Scaffold preparation and parallel synthesis of arrays of 5,6,7,8-tetrahydropyrrolo-azepinones in the solution phase

Article abstract of DOI:10.1002/ejoc.200701024

An efficient synthesis of a pyrrolo-azepine scaffold for the parallel preparation of an array of (oxo-pyrrolo-azepinyl)-acetamides is described. The Stetter cyclisation of 1,3-cyclohexanedione with ethyl bromopyruvate was the key reaction in the assembly of a tetrahydrobenzofuran substrate which was submitted to a rapid transformation into a tetrahydroindole by microwave-assisted cyclocondensation in the presence of glycine. The carbonyl group was then stereoselectively transformed into the corresponding (Z)-oxime which gave the pyrrolo-azepinone by Beckmann rearrangement in the presence of polyphosphoric acid. Trimethylaluminiummediated amidation gave the corresponding amides which were finally N-alkylated at the 5-position to give 52 diverse (pyrrolo-azepinyl)acetamides, showing an appreciable exploration of the chemical space around the central heterocyclic core. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701024

FULL PAPER
DOI: 10.1002/ejoc.200701024
Scaffold Preparation and Parallel Synthesis of Arrays of
5,6,7,8-Tetrahydropyrrolo-azepinones in the Solution Phase
Leonarda Piras,[a] Eva Genesio,[b] Chiara Ghiron,[b] and Maurizio Taddei*[a]
Keywords: Combinatorial chemistry / Heterocycles / Microwaves / Ring expansion / Amidation
An efficient synthesis of a pyrrolo-azepine scaffold for the
parallel preparation of an array of (oxo-pyrrolo-azepinyl)-
acetamides is described. The Stetter cyclisation of 1,3-cyclo-
hexanedione with ethyl bromopyruvate was the key reaction
in the assembly of a tetrahydrobenzofuran substrate which
was submitted to a rapid transformation into a tetrahydroin-
dole by microwave-assisted cyclocondensation in the pres-
ence of glycine. The carbonyl group was then stereoselec-
tively transformed into the corresponding (Z)-oxime which
gave the pyrrolo-azepinone by Beckmann rearrangement in
the presence of polyphosphoric acid. Trimethylaluminium-
mediated amidation gave the corresponding amides which
were finally N-alkylated at the 5-position to give 52 diverse
(pyrrolo-azepinyl)acetamides, showing an appreciable ex-
ploration of the chemical space around the central heterocy-
clic core.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
from 1-substituted-6,7-dihydroindol-4(5H)-one (II).[10] This
compound is reported[11] to be available from 6,7-dihydro-
benzofuran-4(5H)-one (III) (Scheme 1). The main limita-
tions preventing extensive application of this last transfor-
mation are the harsh conditions required, typically heating
at 150 °C for 12–24 hours in a Carius tube. However, confi-
dent that microwave irradiation could be employed to ob-
tain 6,7-dihydroindol-4(5H)-ones and all other intermedi-
ates requiring long-term heating more easily, we decided to
study the general synthesis of compounds of type II and
their transformation into the azepine scaffold I. The intro-
duction of an R1 group suitable for further functionali-
sation allows the solution-phase synthesis of an array of
azepines based on scaffold I with a diverse range of substit-
uents in the 1- and 5-positions.
Introduction
Combinatorial synthesis of small molecules is a powerful
tool for the identification of new lead compounds for drug
discovery.[1] One possible library design is based on building
a central core scaffold carrying different functional groups
that can be further decorated. The choice of a rigid scaffold
in which substituents point in well-defined directions is
often important for biological activity and establishes the
nature of the library. The possibility of accessing new scaf-
folds allows the preparation of original proprietary and pat-
entable libraries that can be used in high-throughput
screening.
Amongst the broad range of templates available, hetero-
cyclic molecules represent one of the most utilised scaffolds
for the discovery of biologically active compounds.[2] Pyr-
rolo-azepines and pyrrolo-benzoazepines have been re-
ported to display biological activity as cytotoxic,[3] H1 anti-
histaminic,[4] as well as antihypertensive and antiplatelet ag-
gregation agents.[5] They can also be considered peptidomi-
metic scaffolds[6] and some natural products containing this
moiety have been isolated.[7] In spite of their evident bio-
logical interest, not many combinatorial approaches to this
family of molecules have been described in the literature.[8]
As one of the most efficient procedures for preparing
benzoazepines involves the Beckman rearrangement of tet-
ralone-derived oximes,[9] we decided to investigate the pos-
sibility of preparing the pyrrolo-azepine scaffold I starting
Scheme 1. General scheme for the preparation of the pyrrolo-azep-
ine scaffold.
Results and Discussion
Amongst the several possible methods for the prepara-
tion of dihydrobenzofurans of general formula III, we chose
the Stetter cyclocondensation starting from 1,3-cyclohexa-
nedione (1).[11] Reaction with ethyl bromopyruvate in
MeOH/KOH afforded compound 5 probably via intermedi-
[a] Dipartimento Farmaco Chimico Tecnologico, Università degli
Studi di Siena,
Via A. Moro 2, 53100 Siena, Italy
E-mail: taddei.m@unisi.it
[b] Siena Biotech SpA,
Via Fiorentina 1, 53100 Siena, Italy
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ates 3 and 4 (Scheme 2). Although isolable, compound 5
was directly transformed into 2 by acidifying the reaction
mixture and heating it at reflux.[12] After this two-step/one-
pot reaction, compound 2 was isolated as a white solid in
80% overall yield.
Scheme 2. Preparation of dihydrobenzofuran-3-carboxylic acid.
Transformation of 2 into pyrrole 6 is reported to take
place by heating benzofuran 2 in the presence of ammo-
nium hydroxide in a sealed tube for 12 hours (Scheme 3).[13]
Analogously, the preparation of several 1-substituted tetra-
hydroindol-4-ones by heating furan 2 at 100 °C in the pres-
Scheme 3.
Attempts to transform acid 8 into oxime 11 proved suc-
ence of different amines as solvent has been described.[14] cessful using hydroxylamine hydrochloride and AcONa
With the goal of introducing a carboxylic group into the 1- (Scheme 4).[16] Beckmann rearrangement of product 11 was
position to allow further functionalisation, we explored the attempted under different reaction conditions. Mildly acidic
possibility of using glycine as the amine in the cycloconden- conditions did not give any results,[17] whereas the starting
sation step. Following our experience in the field,[15] we material (TLC analysis) totally disappeared on addition of
found that the expected reaction occurred rapidly by micro- 11 to polyphosphoric acid (PPA) at 120 °C and by stirring
wave irradiation of a mixture of 2 and glycine ethyl ester the mixture at this temperature for 15 min. Pyrrolo-azepine-
hydrochloride in EtOH/H2O (5:1). However, the product carboxylic acid 12 was obtained in high conversion (all the
obtained after heating the mixture in a sealed tube at starting material was consumed after 15 min), but in poor
120 °C for 8 min was a mixture of ester 7 and acid 8. We isolated yields. The highly hydrophilic character of acid 12
tried to change the reaction conditions in order to prevent probably prevents its complete extraction from the PPA
decarboxylation at the 3-position and to reduce the extent solution. Acid neutralisation and saturation of the aqueous
of the hydrolysis, but unfortunately we were not able to stop phase with sodium chloride did not improve the extraction
the decarboxylation or to achieve the required cycloconden- efficiency. Although the isolation of acid 12 would probably
sation to furnish ester 7 in acceptable yields.
be possible by continuous liquid–liquid extraction, we tried
As compound 7 could not be isolated in appreciable to bypass the problem by bringing forward the amide for-
yields, we modified the reaction conditions, focusing on the mation step in the synthetic scheme. Thus, in an initial trial,
preparation of acid 8. Thus, compound 2 was treated with acid 8 was coupled with isobutylamine with DMTMM[18]
glycine ethyl ester hydrochloride in the presence of as the coupling agent to produce amide 13 in 78% isolated
4.5 equiv. of NaOH and with a higher amount of water in yield. From this amide, oxime 14 was obtained in good
the solvent system. Microwave-assisted heating for 10 min- yield with hydroxylamine hydrochloride in the presence of
utes at 120 °C exclusively afforded compound 8 which was AcONa.
isolated in 80% yield after acidification of the reaction mix-
Compound 14 was submitted to a Beckmann rearrange-
ture and extraction with AcOEt. Unfortunately, when we ment under the same conditions as those used for 11. Un-
tried to increase the scope of substitution at the 1-position fortunately, in this case we observed two spots by TLC that,
by reacting 2 with phenylalanine ethyl ester, partial hydroly- when isolated, turned out to be the two isomeric pyrrolo-
sis of the ethyl ester followed by decarboxylation was ob- azepines 15 and 16 (15 and 20% isolated yields, respec-
served, giving predominantly compound 10 (Scheme 3).
tively).
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Scaffold Preparation of Tetrahydropyrrolo-azepinones
Scheme 5. Reagents and conditions: a) SOCl2, MeOH, reflux, 2 h;
b) PPA, 120 °C, 15 min; c) NaOH, MeOH/H2O.
Ester 18 was then hydrolysed to form 12 in a very good
yield [45% overall yield from (Z)-9]. Unfortunately, this
acid proved very unreactive towards coupling with second-
ary amines. The use of a variety of coupling agents (DMTT,
DCC, EDC or PyBOP) in the reaction of 12 with N-methyl-
piperazine led to the recovery of the starting material.[21]
Direct aminolysis of ester 18 mediated by Me3Al was
Scheme 4. Reagents and conditions: a) NH2OH·HCl, AcONa,
MeOH/H2O, room temp., 24 h; b) PPA, 120 °C, 15 min; c)
Me2CHCH2NH2, DMTMM, NMM, THF, room temp., 12 h.
Given the stereospecificity of the Beckmann rearrange-
ment, this outcome should result from the formation of ox- then attempted with the aim of preparing the corresponding
ime 14 as a mixture of E/Z isomers.[19] With the aim of amides. Morpholine was used to optimise the reaction con-
obtaining a single pyrrolo-azepine, we returned to the ster- ditions (in terms of both yield and purity). By using a ratio
eoselective synthesis of 11, converting it into the more lipo- of 18/morpholine/Me3Al of 1:2:3 in refluxing toluene,
philic oxime methyl ester 17 prior to Beckmann rearrange- amide 19 was obtained in acceptable yields (65%) together
ment.[20] Esterification of (Z)-oxime acid 11 with MeOH/ with unreacted starting material. Surprisingly, attempts to
SOCl2 (1 equiv. with respect to 11) at room temperature force the reaction to completion by using microwave dielec-
produced (Z)-oxime 17 in a very good yield. This com- tric heating did not improve the results (conversion of less
pound was then submitted to standard PPA-mediated that 25% after 1 hour of MW irradiation). To improve the
Beckmann rearrangement to afford pyrrolo-azepinone 18 conversion, the amount of Me3Al was increased up to
in 70% isolated yield. The nature of the product [5,6,7,8- 6 equiv. with respect to the starting material 18. Under
tetrahydropyrrolo[3,2-c]azepin-4-one
vs.
4,6,7,8-tetra- these conditions the starting material disappeared after
hydropyrrolo[3,2-b]azepin-5-one] was determined by 1H heating at reflux for 12 hours, but the formation of approxi-
NMR/COSY analysis. The CH2 at the 6-position showed a mately 35% of ketone 21 was revealed by chromatographic
resonance at δ = 3.32 ppm with a low-field shift compared separation. We attributed the formation of this product to
with the resonance of the same CH2 in compound 11, con- competitive methyl transfer from Me3Al due to the large
sistent with the proposed isomer. Moreover, the COSY excess of reagent used. Finally, we found that the best con-
spectrum showed a cross peak between these protons and ditions were a 1:3:3 ratio of 18/amine/Me3Al, which gave
the amide NH (Scheme 5).
amide 19 in 98% isolated yield (Table 1, Scheme 6).
Table 1. Optimised reaction conditions for trimethylaluminium-mediated amidation.
Ratio 18/morpholine/MeAl3
Conditions
Products (% yield)
1:2:3
1:2:3
1:2:6
1:3:3
toluene, reflux, 12 h
toluene, reflux, MW, 1 h
CH2Cl2, reflux, 12 h
CH2Cl2, reflux, 12 h
19 (65%)
19 (Ͻ25%)
19 (50%), 21 (35%)
19 (98%)
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L. Piras, E. Genesio, C. Ghiron, M. Taddei
FULL PAPER
thus obtained with a purity higher than 95% after a short
passage through a silica gel cartridge.
An array of molecules related to compound 20 was then
prepared starting from ester 18 (Scheme 7) in a parallel
fashion using the above described conditions. Four different
amines (23a–d in Figure 1) were employed to give amides
24a–d (Table 3), which were treated (on a 200 mg scale) with
12 different benzyl halides (25[1–12]) plus MeI (25[13])
(Figure 2) to give 52 new products (24a[1–13], 24b[1–13],
24c[1–13] and 24d[1–13]), which were all isolated by short
silica gel cartridge purification in amounts varying from 11
to 237 mg, with purities higher than 91% (except in a few
cases, see Table 4) and variable overall yields. The struc-
tures, yields and purities of the components of the array are
reported in Table 4.
Scheme 6.
