A Short and Efficient Approach to Pyrrolo[2,1- a ]isoquinoline and Pyrrolo[2,1-a]benzazepine Derivatives

Article abstract of DOI:10.1055/s-0035-1561398

A Br?nsted acid promoted intramolecular Friedel-Crafts cyclization of β-benzoyl- and β-acetylpyrrol-2(5H)-one derivatives tethered via nitrogen to an electron-rich arene nucleus is developed. Using this efficient methodology, various pyrrolo[2,1-a]isoquinoline and pyrrolo[2,1-a]benzazepine derivatives are prepared in a two-step sequence starting from readily available ethyl (Z)-3-bromomethyl-4-oxo-4-phenylbut-2-enoate or ethyl (Z)-3-bromomethyl-4-oxopent-2-enoate.

Full text of DOI:10.1055/s-0035-1561398

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, 1502–1517
paper
1502
K. Jebali et al.
Paper
Synthesis
A Short and Efficient Approach to Pyrrolo[2,1-a]isoquinoline and
Pyrrolo[2,1-a]benzazepine Derivatives
Khaoula Jebalia,b
CO2Et
Aurélien Planchata
Hassen Amri*b
O
O
Br
R1
R2 TFA (2.5 equiv)
neat, r.t.
N
Monique Mathé-Allainmat*a
Jacques Lebreton*a
O
N
PhMe
R1
R1
+
n
n
H2N
40 °C
R2
O
O
n
R2
n = 0–2
R
R
a Université de Nantes, CNRS, Laboratoire CEISAM-UMR CNRS
6230, Faculté des Sciences et des Techniques, 2 rue de la
Houssinière, BP 92208, 44322 Nantes Cedex 3, France
jacques.lebreton@univ-nantes.fr
1 = Ph, Me
2 = electron-donating group
15 examples with
19–79% overall yield
monique.mathe@univ-nantes.fr
b Département de Chimie, Université de Tunis El Manar, Faculté
des Sciences, Campus, 2092 Tunis, Tunisia
hassen.amri@fst.rnu.tn
Received: 15.01.2016
Accepted after revision: 12.02.2016
Published online: 09.03.2016
2004, exhibits antibacterial activity against respiratory bac-
teria4 such as Staphylococcus aureus, Streptococcus pneumo-
niae and Klebsiella pneumoniae, as well as moderate antivi-
ral activity against influenza viruses A and B. Interestingly,
(+)-oleracein E, the antipode of (–)-trolline isolated from
Portulaca oleracea L., displays 1,1-diphenyl-2-picryl-hydra-
zyl (DPPH) radical scavenging activity5 and can be regarded
as an antioxidant. Lamellarin D,6 isolated from the marine
mollusk, Lamellaria, has been identified as a potent inhibi-
tor of human topoisomerase I inducing apoptosis through a
mitochondria-mediated pathway.7 Jamtine, an antiglycemic
alkaloid, is found in the aqueous extract of leaves of the
climbing shrub, Cocculus hirsutus, which is commonly used
in folk medicine, mainly in Pakistan.8 Other alkaloids isolat-
ed from the Erythrina species, such as (+)-erysotramidine,
present a large range of pharmacological effects including
sedative, hypotensive, muscle-relaxant, anticonvulsant and
CNS-depressant activities.9 In the field of the potential
treatment of inflammatory diseases, synthetic compound 1
inhibits PARP-1 (also known as Poly [ADP-ribose] poly-
merase 1) activity and protects cells against oxidative DNA
damage.10
DOI: 10.1055/s-0035-1561398; Art ID: ss-2016-z0032-op
Abstract A Brønsted acid promoted intramolecular Friedel–Crafts cy-
clization of β-benzoyl- and β-acetylpyrrol-2(5H)-one derivatives teth-
ered via nitrogen to an electron-rich arene nucleus is developed. Using
this efficient methodology, various pyrrolo[2,1-a]isoquinoline and pyr-
rolo[2,1-a]benzazepine derivatives are prepared in a two-step sequence
starting from readily available ethyl (Z)-3-bromomethyl-4-oxo-4-phen-
ylbut-2-enoate or ethyl (Z)-3-bromomethyl-4-oxopent-2-enoate.
Key words Friedel–Crafts reaction, nitrogen heterocycles, alkaloids,
lactams, Brønsted acids
The 1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline1
ring system is present in many naturally occurring prod-
ucts, as either a simple tricyclic pyrroloisoquinoline core A
or as more complex compounds bearing additional fused
rings, as well as closed structures such as 1H-pyrrolo[2,1-
a]benzazepine B (Figure 1).2
6a
7a
Numerous methodologies have been developed over the
years enabling efficient access to a range of pyrrolo[2,1-
a]isoquinoline- and pyrrolo[2,1-a]benzazepine-based natu-
ral products and related compounds.11 Although many of
these strategies have proved effective for the synthesis of
these products, N-acyliminium chemistry has emerged as
one of the most efficient methodologies. Since the pioneer-
ing work of Speckamp12 and others,13 the intramolecular
acid-mediated cyclization of N-acyliminium ion intermedi-
ates,14 or related species,15 on electron-rich aromatic rings
as π-nucleophile partners has been widely used for the syn-
thesis of these N-heterocyclic compounds. In this context, it
10b
1
N
11b
3
10a
N
11a
2
1
B
A
Figure 1 Frameworks of pyrrolo[2,1-a]isoquinoline A and pyrrolo[2,1-
a]benzazepine B
The pyrroloisoquinoline ring system A is an important
privileged core structure that forms the nucleus of numer-
ous natural and synthetic biologically active compounds as
depicted in Figure 2. For example, (S)-(–)-trolline,3 an alka-
loid isolated from the flowers of Trollius chinensis Bunge in
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1502–1517

