synthetic scheme, chalcones 13a–h were
8 were obtained from an intramolecular Schmidt reac- readily obtained from acetophenone 12 and aldehydes a–h
tion[2d] and from a Pd-catalyzed intramolecular cyclization (see Table 1) according to the procedure we described pre-
of some amides,[2e] respectively. Cephalotaxine 9 is reported viously.[3f]
as the major alkaloid found in the evergreen plum yews
Continuing with the second step and seeking to obtain
Cephalotaxus, which is indigenous in South-East Asia. the pyrrolyl chalcone intermediates 14, a mixture of chal-
Compound 9 by itself shows no pronounced biological ac- cone 13a (1 equiv.) and 2,5-dimethoxytetrahydrofuran
tivity, but its 2-alkylhydroxysuccinate, known as deoxyhar- (3 equiv.) in AcOH (5 mL, as solvent and catalyst) was
ringtonine (10), has displayed the highest IC50 value against heated at 80 °C for 1 h, according to a reported procedure
leukaemic cells.[2f–2k] Finally, compounds 11 were obtained for the synthesis of arylpyrroles.[4a] Unfortunately, this well-
by a KH-induced cyclization of thioimides in a new ap- known procedure was unsuccessful in our case and no
proach to the ABC core of cephalotaxine 9.[2l]
product was formed even after 2 h of heating.
To overcome this failed attempt, we decided to repeat the
same reaction under reflux in toluene (5 mL) with AcOH
(1.5 mL) as catalyst. This time the reaction proceeded quite
well and after complete consumption of the chalcone 13a
(TLC control), a mixture of two products was obtained and
separated by column chromatography by using a mixture of
CHCl3/AcOEt as eluent. This will be referred to as ap-
proach A (Scheme 4). Spectroscopic analysis of the isolated
compounds showed that the first eluted fraction corre-
sponded to the expected pyrrolyl chalcone 14a in 13% yield
and the second one, surprisingly, corresponded to our cy-
clized target product 15a in 37% yield.
Results and Discussion
Continuing with our studies directed towards the synthe-
sis and chemical transformation of 1-(6-amino-1,3-benzo-
dioxol-5-yl)-3-arylprop-2-en-1-ones 13,[3] we describe herein
a short two-step protocol aimed at obtaining the novel 4-
aryl-4,5-dihydro-6H-[1,3]dioxolobenzo[4,5-h]pyrrolo[1,2-a]-
[1]benzazepin-6-one of type 15, compounds closely related
to the pharmacologically active structures 6, sharing the
same ABC core.
Before beginning with the experiments, the synthesis of
the target compounds 15 was visualized according to the
retrosynthetic analysis shown in Scheme 3. A three-step se-
quence was proposed, which includes the synthesis and iso-
lation of the chalcone and pyrrolyl chalcone intermediates
13 and 14, respectively.
Scheme 4. Reaction products obtained by approach A. Reagents
and conditions: i. EtOH (15 mL), 20% NaOH (1 mL), reflux; ii.
2,5-dimethoxytetrahydrofuran (3 equiv.), toluene (5 mL), AcOH
(1.5 mL), reflux.
Taking into account the relative success of the above ap-
proach, it was extended to the other chalcones 13b–h with
similar results, that is, the formation of mixtures of both
Scheme 3. Retrosynthetic analysis of the synthesis of the target
compounds 15.
Table 1. Analytical data for intermediates 14 and products 15.
Entry
Ar
Approach A
M.p. [°C]
Approach B
% Yield of 14
% Yield of 15
% Yield of 15[a]
M.p. [°C]
a
b
c
d
e
f
p-BrC6H4
p-ClC6H4
3,4,5-(MeO)3C6H2
p-NO2C6H4
p-CF3C6H4
pyridin-3-yl
1,3-benzodioxol-5-yl
naphthalen-2-yl
13[a]
170–171
144–145
–
185–186
161–163
155–157
–
37[a]
40[a]
20[b]
27[a]
48[a]
34[a]
57[b]
50[b]
93
90
87
96
89
91
85
86
200–202
191–192
167–169
250–251
256–257
193–194
162–164
192–193
8[a]
26[b]
43[a]
29[a]
22[a]
12[b]
7[b]
g
h
–
1
[a] Isolated yield. [b] Determined by H NMR spectroscopy.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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R. Abonia et al.