The last step, to functionalise our pyrrolo-azepine scaf-
fold at the 5-position (the amidic NH), was first attempted
by reacting substrate 19 with NaH in DMF at room tem-
perature followed by alkylation with benzyl bromide. The
use of stoichiometric amounts of NaH and benzyl bromide
gave a relatively low conversion to 20 with some starting
material recovered at the end of the reaction. Use of an
excess of the alkylating mixture gave complete conversion
of the starting material, but the reaction was accompanied
by the formation of different amounts of dialkylated prod-
uct 22.
Scheme 7.
In order to prevent α alkylation of the terminal carbox-
amide, different bases were tried for selective deprotonation
at the 5-position. Unfortunately, the use of KOtBu in DMF
at room temperature, or Cs2CO3/DMF, K2CO3/KOH/
Bu4NI or phosphazene base in CH2Cl2, either at room tem-
perature or under MW dielectric heating, returned exclu-
sively the starting material (Table 2). Finally, the best reac-
tion conditions were found to be the use of 2.5 equiv. of
NaH and 1.1 equiv. of benzyl bromide in DMF at room
temperature for 15 minutes (Scheme 6). Compound 20 was
Figure 1. Structures of amines 23a–d.
Table 2. Other reaction conditions tested for the N-alkylation of
compound 19.
All the members of the final array are in good agreement
with the Lipinski “Rule of Five” (see Figures 3 and 4 for
selected calculated properties which show a good distribu-
tion across the range of product molecular weights; the ro-
tatable bonds as well as hydrogen-bond donor and acceptor
counts are well within the rules).[22]
Bases
Conditions
KOtBu
Cs2CO3
K2CO3, KOH, Bu4NI
Phosphazene base
DMF, room temp., 12 h
DMF, 120 °C, 5 min, MW
DMF, 2 min, MW
CH2Cl2, reflux, 12 h
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Scaffold Preparation of Tetrahydropyrrolo-azepinones
Table 3. Structures, purities and yields of amides 24a–d.
Table 4. Structures, purities and yields of final azepines.
R3
% Purity
% Yield
1H NMR LC–MS
24a[1]
24a[2]
24a[3]
24a[4]
24a[5]
24a[6]
24a[7]
24a[8]
24a[9]
o-Cl-C6H4CH2
m-Cl-C6H4CH2
p-Cl-C6H4CH2
o-F-C6H4CH2
m-F-C6H4CH2
p-F-C6H4CH2
o-H3C-C6H4CH2
m-H3C-C6H4CH2
p-H3C-C6H4CH2
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
85
97.70
100
100
100
100
100
100
100
100
100
100
100
100
100
100
97.87
100
98.43
96.07
96.96
96.85
76.91
87.94
91.49
93.68
100
100
100
100
100
100
100
100
100
100
100
100
100
–
43
41
34
39
47
32
45
42
43
30
33
47
64
51
59
57
68
60
70
36
20
16
46
47
71
95
–
24a[10] m-H3CO-C6H4CH2
[a] Not determined as compound 24c runs very close to the solvent
front.
24a[11]
24a[12]
24a[13]
24b[1]
24b[2]
24b[3]
24b[4]
24b[5]
24b[6]
24b[7]
24b[8]
24b[9]
p-H3CO-C6H4CH2
PhCH2
CH3
o-Cl-C6H4CH2
m-Cl-C6H4CH2
p-Cl-C6H4CH2
o-F-C6H4CH2
m-F-C6H4CH2
p-F-C6H4CH2
o-H3C-C6H4CH2
m-H3C-C6H4CH2
p-H3C-C6H4CH2
24b[10] m-H3CO-C6H4CH2
93
94
95
Ͼ95
25
24b[11]
24b[12]
24b[13]
24c[1]
24c[2]
24c[3]
24c[4]
24c[5]
24c[6]
24c[7]
24c[8]
24c[9]
p-H3CO-C6H4CH2
PhCH2
CH3
o-Cl-C6H4CH2
m-Cl-C6H4CH2
p-Cl-C6H4CH2
o-F-C6H4CH2
m-F-C6H4CH2
p-F-C6H4CH2
o-H3C-C6H4CH2
m-H3C-C6H4CH2
p-H3C-C6H4CH2
20
–
8
Figure 2. Structures of alkylating agents 25[1–13].
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
98
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
30
26
16
22
18
17
11
4
19
10
17
19
26
23
29
24
31
14
16
10
17
20
40
24c[10] m-H3CO-C6H4CH2
24c[11]
24c[12]
24c[13]
24d[1]
24d[2]
24d[3]
24d[4]
24d[5]
24d[6]
24d[7]
24d[8]
24d[9]
p-H3CO-C6H4CH2
PhCH2
CH3
o-Cl-C6H4CH2
m-Cl-C6H4CH2
p-Cl-C6H4CH2
o-F-C6H4CH2
m-F-C6H4CH2
p-F-C6H4CH2
o-H3C-C6H4CH2
m-H3C-C6H4CH2
p-H3C-C6H4CH2
100
100
100
100
100
100
100
100
100
100
100
100
100
Figure 3. Distribution of molecular weight and log S in the array.
24d[10] m-H3CO-C6H4CH2
24d[11]
24d[12]
24d[13]
p-H3CO-C6H4CH2
PhCH2
CH3
Conclusion
We have developed an optimised procedure for the prep-
aration of novel scaffold 18 in multigram scale and a simple
procedure for the parallel decoration of the 1- and 5-posi-
tions of the ring. An efficient route was then developed for
the rapid solution-phase combinatorial synthesis of an ar-
ray of disubstituted pyrrolo-azepinyl)acetamides by using
this scaffold.
Figure 4. Distribution of molecular weight and log P in the array.
Eur. J. Org. Chem. 2008, 2789–2800
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Synthesis of 2-[4,5,6,7-Tetrahydro-4-(hydroxyimino)indol-1-yl]acetic
Acid [(Z)-11]: A mixture of acid 8 (1.5 g, 7.77 mmol), hydroxyl-
amine hydrochloride (1.62 g, 23.31 mmol), sodium acetate (1.9 g,
23.31 mmol), methanol (105 mL) and H2O (42 mL) was stirred at
room temperature for 24 h. The reaction mixture was evaporated
under reduced pressure to about half its initial volume and diluted
with water (50 mL). The resulting crystals were collected, washed
with water and dried. Recrystallisation from chloroform/hexane
Experimental Section
General Information: All commercially available reagents and sol-
vents were used without further purification unless mentioned
otherwise. Solution-phase reactions were monitored by analytical
thin-layer chromatography (TLC; silica gel 60 F254 plates
0.25 mm) and purified by column chromatography on silica gel 60.
LC–MS data were recorded with a Waters Alliance HT 2792 elec-
trospray mass spectrometer equipped with a detector Photodiode
Array 2996 and micromass ZQ using a Phenomenex C18 column.
HPLC–MS method: mixture A (99.9% water, 0.1% HCOOH) and
mixture B (99.9% acetonitrile, 0.1% HCOOH) were used as the
eluents as follows: 0–6.85 min, 95% mixture A; 6.85–9.10 min 95–
0% mixture A; 9.10–9.15 min 0–95% mixture A, 9.15–10 min 95%
mixture A; flow 1.0 mL/min, T = 40 °C. 1H and 13C NMR spectra
were recorded with Bruker 200 MHz and 400 MHz instruments;
chemical shifts were quoted in parts per million and referenced to
the solvent used. The cyclisations were performed in a CEM Dis-
cover microwave reactor. The alkylation step to deliver the final
library was performed in a Büchi-Syncore parallel synthesiser.
Compound 2 was obtained as described in ref.[13]
1
gave 11 (1.5 g, yield 93%); m.p. 208 °C. H NMR (200 MHz, [D]-
methanol): δ = 6.76 (d, J = 3.2 Hz, 1 H, CHN), 6.48 (d, J = 3.2 Hz,
1 H, CH), 4.45 (s, 2 H, CH2N), 2.49 (m, 2 H, CH2C), 2.32 (m, 2
H, 2 H, CH2CO), 2.25 (m, 2 H, 2H CH2CH2CH2) ppm. MS (EI,
70 eV): m/z = 209 [M + H]+.
Synthesis of N-Isobutyl-2-(4,5,6,7-tetrahydro-4-oxoindol-1-yl)acet-
amide (13): Isobutylamine (0.103 mL, 1.04 mmol), DMTMM
(316 mg, 1.14 mmol) and N-methylmorpholine (0.228 mL,
2.08 mmol) were added to a stirred suspension of 8 (200 mg,
1.04 mmol) in THF (8 mL),. The mixture was stirred at room tem-
perature for 12 h, then THF was evaporated under reduced pres-
sure and the residue was dissolved in ethyl acetate. The organic
layer was washed with 1  HCl (twice), Na2CO3 (twice), dried with
anhydrous Na2SO4 and the solvent was evaporated under reduced
Synthesis of 2-(4,5,6,7-Tetrahydro-4-oxoindol-1-yl)acetic Acid (8):
NaOH (1 g, 25 mmol) was dissolved in a H2O/EtOH (1:1, 12 mL)
solution. Acid 2 (1 g, 5.55 mmol) and glycine ethyl ester hydrochlo-
ride (2.32 g, 16.83 mmol) were added to the stirred solution and
the reaction mixture was heated under microwave irradiation
(250 W) at 120 °C for 10 min. The ethanol was evaporated under
reduced pressure and the aqueous solution was acidified with 4 
HCl and extracted with ethyl acetate. The organic layer was dried
with anhydrous Na2SO4 and the solvent was evaporated under re-
duced pressure to give 8 (0.85 g, yield 80%) as a yellow crystalline
solid; m.p. 202 °C. 1H NMR (200 MHz, [D]methanol): δ = 6.53 (d,
J = 2.8 Hz, 1 H, CHN), 6.47 (d, J = 2.8 Hz, 1 H, CH), 4.45 (s, 2
H, CH2N), 2.61 (m, 2 H, CH2CO), 2.38 (m, 2 H,CH2C), 2.08 (m, 2
H, CH2CH2CH2) ppm. 13C NMR ([D]methanol): δ = 197.6, 171.4,
150.2, 147.6, 125.2, 121.5, 106.1, 38.3, 24.7, 22.3 ppm. MS (EI,
70 eV): m/z = 192 [M – H]+. C10H11NO3 (193.07): calcd. C 62.17,
H 5.74, N 7.25; found C 62.15, H 5.76, N 7.27.
1
pressure to give 13 (201 mg, yield 78%). H NMR (200 MHz, [D]-
chloroform): δ = 6.63 (d, J = 3.0 Hz, 1 H, CHN), 6.57 (d, J =
3.0 Hz, 1 H, CH), 5.27 (br., 1 H, NH), 4.52 (s, 2 H, CH2N), 3.04
(m, 2 H, CH2NH), 2.69 (m, 2 H, CH2CO), 2.56 (m, 2 H, CH2C),
2.22 (m, 2 H, CH2CH2CH2), 1.68 (q, J = 6.60 Hz, 1 H, CHCH3),
0.92 (d, J = 6.58 Hz, 6 H, CH3) ppm. MS (EI, 70 eV): m/z = 249
[M + H]+.
Synthesis of N-Isobutyl-2-[4,5,6,7-tetrahydro-4-(hydroxyimino)indol-
1-yl]acetamide [(E,Z)-14]: A mixture of 13 (160 mg, 0.63 mmol),
hydroxylamine hydrochloride (134 mg, 1.94 mmol), sodium acetate
(159 mg, 1.94 mmol), methanol (8.6 mL) and H2O (3.45 mL) was
heated at reflux until disappearance of the starting amide by TLC
analysis (4 h). The reaction mixture was evaporated under reduced
pressure to about half its initial volume, diluted with water (10 mL)
and then extracted with ethyl acetate; the organic phase was dried
with anhydrous Na2SO4 and crystallised from chloroform/hexane
to give 14 [E:Z = 1:1] as a white solid (130 mg, yield 78%); m.p.
171–174 °C. 1H NMR (400 MHz, [D]chloroform): δ = 6.90 (d, J =
2.8 Hz, 1 H, CHN, isomer E or Z), 6.67 (d, J = 3.2 Hz, 1 H, CHN,
isomer E or Z), 6.58 (d, J = 2.8 Hz, 1 H, CH, isomer E or Z), 6.35
(d, J = 3.2 Hz, 1 H, CH, isomer E or Z), 4.51 (s, 2 H, CH2N,
isomer E or Z), 4.49 (s, 2 H, CH2N, isomer E or Z), 3.02 (d, J =
5.6 Hz, 2 H, CH2NH), 2.60 (m, 2 H, CH2CO), 2.37 (m, 2 H,
CH2C), 1.95 (m, 2 H, CH2CH2CH2), 1.75 (q, J = 6.61 Hz, 1 H,
CHCH3), 0.87 (d, J = 6.60 Hz, 6 H, CH3) ppm. MS (EI, 70 eV):
m/z = 264 [M + H]+.