1503
K. Jebali et al.
Paper
Synthesis
HO
HO
HO
HO
O
N
N
N
O
O
HO
MeO
H
H
O
(R)-(+)-oleracein E
(S)-(–)-trolline
HO
OH
MeO
MeO
lamellarin D
MeO
MeO
MeO
MeO
MeO
N
N
N
O
O
HO
HO
H
MeO2C
MeO
(+)-jamtine
(+)-erysotramidine
1
Figure 2 Selected pyrrolo[2,1-a]isoquinoline compounds
is important to mention the recent example of a Friedel–
Crafts-type cyclization of hydroxylactam derivatives via N-
acyliminium species catalyzed with tin(IV) triflimidate
[Sn(NTf2)4] as a Lewis superacid, as published by Dalla,
Duñach and co-workers.16
In continuation of our current investigations on the use
of ethyl (Z)-3-bromomethyl-4-oxo-4-phenylbut-2-enoate
(2) or ethyl (Z)-3-bromomethyl-4-oxopent-2-enoate (3) as
versatile building blocks for the preparation of novel tem-
plates for drug discovery, as well as scaffolds for combinato-
rial libraries, we herein describe a practical and original
synthetic route to the pyrrolo[2,1-a]isoquinoline and pyr-
rolo[2,1-a]benzazepine frameworks based on the retrosyn-
thesis shown in Scheme 1.
Our goal was to develop a short sequence, in just two
basic transformations, to prepare nitrogen polyheterocyclic
compounds E. In this way, condensation of reactive bro-
mide derivatives 2 or 3 with the appropriate amine N-teth-
ered to an electron-rich arene nucleus C afforded the α,β-
unsaturated γ-lactam intermediate D. The latter, by an in-
tramolecular Friedel–Crafts cyclization,17,18 via the forma-
tion of an N-acyliminium species, provided the C10a–C10b
bond formation leading to the desired target derivatives E.
It should be emphasized at this point that the presence of
an acyl group at C-1 in compounds E affords an additional
point of diversification by postsynthetic modification of
these substituted tricyclic systems.
Our synthetic efforts started with the preparation of the
required lactams for the intramolecular Friedel–Crafts cy-
clization. In previous work, we demonstrated that pyrrol-
2(5H)-one derivatives D were easily accessible through a
condensation reaction between ethyl (Z)-3-bromomethyl-
4-oxopent-2-enoate (3) in the presence of two equivalents
of amine in refluxing bromobenzene.19 However, in order to
use only one equivalent of amine, we investigated several
sets of reaction conditions without success. For example,
compound 5a (see Table 1) was formed in low yield (<10%)
when one equivalent of Et3N was used to trap the HBr
formed during the reaction (data not shown). Nevertheless,
we were pleased to note that this condensation could be
carried out in toluene at 40 °C with two equivalents of
amine, instead of refluxing bromobenzene, with the same
efficiency. In this manner, various β-benzoyl- and β-
acetylpyrrol-2(5H)-one derivatives N-tethered to an elec-
tron-rich arene moiety, such as 4a–n, were obtained in
moderate to good yields (37–85%) (see Table 1).
Having secured the preparation of a wide range of sub-
strates, we next evaluated the intramolecular Friedel–
Crafts-type Michael addition sequence. In order to identify
the most efficient conditions, we performed a systematic
optimization of this sequence using various Lewis and
Brønsted acids. For a greater electron-donating effect for
this cyclization step, we selected the substrate 5a, which
H2N
n
O
C
R2
CO2Et
Br
O
n
N
n
N
R2
X
R1
1
10a
10b
R1
X
X
R2
O
O
R1
E
D
O
2 R1 = Ph
3 R1 = Me
Scheme 1 Retrosynthesis of the target heterocyclic compounds E
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1502–1517

1504
K. Jebali et al.
Paper
Synthesis
contains an aromatic ring bearing two methoxy groups
with one located at the para position relative to the poten-
tial cyclization site.
Table 1 Synthesis of β-Benzoyl- or β-Acetyl-α,β-unsaturated γ-Lactams 5a–q
O
H2N
CO2Et
n
R2
N
R2
PhMe, 40 °C
R1
Br
n
R1
+
(1 mmol scale)
n = 0–2
O
O
4a–q
(2 equiv)
5a–q
2 R1 = Ph
3 R1 = Me
R2 = electron-donating group
Amine
Time Pyrrol-2(5H)-one
(h)
Yield (%)a
Amine
Time Pyrrol-2(5H)-one
(h)
Yield
(%)a
O
O
N
N
NH2
MeO
NH2
4
78
6
78
N
O
O
O
O
H
MeO
4a
NH
4j
MeO
OMe
5a
5j
O
OMe
OMe
N
O
MeO
MeO
NH2
NH2
5
85
24
46
N
MeO
4k
4b
O
OMe
5k
5b
O
O
N
N
MeO
NH2
O
NH2
3
37
45
69
O
O
4c
MeO
4l
MeO
O
O
OMe
5l
5c
O
O
OMe
MeO
NH2
NH2
N
N
32
59
5
48
OMe
O
OMe
OMe
O
4d
MeO
5d
4m
5m
O
OMe
NH2
O
N
NH2
O
N
6
83
5
63
MeO
OMe
MeO
4e
O
5e
4n
5n
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1502–1517

1505
K. Jebali et al.
Paper
Synthesis
Table 1 (continued)
Amine
Time Pyrrol-2(5H)-one
(h)
Yield (%)a
Amine
Time Pyrrol-2(5H)-one
(h)
Yield
(%)a
O
O
N
N
MeO
NH2
MeO
NH2
2
64
24
50
O
O
MeO
4a
4f
MeO
OMe
OMe
5f
5o
O
O
NH2
MeO
NH2
N
N
4
53
7
45
N
O
N
MeO
O
OMe
4d
4g
OMe
5g
5p
O
O
NH2
O
S
N
N
NH2
72
55
85
13
80
4h
O
O
4i
S
O
5h
5q
O
NH2
S
N
4
O
4i
S
5i
a Yields refer to those of pure isolated products after chromatography.
Attempted intramolecular cyclization of this model sub-
strate 5a in the presence of 2.5 equivalents of different Lewis
acids, such as SnBr4, TiCl4 or BCl3, at room temperature in
dichloromethane led to the recovery of unchanged starting
material (Table 2, entries 1–3) or to decomposition with
FeCl3 (Table 2, entry 4). Under the same conditions with
BF3·Et2O, a trace amount of the desired cyclized adduct 6a
was isolated (<5% yield) (Table 2, entry 5), but in refluxing
1,2-dichloroethane the yield increased to around 25% (Table
2, entry 6). In this series, AlCl3 gave the best yield with 40%
of isolated cyclized compound 6a (Table 2, entry 7). On the
other hand, AlBr3 was less efficient and only a trace amount
(<10% yield) of the desired product 6a was obtained (Table
2, entry 8). Among the tested Lewis acids, the best results
were obtained with trimethylsilyl trifluoromethanesulfon-
ate (TMSOTf) with a 62% yield of isolated cyclized com-
pound 6a being obtained (Table 2, entry 9). However, with
this moisture-sensitive Lewis acid, the presence of trifluo-
romethanesulfonic acid (TfOH) is to be expected under
these reaction conditions. So, to our delight, it transpired
that TfOH promoted the desired intramolecular Friedel–
Crafts-type Michael addition to afford compound 6a in 78%
yield by simple treatment at room temperature in dichloro-
methane (Table 2, entry 10). Moreover, when the cycliza-
tion reaction was performed with neat TFA (only 2.5 equiv-
alents), the desired compound 6a was also isolated in 78%
yield (Table 2, entry 11). Finally, we attempted this cycliza-
tion using neat acetic acid at room temperature without
success: most of the starting material was recovered un-
changed (Table 2, entry 12). When heated at reflux tem-
perature in a mixture of 1,2-dichloroethane and acetic acid,
no cyclization occurred and significant decomposition of 5a
was noted (Table 2, entry 13).
It should be pointed out that the cyclized product 6a
was formed as a single diastereoisomer within the detec-
1
tion limits of H and 13C NMR spectroscopy of the crude
mixture. The X-ray single-crystal diffraction analysis of
pure (±)-6a confirmed the trans-stereochemical relation-
ship between the benzoyl group at C-1 and the C10a–C10b
bond, as illustrated in Figure 3. To complete this study, it is
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1502–1517