FULL PAPER
compounds 14 and 15, some of them separable by column in the MS spectra of the target compounds 15 (Scheme 6).
chromatography, as shown in Table 1. According to these The loss of the aryl ring is accompanied by other common
results, the conversion process from 13 to 15 may proceed ring-contraction processes for the azepinic moiety. In this
mainly in only one step in which the chalcone 14 thus way, a decarbonylation process with the loss of 28 a.m.u.
formed could behave as an intermediate, partially cyclizing furnished the quite stable pyrroloquinolinic species 17 with
to the final product 15 in the reaction medium. Attempts relative stabilities of between 30–76%.
to complete the conversion of 14 into 15 by heating for
longer times caused the formation of resinous materials and
a lowering of the yields.
The latter results prompted us to search for a more ef-
ficient and selective procedure to chalcone intermediates 14
as the only product or, preferably, the target compounds 15
directly from chalcones 13 in a single step. After several
attempts using different reaction conditions (i.e., TsOH/
MeOH/reflux, Amberlyst-15®/AcOH/60 °C, sulfamic acid/
ACN/60 °C or microwave irradiation without solvent), we
found that when chalcones 13 were mixed with 2,5-dimeth-
oxytetrahydrofuran (3 equiv.) and gently heated at 70 °C for
about 5 min adding a drop of 85% H3PO4, compounds 15
were obtained as unique products (TLC control) in excel-
lent yields, as depicted in Scheme 5 and Table 1. This will
be referred to as approach B.
Scheme 6. Main MS fragmentations for compounds 15.
Finally, to confirm the above assertion that chalcones 14
behave as intermediates for compounds 15, a sample of the
isolated compound 14a (0.2 g) and a drop of 85% H3PO4
were heated at 70 °C for 3 min. In this way compound 15a
was readily obtained in quantitative yield, as depicted in
Scheme 7.
Scheme 5. Direct synthesis of the target compounds 15 by pro-
cedure B. Reagents and conditions: ii. 2,5-dimethoxytetra-
hydrofuran (3 equiv.), 85% H3PO4 (1 drop), 70 °C, 5 min.
All the obtained pyrrolyl chalcones 14 were yellow solids,
pyrrolobenzazepines 15 were pale-yellow solids, whereas the
starting chalcones 13 were orange-to-dark-red solids. These
characteristics permitted us to follow the reaction progress
easily by TLC and to check the purity of compounds 14
and 15. All compounds 14 and 15 were fully characterized
Scheme 7. Synthesis of target compound 15a from chalcone inter-
mediate 14a. Reagents and conditions: i. 2,5-dimethoxytetra-
hydrofuran (3 equiv.), toluene (5 mL), AcOH (1.5 mL), reflux; ii.
1
by analytical and spectroscopic methods (IR, H and 13C
NMR, elemental analysis and MS). The main characteristic 85% H3PO4 (1 drop), 70 °C, 3 min.
of the IR spectra of both 14 and 15 is the lack of NH2
absorption bands. This agrees with their assigned struc-
According to Scheme 7 the conversion of intermediates
tures. It is relevant that the 1H NMR spectra of compounds 14 into the target compounds 15 occurred by an intramo-
14 show two sets of doublets at 6.11–6.23 and 7.27– lecular Michael-type addition from the 2-position of the
7.34 ppm with coupling constants of 15.7–16.4 Hz, which pyrrolyl moiety towards the β-carbon atom of the α,β-un-
correspond to the vinylic protons of the α,β-unsaturated saturated chalcone moiety in 14. At this point it is worth
moiety. There are also two additional sets of signals at 6.15– mentioning that like other authors,[4a–4d] we have previously
6.17 and 6.89–6.92 ppm assigned to the four protons of the reported[4e] the utility of the pronounced nucleophilic char-
new pyrrole ring formed. For compounds 15, the most rel- acter of the 2-position of the pyrrolyl moiety in the inter-