Synthesis of Ethyl 2-(4,5,6,7-Tetrahydro-4-oxoindol-1-yl)-3-phenyl-
propanoate (9) and 6,7-Dihydro-1-phenethyl-1H-indol-4(5H)-one
(10): Phenylalanine ethyl ester (716 mg, 3.33 mmol) and triethyl-
amine (0.7 mL, 4.99 mmol) were added to a solution of 2 (200 mg,
1.11 mmol) in a mixture of H2O/EtOH (5:1, 2 mL). The reaction
mixture was heated under microwave irradiation (250 W) at 120 °C
for 10 min. The ethanol was evaporated under reduced pressure
and the aqueous solution was acidified with 1  HCl and extracted
with ethyl acetate. The organic layer was dried with anhydrous
Na2SO4, the solvent was evaporated under reduced pressure and
the crude obtained was purified by flash chromatography (SiO2
chloroform/ethyl acetate, 3:1) to give 83 mg of 9 (yield 25%) and
146 mg of 10 (yield 55%). 9: 1H NMR (200 MHz, [D]chloroform):
Synthesis of N-Isobutyl-2-[5,6,7,8-tetrahydro-4-oxopyrrolo[3,2-c]-
azepin-1(4H)-yl]acetamide (15) and N-Isobutyl-2-[5,6,7,8-tetra-
hydro-5-oxopyrrolo[3,2-b]azepin-1(4H)-yl]acetamide (16): Acet-
δ = 6.70–6.60 (m, 5 H, CH arom.), 6.63 (d, J = 2.8 Hz, 1 H, CHN), amide 14 (200 mg, 0.76 mmol) was added to stirred PPA (2.3 g)
6.51 (d, J = 2.8 Hz, 1 H, CH), 5.23 (t, J = 7.3 Hz, CHN), 4.25 (q,
J = 7.0 Hz, 2 H, CH2O), 3.41 (d, J = 7.3 Hz, 2 H, CH2Ph), 2.35
preheated at 120 °C. After 15 min, the solution was poured into ice
and water and the aqueous solution was extracted with chloroform.
(m, 2 H, CH2CO), 1.87 (m, 2 H, CH2C), 1.78 (m, 2 H, The organic layer was dried with anhydrous Na2SO4 and the sol-
CH2CH2CH2), 1.3 (t, J = 7.0 Hz, 3 H, 3 H, OCH2CH3) ppm. MS vent was evaporated under reduced pressure to give the crude prod-
(EI, 70 eV): m/z = 312 [M + H]+. 10: 1H NMR (200 MHz, [D]-
chloroform): δ = 7.35–6.65 (m, 5 H, CH arom.), 6.63 (d, J = 3.2 Hz,
uct that was purified by flash chromatography (SiO2, chloroform/
methanol, 98:2); 30 mg of 15 (yield 15%) and 40 mg of 16 (yield
1
1 H, CHN), 6.52 (d, J = 3.2 Hz, 1 H, CH), 4.03 (t, J = 6.4 Hz, 2 20%) were obtained. 15: H NMR (400 MHz, [D]chloroform): δ =
H, CH2N), 3.01 (t, J = 6.4 Hz, 2 H, CH2Ph), 2.4 (m, 2 H, CH2CO), 6.82 (d, J = 2.8 Hz, 1 H, CHN), 6.64 (d, J = 2.8 Hz, 1 H, CH),
2.27 (m, 2 H, CH2C), 1.87 (m, 2 H, CH2CH2CH2) ppm. MS (EI, 5.45 (br., 1 H, NH), 4.50 (s, 2 H, CH2N), 3.78 (m, 2 H, CH2NH),
70 eV): m/z = 240 [M + H]+.
3.02 (m, 2 H, CH2CO), 2.78 (m, 2 H, CH2C), 2.06 (m, 2 H,
2794
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2789–2800

Scaffold Preparation of Tetrahydropyrrolo-azepinones
CH2CH2CH2), 1.68 (q, J = 6.60 Hz, 1 H, CHCH3), 0.87 (d, J = duced pressure to give the crude product that was purified by flash
6.58 Hz, 6 H, CH3) ppm. MS (EI, 70 eV): m/z = 264 [M + H]+. 16:
1H NMR (400 MHz, [D]chloroform): δ = 6.57 (d, J = 2.4 Hz, 1 H,
chromatography (SiO2, chloroform/methanol, 98:2). The product
24a was obtained as a white solid (1.2 g, yield 95%); m.p. 216 °C.
CHN), 6.55 (d, J = 2.4 Hz, 1 H, CH), 5.25 (br., 1 H, NH), 4.52 (s, 1H NMR (400 MHz, [D]chloroform): δ = 6.61 (d, J = 3.2 Hz, 1 H,
2 H, CH2N), 3.03 (m, 2 H, CH2NH), 2.76 (m, 2 H, CH2CO), 2.57
CHN), 6.48 (d, J = 3.2 Hz, 1 H, CH), 4.56 (s, 2 H, CH2N), 3.65–
(m, 2 H, CH2C), 2.10 (m, 2 H, CH2CH2CH2), 1.63 (q, J = 6.60 Hz, 3.63 (m, 4 H, CH2O), 3.553 (m, 2 H, CH2NCH2), 3.41 (m, 2 H,
1 H, CHCH3), 0.88 (d, J = 6.58 Hz, 6 H, CH3) ppm. MS (EI, CH2NCH2), 3.25 (m, CH2NH), 2.68 (m, 2 H, CH2C), 2.01 (m, 2
70 eV): m/z = 264 [M + H]+.
H, CH2CH2CH2) ppm. 13C NMR ([D]chloroform): δ = 167.3,
166.5, 134.8, 122.7, 116.8, 110.1, 66.7, 66.6, 48.6, 45.4, 42.5, 41.6,
40.8, 27.1, 26.8 ppm. LC–MS: m/z = 278 [M + H]+ (Phenomenex®
column, 100%, 254 nm).
Synthesis of Methyl 2-[4,5,6,7-Tetrahydro-4-(hydroxyimino)indol-1-
yl]acetate (17): Thionyl chloride (525 mL, 7.2 mmol) was added to
a stirred solution of 11 (1.5 g, 7.2 mmol) in methanol (83 mL) at
0 °C and the reaction was stirred at reflux for 2 h. The reaction
mixture was evaporated under reduced pressure to give 17 (1.57 g,
98%) as a brown solid; m.p. 168 °C. 1H NMR (400 MHz, [D]meth-
anol): δ = 6.78 (d, J = 2.8 Hz, 1 H, CHN), 6.65 (d, J = 2.8 Hz, 1
H, CH), 4.48 (s, 2 H, CH2N), 3.75 (s, 3 H, CH3O), 2.73 (m, 2 H,
CH2CO), 2.52 (m, 2 H, CH2C), 2.31 (m, 2 H, CH2CH2CH2) ppm.
MS (EI, 70 eV): m/z = 223 [M + H]+, 245 [M + Na]+.
The products 24b, 24c and 24d were obtained by the same pro-
cedure and purified by flash chromatography using chloroform/
MeOH or dichloromethane/MeOH mixtures as eluents.
N,N-Diethyl-2-[5,6,7,8-tetrahydro-4-oxopyrrolo[3,2-c]azepin-1(4H)-
yl]acetamide (24b): M.p. 245 °C. 1H NMR (400 MHz, [D]chloro-
form): δ = 6.71 (d, J = 2.6 Hz, 1 H, CHN), 6.53 (d, J = 2.6 Hz, 1
H, CH), 5.94 (br., 1 H, NH), 4.57 (s, 2 H, CH2N), 3.35–3.23 (m,
6 H, CH2CH3, CH2NH), 2.748 (m, 2 H, CH2C), 2.07 (m, 2 H,
CH2CH2CH2), 1.21 (t, J = 7.2 Hz, 3 H, CH3), 1.12 (t, J = 7.2 Hz,
3 H, CH3) ppm. 13C NMR ([D]chloroform): δ = 167.3, 166.6,
134.7, 122.9, 116.8, 109.9, 48.7, 41.6, 41.3, 40.6, 27.0, 14.7,
13.7 ppm. LC–MS: m/z = 264 [M + H]+ (Phenomenex® column,
100%, 254 nm).
Synthesis of Methyl 2-[5,6,7,8-Tetrahydro-4-oxopyrrolo[3,2-c]-
azepin-1(4H)-yl]acetate (18): Ester 17 (2 g, 9 mmol) was added por-
tionwise to stirred PPA (27 g) preheated at 120 °C. After 15 min,
the solution was poured into ice/water and the aqueous solution
was extracted with chloroform. The organic layer was dried with
anhydrous Na2SO4 and the solvent was evaporated under reduced
pressure to give the crude product that was purified by flash
chromatography (SiO2, chloroform/methanol, 98:2); 1.32 g of the
pure title compound 18 was isolated as a white solid (yield 70%);
m.p. 170 °C. 1H NMR (400 MHz, [D]chloroform): δ = 6.72 (d, J =
2.8 Hz, 1 H, CHN), 6.56 (d, J = 2.8 Hz, 1 H, CH), 6.04 (br., 1 H,
NH), 4.54 (s, 2 H, CH2N), 3.75 (s, 3 H, CH3O), 3.32 (m, 2 H,
CH2NH), 2.76 (m, 2 H, CH2C), 2.09 (m, 2 H, CH2CH2CH2) ppm.
13C NMR ([D]chloroform): δ = 168.5, 168.0, 133.9, 121.9, 116.9,
111.5, 52.8, 48.5, 41.8, 26.9, 26.3 ppm. MS (EI, 70 eV): m/z = 223
[M + H]+, 245 [M + Na]+. C11H14N2O3 (222): C 59.45, H 6.35, N
12.60; found 59.43, H 6.38, N 12.62.
5,6,7,8-Tetrahydro-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]pyrrolo-
[3,2-c]azepin-4(1H)-one (24c): M.p. 244 °C. 1H NMR (400 MHz,
[D]chloroform): δ = 7.22 (d, J = 3.2 Hz, 1 H, CHN), 6.52 (d, J =
3.2 Hz, 1 H, CH), 5.92 (br., 1 H, NH), 4.58 (s, 2 H, CH2N), 3.63
(m, 2 H, CH2NCH2), 3.45 (m, 2 H, CH2NCH2), 3.31 (m, 2 H,
CH2NH), 2.74 (m, 2 H, CH2C), 2.39 (m, 4 H, CH2NCH3), 2.29 (s,
3 H, CH3N), 2.07 (m, 2 H, CH2CH2CH2) ppm. 13C NMR ([D]-
chloroform): δ = 167.3, 166.2, 134.8, 122.8, 116.8, 110.1, 55.2, 54.9,
48.7, 46.3, 44.7, 42.1, 41.6, 27.1, 26.9 ppm.
1-[2-(4-Benzylpiperazin-1-yl)-2-oxoethyl]-5,6,7,8-tetrahydropyrrolo-
[3,2-c]azepin-4(1H)-one (24d): M.p. 261 °C. NMR (400 MHz, [D]-
chloroform): δ = 7.30–7.22 (m, 5 H, CH arom.), 6.62 (d, J = 3.2 Hz,
1 H, CHN), 6.48 (d, J = 3.2 Hz, 1 H, CH), 4.56 (s, 2 H, CH2N),
3.57 (m, 2 H, CH2NCH2), 3.48 (s, 2 H, NCH2Ph), 3.41 (m, 2 H,
CH2NCH2), 3.25 (m, 2 H, CH2NH), 2.67 (m, 2 H, CH2C), 2.42
(m, 4 H, CH2NCH2Ph), 2.01 (m, 2 H, CH2CH2CH2) ppm. 13C
NMR ([D]chloroform): δ = 168.6, 165.1, 137.1, 134.7, 129.2, 128.4,
127.4, 122.0, 116.1, 111.1, 62.8, 52.8, 52.5, 48.6, 44.9, 42.3, 41.7,
27.0, 26.1 ppm. LC–MS: m/z = 367 [M + H]+ (Phenomenex® col-
umn, 100%, 254 nm).
Synthesis 2-[5,6,7,8-Tetrahydro-4-oxopyrrolo[3,2-c]azepin-1(4H)-yl]-
acetic Acid (12): NaOH (120 mg dissolved in 1 mL of H2O,
2.55 mmol) was added to a suspension of 18 (335 mg, 1.27 mmol)
in MeOH (5 mL) cooled to 0 °C with an ice bath. The mixture was
removed from the ice bath and the reaction was monitored by TLC
(chloroform/methanol, 95:5) until disappearance of the starting
material. Then HCl (0.212 mL of 37% HCl, 2.55 mmol) was added
and the methanol was evaporated under reduced pressure to afford
product 12 as a white crystalline residue that was filtered and dried
(212 mg, yield 85%); m.p. 128 °C. 1H NMR (400 MHz, [D]meth-
anol): δ = 6.67 (d, J = 2.8 Hz, 1 H, CHN), 6.51 (d, J = 2.8 Hz, 1
H, CH), 5.66 (s, 2 H, CH2N), 3.29 (m, 2 H, CH2NH), 2.82 (m, 2
H, CH2C), 2.09 (m, 2 H, CH2CH2CH2) ppm. MS (EI, 70 eV): m/z
= 207 [M – H]+.
Synthesis 5,6,7,8-Tetrahydro-1-(2-oxopropyl)pyrrolo[3,2-c]azepin-
4(1H)-one (21): This product was obtained by the general pro-
cedure for the Weinreb reaction using a ratio 18/morpholine/AlMe3
of 1:2:6 after purification of the crude by flash chromatography
(SiO2, chloroform/methanol, 98:2) as a white solid (yield 35%);
m.p. 180 °C. NMR (400 MHz, [D]chloroform): δ = 6.74 (d, J =
2.8 Hz, 1 H, CHN), 6.52 (d, J = 2.8 Hz, 1 H, CH), 4.81 (s, 2 H,
CH2N), 3.31 (m, 2 H, CH2NH), 2.66 (m, 2 H, CH2C), 2.14–1.98
(m, 5 H, CH3, CH2CH2CH2) ppm. MS (EI, 70 eV): m/z (%) = 208
[M + H]+.