1506
K. Jebali et al.
Paper
Synthesis
Table 2 Optimization of the Cyclization Conditionsa
worth noting that Dalla and co-workers recently reported
an original and efficient methodology using 1,1,2,2-tetra-
chloroethane (TCE) as the solvent at reflux (146 °C) to gen-
erate a very small amount of HCl in situ.20 This promoted
the intramolecular Friedel–Crafts cyclization of N,O-acetals
N-tethered to an electron-rich arene nucleus. Unfortunate-
ly, none of the expected compound 6a was formed in re-
fluxing TCE with our model substrate 5a. The presence of a
benzoyl group at C-4 seemed to have a significant effect on
this cascade reaction and under our conditions (vide infra).
In fact, an analogue of 6a without a benzoyl group at C-4
was successfully obtained in 84% yield from the intramolec-
ular cyclization of the corresponding N,O-acetal precursor
by refluxing in TCE.20 Although TfOH gave similar yields to
TFA, the latter was chosen for investigation with other sub-
strates as it is a cheaper reagent.
O
O
OMe
acid
N
N
Ph
Ph
OMe
O
O
5a
MeO
)-6a
OMe
(
Entry
Acid
SnBr4
Solvent
Temp (°C) Time (h)
Yield (%)b
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25
25
25
25
25
84
25
25
25
25
25
25
84
24
24
48
7
0c
0c
0c
0d
3
2
TiCl4
BCl3
3
4
FeCl3
5
BF3·Et2O
BF3·Et2O
AlCl3
24
12
48
24
16
2
6
ClCH2CH2Cl
CH2Cl2
25
40
7
7
8
AlBr3
CH2Cl2
9
TMSOTf
TfOH
CH2Cl2
62
78
78
0c
0d
10
11
12
13
CH2Cl2
e
TFA
–
6
e
AcOH
AcOH
–
4
Figure 3 Single-crystal X-ray diffraction structure of (±)-6a
ClCH2CH2Cl
48
a Acid (2.5 equiv), 5a (0.3 mmol), solvent (1.5 mL).
b Yield of isolated product.
On the basis of the experimental results, a plausible
mechanism for the formation of compound E is depicted in
Scheme 2.
The process started with the isomerization of the dou-
ble bond of the α,β-unsaturated γ-lactam derivative D via
the intermediate F to give the corresponding key enamine
intermediate G. Next, this latter intermediate G, in the pres-
c Quantitative recovery of the starting material.
d Starting material decomposed.
e Neat TFA or AcOH (2.5 equiv) was used.
O
HO
O
N
N
N
H
n
n
n
R1
R1
R1
R2
R2
R2
O
O
O
O
D
F
G
R1 = Ph, Me
H
H
O
N
N
n
n
R1
R1
R2
R2
O
O
H
H
Friedel–Crafts type Michael
addition
O
O
O
H
N
N
N
n
n
n
1
10a
10b
R1
R1
R1
H
R2
R2
O
R2
O
O
cyclization via
H
N-acyliminium ion
I
E
H
Scheme 2 Proposed mechanism of the acid-promoted cyclization
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1502–1517

1507
K. Jebali et al.
Paper
Synthesis
ence of TFA, gave the reactive N-acyliminium species H,
which subsequently underwent an aromatic π-cyclization
reaction to provide the C10a–C10b bond formation fol-
lowed by rearomatization affording the desired tricyclic
pyrrolo derivative E.21 It is interesting to note that the pres-
ence of an acyl moiety at C-4 in D could favor the isomeri-
zation of the double bond into the corresponding conjugat-
ed acylenamine G (vide infra). Moreover, in this context
from intermediate G, an acid-promoted intramolecular
Friedel–Crafts-type Michael addition process could also oc-
cur to afford the tricyclic pyrrolo derivative E via the inter-
mediate I. With optimized experimental conditions in
hand, we proceeded to investigate other α,β-unsaturated γ-
lactams N-tethered to an electron-rich arene nucleus as π-
nucleophiles. Therefore, all the subsequent cyclizations
were carried out under these optimized conditions and the
results are depicted in Table 3.
Table 3 Synthesis of β-Benzoyl- and β-Acetylpyrrol-2(5H)-one Derivatives 6a–q
O
O
N
R1
R2
N
TFA (2.5 equiv)
n
R1
n
O
neat, r.t.
R2
O
5a–q
(
)-6a–q
n = 0–2
R1 = Ph, Me
R2 = electron-donating group
En- Substrate
try
Time Product
(h)
Yield En- Substrate
(%)a try
Time Product
(h)
Yield
(%)a
O
O
O
O
N
N
N
N
Ph
1
6
78 10
6
85
O
O
O
O
NH
NH
MeO
MeO
OMe
OMe
(±)-6j
5a
(±)-6a
5j
O
O
OMe
N
N
O
OMe
Ph
O
2
5
68 11
72 no cyclization (±)-6k
0
N
O
O
OMe
OMe
5k
5b
(±)-6b
O
O
N
O
N
O
N
N
3
3
73 12
7
47
O
O
O
O
MeO
OMe
MeO
O
O
O
O
OMe
5l
(±)-6l
5c
(±)-6c
(±)-6d
O
O
N
O
O
N
N
N
4
4
78 13
7
47
OMe
OMe
O
O
OMe
OMe
O
O
MeO
MeO
5d
5m
(±)-6m
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1502–1517