1
evant feature in the H NMR spectra is the disappearance molecular formation of diverse six- and seven-membered
of the signals corresponding to the α,β-unsaturated moiety rings mediated by Mannich-type reactions. However, we are
protons, whilst the appearance of three new aliphatic sets not aware of other reports that describe the involvement of
of doublet of doublets at 3.03–3.29, 3.35–3.56 and 4.36– this pyrrolyl moiety in the formation of the above rings by
4.73 ppm support the AMX system of the new azepinic ring an intramolecular Michael-type addition, with the excep-
formed. A set of three signals at 5.37–5.61, 6.11–6.19 and tion of one report in which some pyrrolohydropyridine in-
6.90–7.19 ppm for the now 2-substituted pyrrolyl moiety is termediates were obtained in the total synthesis of (–)-tashi-
also consistent with the proposed structure. On the other romine.[5] Thus these results provide new and useful syn-
hand, loss of the Ar ring leads to the typical base peak 16 thetic possibilities for the widely studied pyrrole chemistry.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4684–4689

Novel Benzo-Pyrrolo-Fused Azepin Frameworks
(OCH2O) cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 6.11 (d, J
= 15.8 Hz, 1 H, 6-H), 6.15 (t, J = 2.2 Hz, 2 H, 9-H), 6.19 (s, 2 H,
2-H), 6.89 (t, J = 2.2 Hz, 2 H, 8-H), 7.13 (br. s, 2 H, 4-H and 10-
H), 7.27 (d, J = 16.1 Hz, 1 H, 7-H), 7.41 (br. d, 4 H, Ar-H) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 102.6 (OCH2O), 106.7,
108.1, 110.2 (C-9), 122.8 (C-8), 124.6 (C-6), 128.6, 128.7, 129.9,
133.5, 134.7, 135.1, 140.5 (C-7), 146.8, 150.3, 190.6 (C=O) ppm.
MS (70 eV, EI): m/z (%) = 351/353 (85/28) [M]+, 322/324 (28/9),
212 (85). C20H14ClNO3 (351.78): calcd. C 68.28, H 4.01, N 3.98;
found C 68.43, H 3.87, N 4.07.
Conclusions
We have implemented an efficient and selective procedure
for the synthesis of novel 6H-[1,3]dioxolobenzo[4,5-h]pyr-
rolo[1,2-a][1]benzazepin-6-one-11-one derivatives 15 in high
yields from a short two-step sequence promoted by com-
mercial phosphoric acid. In this approach, pyrrolyl chal-
cones 14 were proven to behave as intermediates for com-
pounds 15. To the best of our knowledge, this is the first
report involving an intramolecular Michael-type addition
mediated by a pyrrolyl moiety for the construction of pyr-
rolo-azepin frameworks. The commercial availability of nu-
merous benzaldehydes, along with some amino ketones 12,
confers a general character on this method that allows li-
braries of azepins 15 to be constructed for structure–ac-
tivity relationship studies.
3-(p-Nitrophenyl)-1-[6-(pyrrol-1-yl)-1,3-benzodioxol-5-yl]prop-2-en-
1-one (14d): Yield 90 mg. IR (KBr): ν = 1656 (C=O), 1511, 1341
˜
(NO2), 1253 (OCH2O) cm–1. 1H NMR (400 MHz, [D6]DMSO): δ
= 6.15 (t, J = 2.1 Hz, 2 H, 9-H), 6.21 (s, 2 H, 2-H), 6.23 (d, J =
16.3 Hz, 1 H, 6-H), 6.92 (t, J = 2.06 Hz, 2 H, 8-H), 7.17 (s, 1 H,
10-H), 7.18 (s, 1 H, 4-H), 7.34 (d, J = 15.9 Hz, 1 H, 7-H), 7.64 (d,
J = 8.7 Hz, 2 H, Ar-H), 8.15 (d, J = 8.7 Hz, 2 H, Ar-H) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 102.7 (OCH2O), 106.7, 108.1,
110.4 (C-9), 122.9 (C-8), 123.8, 127.4 (C-6), 128.6, 129.1, 135.3,
138.5 (C-7), 141.1, 146.8, 147.7, 150.6, 190.5 (C=O) ppm. MS
(70 eV, EI): m/z (%) = 362 (100) [M]+, 333 (26), 212 (91).
Experimental Section
General: Melting points were determined on a Büchi melting point
apparatus and are uncorrected. IR spectra were recorded with a
Shimadzu FTIR 8400 on KBr disks. 1H and 13C NMR spectra
were recorded with Bruker 500, AMX 400, DPX 300 and Varian
Gemini 200 instruments; chemical shifts (δ) are reported in ppm
relative to internal tetramethylsilane and coupling constants in Hz.