General Procedure for the Weinreb Reaction. Preparation of 5,6,7,8-
Tetrahydro-1-(2-morpholino-2-oxoethyl)pyrrolo[3,2-c]azepin-4(1H)-
one (24a): A 2  solution of AlMe3 in toluene (6.7 mL, 13.51 mL)
was added to a stirred solution of freshly distilled morpholine
(13.51 mmol, 1.3 mL) in dry dichloromethane (20 mL) at 0 °C un-
der an inert atmosphere and the reaction mixture was stirred at
room temperature for 15 min. Acetate 18 (1 g, 4.5 mmol) was added
portionwise and the mixture was heated at reflux overnight and
then cooled to room temperature. The mixture was cooled to 0 °C,
distilled water was added dropwise until the excess of AlMe3 had
been quenched and then anhydrous Na2SO4 was added. The sus-
pension was stirred for 30 min then filtered through Celite® and
washed with chloroform. The solvent was evaporated under re-
General Procedure for the Synthesis of the Final Products 24a[1–13],
24b[1–13], 24c[1–13] and 24d[1–13]
Preparation of 5-(3-Chlorobenzyl)-5,6,7,8-tetrahydro-1-(2-morphol-
ino-2-oxoethyl)pyrrolo[3,2-c]azepin-4(1H)-one (24a[2]): Sodium hy-
dride (60% oil dispersion, 43 mg, 1.81 mmol) was added to a flask
equipped with a magnetic stirring bar and N2 inlet. The sodium
hydride was washed with hexane (3ϫ) and the waste hexane was
Eur. J. Org. Chem. 2008, 2789–2800
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2795

L. Piras, E. Genesio, C. Ghiron, M. Taddei
FULL PAPER
removed each time with a glass pipette. Anhydrous DMF (1.25 mL)
was added to the washed sodium hydride and the resulting suspen-
sion was cooled in an ice/water bath. 5,6,7,8-Tetrahydro-1-(2-mor-
pholino-2-oxoethyl)pyrrolo[3,2-c]azepin-4(1H)-one (200 mg,
0.72 mmol) was added to the cooled mixture and then the reaction
mixture was allowed to stir for 20 min; 3-chlorobenzyl bromide
(163 mg, 0.79 mmol) was added dropwise. The reaction mixture
was warmed to room temperature and stirred for 30 min. The ex-
cess sodium hydride was quenched with H2O (1 mL). The solvent
was removed under reduced pressure to give a residue that was
purified on a silica gel cartridge (chloroform/methanol, 99:1) to
26.3, 26.2 ppm. LC–MS: m/z = 386 [M + H]+ (Phenomenex® col-
umn, 100%, 254 nm).
5-(4-Fluorobenzyl)-5,6,7,8-tetrahydro-1-(2-morpholino-2-oxoethyl)-
pyrrolo[3,2-c]azepin-4(1H)-one (24a[6]): 1H NMR (400 MHz, [D]-
chloroform): δ = 7.25 (d, J = 8 Hz, 2 H, CH arom.), 6.96 (m, 2 H,
CH arom.), 6.78 (s, 1 H, CHN), 6.53 (s, 1 H, CH), 4.69 (s, 2 H,
CH2Ph), 4.58 (s, 2 H, CH2N), 3.67 (m, 4 H, CH2O), 3.60 (m, 2 H,
CH2NCH2), 3.44 (m, 2 H, CH2NCH2), 3.36 (m, 2 H, CH2NCO),
2.65 (m, 2 H, CH2C), 1.93 (m, 2 H, CH2CH2CH2) ppm. LC–MS:
m/z = 386 [M + H]+ (Phenomenex® column, 100%, 254 nm).
1
5,6,7,8-Tetrahydro-5-(2-methylbenzyl)-1-(2-morpholino-2-oxoethyl)-
pyrrolo[3,2-c]azepin-4(1H)-one (24a[7]): 1H NMR (400 MHz, [D]-
chloroform): δ = 7.16–7.14 (m, 4 H, CH arom.), 6.79 (s, 2 H, CH
arom.), 6.54 (s, 2 H, CHN), 4.76 (s, 2 H, CH2Ph), 4.58 (s, 2 H,
CH2N), 3.68 (m, 4H. CH2O), 3.61 (m, 2 H, CH2NCH2), 3.45 (m,
2 H, CH2NCH2), 3.34 (m, 2H CH2NCO), 2.66 (m, 2 H, CH2C),
2.30 (s, 3 H, CH3), 1.91 (m, 2 H, CH2CH2CH2) ppm. LC–MS: m/z
= 382 [M + H]+ (Phenomenex® column, 100%, 254 nm).
give 99 mg of 24a[2] (yield 41%). H NMR (400 MHz, [D]chloro-
form): δ = 7.22–7.12 (m, 5 H, CH arom.), 7.74 (d, J = 2.8 Hz, 1
H, CHN), 6.49 (d, J = 2.8 Hz, 1 H, CH), 4.66 (s, 2 H, CH2Ph),
4.45 (s, 2 H, CH2N), 3.64–3.62 (m, 4 H, CH2O), 3.56 (m, 2 H,
CH2NCH2), 3.39 (m, 2 H, CH2NCH2), 3.32 (m, 2 H, CH2NH),
2.62 (m, 2 H, CH2C), 1.94–1.88 (m, 2 H, CH2CH2CH2) ppm. 13C
NMR ([D]chloroform): δ = 166.5, 166.0, 142.3, 134.8, 133.7, 131.0,
128.0, 127.5, 127.0, 122.8, 116.7, 110.7, 66.7, 66.6, 51.4, 48.6, 48.4,
45.4, 42.5, 26.3, 26.2 ppm. LC–MS: m/z = 402 [M + H]+ (Phe-
nomenex® column, 100, 254 nm).
5,6,7,8-Tetrahydro-5-(3-methylbenzyl)-1-(2-morpholino-2-oxoethyl)-
pyrrolo[3,2-c]azepin-4(1H)-one (24a[8]): 1H NMR (400 MHz, [D]-
chloroform): δ = 7.14 (m, 1 H, CH arom.), 7.09–7.02 (m, 3 H, CH
arom.), 7.77 (d, J = 2.8 Hz, 1 H, CHN), 6.51 (d, J = 2.8 Hz, 1 H,
CH), 4.69 (s, 2 H, CH2Ph), 4.57 (s, 2 H, CH2N), 3.68–3.66 (m, 4
H, CH2O), 3.59 (m, 2 H, CH2NCH2), 3.44 (m, 2 H, CH2NCH2),
3.34 (m, 2 H, CH2NCO), 2.64 (m, 2 H, CH2C), 2.29 (s, 3 H, CH3),
1.95–1.89 (m, 2 H, CH2CH2CH2) ppm. 13C NMR ([D]chloroform):
δ = 166.5, 165.9, 139.5, 138.1, 134.5, 129.0, 128.8, 128.2, 125.4,
122.7, 116.9, 110.7, 66.7, 66.6, 51.7, 48.6, 48.1, 45.3, 42.5, 26.3,
26.2, 21.7 ppm. LC–MS: m/z = 382 [M + H]+ (Phenomenex® col-
umn, 100%, 254 nm).
All the compounds of the library were obtained by the same pro-
cedure and purified on a silica gel cartridge (chloroform/methanol
or dichloromethane/methanol).
5-(2-Chlorobenzyl)-5,6,7,8-tetrahydro-1-(2-morpholino-2-oxoethyl)-
pyrrolo[3,2-c]azepin-4(1H)-one (24a[1]): 1H NMR (400 MHz, [D]-
chloroform): δ = 7.29–7.26 (m, 2 H, CH arom.), 7.15–7.08 (m, 2
H, CH arom.), 6.72 (d, J = 3.2 Hz, 1 H, CHN), 6.48 (d, J = 3.2 Hz,
1 H, CH), 4.81 (s, 2 H, CH2Ph), 4.53 (s, 2 H, CH2N), 3.63–3.62
(m, 4 H, CH2O), 3.56 (m, 2 H, CH2NCH2), 3.39–3.35 (m, 4 H,
CH2NCH2, CH2NCO), 2.63 (m, 2 H, CH2C), 1.98–1.92 (m, 2 H,
CH2CH2CH2) ppm. LC–MS: m/z = 402 [M + H]+ (Phenomenex®
column, 97.7%, 254 nm).
5,6,7,8-Tetrahydro-5-(4-methylbenzyl)-1-(2-morpholino-2-oxoethyl)-
pyrrolo[3,2-c]azepin-4(1H)-one (24a[9]): 1H NMR (400 MHz, [D]-
chloroform): δ = 7.13 (d, J = 7.6 Hz, 2 H, CH arom.), 7.03 (d, J =
7.6 Hz, 2 H, CH arom.), 6.74 (d, J = 2.4 Hz, 1 H, CHN), 6.48 (d,
J = 2.4 Hz, 1 H, CH), 4.65 (s, 2 H, CH2Ph), 4.52 (s, 2 H, CH2N),
3.62 (m, 4 H, CH2O), 3.55 (m, 2 H, CH2NCH2), 3.38 (m, 2 H,
CH2NCH2), 3.30 (m, 2 H, CH2NCO), 2.59 (m, 2 H, CH2C), 2.25
(m, 3 H, CH3), 1.89–1.84 (m, 2 H, CH2CH2CH2) ppm. LC–MS:
m/z = 382 [M + H]+ (Phenomenex® column, 100%, 254 nm).
5-(4-Chlorobenzyl)-5,6,7,8-tetrahydro-1-(2-morpholino-2-oxoethyl)-
pyrrolo[3,2-c]azepin-4(1H)-one (24a[3]): 1H NMR (400 MHz, [D]-
chloroform): δ = 7.21–7.16 (m, 4 H, CH arom.), 6.73 (d, J = 3.2 Hz,
1 H, CHN), 6.48 (d, J = 3.2 Hz, 1 H, CH), 4.64 (s, 2 H, CH2Ph),
4.53 (s, 2 H, CH2N), 3.64–3.61 (m, 4 H, CH2O), 3.55 (m, 2 H,
CH2NCH2), 3.39 (m, 2 H, CH2NCH2), 3.30 (m, 2 H, CH2NCO),
2.60 (m, 2 H, CH2C), 1.91–1.86 (m, 2 H, CH2CH2CH2) ppm. LC–
MS: m/z = 402 [M + H]+ (Phenomenex® column, 100%, 254 nm).
5,6,7,8-Tetrahydro-5-(3-methoxybenzyl)-1-(2-morpholino-2-oxo-
ethyl)pyrrolo[3,2-c]azepin-4(1H)-one (24a[10]): 1H NMR (400 MHz,
[D]chloroform): δ = 7.14 (m, 1 H, CH arom.), 6.82 (d, J = 7.6 Hz,
1 H, CH arom.), 6.78 (s, 1 H, CH arom.), 6.73 (d, J = 2.8 Hz, 1
H, CHN), 6.71 (d, J = 7.6 Hz, 1 H, CH arom.), 6.47 (d, J = 2.8 Hz,
1 H, CH), 4.61 (s, 2 H, CH2Ph), 4.54 (s, 2 H, CH2N), 3.71 (s, 3 H,
CH3O), 3.63–3.61 (m, 4 H, CH2O), 3.55 (m, 2 H, CH2NCH2),
3.340 (m, 2 H, CH2NCH2), 3.31 (m, 2 H, CH2NCO), 2.60 (m, 2
H, CH2C), 1.88 (m, 2 H, CH2CH2CH2) ppm. 13C NMR ([D]-
chloroform): δ = 166.5, 165.9, 160.0, 141.2, 134.6, 130.1, 122.7,
120.4, 116.9, 114.0, 112.8, 110.7, 66.7, 66.6, 55.6, 51.7, 48.6, 48.2,
45.3, 42.5, 26.3, 26.2 ppm. LC–MS: m/z = 398 [M + H]+ (Phe-
nomenex® column, 100%, 254 nm).
5-(2-Fluorobenzyl)-5,6,7,8-tetrahydro-1-(2-morpholino-2-oxoethyl)-
pyrrolo[3,2-c]azepin-4(1H)-one (24a[4]): 1H NMR (400 MHz, [D]-
chloroform): δ = 7.34 (m, 1 H, CH arom.), 7.12 (m, 1 H, CH
arom.), 7.02–6.93 (m, 2 H, CH arom.), 6.71 (d, J = 2.4 Hz, 1 H,
CHN), 6.47 (d, J = 2.4 Hz, 1 H, CH), 4.74 (s, 2 H, CH2Ph), 4.51
(s, 2 H, CH2N), 3.62 (m, 4 H, CH2O), 3.55 (m, 2 H, CH2NCH2),
3.39–3.37 (m, 4 H, CH2NCH2, CH2NCO), 2.60 (m, 2 H, CH2C),
1.95–1.89 (m, 2 H, CH2CH2CH2) ppm. LC–MS: m/z = 386 [M +
H]+ (Phenomenex® column, 100%, 254 nm).