1508
K. Jebali et al.
Paper
Synthesis
Table 3 (continued)
En- Substrate
try
Time Product
(h)
Yield En- Substrate
(%)a try
Time Product
(h)
Yield
(%)a
O
O
OMe
OMe
O
N
N
O
O
N
5
96 no cyclization (±)-6e
0
14
6
88
MeO
MeO
O
5e
5n
(±)-6n
O
O
N
O
O
N
N
N
6
4
67 15
24
54
O
O
O
O
MeO
MeO
OMe
OMe
OMe
OMe
5f
(±)-6f
5o
(±)-6o
O
O
O
O
N
N
N
N
7
5
86 16
12
43
O
O
N
N
O
O
MeO
MeO
OMe
5g
(±)-6g
OMe
5p
(±)-6p
O
O
O
O
N
N
N
N
8
7
85 17
13
47
O
O
O
O
O
S
S
O
5h
(±)-6h22
5q
(±)-6q
O
O
N
N
9
24
93
O
O
S
S
5i
(±)-6i
a Yields refer to those of pure isolated products after chromatography.
A series of substrates with a phenyl ring bearing elec-
tron-donating substituents afforded the corresponding de-
sired adducts 6a–d in good yields (68–78%) (Table 3, entries
1–4). The position of the electron-donating groups appar-
ently had no influence on the efficiency of the reaction.
However, with non-substituted phenyl ring compound
5e (Table 3, entry 5), no reaction was observed. This clearly
illustrates the electronic effect on this cyclization process.
Interestingly, with substrates 5a–c (Table 3, entries 1–3), no
regioisomeric product resulting from cyclization at the or-
tho position was observed, which is probably due to steric
reasons. We also examined the cyclization sequence with
substrate 5f having an N-ethyl chain with a gem-dimethyl
carbon. The cyclized compound (±)-6f was isolated in 67%
yield (Table 3, entry 6). Other substrates 5g–j, containing
electron-rich heteroaromatics such as pyrrole, furan, thio-
phene and indole, afforded the desired cyclized compounds
6g–j in good to excellent 85–93% yields (Table 3, entries 7–
10).
Next, to illustrate the synthetic viability of our method-
ology, we examined the effects of chain length with the N-
methyl derivative 5k and its corresponding N-propyl-teth-
ered substrate 5l, both with a phenyl ring bearing two me-
thoxy groups, as in our model 5a. In sharp contrast to the
latter compound 5a, no cyclization occurred with the N-
methyl-tethered substrate 5k (Table 3, entry 11). However,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1502–1517

1509
K. Jebali et al.
Paper
Synthesis
on exposure of the N-propyl-tethered substrate 5l to the
optimized reaction conditions, the desired seven-mem-
bered annulated compound 6l was obtained in a modest
47% yield (Table 3, entry 12) after purification by silica gel
chromatography. This clearly indicated that the lactam-
tethered aromatic ring with one carbon linker 5k is too
short to enable cyclization. To diversify the structural
framework further, we examined in this sequence the reac-
tivity of the naphthyl group as the π-electrophile. In this
way, substrates 5m and 5n furnished the expected cyclized
compounds 6m and 6n in 47% and 88% yields, respectively
(Table 3, entries 13 and 14). The lower yield observed with
pyrrol-2(5H)-one 5m may result from the absence of the
methoxy group at the C-7 position on the naphthyl ring
compared to substrate 5n. When the optimized conditions
were applied to the acetyl pyrrol-2-one series, starting
from the α,β-unsaturated γ-lactams 5o–q, the expected cy-
clized products 6o–q were isolated as well, although some-
what lower yields were obtained compared to their ana-
logues in the benzoyl series (Table 3, entries 15–17, for 6a
and 6o: 78% versus 54%, for 6d and 6p: 78% versus 43%, for
6i and 6q: 93% versus 47%). We assumed that the lower effi-
ciency of these cyclization reactions is due to the sensitivity
of the enolizable acetyl group to the strongly acidic reaction
conditions.
mized cyclization conditions, a higher reaction temperature
of 50 °C and a longer time were necessary to complete the
conversion and afford the desired adduct (±)-9 in 90% yield.
This indicated that the rate of the cyclization of compound
8 was slightly decreased compared to the acyl parent 5a.
After exploring different aspects of this intramolecular
sequence with various substrates, we examined the bimo-
lecular version with anisole and furan as electron-rich sub-
strates under the optimized conditions. Unfortunately, all
attempts failed with anisole, and only the formation of a
complex mixture of compounds was observed. Thus, we
turned our attention to furan. Despite screening various
conditions, starting from the α,β-unsaturated γ-lactam 5e,
the desired adduct 10 was isolated in only 32% yield after
purification on a silica gel column when the reaction was
performed in DCE as the solvent with 10 equivalents of fu-
ran in the presence of 2.5 equivalents of TFA (Scheme 4).
In summary, we have successfully developed a simple,
short and efficient stereoselective methodology for the con-
struction of 1,2,3,5,6,7,10b-hexahydropyrrolo[2,1-a]iso-
quinoline and 1H-pyrrolo[2,1-a]benzazepine frameworks
from the corresponding readily available ethyl (Z)-3-bro-
momethyl-4-oxo-4-phenylbut-2-enoate (2) or ethyl (Z)-3-
bromomethyl-4-oxopent-2-enoate (3). The key step of this
strategy involves a TFA-promoted intramolecular Friedel–
Crafts cyclization on β-acyl-α,β-unsaturated γ-lactam in-
termediates N-tethered to a π-nucleophilic aryl or a het-
eroaromatic group, which are more suitable for the Friedel–
Crafts reaction. Further improvements and applications in
the field of medicinal chemistry are underway and the re-
sults will be reported in due course.
In addition, to evaluate whether an acyl residue at the C-
4 position in compound 5a could influence the reaction by
favoring the formation of the expected conjugated enamine
G (see Scheme 2), the derivative 8 was prepared as depicted
in Scheme 3. It should be pointed out that in this case the
intramolecular aromatic π-cyclization could only occur
through an N-acyliminium ion (see Scheme 2). Under opti-
MeO
MeO
N
MeO
MeO
NH2
MeO
MeO
N
(iii)
(i), (ii)
O
O
68%
63%
(two steps)
8
7
(iv)
4a
90%
OMe
MeO
N
(
)-9
O
Scheme 3 Reagents and conditions: (i) allylbromide, K2CO3, THF; (ii) acryloyl chloride, Et3N, CH2Cl2; (iii) Grubbs’ second generation catalyst, toluene,
40 °C; (iv) TFA (2.5 equiv), 50 °C, 26 h.
O
O
TFA (2.5 equiv)
N
+
N
Ph
O
DCE, 48 h
r.t., 32%.
Ph
(10 equiv)
O
O
O
5e
(
)-10
Scheme 4 Synthesis of adduct 10 using an intermolecular process from 5e
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1502–1517