CDCl3 and [D6]DMSO were used as solvents. Silica gel plates
(Merck F254) were used for analytical TLC. Mass spectra were re-
corded with Varian Model MAT MS-311 and SHIMADZU-
C
20H14N2O5 (362.34): calcd. C 66.30, H 3.89, N 7.73; found C
66.13, H 3.97, N 7.88.
1-[6-(Pyrrol-1-yl)-1,3-benzodioxol-5-yl]-3-[p-(trifluoromethyl)phen-
yl]prop-2-en-1-one (14e): IR (KBr): ν˜ = 1654 (C=O), 1241
(OCH2O) cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 6.16 (s, 2
H, 2-H), 6.17 (t, J = 2.2 Hz, 2 H, 9-H), 6.19 (d, J = 16.2 Hz, 1 H,
6-H), 6.92 (t, J = 2.2 Hz, 2 H, 8-H), 7.16 (br. s, 2 H, 4-H and 10-
H), 7.34 (d, J = 15.9 Hz, 1 H, 7-H), 7.59 (d, J = 8.0 Hz, 2 H, Ar-
GCMS 2010-DI-2010 spectrometers at 70 eV. Microanalyses were H), 7.68 (d, J = 8.2 Hz, 2 H, Ar-H) ppm. 13C NMR (75 MHz, [D6]
performed with a LECO CHNS-932 elemental analyzer and the
values are within Ϯ0.4% of the theoretical values. The starting 2,5-
dimethoxytetrahydrofuran, aldehydes a–h and 6-amino-3,4-methyl-
enedioxyacetophenone (12) were purchased from Aldrich, Fluka
and Acros (analytical reagent grades) and were used without fur-
ther purification.
DMSO): δ = 102.7 (OCH2O), 106.7, 108.1, 110.4 (C-9), 122.9 (C-
8), 126.3 (C-6), 128.4, 128.8, 129.0, 135.3, 138.6, 139.6 (C-7), 146.8,
145.6, 150.5, 190.6 (C=O) ppm. MS (70 eV, EI): m/z (%) = 385
(100) [M]+, 357 (54), 212 (83). C21H14F3NO3 (385.34): calcd. C
65.46, H 3.66, N 3.63; found C 65.56, H 3.75, N 3.54.
3-(Pyridin-3-yl)-1-[6-(pyrrol-1-yl)-1,3-benzodioxol-5-yl]prop-2-en-1-
one (14f): Yield 40 mg. IR (KBr): ν˜ = 1657 (C=O), 1239
(OCH2O) cm–1. 1H NMR (500 MHz, [D6]DMSO): δ = 6.15 (t, J =
2.1 Hz, 2 H, 9-H), 6.20 (s, 2 H, 2-H), 6.23 (d, J = 15.9 Hz, 1 H, 6-
H), 6.91 (t, J = 2.1 Hz, 2 H, 8-H), 7.15 (s, 1 H, 10-H), 7.16 (s, 1
H, 4-H), 7.31 (d, J = 16.0 Hz, 1 H, 7-H), 7.35 (dd, J = 7.3, 4.8 Hz,
1 H, Py-H), 7.76 (dd, J = 8.0, 1.6 Hz, 1 H, Py-H), 8.50 (dd, J =
4.8, 1.6 Hz, 1 H, Py-H), 8.57 (s, 1 H, Py-H) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 102.7 (OCH2O), 106.7, 108.1, 110.2
(C-9), 122.9 (C-8), 123.7, 125.6 (C-6), 128.5, 130.3, 134.5, 135.2,
138.3 (C-7), 146.8, 149.7, 150.4, 150.6, 190.5 (C=O) ppm. MS
(70 eV, EI): m/z (%) = 318 (83) [M]+, 289 (37), 212 (100).
C19H14N2O3 (318.33): calcd. C 71.69, H 4.43, N 8.80; found C
71.90, H 4.57, N 8.66.
General Procedure for the Synthesis of Mixtures of Compounds 14
and 15. Approach A: By gentle warming, chalcone 13 (0.58 mmol)
was dissolved in toluene (5 mL) and then 2,5-dimethoxytetra-
hydrofuran (1.74 mmol) and AcOH (1.5 mL) were added. The mix-
ture was heated at reflux for 2 h until no presence of the starting
chalcone 13 was detected (monitored by TLC). Removal of the
solvent under reduced pressure afforded the crude product, which
was purified by column chromatography on silica gel by using a
mixture of CHCl3/AcOEt (5:1) as eluent. The first chromatographic
fraction corresponded to compound 14 in all cases and the second
one corresponded to compound 15.