5-(3-Fluorobenzyl)-5,6,7,8-tetrahydro-1-(2-morpholino-2-oxoethyl)-
pyrrolo[3,2-c]azepin-4(1H)-one (24a[5]): 1H NMR (400 MHz, [D]-
chloroform): δ = 7.20–7.15 (m, 1 H, CH arom.), 6.99 (d, J = 7.6 Hz,
1 H, CH arom.), 6.93 (d, J = 9.6 Hz, 1 H, CH arom.), 6.84 (m, 1
5,6,7,8-Tetrahydro-5-(4-methoxybenzyl)-1-(2-morpholino-2-oxo-
ethyl)pyrrolo[3,2-c]azepin-4(1H)-one (24a[11]): 1H NMR (400 MHz,
H, CH arom.), 6.69 (d, J = 2.8 Hz, 1 H, CHN), 6.46 (d, J = 2.8 Hz, [D]chloroform): δ = 7.16 (d, J = 8.2 Hz, 2 H, CH arom.), 6.75 (d,
1 H, CH), 4.65 (s, 2 H, CH2Ph), 4.51 (s, 2 H, CH2N), 3.62–3.60 J = 8.1 Hz, 2 H, CH arom.), 6.71 (d, J = 2.8 Hz, 1 H, CHN), 6.45
(m, 4 H, CH2O), 3.53 (m, 2 H, CH2NCH2), 3.38 (m, 2 H, (d, J = 2.8 Hz, 1 H, CH), 4.60 (s, 2 H, CH2Ph), 4.51 (s, 2 H,
CH2NCH2), 3.30 (m, 2 H, CH2NCO), 2.59 (m, 2 H, CH2C), 1.92– CH2N), 3.71 (s, 3 H, OCH3), 3.61 (m, 4 H, CH2O), 3.53 (m, 2 H,
1.86 (m, 2 H, CH2CH2CH2) ppm. 13C NMR ([D]chloroform): δ =
166.5, 166.0, 164.1, 161.7, 142.7, 142.6, 134.7, 131.1, 131.0, 124.29,
124.27, 122.8, 116.7, 110.7, 66.7, 66.6, 51.5, 48.6, 48.4, 45.3, 42.5,
CH2NCH2), 3.38 (m, 2 H, CH2NCH2), 3.28 (m, 2 H, CH2NCO),
2.57 (m, 2 H, CH2C), 1.87–1.81 (m, 2 H, CH2CH2CH2) ppm. LC–
MS: m/z = 398 [M + H]+ (Phenomenex® column, 100%, 254 nm).
2796
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2789–2800

Scaffold Preparation of Tetrahydropyrrolo-azepinones
5-Benzyl-5,6,7,8-tetrahydro-1-(2-morpholino-2-oxoethyl)pyrrolo-
[3,2-c]azepin-4(1H)-one (24a[12]): 1H NMR (400 MHz, [D]chloro-
form): δ = 7.23–7.17 (m, 5 H, CH arom.), 6.75 (d, J = 2.8 Hz, 1
CH2NCO), 2.66 (m, 2 H, CH2C), 1.95 (m, 2 H, CH2CH2CH2),
1.19 (t, J = 6.8 Hz, 3 H, CH3), 1.10 (t, J = 6.8 Hz, 3 H, CH3) ppm.
LC–MS: m/z = 372 [M + H]+ (Phenomenex® column, 98.43 %,
H, CHN), 6.48 (d, J = 2.8 Hz, 1 H, CH), 4.70 (s, 2H. CH2Ph), 4.54 254 nm).
(s, 2 H, CH2N), 3.62 (m, 4 H, CH2O), 3.55 (m, 2 H, CH2NCH2),
N,N-Diethyl-2-[5-(4-fluorobenzyl)-5,6,7,8-tetrahydro-4-oxopyrrolo-
3.39 (m, 2 H, CH2NCH2), 3.32 (m, 2 H, CH2NCO), 2.60 (m, 2 H,
CH2C), 1.88 (m, 2 H, CH2CH2CH2) ppm. LC–MS: m/z = 368 [M
+ H]+ (Phenomenex® column, 100%, 254 nm).
[3,2-c]azepin-1(4H)-yl]acetamide (24b[6]): 1H NMR (400 MHz, [D]-
chloroform): δ = 7.26 (m, 2 H, CH arom.), 6.95 (m, 2 H, CH
arom.), 6.76 (d, J = 2.8 Hz, 1 H, CHN), 6.54 (d, J = 2.8 Hz, 1 H,
5,6,7,8-Tetrahydro-5-methyl-1-(2-morpholino-2-oxoethyl)pyrrolo- CH), 4.69 (s, 2 H, CH2Ph), 4.55 (s, 2 H, CH2N), 3.40–3.28 (m,
[3,2-c]azepin-4(1H)-one (24a[13]): 1H NMR (400 MHz, [D]chloro-
form): δ = 6.60 (d, J = 2.4 Hz, 1 H, CHN), 6.41 (d, J = 2.4 Hz, 1
H, CH), 4.50 (s, 2 H, CH2N), 3.60 (m, 4 H, CH2O), 3.53 (m, 2 H,
6 H, CH2CH3, CH2NCO), 2.65 (m, 2 H, CH2C), 1.92 (m, 2 H,
CH2CH2CH2), 1.19 (t, J = 7.2 Hz, 3 H, CH3), 1.11 (t, J = 7.2 Hz,
3 H, CH3) ppm. 13C NMR ([D]chloroform): δ = 166.5, 165.9,
CH2NCH2), 3.37 (m, 2 H, CH2NCH2), 3.33 (m, 2 H, CH2NCO), 163.1, 160.7, 135.79, 135.76, 134.5, 130.4, 130.33, 130.25, 122.9,
3.02 (s, 3 H, CH3 ), 2.60 (m, 2 H, CH2 C), 1.98 (m, 2 H, 116.8, 115.9, 115.7, 110.5, 51.0, 48.7, 48.1, 26.3, 26.1, 14.73,
CH2CH2CH2) ppm. 13C NMR ([D]chloroform): δ = 166.5, 165.9,
134.2, 122.5, 117.1, 110.4, 66.7, 66.6, 50.0, 48.6, 45.4, 42.5, 36.8,
26.1, 26.0 ppm. LC–MS: m/z = 292 [M + H]+ (Phenomenex® col-
umn, 100%, 254 nm).
13.65 ppm. LC–MS: m/z = 372 [M + H]+ (Phenomenex® column,
96.07%, 254 nm).
N,N-Diethyl-5,6,7,8-tetrahydro-2-[5-(2-methylbenzyl)-4-oxopyrrolo-
[3,2-c]azepin-1(4H)-yl]acetamide (24b[7]): 1H NMR (400 MHz, [D]-
2-[5-(2-Chlorobenzyl)-N,N-diethyl-5,6,7,8-tetrahydro-4-oxopyrrolo- chloroform): δ = 7.15–7.13 (m, 5 H, CH arom.), 6.77 (d, J = 2 Hz,
[3,2-c]azepin-1(4H)-yl]acetamide (24b[1]): 1H NMR (400 MHz, [D]-
chloroform): δ = 7.31 (m, 2 H, CH arom.), 7.15 (m, 2 H, CH
1 H, CHN), 6.54 (d, J = 2 Hz, 1 H, CH), 4.75 (s, 2 H, CH2Ph),
4.55 (m, 2 H, CH2N), 3.38–3.29 (m, 6 H, CH2CH3, CH2NCO),
arom.), 6.75 (s, 1 H, CHN), 6.53 (s, 1 H, CH), 4.85 (s, 2 H, CH2Ph), 2.65 (m, 2 H, CH2 C), 2.29 (s, 3 H, CH3 ), 1.89 (m, 2 H,
4.55 (s, 2 H, CH2N), 3.41–3.28 (m, 6 H, CH2CH3, CH2NCO), 2.67 CH2CH2CH2), 1.18 (t, J = 6.8 Hz, 3 H, CH2CH3), 1.11 (t, J =
(m, 2 H, CH2C), 1.98 (m, 2 H, CH2CH2CH2), 1.19 (t, J = 6.8 Hz,
6.8 Hz, 3 H, CH2CH3) ppm. LC–MS: m/z = 368 [M + H]+ (Phe-
3 H, CH3), 1.10 (t, J = 6.8 Hz, 3 H, CH3) ppm. LC–MS: m/z = 388 nomenex® column, 96.96%, 254 nm).
[M + H]+ (Phenomenex® column, 100%, 254 nm).
N,N-Diethyl-5,6,7,8-tetrahydro-2-[5-(3-methylbenzyl)-4-oxopyrrolo-
2-[5-(3-Chlorobenzyl)-N,N-diethyl-5,6,7,8-tetrahydro-4-oxopyrrolo- [3,2-c]azepin-1(4H)-yl]acetamide (24b[8]): 1H NMR (400 MHz, [D]-
[3,2-c]azepin-1(4H)-yl]acetamide (24b[2]): 1H NMR (400 MHz, [D]-
chloroform): δ = 7.26 (s, 1 H, CH arom.), 7.18 (m, 3 H, CH arom.),
6.77 (d, J = 2 Hz, 1 H, CHN), 6.54 (d, J = 2 Hz, 1 H, CH), 4.70
(s, 2 H, CH2Ph), 4.55 (s, 2 H, CH2N), 3.39–3.28 (m, 6 H, CH2CH3,
chloroform): δ = 7.14 (m, 1 H, CH arom.), 7.08–7.01 (m, 3 H, CH
arom.), 6.78 (d, J = 2.8 Hz, 1 H, CHN), 6.54 (d, J = 2.8 Hz, 1 H,
CH), 4.71 (s, 2 H, CH2Ph), 4.55 (s, 2 H, CH2N), 3.40–3.28 (m, 6
H, CH2CH3, CH2NCO), 2.25 (m, 2 H, CH2C), 2.29 (s, 3 H, CH3),
CH2NCO), 2.66 (m, 2 H, CH2C), 1.94 (m, 2 H, CH2CH2CH2), 1.92 (m, 2 H, CH2CH2CH2), 1.19 (t, J = 7.2 Hz, 3 H, CH2CH3),
1.19 (t, J = 7.2 Hz, 3 H, CH3), 1.11 (t, J = 7.2 Hz, 3 H, CH3) ppm.
LC–MS: m/z = 388 [M + H]+ (Phenomenex® column, 100 %,
254 nm).
1.11 (t, J = 7.2 Hz, 3 H, CH2CH3) ppm. 13C NMR ([D]chloro-
form): δ = 166.5, 165.9, 139.5, 138.1, 134.5, 128.9, 128.8, 128.2,
125.4, 122.9, 116.9, 110.6, 51.7, 48.7, 48.1, 41.3, 26.3, 26.1, 21.7,
14.74, 14.68, 13.6 ppm. LC–MS: m/z = 368 [M + H]+ (Phe-
nomenex® column, 96.85%, 254 nm).
2-[5-(4-Chlorobenzyl)-N,N-diethyl-5,6,7,8-tetrahydro-4-oxopyrrolo-
[3,2-c]azepin-1(4H)-yl]acetamide (24b[3]): 1H NMR (400 MHz, [D]-
chloroform): δ = 7.23 (m, 4 H, CH arom.), 6.75 (d, J = 2 Hz, 1 H, N,N-Diethyl-5,6,7,8-tetrahydro-2-[5-(4-methylbenzyl)-4-oxopyrrolo-
CH), 6.53 (d, J = 2 Hz, 1 H, CHN), 4.68 (s, 2 H, CH2Ph), 4.54 (s, [3,2-c]azepin-1(4H)-yl]acetamide (24b[9]): 1H NMR (400 MHz, [D]-
2 H, CH2N), 3.39–3.27 (m, 6 H, CH2CH3, CH2NCO), 2.64 (s, 2
chloroform): δ = 7.17 (d, J = 7.6 Hz, 2 H, CH arom.), 7.07 (d, J =
H, CH2C), 1.92 (m, 2 H, CH2CH2CH2), 1.19 (t, J = 7.2 Hz, 3 H, 7.6 Hz, 2 H, CH arom.), 6.77 (d, J = 2.8 Hz, 1 H, CHN), 6.53 (d,
CH3), 1.10 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR ([D]chloro-
form): δ = 166.5, 166.0, 138.7, 134.6, 132.1, 130.2, 129.0, 122.9,
116.7, 110.5, 51.2, 48.7, 48.3, 41.3, 40.8, 26.4, 62.1, 14.7, 13.7 ppm.
LC–MS: m/z = 388 [M + H]+ (Phenomenex® column, 97.87 %,
254 nm).
J = 2.8 Hz, 1 H, CH), 4.69 (s, 2 H, CH2Ph), 4.54 (s, 2 H, CH2N),
3.39–3.27 (s, 6 H, CH2CH3, CH2NCO), 2.64 (m, 2 H, CH2C), 1.91
(m, 2 H, CH2CH2CH2), 1.18 (t, J = 6.8 Hz, 3 H, CH2CH3), 1.11
(t, J = 6.8 Hz, 3 H, CH2CH3) ppm. LC–MS: m/z = 368 [M + H]+
(Phenomenex® column, 76.91%, 254 nm).