1510
K. Jebali et al.
Paper
Synthesis
All solvents used were reagent grade. Non-commercial amines 4m
and 4n were prepared as described in the literature.23 TLC was per-
formed on silica-covered aluminum (Kieselgel 60F254, Merck). Eluted
TLCs were revealed using UV radiation (λ = 254 nm) and molybdate
solution. Flash column chromatography was performed on silica gel
60 (ACC 40–63 μm 5SDS-CarloErba). Infrared spectroscopic analyses
were recorded on an IRTF Bruker Tensor, Spectrophotometer Specac
Quest ATK system (samples were neat). NMR spectra were recorded
on a Bruker AC300 (300 MHz for 1H and 75 MHz for 13C) and a Bruker
400 (400 MHz for 1H and 100 MHz for 13C) at room temperature, on
samples dissolved in an appropriate deuterated solvent. Tetramethyl-
silane (TMS) for 1H and the deuterated solvent signal for 13C were
used as references. Assignments of individual signals were carried out
using COSY, HSQC, HMBC and DEPT experiments. Chemical shifts (δ)
are expressed in parts per million (ppm), and coupling constants (J) in
hertz (Hz). CIV refers to quaternary carbons in the 13C spectra. Low-
resolution mass spectrometry (MS) were performed in the CEISAM
laboratory on a Thermo-Finnigan DSQII quadripolar spectrometer us-
ing chemical ionization (CI) at 70 eV with NH3 gas. High-resolution
mass spectrometry (HRMS in Da units) was performed on an LC-Q-
TOF (Synapt-G2 HDMS, Waters) instrument in the IRS-UN center
(Mass Spectrometry platform, Nantes), or an LTQ-Orbitrap Ther-
moFisher Scientific instrument in the Oniris center (LABERCA labora-
tory, Nantes), or a MALDI-TOF apparatus (Autoflex III from Muker) in
the INRA center (BIBS platform, Nantes).
4-Benzoyl-1-(3,4-dimethoxyphenethyl)-1,5-dihydro-2H-pyrrol-2-
one (5a)
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5a was obtained as an orange oil
in 78% yield (272 mg).
IR: 3060, 2935, 2835, 1717, 1514, 1260, 1235, 1154, 1141, 1026 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.50–7.38 (m, 5 H, HAr), 6.84–6.82 (m,
1 H, HAr), 6.72–6.69 (m, 3 H, HAr, =CH), 3.88 (s, 3 H, OCH3), 3.85 (s, 3 H,
OCH3), 3.77 (t, J = 6.0 Hz, 2 H, CH2CH2), 3.46 (d, J = 3.0 Hz, 2 H, CH2N),
2.87 (t, J = 6.0 Hz, 2 H, CH2CH2).
13C NMR (75 MHz, CDCl3): δ = 188.9 (COPh), 176.2 (CON), 149.5 (CIV),
148.3 (CIV), 147.1 (=CH), 138.4 (CIV), 131.7 (CAr), 130.3 (CIV), 128.5
(2 × CAr), 128.3 (2 × CAr), 121.3 (CAr), 117.1 (CIV), 112.1 (CAr), 111.7 (CAr),
56.1 (OCH3), 56.0 (OCH3), 44.5 (CH2), 36.3 (CH2), 35.0 (CH2).
.
MS (CI+): m/z = 352 [M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C21H21O4NNa: 374.1362; found:
374.1359.
4-Benzoyl-1-(3-methoxyphenethyl)-1,5-dihydro-2H-pyrrol-2-one
(5b)
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5b was obtained as a brown oil in
85% yield (272 mg).
IR: 2939, 2835, 1706, 1623, 1259, 1151 cm–1
.
Ethyl (Z)-3-(Bromomethyl)-4-oxo-4-phenylbut-2-enoate (2)
1H NMR (300 MHz, CDCl3): δ = 7.52–7.47 (m, 1 H, HAr), 7.40–7.37 (m,
4 H, HAr), 7.29–7.24 (m, 1 H, HAr), 6.87–6.83 (m, 1 H, HAr), 6.77–6.75
(m, 1 H, HAr), 6.72–6.70 (m, 2 H, = CH, HAr), 3.81–3.77 (m, 5 H, OCH3,
CH2CH2), 3.46 (d, J = 1.5 Hz, 2 H, CH2N), 2.90 (t, J = 6.6 Hz, 2 H,
CH2CH2).
13C NMR (75 MHz, CDCl3): δ = 188.9 (COPh), 176.2 (CON), 160.2 (CIV),
147.2 (=CH), 139.5 (CIV), 138.4 (CIV), 131.6 (CAr), 130.1 (CAr), 128.5
(2 × CAr), 128.3 (2 × CAr), 121.4 (CAr), 117.1 (CIV), 114.9 (CAr), 112.3 (CAr),
55.3 (OCH3), 44.3 (CH2), 36.2 (CH2), 35.4 (CH2).
According to previous work,19 to a stirred solution of ethyl 3-benzoyl-
but-3-enoate (10 g, 45 mmol) in CCl4 (100 mL), Br2 (55 mmol, 2.8 mL,
1.2 equiv) was added at –10 °C. The resulting mixture was left for 1 h
at r.t. and then washed with sat. Na2S2O3 solution, dried over MgSO4
and filtered. Et3N (100 mmol, 13.6 mL) was then added at –10 °C
and stirring was continued for 10 h at r.t. The mixture was filtered
and concentrated under reduced pressure. The crude residue was pu-
rified by column chromatography on silica gel (PE–Et2O, 90:10) to
give the desired product 2 as a yellow solid (10.2 g, 75%).
MS (CI+): m/z = 322 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C20H20O3N: 322.1438; found:
IR: 1716, 1664, 1270, 1208, 1154, 932, 713 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.84–7.82 (m, 2 H, HAr), 7.64–7.61 (m,
1 H, HAr), 7.52–7.48 (m, 2 H, HAr), 6.11 (s, 1 H, =CH), 4.91 (s, 2 H,
CH2Br), 4.28 (qd, J = 7.1 Hz, 2 H, CH2CH3), 1.32 (t, J = 7.1 Hz, 3 H,
CH3CH2).
13C NMR (100 MHz, CDCl3): δ = 195.5 (COPh), 164.8 (CO2Et), 149.4
(CIV), 136.0 (CIV), 133.7 (CAr), 130.0 (2 × CAr), 128.8 (2 × CAr), 126.2
(=CH), 61.5 (CH2), 23.9 (CH2Br), 14.2 (CH3).
322.1441.
1-[2-(Benzo[d][1,3]dioxol-5-yl)ethyl]-4-benzoyl-1,5-dihydro-2H-
pyrrol-2-one (5c)
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5c was obtained as a brown oil in
37% yield (123 mg).
IR: 2922, 2778, 1676, 1487, 1442, 1243, 1035 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.53–7.49 (m, 1 H, HAr), 7.46–7.38 (m,
4 H, HAr), 6.79 (d, J = 8.0 Hz, 1 H, HAr), 6.73 (t, J = 1.8 Hz, 1 H, =CH),
6.66–6.61 (m, 2 H, HAr), 5.95 (s, 2 H, CH2), 3.74 (t, J = 6.4 Hz, 2 H,
CH2CH2), 3.46 (d, J = 1.8 Hz, 2 H, CH2N), 2.84 (t, J = 6.4 Hz, 2 H,
CH2CH2).
MS (CI+): m/z = 296 [M]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C13H13O3BrNa: 318.9940; found:
.
318.9937.
β-Benzoyl-α,β-unsaturated γ-Lactams 5a–n and β-Acetyl-α,β-un-
saturated γ-Lactams 5o–q; General Procedure 1
Primary amine 4 (2.5 mmol, 2 equiv) was added dropwise to a solu-
tion of ethyl (Z)-3-(bromomethyl)-4-oxo-4-phenylbut-2-enoate (2)
(300 mg, 1.00 mmol, 1 equiv) or ethyl (Z)-3-(bromomethyl)-4-oxo-
pent-2-enoate (3) (300 mg, 1.20 mmol, 1 equiv) in toluene (7 mL) and
the solution was heated at 40 °C until total consumption of the start-
ing material. The solvent was removed in vacuo and the crude residue
was purified by column chromatography on silica gel (CH2Cl2–Et2O,
98:2 to 95:5).
13C NMR (100 MHz, CDCl3): δ = 188.9 (COPh), 176.2 (CON), 148.2 (CIV),
147.0 (=CH), 146.8 (CIV), 138.5 (CIV), 131.7 (CAr), 131.6 (CIV), 128.5
(2 × CAr), 128.3 (2 × CAr), 122.2 (CAr), 117.3 (CIV), 109.3 (CAr), 108.8 (CAr),
101.2 (CH2), 44.5 (CH2), 36.3 (CH2), 35.1 (CH2).
MS (CI+): m/z = 336 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C20H18O4N: 336.1230; found:
336.1230.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1502–1517