3-(p-Bromophenyl)-1-[6-(pyrrol-1-yl)-1,3-benzodioxol-5-yl]prop-2-
en-1-one (14a): Yield 30 mg. IR (KBr): ν = 1650 (C=O), 1237
˜
(OCH2O) cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 6.12 (d, J
= 15.9 Hz, 1 H, 6-H), 6.15 (t, J = 2.2 Hz, 2 H, 9-H), 6.19 (s, 2 H,
2-H), 6.89 (t, J = 2.2 Hz, 2 H, 8-H), 7.13 (br. s, 2 H, 4-H and 10-
H), 7.27 (d, J = 15.9 Hz, 1 H, 7-H), 7.33 (d, J = 8.6 Hz, 2 H, Ar-
General Procedure for the Direct Synthesis of Compounds 15. Ap-
proach B: A mixture of chalcone 13 (0.58 mmol), 2,5-dimethoxyte-
trahydrofuran (1.74 mmol) and H3PO4 (85%, 1 drop) was gently
heated at 70 °C for 5 min. After no presence of chalcone 13 was
H), 7.52 (d, J = 8.6 Hz, 2 H, Ar-H) ppm. 13C NMR (100 MHz, detected (TLC control), the reaction mixture was cooled to room
[D6]DMSO): δ = 102.7 (OCH2O), 106.7, 108.1, 110.2 (C-9), 122.8 temperature, aq. NaHCO3 (10%, 5 mL) was added and the mixture
(C-8), 123.5, 124.6 (C-6), 128.6, 130.1, 131.7, 133.8, 135.1, 140.5
extracted with AcOEt (3 ϫ 5 mL). The combined extracts were
(C-7), 146.8, 152.0, 190.6 (C=O) ppm. MS (70 eV, EI): m/z (%) =
dried with anh. Na2SO4 and the solvent was removed under vac-
395/397 (28/27) [M]+, 366/367 (31/30), 212 (83). C20H14BrNO3 uum. The crudes thus obtained were purified by column
(396.23): calcd. C 60.62, H 3.56, N 3.53; found C 60.50, H 3.67, N
3.45.
chromatography on silica gel and DCM as eluent to yield com-
pounds 15 as unique products.
3-(p-Chlorophenyl)-1-[6-(pyrrol-1-yl)-1,3-benzodioxol-5-yl]prop-2-
4-(p-Bromophenyl)-4,5-dihydro-6H-[1,3]dioxolobenzo[4,5-h]pyrrolo-
en-1-one (14b): Yield 16 mg. IR (KBr): ν = 1652 (C=O), 1239 [1,2-a][1]benzazepin-6-one (15a): Yield 213 mg. IR (KBr): ν = 1665
˜
˜
Eur. J. Org. Chem. 2008, 4684–4689
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4687

R. Abonia et al.
FULL PAPER
(C=O), 1251 (OCH2 O) cm– 1
.
1 H NMR (400 MHz, [D6 ]- 7.33 (d, J = 8.2 Hz, 2 H, Ar-H), 7.61 (d, J = 8.2 Hz, 2 H, Ar-
DMSO): δ = 3.05 (dd, J = 2.7, 18.8 Hz, 1 H, 5-H), 3.42 (dd, J =
11.4, 18.8 Hz, 1 H, 5-H), 4.49 (dd, J = 2.1, 11.4 Hz, 1 H, 4-H), 102.4 (OCH2O), 104.4, 107.6, 109.2, 109.8, 121.6, 125.2, 125.5,
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 37.9 (C-4), 50.3 (C-5),
5.43 (br. s, 1 H, 3-H), 6.12 (t, J = 3.3 Hz, 1 H, 2-H), 6.16 (s, 2 H,
125.6, 128.3, 129.4, 135.2, 135.5, 143.9, 145.9, 152.4, 199.1
9-H), 7.08 (s, 1 H, 11-H), 7.12 (s, 1 H, 7-H), 7.16 (t, J = 2.9 Hz, 1 (C=O) ppm. MS (70 eV, EI): m/z (%) = 385 (52) [M]+, 357 (58) [M –
H, 1-H), 7.28 (d, J = 8.5 Hz, 2 H, Ar-H), 7.51 (d, J = 8.5 Hz, 2 H, CO]+, 240 (100) [M – C7H4F3]+. C21H14F3NO3 (385.34): calcd. C
Ar-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 36.6 (C-4), 50.2
(C-5), 102.7 (OCH2O), 104.5, 107.2, 108.2, 109.3, 119.9, 121.9,
124.9, 130.3, 131.2, 134.4, 135.4, 139.7, 145.5, 152.0, 199.3
(C=O) ppm. MS (70 eV, EI): m/z (%) = 395/397 (27/28) [M]+, 367/
369 (31/30) [M – CO]+, 240 (100) [M – C6H4Br]+. C20H14BrNO3
(396.23): calcd. C 60.62, H 3.56, N 3.53; found C 60.44, H 3.67, N
3.41.