N,N-Diethyl-2-[5-(2-fluorobenzyl)-5,6,7,8-tetrahydro-4-oxopyrrolo- N,N-Diethyl-5,6,7,8-tetrahydro-2-[5-(3-methoxybenzyl)-4-oxopyr-
[3,2-c]azepin-1(4H)-yl]acetamide (24b[4]): 1H NMR (400 MHz, [D]-
chloroform): δ = 7.36 (m, 1 H, CH arom.), 7.16 (m, 1 H, CH
rolo[3,2-c]azepin-1(4H)-yl]acetamide (24b[10]): 1H NMR
(400 MHz, [D]chloroform): δ = 7.16 (m, 1 H, CH arom.), 6.83 (m,
arom.), 7.04–6.95 (m, 2 H, CH arom.), 6.71 (s, 2 H, CHN), 6.50 3 H, CH arom.), 6.67 (d, J = 3.2 Hz, 1 H, CHN), 6.50 (d, J =
(s, 2 H, CH), 4.71 (s, 2 H, CH2Ph), 4.52 (s, 2 H, CH2N), 3.41–3.26 3.2 Hz, 1 H, CH), 4.68 (s, 2 H, CH2Ph), 4.521 (s, 2 H, CH2N), 3.73
(m, 6 H, CH2CH3, CH2NCO), 2.62 (m, 2 H, CH2C), 1.94 (m, 2 H, (s, 3 H, CH3), 3.36–3.21 (m, 6 H, CH2CH3, CH2NCO), 2.61 (m, 2
CH2CH2CH2), 1.17 (t, J = 7.2 Hz, 3 H, CH3), 1.08 (t, J = 7.2 Hz,
3 H, CH3) ppm. LC–MS: m/z = 372 [M + H]+ (Phenomenex® col-
umn, 100%, 254 nm).
H, CH2C), 1.90 (m, 2 H, CH2CH2CH2), 1.16 (t, J = 6.8 Hz, 3 H,
CH2CH3), 1.08 (t, J = 6.8 Hz, 3 H, CH2CH3) ppm. LC–MS: m/z
= 384 [M + H]+ (Phenomenex® column, 87.94%, 254 nm).
N,N-Diethyl-2-[5-(3-fluorobenzyl)-5,6,7,8-tetrahydro-4-oxopyrrolo- N,N-Diethyl-5,6,7,8-tetrahydro-2-[5-(4-methoxybenzyl)-4-oxopyr-
[3,2-c]azepin-1(4H)-yl]acetamide (24b[5]): 1H NMR (400 MHz, [D]-
chloroform): δ = 7.21 (m, 1 H, CH arom.), 7.05 (d, J = 7.6 Hz, 1
H, CH arom.), 6.99 (d, J = 9.6 Hz, 1 H, CH arom.), 6.76 (d, J =
rolo[3,2-c]azepin-1(4H)-yl]acetamide (24b[11]): 1H NMR
(400 MHz, [D]chloroform): δ = 7.18 (d, J = 8 Hz, 2 H, CH arom.),
6.78 (d, J = 8.2 Hz, 2 H, CH arom.), 6.72 (d, J = 2.8 Hz, 1 H,
2.8 Hz, 1 H, CHN), 6.53 (d, J = 2.8 Hz, 1 H, CH), 4.71 (s, 2 H, CHN), 6.49 (d, J = 2.8 Hz, 1 H, CH), 4.63 (s, 2 H, CH2Ph), 4.51
CH2Ph), 4.55 (s, 2 H, CH2N), 3.40–3.27 (m, 6 H, CH2CH3, (s, 2 H, CH2N), 3.73 (s, 3 H, CH3O), 3.36–3.24 (m, 6 H, CH2CH3,
Eur. J. Org. Chem. 2008, 2789–2800
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2797

L. Piras, E. Genesio, C. Ghiron, M. Taddei
FULL PAPER
CH2NCO), 2.56 (m, 2 H, CH2C), 1.86 (m, 2 H, CH2CH2CH2), (m, CH2NCO), 2.61 (m, 2 H, CH2C), 2.36 (m, 4 H, CH2NCH3),
1.15 (t, J = 6.8 Hz, 3 H, CH2CH3), 1.07 (t, J = 7.2 Hz, 3 H, 2.26 (s, 3 H, CH3N), 1.94 (m, 2 H, CH2CH2CH2) ppm. LC–MS:
CH2CH3) ppm. 13C NMR ([D]chloroform): δ = 166.5, 165.8, 158.9,
134.4, 131.4, 129.7, 122.8, 117.0, 114.4, 110.5, 55.7, 51.0, 48.7, 47.9,
41.3, 26.4, 26.1, 14.7, 13.7 ppm. LC–MS: m/z = 384 [M + H]+ (Phe-
nomenex® column, 91.49%, 254 nm).
m/z = 399 [M + H]+ (Phenomenex® column, 100%, 254 nm).
5,6,7,8-Tetrahydro-5-(2-methylbenzyl)-1-[2-(4-methylpiperazin-1-yl)-
2-oxoethyl]pyrrolo[3,2-c]azepin-4(1H)-one (24c[7]): 1H NMR
(400 MHz, [D]chloroform): δ = 7.12 (m, 4 H, CH arom.), 6.74 (d,
J = 2.8 Hz, 1 H, CHN), 6.50 (d, J = 2.8 Hz, 1 H, CH), 4.73 (s, 2
H, CH2Ph), 4.55 (s, 2 H, CH2N), 3.59 (m, 2 H, CH2NCH2), 3.43
(m, 2 H, CH2NCH2), 2.63 (m, 2 H, CH2NCO), 2.36 (m, 4 H,
CH2NCH3), 2.27 (m, 6 H, CH3N, CH3Ph), 1.88 (m, 2 H,
2-[5-Benzyl-5,6,7,8-tetrahydro-4-oxopyrrolo[3,2-c]azepin-1(4H)-yl]-
1
N,N-diethylacetamide (24b[12]): H NMR (400 MHz, [D]chloro-
form): δ = 7.26–7.23 (m, 5 H, CH arom.), 6.75 (d, J = 3.2 Hz, 1
H, CHN), 6.51 (d, J = 3.2 Hz, 1 H, CH), 4.71 (s, 2 H, CH2Ph),
4.52 (s, 2 H, CH2N), 3.37–3.25 (m, 6 H, CH2CH3, CH2NCO), 2.62 CH2CH2CH2) ppm. 13C NMR ([D]chloroform): δ = 166.2, 165.9,
(m, 2 H, CH2C), 1.89 (m, 2 H, CH2CH2CH2), 1.16 (t, J = 7.2 Hz,
3 H, CH3), 1.09 (t, J = 7.2 Hz, 3 H, CH3) ppm. LC–MS: m/z = 354 51.8, 48.7, 48.2, 46.3, 44.7, 42.1, 26.3, 26.2 ppm. LC–MS: m/z =
[M + H]+ (Phenomenex® column, 93.68%, 254 nm). 395 [M + H]+ (Phenomenex® column, 100%, 254 nm).
139.5, 134.6, 129.0, 128.3, 127.5, 122.8, 116.9, 110.6, 55.2, 54.9,
N,N-Diethyl-2-[5,6,7,8-tetrahydro-5-methyl-4-oxopyrrolo[3,2-c]- 5,6,7,8-Tetrahydro-5-(3-methylbenzyl)-1-[2-(4-methylpiperazin-1-yl)-
1
azepin-1(4H)-yl]acetamide (24b[13]): H NMR (400 MHz, [D]chlo-
roform): δ = 6.66 (d, J = 2.8 Hz, 1 H, CHN), 6.47 (d, J = 2.8 Hz,
1 H, CH), 4.52 (s, 2 H, CH2N), 3.38–3.25 (m, 6 H, CH2CH3,
CH2NCO), 3.07 (s, 3 H, CH3), 2.65 (m, 2 H, CH2C), 2.02 (m, 2 H,
2-oxoethyl]pyrrolo[3,2-c]azepin-4(1H)-one (24c[8]): 1H NMR
(400 MHz, [D]chloroform): δ = 7.14 (m, 1 H, CH arom.), 7.08–
6.99 (m, 3 H, CH arom.), 6.79 (d, J = 3.2 Hz, 1 H, CHN), 6.50 (d,
J = 3.2 Hz, 1 H, CH), 4.68 (s, 2 H, CH2Ph), 4.55 (s, 2 H, CH2N),
CH2CH2CH2), 1.16 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.09 (t, J = 3.59 (m, 2 H, CH2NCH2), 3.43 (m, 2 H, CH2NCH2), 3.33 (m, 2
7.2 Hz, 3 H, CH2CH3) ppm. LC–MS: m/z = 278 [M + H]+ (Phe-
H, CH2NCO), 2.62 (m, 2 H, CH2C), 2.32 (m, 4 H, CH2NCH3),
2.27 (m, 6 H, CH3N, CH3Ph), 1.912 (m, 2 H, CH2CH2CH2) ppm.
LC–MS: m/z = 395 [M + H]+ (Phenomenex® column, 100 %,
254 nm).
nomenex® column, 100%, 254 nm).
5-(4-Chlorobenzyl)-5,6,7,8-tetrahydro-1-[2-(4-methylpiperazin-1-yl)-
2-oxoethyl]pyrrolo[3,2-c]azepin-4(1H)-one (24c[3]): 1H NMR
(400 MHz, [D]chloroform): δ = 7.25 (m, 4 H, CH arom.), 6.76 (d, 5,6,7,8-Tetrahydro-5-(4-methylbenzyl)-1-[2-(4-methylpiperazin-1-yl)-
J = 2.4 Hz, 1 H, CHN), 6.52 (d, J = 2.4 Hz, 1 H, CH), 4.68 (s, 2 2-oxoethyl]pyrrolo[3,2-c]azepin-4(1H)-one (24c[9]): 1H NMR
H, CH2Ph), 4.56 (s, 2 H, CH2N), 3.61 (m, 2 H, CH2NCH2), 3.44 (400 MHz, [D]chloroform): δ = 7.165 (d, J = 8 Hz, 2 H, CH arom.),
(m, 2 H, CH2NCH2), 3.34 (m, 2 H, CH2NCO), 2.64 (m, 2 H, 7.07 (d, J = 8 Hz, 2 H, CH arom.), 6.77 (d, J = 2.8 Hz, 1 H, CHN),
CH2C), 2.38 (m, 4 H, CH2NCH3), 2.28 (s, 3 H, CH3N), 1.92 (m,
2 H, CH2CH2CH2) ppm. 13C NMR ([D]chloroform): δ = 166.4,
165.0, 137.0, 133.0, 129.5, 128.6, 121.6, 117.5, 111.80, 54.9, 54.5,
51.4, 48.7, 47.6, 46.0, 44.8, 42.2, 26.1 ppm. LC–MS: m/z = 415 [M
+ H]+ (Phenomenex® column, 100%, 254 nm).
6.51 (d, J = 8 Hz, 1 H, CH), 4.68 (s, 2 H, CH2Ph), 4.55 (s, 2 H,
CH2N), 3.60 (m, 2 H, CH2NCH2), 3.43 (m, 2 H, CH2NCH2), 3.33
(m, 2 H, CH2NCO), 2.63 (m, 2 H, CH2C), 2.37 (m, 4 H,
CH2NCH3), 2.28 (m, 6 H, CH3Ph, CH3N), 1.90 (m, 2 H,
CH2CH2CH2) ppm. LC–MS: m/z = 395 [M + H]+ (Phenomenex®
column, 100%, 254 nm).
5-(2-Fluorobenzyl)-5,6,7,8-tetrahydro-1-[2-(4-methylpiperazin-1-yl)-
2-oxoethyl]pyrrolo[3,2-c]azepin-4(1H)-one (24c[4]): 1H NMR 5,6,7,8-Tetrahydro-5-(3-methoxybenzyl)-1-[2-(4-methylpiperazin-1-
1
(400 MHz, [D]chloroform): δ = 7.35 (m, 1 H, CH arom.), 7.16 (m,
1 H, CH arom.), 7.04–6.94 (m, 2 H, CH arom.), 6.71 (d, J = 2.8 Hz,
1 H, CHN), 4.75 (s, 2 H, CH2Ph), 4.53 (s, 2 H, CH2N), 3.57 (m, 2
H, CH2NCH2), 3.40 (m, 4 H, CH2NCH2, CH2NCO), 2.61 (m, 2
yl)-2-oxoethyl]pyrrolo[3,2-c]azepin-4(1H)-one (24c[10]): H NMR
(400 MHz, [D]chloroform): δ = 7.18 (m, 1 H, CH arom.), 6.85 (d,
J = 7.6 Hz, 1 H, CH arom.), 6.82 (s, 1 H, CH, arom.), 6.77 (d, J
= 2.8 Hz, 1 H, CH arom.), 6.74 (d, J = 2 Hz, 1 H, CH arom.), 6.51
H, CH2C), 2.35 (m, 4 H, CH2NCH3), 2.26 (s, 3 H, CH3N), 1.92 (d, J = 2.8 Hz, 1 H, CH), 4.70 (s, 2 H, CH2Ph), 4.56 (s, 2 H,
(m, 2 H, CH2CH2CH2) ppm. LC–MS: m/z = 399 [M + H]+ (Phe-
CH2N), 3.75 (s, 3 H, CH3O), 3.60 (m, 2 H, CH2NCH2), 3.44 (m,
2 H, CH2NCH2), 3.33 (m, 2 H, CH2NCO), 2.63 (m, 2 H, CH2C),
2.37 (4 H, CH2NCH3), 2.28 (s, 3 H, CH3N), 1.92 (m, 2 H,
CH2CH2CH2) ppm. LC–MS: m/z = 411 [M + H]+ (Phenomenex®
column, 100%, 254 nm).
nomenex® column, 100%, 254 nm).