1511
K. Jebali et al.
Paper
Synthesis
4-Benzoyl-1-(3,5-dimethoxyphenethyl)-1,5-dihydro-2H-pyrrol-2-
IR: 3056, 2936, 2872, 1717, 1684, 1264, 1157 cm–1
.
one (5d)
1H NMR (300 MHz, CDCl3): δ = 7.54–7.36 (m, 5 H, HAr), 6.63 (t, J = 2.1
Hz, 2 H, =CH), 6.26–6.23 (m, 3 H, =CH), 4.12–4.09 (m, 2 H, CH2CH2),
3.84–3.81 (m, 2 H, CH2CH2), 3.47 (d, J = 1.8 Hz, 2 H, CH2N).
13C NMR (75 MHz, CDCl3): δ = 189.0 (COPh), 176.1 (CON), 146.2 (=CH),
138.0 (CIV), 131.7 (CAr), 128.5 (2 × CAr), 128.4 (2 × CAr), 120.7 (2 × =CH),
117.9 (CIV), 109.8 (2 × =CH), 48.4 (CH2), 44.3 (CH2), 36.0 (CH2).
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5d was obtained as a brown oil
in 59% yield (206 mg).
IR: 2936, 2838, 2853, 1706, 1594, 1458, 1204, 1150 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.53–7.35 (m, 5 H, HAr), 6.74 (t, J = 1.8
Hz, 1 H, =CH), 6.40 (t, J = 2.1 Hz, 1 H, HAr), 6.32 (d, J = 2.1 Hz, 2 H, HAr),
3.78–3.74 (m, 8 H, CH2CH2, 2 × OCH3), 3.46 (d, J = 1.8 Hz, 2 H, CH2N),
2.86 (t, J = 6.6 Hz, 2 H, CH2CH2).
13C NMR (75 MHz, CDCl3): δ = 188.9 (COPh), 176.2 (CON), 161.3
(2 × CIV), 147.2 (=CH), 140.2 (CIV), 138.4 (CIV), 131.6 (CAr), 128.5
(2 × CAr), 128.2 (2 × CAr), 117.1 (CIV), 107.1 (2 × CAr), 98.8 (CAr), 55.4
(2 × OCH3), 44.2 (CH2), 36.2 (CH2), 35.6 (CH2).
.
MS (CI+): m/z = 281 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C17H17O2N2: 281.1285; found:
281.1285.
4-Benzoyl-1-[2-(furan-2-yl)ethyl]-1,5-dihydro-2H-pyrrol-2-one
(5h)
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5h was obtained as a brown oil
in 55% yield (155 mg).
MS (CI+): m/z = 352 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C21H22O4N: 352.1543; found:
IR: 2937, 1721, 1593, 1449, 1448, 695, 660 cm–1
.
352.1545.
1H NMR (400 MHz, CDCl3): δ = 7.54–7.50 (m, 3 H, HAr), 7.43–7.39 (m,
2 H, HAr), 7.36 (d, J = 1.6 Hz, 1 H, =CH), 6.81 (t, J = 1.6 Hz, 1 H, =CH),
6.35–6.34 (m, 1 H, =CH), 6.12–6.11 (m, 1 H, =CH), 3.83 (t, J = 6.4 Hz, 2
H, CH2CH2), 3.47 (d, J = 1.6 Hz, 2 H, CH2N), 2.96 (t, J = 6.4 Hz, 2 H,
CH2CH2).
4-Benzoyl-1-phenethyl-1,5-dihydro-2H-pyrrol-2-one (5e)
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5e was obtained as a brown oil in
83% yield (241 mg).
IR: 1720, 1590, 1351, 1141, 697, 658 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 189.0 (COPh), 176.2 (CON), 151.5 (CIV),
146.7 (=CH), 142.0 (=CH), 138.5 (CIV), 131.7 (CAr), 128.5 (2 × CAr), 128.4
(2 × CAr), 117.6 (CIV), 110.7 (=CH), 108.0 (=CH), 41.5 (CH2), 36.3 (CH2),
27.8 (CH2).
MS (CI+): m/z = 282 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C17H16O3N: 282.1130; found:
1H NMR (400 MHz, CDCl3): δ = 7.36–7.05 (m, 10 H, HAr), 6.57 (t, J = 2.0
Hz, 1 H, =CH), 3.68 (t, J = 6.8 Hz, 2 H, CH2CH2), 3.33 (d, J = 2.0 Hz, 2 H,
CH2N), 2.82 (t, J = 6.8 Hz, 2 H, CH2CH2).
13C NMR (100 MHz, CDCl3): δ = 188.9 (COPh), 176.1 (CON), 147.0
(=CH), 138.4 (CIV), 137.9 (CIV), 131.6 (CAr), 129.1 (2 × CAr), 129.1
(2 × CAr), 128.4 (2 × CAr), 128.3 (2 × CAr), 127.1 (CAr), 117.1 (CIV), 44.4
(CH2), 36.2 (CH2), 35.3 (CH2).
282.1135.
MS (CI+): m/z = 292 [M + H]+.
4-Benzoyl-1-[2-(thiophen-2-yl)ethyl]-1,5-dihydro-2H-pyrrol-2-
one (5i)
HRMS (ESI+): m/z [M + Na]+ calcd for C19H17O2NNa: 314.1157; found:
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5i was obtained as a brown oil in
85% yield (253 mg).
IR: 3065, 2922, 2852, 1705, 1447, 1231, 1174 cm–1
.
314.1155.
4-Benzoyl-1-[2-(3-methoxyphenyl)-2-methylpropyl]-1,5-dihydro-
2H-pyrrol-2-one (5f)
1H NMR (300 MHz, CDCl3): δ = 7.54–7.37 (m, 5 H, HAr), 7.26 (dd, J = 5.2
Hz, J = 1.6 Hz, 1 H, =CH), 7.00 (dd, J = 3.4 Hz, J = 1.6 Hz, 1 H, =CH),
6.86–6.84 (m, 1 H, =CH), 6.83 (t, J = 1.8 Hz, 1 H, =CH), 3.81 (t, J = 6.6 Hz,
2 H, CH2CH2), 3.48 (d, J = 1.8 Hz, 2 H, CH2N), 3.17 (t, J = 6.6 Hz, 2 H,
CH2CH2).
13C NMR (75 MHz, CDCl3): δ = 189.0 (COPh), 176.2 (CON), 146.7 (=CH),
140.0 (CIV), 138.5 (CIV), 131.7 (CAr), 128.5 (2 × CAr), 128.4 (2 × CAr),
127.5 (=CH), 126.5 (=CH), 124.8 (=CH), 117.5 (CIV), 44.8 (CH2), 36.3
(CH2), 29.5 (CH2).
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5f was obtained as a yellow oil in
64% yield (223 mg).
IR: 2965, 1733, 1598, 1489, 1210 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.49–7.43 (m, 1 H, HAr), 7.35–7.22 (m,
5 H, HAr), 6.97–6.94 (m, 1 H, HAr), 6.89 (t, J = 1.8 Hz, 1 H, HAr), 6.84–
6.81 (m, 1 H, HAr), 6.22 (t, J = 1.8 Hz, 1 H, =CH), 3.79 (s, 3 H, OCH3), 3.66
(s, 2 H, CH2), 3.42 (d, J = 1.8 Hz, 2 H, CH2N), 1.37 (s, 6 H, 2 × CH3).
13C NMR (75 MHz, CDCl3): δ = 188.7 (COPh), 176.8 (CON), 160.0 (CIV),
147.6 (CIV), 147.2 (=CH), 138.5 (CIV), 131.4 (CAr), 129.9 (CAr), 128.3
(2 × CAr), 128.2 (2 × CAr), 118.9 (CAr), 116.6 (CIV), 113.3 (CAr), 111.2 (CAr),
55.4 (OCH3), 54.4 (CH2), 40.0 (CIV), 35.7 (CH2), 26.3 (2 × CH3).
MS (CI+): m/z = 298 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C17H16O2NS: 298.0896; found:
298.0896.
MS (CI+): m/z = 350 [M + H]+.
1-[2-(1H-Indol-2-yl)ethyl]-4-benzoyl-1,5-dihydro-2H-pyrrol-2-
one (5j)
HRMS (ESI+): m/z [M + H]+ calcd for C22H24O3N: 350.1751; found:
350.1757.
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5j was obtained as a yellow oil in
78% yield (256 mg).
1-[2-(1H-Pyrrol-1-yl)ethyl]-4-benzoyl-1,5-dihydro-2H-pyrrol-2-
one (5g)
IR: 2921, 1703, 1591, 1143, 734, 659 cm–1
.
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5g was obtained as a brown oil in
53% yield (148 mg).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1502–1517