65.46, H 3.66, N 3.63; found C 65.54, H 3.73, N 3.52.
4-(Pyridin-3-yl)-4,5-dihydro-6H-[1,3]dioxolobenzo[4,5-h]-
pyrrolo[1,2-a][1]benzazepin-6-one (15f): Yield 168 mg. IR (KBr): ν
˜
= 1665 (C=O), 1251 (OCH2O) cm–1. 1H NMR (400 MHz, [D6]-
DMSO): δ = 3.09 (dd, J = 2.7, 18.8 Hz, 1 H, 5-H), 3.49 (dd, J =
11.7, 18.8 Hz, 1 H, 5-H), 4.60 (dd, J = 2.4, 11.8 Hz, 1 H, 4-H),
5.37 (br. s, 1 H, 3-H), 6.12 (t, J = 3.13 Hz, 1 H, 2-H), 6.18 (d, J =
1.6 Hz, 2 H, 9-H), 7.10 (s, 1 H, 11-H), 7.13 (s, 1 H, 7-H), 7.18 (t,
J = 2.4 Hz, 1 H, 1-H), 7.38 (dd, J = 7.8, 4.7 Hz, 1 H, Py-H), 7.80
(td, J = 8.0, 1.8 Hz, 1 H, Py-H), 8.47 (dd, J = 4.7, 1.6 Hz, 1 H, Py-
H), 8.52 (d, J = 2.2 Hz, 1 H, Py-H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 34.9 (C-4), 50.0 (C-5), 102.7 (OCH2O), 104.5,
107.2, 108.2, 109.4, 122.0, 123.4, 125.1, 134.2, 135.3, 135.5, 135.8,
145.5, 148.2, 149.4, 152.0, 199.4 (C=O) ppm. MS (70 eV, EI): m/z
(%) = 318 (80) [M]+, 290 (76) [M – CO]+, 240 (100) [M –
C5H4N]+. C19H14N2O3 (318.33): calcd. C 71.69, H 4.43, N 8.80;
found C 71.59, H 4.38, N 8.92.
4-(p-Chlorophenyl)-4,5-dihydro-6H-[1,3]dioxolobenzo[4,5-h]pyrrolo-
[1,2-a][1]benzazepin-6-one (15b): Yield 183 mg. IR (KBr): ν = 1665
˜
(C=O), 1250 (OCH2O) cm–1. 1H NMR (200 MHz, CDCl3): δ =
3.14 (dd, J = 2.6, 18.7 Hz, 1 H, 5-H), 3.38 (dd, J = 11.4, 18.7 Hz,
1 H, 5-H), 4.41 (dd, J = 2.2, 11.4 Hz, 1 H, 4-H), 5.53 (br. s, 1 H,
3-H), 6.06 (s, 2 H, 9-H), 6.17 (t, J = 3.2 Hz, 1 H, 2-H), 6.78 (s, 1
H, 11-H), 6.90 (t, J = 2.4 Hz, 1 H, 1-H), 7.18 (d, J = 8.6 Hz, 2 H,
Ar-H), 7.27 (s, 1 H, 7-H), 7.30 (d, J = 8.6 Hz, 2 H, Ar-H) ppm.
13C NMR (50 MHz, CDCl3): δ = 37.4 (C-4), 50.5 (C-5), 102.3
(OCH2O), 104.3, 107.4, 109.1, 109.7, 121.4, 125.2, 128.6, 129.2,
132.8, 135.1, 136.0, 138.3, 145.8, 152.3, 199.3 (C=O) ppm. MS
(70 eV, EI): m/z (%) = 351/353 (62/21) [M]+, 323/325 (50/17) [M –
CO]+, 240 (100) [M – C6H4Cl]+. C20H14ClNO3 (351.78): calcd. C
68.28, H 4.01, N 3.98; found C 68.46, H 4.22, N 4.00.