5-(3-Fluorobenzyl)-5,6,7,8-tetrahydro-1-[2-(4-methylpiperazin-1-yl)-
2-oxoethyl]pyrrolo[3,2-c]azepin-4(1H)-one (24c[5]): 1H NMR
(400 MHz, [D]chloroform): δ = 7.21 (m, 1 H, CH arom.), 7.02 (d,
J = 7.6 Hz, 1 H, CH arom.), 6.96 (d, J = 9.2 Hz, 1 H, CH arom.),
5,6,7,8-Tetrahydro-5-(4-methoxybenzyl)-1-[2-(4-methylpiperazin-1-
1
6.88 (m, 1 H, CH arom.), 6.73 (d, J = 2.4 Hz, 1 H, CHN), 6.49 (d, yl)-2-oxoethyl]pyrrolo[3,2-c]azepin-4(1H)-one (24c[11]): H NMR
J = 2.4 Hz, 1 H, CH), 4.68 (s, 2 H, CH2Ph), 4.55 (s, 2 H, CH2N),
(400 MHz, [D]chloroform): δ = 7.21 (d, J = 8.00 Hz, 2 H, CH
3.58 (m, 2 H, CH2NCH2), 3.43 (m, 2 H, CH2NCH2), 3.34 (m, 2 arom.), 6.80 (d, J = 8.00 Hz, 2 H, CH arom.), 6.77 (d, J = 2.8 Hz,
H, CH2NCO), 2.62 (m, 2 H, CH2C), 2.36 (m, 4 H, CH2NCH3),
2.26 (s, 3 H, CH3N), 1.92 (m, 2 H, CH2CH2CH2) ppm. 13C NMR
([D]chloroform): δ = 166.2, 165.9, 137.0, 136.4, 134.6, 130.7, 127.9,
127.4, 126.4, 122.8, 116.9, 110.7, 55.2, 54.9, 49.8, 48.7, 48.0, 46.3,
44.7, 42.1, 26.2, 26.1, 19.4 ppm. LC–MS: m/z = 399 [M + H]+ (Phe-
nomenex® column, 100%, 254 nm).
1 H, CHN), 6.52 (d, J = 2.8 Hz, 1 H, CH), 4.66 (s, 2 H, CH2Ph),
4.56 (s, 2 H, CH2N), 3.76 (s, 3 H, CH3O), 3.61 (m, 2 H,
CH2NCH2), 3.44 (m, 2 H, CH2NCH2), 3.34 (m, 2 H, CH2NCO),
2.62 (m, 2 H, CH2CO), 2.38 (m, 4 H, CH2NCH3), 2.29 (s, 3 H,
CH3N), 1.89 (m, 2 H, CH2CH2CH2) ppm. LC–MS: m/z = 411 [M
+ H]+ (Phenomenex® column, 100%, 254 nm).
5-(4-Fluorobenzyl)-5,6,7,8-tetrahydro-1-[2-(4-methylpiperazin-1-yl)-
5-Benzyl-5,6,7,8-tetrahydro-1-[2-(4-methylpiperazin-1-yl)-2-oxo-
2-oxoethyl]pyrrolo[3,2-c]azepin-4(1H)-one (24c[6]): 1H NMR ethyl]pyrrolo[3,2-c]azepin-4(1H)-one (24c[12]): 1H NMR (400 MHz,
(400 MHz, [D]chloroform): δ = 7.22 (d, J = 7.6 Hz, 2 H, CH [D]chloroform): δ = 7.24–7.18 (m, 5 H, CH arom.), 6.75 (d, J =
arom.), 6.93 (m, 2 H, CH arom.), 6.73 (d, J = 2.8 Hz, 1 H, CHN),
2.8 Hz, 1 H, CHN), 6.49 (d, J = 2.8 Hz, 1 H, CH), 4.71 (s, 2 H,
6.49 (d, J = 2.8 Hz, 1 H, CH), 4.66 (s, 2 H, CH2Ph), 4.54 (s, 2 H, CH2Ph), 4.54 (s, 2 H, CH2N), 3.58 (m, 2 H, CH2NCH2), 3.42 (m,
CH2N), 3.58 (m, 2 H, CH2NCH2), 3.43 (m, 2 H, CH2NCH2), 3.32 2 H, CH2NCH2), 3.33 (m, 2 H, CH2NCO), 2.61 (m, 2 H, CH2C),
2798
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2789–2800

Scaffold Preparation of Tetrahydropyrrolo-azepinones
2.35 (m, 4 H, CH2NCH3), 2.35 (s, 3 H, CH3N), 1.89 (m, 2 H, 2 H, 3.42 (m, 2 H, CH2NCH2), 3.34 (m, 2 H, CH2NCO), 2.64 (m, 2 H,
CH2CH2CH2) ppm. 13C NMR ([D]chloroform): δ = 166.2, 165.9,
139.5, 134.5, 129.0, 128.3, 127.5, 122.8, 116.9, 110.6, 55.2, 54.9,
51.7, 48.7, 46.3, 44.7, 42.1, 26.3, 26.2 ppm. LC–MS: m/z = 381 [M
+ H]+ (Phenomenex® column, 100%, 254 nm).
CH2C), 2.42 (m, CH2NCH2Ph), 1.93 (m, 2 H, CH2CH2CH2) ppm.
LC–MS: m/z = 475 [M + H]+ (Phenomenex® column, 100 %,
254 nm).
1-[2-(4-Benzylpiperazin-1-yl)-2-oxoethyl]-5-(4-fluorobenzyl)-5,6,7,8-
tetrahydropyrrolo[3,2-c]azepin-4(1H)-one (24d[6]): 1H NMR
(400 MHz, [D]chloroform): δ = 7.34–7.23 (m, 7 H, CH arom.), 6.95
(t, J = 8.80Hz, 2 H, CH arom.), 6.75 (d, J = 2.8 Hz, 1 H, CHN),
6.50 (d, J = 2.8 Hz, 1 H, CH), 4.67 (s, 2 H, CONCH2Ph), 4.54 (s,
5,6,7,8-Tetrahydro-5-methyl-1-[2-(4-methylpiperazin-1-yl)-2-oxo-
ethyl]pyrrolo[3,2-c]azepin-4(1H)-one (24c[13]): 1H NMR (400 MHz,
[D]chloroform): δ = 6.59 (d, J = 2.8 Hz, 1 H, CHN), 6.42 (d, J =
2.8 Hz, 1 H, CH), 4.53 (s, 2 H, CH2N), 3.54 (m, 2 H, CH2NCH2),
3.39 (m, 2 H, CH2NCH2), 3.33 (m, 2 H, 2 H, CH2NCO), 3.01 (s, 2 H, CH2N), 3.59 (m, 2 H, CH2NCH2), 3.50 (s, 2 H, NCH2Ph),
3 H, CH3NCO), 2.60 (m, 2 H, CH2C), 2.31 (m, 4 H, CH2NCH3), 3.42 (m, 2 H, CH2NCH2), 3.33 (m, 2 H, CH2NCO), 2.62 (m, 2 H,
2.22 (s, 3 H, CH3N), 1.98 (m, 2 H, CH2CH2CH2) ppm. LC–MS: C H 2 C ) , 2 . 4 2 ( m , 4 H , C H 2 N C H 2 P h ) , 1 . 9 0 ( m , 2 H ,
m/z = 305 [M + H]+.
CH2CH2CH2) ppm. LC–MS: m/z = 475 [M + H]+ (Phenomenex®
column, 100%, 254 nm).
1-[2-(4-Benzylpiperazin-1-yl)-2-oxoethyl]-5-(2-chlorobenzyl)-5,6,7,8-
tetrahydropyrrolo[3,2-c]azepin-4(1H)-one (24d[1]): 1H NMR 1-[2-(4-Benzylpiperazin-1-yl)-2-oxoethyl]-5,6,7,8-tetrahydro-5-(2-
(400 MHz, [D]chloroform): δ = 7.27–7.24 (m, 7 H, CH arom.), 7.16
(m, 2 H, CH arom.), 6.76 (d, J = 3.2 Hz, 1 H, CHN), 6.51 (d, J = (400 MHz, [D]chloroform): δ = 7.34–7.24 (m, 5 H, CH arom.), 7.16
3.2 Hz, 1 H, CH), 4.85 (s, 2 H, CONCH2Ph), 4.56 (s, 2 H, CH2N), (m, 4 H, CH arom.), 6.76 (d, J = 3.2 Hz, 1 H, CHN), 6.51 (d, J =
methylbenzyl)pyrrolo[3,2-c]azepin-4(1H)-one (24d[7]): 1H NMR
3.61 (m, 2 H, CH2NCH2), 3.51 (s, 2 H, NCH2Ph), 3.41 (m, 4 H, 3.2 Hz, 1 H, CH), 4.74 (s, 2 H,CONCH2Ph), 4.54 (s, 2 H, CH2N),
CH2NCH2, CH2NCO), 2.66 (m, 2 H, CH2C), 2.43 (m, 4 H, 3.60 (m, 2 H, CH2NCH2), 3.50 (s, 2 H, NCH2Ph), 3.42 (m, 2 H,
CH2NCH2Ph), 1.98 (m, 2 H, CH2CH2CH2) ppm. 13C NMR ([D]- CH2NCH2), 3.32 (m, 2 H, CH2NCO), 2.63 (m, 2 H, CH2C), 2.42
chloroform): δ = 166.6, 165.1, 137.4, 135.7, 133.7, 133.3, 129.5,
129.4, 129.1, 128.4, 128.3, 127.4, 127.0, 121.6, 117.4, 111.7, 62.8,
52.9, 52.6, 49.5, 48.7, 48.1, 45.0, 42.4, 26.1 ppm. LC–MS: m/z =
491 [M + H]+ (Phenomenex® column, 100%, 254 nm).
(m, 4 H, CH2NCH2Ph), 2.29 (s, 3 H, CH3), 1.88 (m, 2 H,
CH2CH2CH2) ppm. 13C NMR ([D]chloroform): δ = 137.4, 136.6,
135.9, 133.6, 130.4, 129.1, 128.4, 127.4, 127.1, 126.0, 121.5, 117.6,
111.7, 62.8, 52.9, 52.6, 49.5, 48.7, 47.1, 45.0, 42.4, 26.0, 19.3 ppm.
LC–MS: m/z = 471 [M + H]+ (Phenomenex® column, 100 %,
254 nm).
1-[2-(4-Benzylpiperazin-1-yl)-2-oxoethyl]-5-(3-chlorobenzyl)-5,6,7,8-
tetrahydropyrrolo[3,2-c]azepin-4(1H)-one (24d[2]): 1H NMR
(400 MHz, [D]chloroform): δ = 7.32–7.24 (m, 6 H, CH arom.),
7.20–7.14 (m, 3 H, CH arom.), 6.75 (d, J = 2.8 Hz, 1 H, CHN),
6.50 (d, J = 2.8 Hz, 1 H, CH), 4.69 (s, 2 H, CONCH2Ph), 4.55 (s,
1-[2-(4-Benzylpiperazin-1-yl)-2-oxoethyl]-5,6,7,8-tetrahydro-5-(3-
methylbenzyl)pyrrolo[3,2-c]azepin-4(1H)-one (24d[8]): 1H NMR
(400 MHz, [D]chloroform): δ = 7.35–7.24 (m, 5 H, CH arom.), 7.16
2 H, CH2N), 3.60 (m, 2 H, CH2NCH2), 3.50 (s, 2 H, NCH2Ph), (m, 1 H, CH arom.), 7.10–7.01 (m, 3 H, CH arom.), 6.78 (d, J =
3.42 (m, 2 H, CH2NCH2), 3.34 (m, 2 H, CH2NCO), 2.63 (m, 2 H, 2.8 Hz, 1 H, CHN), 6.51 (d, J = 2.8 Hz, 1 H, CH), 4.70 (s, 2 H,
C H 2 C ) , 2 . 4 2 ( m , 4 H , C H 2 N C H 2 P h ) , 1 . 9 3 ( m , 2 H , CONCH2Ph), 4.55 (s, 2 H, CH2N), 3.60 (m, 2 H, CH2NCH2), 3.50
CH2CH2CH2) ppm. LC–MS: m/z = 491 [M + H]+ (Phenomenex®
column, 100%, 254 nm).
(s, 2 H, NCH2Ph), 3.42 (s, 2 H, CH2NCH2), 3.34 (m, 2 H,
CH2NCO), 2.63 (m, 2 H, CH2C), 2.42 (m, 4 H, CH2NCH2Ph),
2.30 (s, 3 H, CH3), 1.91 (m, 2 H, CH2CH2CH2) ppm. LC–MS: m/z
= 471 [M + H]+ (Phenomenex® column, 100%, 254 nm).