1512
K. Jebali et al.
Paper
Synthesis
1H NMR (300 MHz, CDCl3): δ = 8.07 (br s, 1 H, NH), 7.56–7.54 (m, 1 H,
HAr), 7.45–7.39 (m, 2 H, HAr), 7.27–7.23 (m, 2 H, HAr), 7.16–7.10 (m, 3
H, HAr), 7.02 (d, J = 3.2 Hz, 1 H, =CH), 6.59 (t, J = 1.6 Hz, 1 H, =CH), 3.87
(t, J = 6.4 Hz, 2 H, CH2CH2), 3.43 (d, J = 1.6 Hz, 2 H, CH2N), 3.12 (t, J = 6.4
Hz, 2 H, CH2CH2).
13C NMR (75 MHz, CDCl3): δ = 188.9 (COPh), 176.3 (CON), 147.5 (=CH),
138.4 (CIV), 136.6 (CIV), 131.4 (CAr), 128.4 (2 × CAr), 128.1 (2 × CAr),
127.1 (CIV), 122.9 (CAr), 122.8 (CAr), 120.2 (CAr), 118.5 (CAr), 116.8 (CIV),
112.2 (CIV), 111.5 (CAr), 43.7 (CH2CH2), 36.3 (CH2N), 25.0 (CH2CH2).
1H NMR (300 MHz, CDCl3): δ = 7.89–7.83 (m, 3 H, HAr), 7.51–7.20 (m,
6 H, HAr), 6.95–6.91 (m, 2 H, HAr), 6.30 (t, J = 1.8 Hz, 1 H, =CH), 3.92 (s,
3 H, OCH3), 3.88 (t, J = 6.6 Hz, 2 H, CH2CH2), 3.44 (t, J = 6.6 Hz, 2 H,
CH2CH2), 3.36 (d, J = 1.8 Hz, 2 H, CH2N).
13C NMR (75 MHz, CDCl3): δ = 188.9 (COPh), 176.6 (CON), 155.1 (CIV),
147.6 (=CH), 138.3 (CIV), 133.3 (CIV), 131.3 (CAr), 129.2 (CIV), 128.9 (CAr),
128.8 (CAr), 128.2 (2 × CAr), 128.1 (2 × CAr), 127.3 (CAr), 123.9 (CAr),
122.4 (CAr), 118.9 (CIV), 116.5 (CIV), 112.8 (CAr), 56.3 (OCH3), 42.8 (CH2),
36.0 (CH2), 24.2 (CH2).
MS (CI+): m/z = 331 [M + H]+.
MS (CI+): m/z = 372 [M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C21H18N2O2Na: 353.1266; found:
HRMS (ESI+): m/z [M + H]+ calcd for C24H22O3N: 372.1594; found:
353.1266.
372.1598.
4-Benzoyl-1-(3,4-dimethoxybenzyl)-1,5-dihydro-2H-pyrrol-2-one
4-Benzoyl-1-[2-(2,7-dimethoxynaphthalen-1-yl)ethyl]-1,5-dihy-
(5k)
dro-2H-pyrrol-2-one (5n)
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5k was obtained as a brown oil
in 46% yield (155 mg).
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5n was obtained as a brown oil
in 63% yield (252 mg).
IR: 2930, 2840, 1717, 1520, 1247 cm–1
.
IR: 2938, 1681, 1262, 733, 661 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.62–7.59 (m, 2 H, HAr), 7.52–7.49 (m,
1 H, HAr), 7.45–7.39 (m, 2 H, HAr), 7.15 (t, J = 2.1 Hz, 1 H, =CH), 6.81–
6.76 (m, 3 H, HAr), 4.64 (s, 2 H, CH2Ar), 3.87 (s, 3 H, OCH3), 3.86 (s, 3 H,
OCH3), 3.57 (d, J = 2.1 Hz, 2 H, CH2N).
13C NMR (100 MHz, CDCl3): δ = 189.0 (COPh), 176.0 (CON), 149.6 (CIV),
149.3 (CIV), 145.4 (=CH), 138.6 (CIV), 131.8 (CAr), 128.6 (2 × CAr), 128.4
(CIV), 128.3 (2 × CAr), 120.5 (CAr), 118.5 (CIV), 111.5 (CAr), 111.3 (CAr),
56.1 (2 × OCH3), 46.2 (CH2), 36.6 (CH2).
1H NMR (300 MHz, CDCl3): δ = 7.78 (d, J = 9.0 Hz, 1 H, HAr), 7.72 (d, J =
9.0 Hz, 1 H, HAr), 7.46–7.40 (m, 1 H, HAr), 7.29–7.24 (m, 2 H, HAr), 7.18
(d, J = 2.7 Hz, 1 H, HAr), 7.13 (d, J = 9.0 Hz, 1 H, HAr), 7.04–6.99 (m, 3 H,
HAr), 6.41 (t, J = 1.8 Hz, 1 H, =CH), 3.93 (s, 3 H, OCH3), 3.91 (s, 3 H,
OCH3), 3.86 (t, J = 6.6 Hz, 2 H, CH2CH2), 3.40 (t, J = 6.6 Hz, 2 H, CH2CH2),
3.35 (d, J = 1.8 Hz, 2 H, CH2N).
13C NMR (75 MHz, CDCl3): δ = 188.9 (COPh), 176.7 (CON), 159.0 (CIV),
155.6 (CIV), 147.7 (=CH), 138.4 (CIV), 134.8 (CIV), 131.4 (CAr), 130.3 (CAr),
128.6 (CAr), 128.2 (2 × CAr), 128.1 (2 × CAr), 124.7 (CIV), 117.5 (CIV),
116.6 (CAr), 116.5 (CIV), 110.0 (CAr), 100.9 (CAr), 56.2 (OCH3), 55.4
(OCH3), 42.5 (CH2), 36.1 (CH2), 24.3 (CH2).