4-(1,3-Benzodioxol-5-yl)-4,5-dihydro-6H-[1,3]dioxolobenzo[4,5-h]pyr-
rolo[1,2-a][1]benzazepin-6-one (15g): Yield 178 mg. IR (KBr): ν =
˜
1667 (C=O), 1248 (OCH2O) cm–1. 1H NMR (200 MHz, CDCl3): δ
= 3.14 (dd, J = 2.8, 18.7 Hz, 1 H, 5-H), 3.35 (dd, J = 11.4, 18.9 Hz,
1 H, 5-H), 4.36 (dd, J = 2.6, 11.4 Hz, 1 H, 4-H), 5.59–5.62 (m, 1
H, 3-H), 5.95 (s, 2 H, 9-H), 6.06 (s, 2 H, 9-H), 6.18 (t, J = 3.4 Hz,
1 H, 2-H), 6.72 (br. d, 1 H), 6.75 (br. d, 1 H), 6.76 (s, 1 H), 6.79
(s, 1 H, 11-H), 6.90 (t, J = 2.3 Hz, 1 H, 1-H), 7.29 (s, 1 H, 7-
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 37.7 (C-4), 50.9 (C-5),
100.9 (OCH2O), 102.3 (OCH2O), 104.3, 107.3, 108.1, 108.4, 109.1,
109.6, 120.9, 121.2, 125.2, 133.6, 135.2, 136.6, 145.7, 146.4, 147.6,
152.2, 199.6 (C=O) ppm. MS (70 eV, EI): m/z (%) = 361 (61)
[M]+, 333 (48) [M – CO]+, 240 (100) [M – C7H5O2]+. C21H15NO5
(361.35): calcd. C 69.80, H 4.18, N 3.88; found C 69.97, H 4.12, N
4.02.
4-(3,4,5-Trimethoxyphenyl)-4,5-dihydro-6H-[1,3]dioxolobenzo[4,5-h]-
pyrrolo[1,2-a][1]benzazepin-6-one (15c): Yield 205 mg. IR (KBr): ν
˜
= 1667 (C=O), 1251 (OCH2O) cm–1. 1H NMR (400 MHz, [D6]-
DMSO): δ = 3.03 (dd, J = 2.7, 18.8 Hz, 1 H, 5-H), 3.46 (dd, J =
12.2, 19.0 Hz, 1 H, 5-H), 3.64 (s, 3 H, OCH3), 3.72 (s, 6 H,
OCH3 ϫ2), 4.44 (dd, J = 2.1, 12.0 Hz, 1 H, 4-H), 5.52 (br. s, 1 H,
3-H), 6.11 (t, J = 3.1 Hz, 1 H, 2-H), 6.18 (s, 2 H, 9-H), 6.66 (s, 2
H), 7.10 (s, 1 H, 11-H), 7.13 (s, 1 H, 7-H), 7.14 (t, J = 3.3 Hz, 1
H, 1-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 37.6 (C-4),
50.9 (C-5), 55.8, 59.9, 102.6 (OCH2O), 104.5, 105.6, 107.1, 108.2,
109.3, 121.6, 125.3, 134.3, 135.9, 135.9, 136.2, 145.5, 151.9, 152.7,
200.0 (C=O) ppm. MS (70 eV, EI): m/z (%) = 407 (100) [M]+, 379
(39) [M – CO]+, 240 (43) [M – C9H11O3]+. C23H21NO6 (407.42):
calcd. C 67.80, H 5.20, N 3.44; found C 67.74, H 5.31, N 3.27.