1-[2-(4-Benzylpiperazin-1-yl)-2-oxoethyl]-5-(4-chlorobenzyl)-5,6,7,8-
tetrahydropyrrolo[3,2-c]azepin-4(1H)-one (24d[3]): 1H NMR
(400 MHz, [D]chloroform): δ = 7.32–7.20 (m, 9 H, CH arom.), 6.75
(d, J = 3.2 Hz, 1 H, CHN), 6.51 (d, J = 3.2 Hz, 1 H, CH), 4.67 (s,
1-[2-(4-Benzylpiperazin-1-yl)-2-oxoethyl]-5,6,7,8-tetrahydro-5-(3-
methylbenzyl)pyrrolo[3,2-c]azepin-4(1H)-one (24d[9]): 1H NMR
2 H, CONCH2Ph), 4.55 (s, 2 H, CH2N), 3.60 (m, 2 H, CH2NCH2), (400 MHz, [D]chloroform): δ = 7.35–7.24 (m, 5 H, CH arom.), 7.17
3.50 (s, 2 H, NCH2Ph), 3.42 (m, 2 H, CH2NCH2), 3.33 (m, 2 H, (d, J = 8 Hz, 2 H, CH arom.), 7.07 (d, J = 8.00 Hz, 2 H, CH
CH2NCO), 2.63 (m, 2 H, CH2C), 2.42 (m, 4 H, CH2NCH2Ph),
1.91 (s, 2 H, CH2CH2CH2) ppm. LC–MS: m/z = 491 [M + H]+
(Phenomenex® column, 100%, 254 nm).
arom.), 6.76 (d, J = 3.2 Hz, 1 H, CHN), 6.50 (d, J = 3.2 Hz, 1 H,
CH), 4.68 (s, 2 H, CONCH2Ph), 4.54 (s, 2 H, CH2N), 3.60 (m, 2
H, CH2NCH2), 3.50 (s, 2 H, NCH2Ph), 3.42 (m, 2 H, CH2NCH2),
3.33 (m, 2 H, CH2NCO), 2.62 (m, 2 H, CH2C), 2.42 (m, 4 H,
C H 2 N C H 2 P h ) , 2 . 2 9 ( s , 3 H , C H 3 ) , 1 . 8 9 ( m , 2 H ,
CH2CH2CH2) ppm. LC–MS: m/z = 471 [M + H]+ (Phenomenex®
column, 100%, 254 nm).
1-[2-(4-Benzylpiperazin-1-yl)-2-oxoethyl]-5-(2-fluorobenzyl)-5,6,7,8-
tetrahydropyrrolo[3,2-c]azepin-4(1H)-one (24d[4]): 1H NMR
(400 MHz, [D]chloroform): δ = 7.40 (m, 1 H, CH arom.), 7.32–
7.16 (m, 6 H, CH arom.), 7.06–6.97 (m, 2 H, CH arom.), 6.74 (d,
J = 3.2 Hz, 1 H, CHN), 6.50 (d, J = 3.2 Hz, 1 H, CH), 4.77 (s, 2 1-[2-(4-Benzylpiperazin-1-yl)-2-oxoethyl]-5,6,7,8-tetrahydro-5-(3-
H, CONCH2Ph), 4.54 (s, 2 H, CH2N), 3.60 (m, 2 H, CH2NCH2), methoxybenzyl)pyrrolo[3,2-c]azepin-4(1H)-one (24d[10]): 1H NMR
3.50 (s, 2 H, NCH2Ph), 3.44–3.40 (m, 4 H, CH2NCH2, CH2NCO), (400 MHz, [D]chloroform): δ = 7.35–7.24 (m, 5 H, CH arom.), 7.19
2.62 (m, 2 H, CH2C), 2.42 (m, 4 H, CH2NCH2Ph), 1.95 (m, 2 H,
CH2CH2CH2) ppm. LC–MS: m/z = 475 [M + H]+ (Phenomenex®
column, 100%, 254 nm).
(t, J = 8 Hz, 1 H, CH arom.), 6.69 (m, 3 H, CH arom.), 6.78 (d, J
= 2.8 Hz, 1 H, CHN), 6.52 (d, J = 2.8 Hz, 1 H, CH), 4.71 (s, 2 H,
CONCH2Ph), 4.55 (s, 2 H, CH2N), 3.76 (s, 3 H, CH3O), 3.61 (m,
2 H, CH2 NCH2 ), 3.51 (s, 2 H, NCH2 Ph), 3.42 (m, 2 H,
CH2NCH2), 3.35 (m, 2 H, CH2NCO), 2.64 (m, 2 H, CH2C), 2.42
(m, 4 H, CH2NCH2Ph), 1.93 (m, 2 H, CH2CH2CH2) ppm. LC–
MS: m/z = 487 [M + H]+ (Phenomenex® column, 100%, 254 nm).
1-[2-(4-Benzylpiperazin-1-yl)-2-oxoethyl]-5-(3-fluorobenzyl)-5,6,7,8-
tetrahydropyrrolo[3,2-c]azepin-4(1H)-one (24d[5]): 1H NMR
(400 MHz, [D]chloroform): δ = 7.34–7.20 (m, 6 H, CH arom.), 7.04
(d, J = 7.6 Hz, 1 H, CH arom.), 6.98 (d, J = 9.6 Hz, 1 H, CH
arom.), 6.89 (m, 1 H, CH arom.), 6.75 (d, J = 2.8 Hz, 1 H, CHN),
6.50 (d, J = 2.8 Hz, 1 H, CH), 4.71 (s, 2 H, CONCH2Ph), 4.55 (s,
1-[2-(4-Benzylpiperazin-1-yl)-2-oxoethyl]-5,6,7,8-tetrahydro-5-(4-
methoxybenzyl)pyrrolo[3,2-c]azepin-4(1H)-one (24d[11]): 1H NMR
2 H, CH2N), 3.60 (m, 2 H, CH2NCH2), 3.50 (s, 2 H, NCH2Ph), (400 MHz, [D]chloroform): δ = 7.35–7.20 (m, 7 H, CH arom.), 6.81
Eur. J. Org. Chem. 2008, 2789–2800
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2799

L. Piras, E. Genesio, C. Ghiron, M. Taddei
FULL PAPER
Yoshida, C. Takiguchi, T. Miyazaki, Chem. Pharm. Bull. 1999,
47, 246.
(d, J = 8.4 Hz, 2 H, CH arom.), 6.77 (d, J = 3.2 Hz, 1 H, CHN),
6.51 (d, J = 3.2 Hz, 1 H, CH), 4.66 (s, 2 H, CONCH2Ph), 4.54 (s,
2 H, CH2N), 3.76 (s, 3 H, CH3O), 3.60 (m, 2 H, CH2NCH2), 3.50
(s, 2 H, NCH2Ph), 3.42 (m, 2 H, CH2NCH2), 3.33 (m, 2 H,
CH2NCO), 2.62 (m, 2H CH2C), 2.42 (m, 4 H, CH2NCH2Ph), 1.89
(m, 2 H, CH2CH2CH2) ppm. 13C NMR ([D]chloroform): δ = 137.4,
133.5, 130.5, 129.4, 129.1, 128.4, 127.4, 121.5, 117.7, 113.9, 111.7,
62.8, 55.3, 52.9, 52.6, 51.1, 48.6, 47.2, 45.0, 42.3, 26.7, 26.1 ppm.
LC–MS: m/z = 487 [M + H]+ (Phenomenex® column, 100 %,
254 nm).
[6]
[7]
F. Gosselin, W. D. Lubell, J. Org. Chem. 2000, 65, 2163.
H. Greger, Planta Med. 2006, 72, 99; J. Schinnerl, E. Kal-
tenegger, T. Pacher, S. Vajrodaya, O. Hofer, H. Greger, Mon-
atsh. Chem. 2005, 136, 1671; A. C. Barrios Sosa, K. Yakushijin,
D. A. Horne, J. Org. Chem. 2002, 67, 4498.
To the best of our knowledge the only syntheses applicable to
the preparation of pyrrolo-azepine arrays are reported in: M.
Nath, R. Mukhopadhyay, A. Bhattacharjya, Org. Lett. 2006,
8, 317; F. Gosselin, W. D. Lubell, J. Org. Chem. 2000, 65, 2163.
K. Hino, Y. Nagai, H. Uno, Y. Matsuda, M. Oka, T. Karasawa,
J. Med. Chem. 1988, 31, 107.
C. Daqher, R. Hanna, P. B. Terentiev, Y. G. Boundel, B. I.
Marksimof, N. S. Kulikov, J. Heterocycl. Chem. 1983, 20, 989.
H. Stetter, Chem. Ber. 1955, 88, 271.
When acidification was carried out without previous removal
of MeOH, a mixture of the acid and the corresponding methyl
ester was obtained.
[8]
[9]
5-Benzyl-1-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]-5,6,7,8-tetrahy-
1
dropyrrolo[3,2-c]azepin-4(1H)-one (24d[12]): H NMR (400 MHz,
[10]
[D]chloroform): δ = 7.35–7.21 (m, 10 H, CH arom.), 6.78 (d, J =
2.8 Hz, 1 H, CHN), 6.51 (d, J = 2.8 Hz, 1 H, CH), 4.73 (s, 2 H,
CONCH2Ph), 4.54 (s, 2 H, CH2N), 3.60 (m, 2 H, CH2NCH2), 3.50
(s, 2 H, NCH2Ph), 3.42 (s, 2 H, CH2NCH2), 3.35 (m, 2 H,
CH2NCO), 2.63 (m, 2H CH2C), 2.42 (m, 4 H, CH2NCH2Ph), 1.91
(m, 2 H, CH2CH2CH2) ppm. LC–MS: m/z = 457 [M + H]+
(Phenomenex® column, 100%, 254 nm).
[11]
[12]
[13]
H. Stetter, R. Lauterbach, Liebigs Ann. Chem. 1962, 655, 20;
see also: E. Bellur, P. Langer, Tetrahedron Lett. 2006, 13, 2151;
S. Wu, A. Fluxe, J. M. Janusz, J. B. Sheffer, G. Browning, B.
Blass, K. Cobum, R. Hedges, M. Murawsky, B. Fang, G. M.
Fadayel, M. Hare, L. Djandjighian, Bioorg. Med. Chem. Lett.
2006, 16, 5859.
1-[2-(4-Benzylpiperazin-1-yl)-2-oxoethyl]-5,6,7,8-tetrahydro-5-meth-
1
ylpyrrolo[3,2-c]azepin-4(1H)-one (24d[13]): H NMR (400 MHz,
[D]chloroform): δ = 7.34–7.24 (m, 5 H, CH arom.), 6.65 (d, J =
2.8 Hz, 1 H, CHN), 6.45 (d, J = 2.8 Hz, 1 H, CH), 4.52 (s, 2 H, [14]
M. Matsumoto, N. Watanabe, Heterocycles 1984, 22, 2313.
As glycine could not be used as the solvent in this reaction, we
used a mixture of ethanol and water as the solvent. For our
recent application of MW to the synthesis of heterocycles, see:
S. Ferrini, F. Ponticelli, M. Taddei, Org. Lett. 2007, 9, 69.
Oxime 11 was obtained as a single isomer after crystallisation.
Z configuration was assigned to 11 on the basis of the structure
of product 12, obtained by Beckmann rearrangement.
Y. Furuya, K. Ishihara, H. Yamamoto, J. Am. Chem. Soc.
2005, 127, 11240, and references cited therein.
[15]
CH2N), 3.58 (m, 2 H, CH2NCH2), 3.49 (s, 2 H, NCH2Ph), 3.41
(m, 2 H, CH2NCH2), 3.36 (m, 2 H, CH2NCO), 3.06 (s, 3 H, CH3),
2.62 (m, 2 H, CH2C), 2.40 (m, 4 H, CH2NCH2Ph), 2.01 (m, 2 H,
CH2CH2CH2) ppm. 13C NMR ([D]chloroform): δ = 166.5, 165.2,
[16]
137.4, 133.4, 129.1, 128.4, 127.4, 121.5, 117.6, 111.2, 62.8, 52.9,
52.6, 49.8, 48.6, 44.9, 42.3, 36.6, 25.8 ppm. LC–MS: m/z = 381 [M
+ H]+ (Phenomenex® column, 100%, 254 nm).
[17]
[18]
DMTMM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmor-
pholinium chloride. See: A. Falchi, G. Giacomelli, A. Por-
cheddu, M. Taddei, Synlett 2000, 277.
Acknowledgments
This work was financially supported by Siena Biotech SpA.
[19]
The 1H and 13C NMR spectra of 14 showed twin signals for
most of the resonances, suggesting the presence of a mixture
of E/Z diastereoisomers.
[1] D. S. Tan, Nature Chem. Biol. 2005, 1, 74; M. Cano, S. Balas-
[20]
Attempts to prepare the oxime starting from ethyl ester 7, pre-
viously isolated from the microwave-assisted reaction of 2
(Scheme 2), gave a mixture of the E and Z isomers, which pro-
duced, as expected, a mixture of pyrrolo-azepinones.
This low reactivity may be attributed to the poor solubility of
15 in many solvents, including DMF.
C. A. Lipinski, F. Lombardo, B. W. Dominy, P. J. Feeney, Adv.
Drug Delivery Rev. 1997, 23, 3. Calculations of the parameters
in Figure 3 and Figure 4 were carried out with the software ilib
diverse 1.02, Inte:Ligand, Maria Enzersdorf, Austria.
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