4-(Naphthalen-2-yl)-4,5-dihydro-6H-[1,3]dioxolobenzo[4,5-h]pyrrolo-
[1,2-a][1]benzazepin-6-one (15h): Yield 183 mg. IR (KBr): ν = 1666
˜
(C=O), 1251 (OCH2O) cm–1. 1H NMR (200 MHz, CDCl3): δ =
3.29 (dd, J = 2.8, 18.9 Hz, 1 H, 5-H), 3.56 (dd, J = 11.6, 18.9 Hz,
1 H, 5-H), 4.62 (dd, J = 2.4, 11.8 Hz, 1 H, 4-H), 5.53–5.55 (m, 1
H, 3-H), 6.08 (s, 2 H, 9-H), 6.18 (t, J = 3.2 Hz, 1 H, 2-H), 6.83 (s,
1 H, 11-H), 6.93 (t, J = 2.4 Hz, 1 H, 1-H), 7.31 (s, 1 H, 7-H), 7.31
(s, 1 H, 7-H), 7.39–7.50 (m, 3 H), 7.71–7.85 (m, 4 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 38.1 (C-4), 50.7 (C-5), 102.3
(OCH2O), 104.4, 107.6, 109.2, 109.7, 121.3, 125.4, 125.8, 126.0,
126.4, 127.5, 127.7, 128.1, 132.5, 133.3, 136.5, 137.3, 145.8, 152.3,
200.0 (C=O) ppm. MS (70 eV, EI): m/z (%) = 367 (51) [M]+, 339
(72) [M – CO]+, 240 (100) [M – C10H7]+. C24H17NO3 (367.4): calcd.
C 78.46, H 4.66, N 3.81; found C 78.60, H 4.53, N 3.93.
4-(p-Nitrophenyl)-4,5-dihydro-6H-[1,3]dioxolobenzo[4,5-h]pyrrolo-
[1,2-a][1]benzazepin-6-one (15d): Yield 202 mg. IR (KBr): ν = 1666
˜
(C=O), 1350, 1520 (NO2), 1249 (OCH2O) cm–1 1H NMR
.
(400 MHz, [D6]DMSO): δ = 3.12 (dd, J = 2.7, 18.6 Hz, 1 H, 5-H),
3.52 (dd, J = 11.2, 18.8 Hz, 1 H, 5-H), 4.73 (dd, J = 2.1, 11.2 Hz,
1 H, 4-H), 5.45 (br. s, 1 H, 3-H), 6.14 (t, J = 3.3 Hz, 1 H, 2-H),
6.16 (s, 2 H, 9-H), 7.10 (s, 1 H, 11-H), 7.13 (s, 1 H, 7-H), 7.19 (t,
J = 2.9 Hz, 1 H, 1-H), 7.61 (d, J = 8.7 Hz, 2 H, Ar-H), 8.18 (d, J
= 8.9 Hz, 2 H, Ar-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
37.0 (C-4), 49.8 (C-5), 102.7 (OCH2O), 104.5, 107.4, 108.2, 109.4,
122.2, 123.4, 125.0, 129.4, 134.3, 134.7, 145.5, 146.4, 148.2, 152.0,
199.0 (C=O) ppm. MS (70 eV, EI): m/z (%) = 362 (52) [M]+, 334
(66) [M – CO]+, 240 (100) [M – C6H4NO2]+. C20H14N2O5 (362.34):
calcd. C 66.30, H 3.89, N 7.73; found C 66.48, H 3.73, N 7.85.
Supporting Information (see also the footnote on the first page of
this article): All 1H, 13C and DEPT spectra for compounds 14 and
15.
4-[p-(Trifluoromethyl)phenyl]-4,5-dihydro-6H-[1,3]dioxolobenzo[4,5-h]-
pyrrolo[1,2-a][1]benzazepin-6-one (15e): Yield 199 mg. IR (KBr): ν
˜
= 1665 (C=O), 1253 (OCH2O) cm–1. 1H NMR (200 MHz, CDCl3):
δ = 3.18 (dd, J = 2.6, 18.7 Hz, 1 H, 5-H), 3.44 (dd, J = 11.0,
18.7 Hz, 1 H, 5-H), 4.52 (dd, J = 2.1, 11.4 Hz, 1 H, 4-H), 5.51 (br.
s, 1 H, 3-H), 6.08 (s, 2 H, 9-H), 6.19 (t, J = 3.2 Hz, 1 H, 2-H), 6.81
(s, 1 H, 11-H), 6.93 (t, J = 2.4 Hz, 1 H, 1-H), 7.29 (s, 1 H, 7-H),
Acknowledgments
R. A. thanks the Fundación para la Promoción de la Investigación
y la Tecnología (Banco de la República) and the Universidad del
Valle for financial support. P. C. thanks COLCIENCIAS for a doc-
4688
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4684–4689

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Técnicos de la Universidad de Jaén for financial support.
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Received: May 20, 2008
Published Online: August 15, 2008
Eur. J. Org. Chem. 2008, 4684–4689
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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