MS (CI+): m/z = 338 [M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C20H19O4NNa: 360.13628; found:
360.13593.
MS (CI+): m/z = 402 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C25H24O4N: 402.1700; found:
402.1704.
4-Benzoyl-1-[3-(3,4-dimethoxyphenyl)propyl]-1,5-dihydro-2H-
pyrrol-2-one (5l)
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5l was obtained as a brown oil in
69% yield (250 mg).
4-Acetyl-1-(3,4-dimethoxyphenethyl)-1,5-dihydro-2H-pyrrol-2-
one (5o)
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5o was obtained as a yellow oil
in 50% yield (144 mg).
IR: 3060, 2924, 2853, 1704, 1514, 1234, 1155 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.66–7.63 (m, 2 H, HAr), 7.57–7.52 (m,
1 H, HAr), 7.49–7.43 (m, 2 H, HAr), 7.16 (t, J = 1.8 Hz, 1 H, =CH), 6.78–
6.75 (m, 1 H, HAr), 6.96–6.66 (m, 2 H, HAr), 3.84 (s, 3 H, OCH3), 3.83 (s, 3
H, OCH3), 3.56 (t, J = 7.2 Hz, 2 H, CH2), 3.50 (d, J = 1.8 Hz, 2 H, CH2), 2.59
(t, J = 7.5 Hz, 2 H, CH2), 1.94 (qt, J = 7.5 Hz, J = 7.2 Hz, 2 H, CH2).
13C NMR (75 MHz, CDCl3): δ = 188.9 (COPh), 176.3 (CON), 149.0 (CIV),
147.6 (CIV), 146.3 (CAr), 138.6 (CIV), 133.0 (CIV), 131.8 (CAr), 128.7
(2 × CAr), 128.2 (2 × CAr), 120.2 (CAr), 118.2 (CIV), 111.6 (CAr), 111.4 (CAr),
56.0 (OCH3), 55.9 (OCH3), 42.4 (CH2), 36.5 (CH2), 32.5 (CH2), 30.6 (CH2).
IR: 2937, 1708, 1515, 1263, 1157 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.97 (t, J = 1.6 Hz, 1 H, =CH), 6.80–6.67
(m, 3 H, HAr), 3.84 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.74 (t, J = 6.8 Hz,
2 H, CH2CH2), 3.25 (d, J = 2.0 Hz, 2 H, CH2N), 2.85 (t, J = 6.8 Hz, 2 H,
CH2CH2), 2.12 (s, 3 H, COCH3).
13C NMR (100 MHz, CDCl3): δ = 190.9 (COCH3), 176.1 (CON), 149.3
(CIV), 148.2 (CIV), 144.0 (=CH), 130.1 (CIV), 121.0 (CAr), 118.8 (CIV), 112.1
(CAr), 111.6 (CAr), 56.0 (2 × OCH3), 44.4 (CH2), 35.6 (CH2), 35.0 (CH2),
25.0 (COCH3).
MS (CI+): m/z = 366 [M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C22H23O4NNa: 388.1519; found:
MS (CI+): m/z = 290 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C16H20O4N: 290.1387; found:
388.1503.
290.1384.
4-Benzoyl-1-[2-(2-methoxynaphthalen-1-yl)ethyl]-1,5-dihydro-
2H-pyrrol-2-one (5m)
4-Acetyl-1-(3,5-dimethoxyphenethyl)-1,5-dihydro-2H-pyrrol-2-
one (5p)
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5m was obtained as a brown oil
in 48% yield (177 mg).
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5p was obtained as a brown oil
in 45% yield (129 mg).
IR: 3062, 2939, 2837, 1724, 1593, 1349, 1250 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1502–1517

1513
K. Jebali et al.
Paper
Synthesis
IR: 2941, 1718, 1646, 1596, 1204, 1151 cm–1
.
1-Benzoyl-8-methoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquin-
olin-3(2H)-one [(±)-6b]
1H NMR (400 MHz, CDCl3): δ = 6.96 (t, J = 1.6 Hz, 1 H, =CH), 6.35–6.34
(m, 1 H, HAr), 6.31–6.30 (m, 2 H, HAr), 3.78–3.75 (m, 8 H, 2 × OCH3,
CH2CH2), 3.27 (d, J = 1.6 Hz, 2 H, CH2N), 2.85 (t, J = 6.8 Hz, 2 H,
CH2CH2), 2.13 (s, 3 H, COCH3).
Following general procedure 2 and after purification by column chro-
matography on silica gel, compound 6b was obtained as an orange oil
in 68% yield (65 mg).
IR: 3056, 2935, 1676, 1679, 1581, 1205, 1181 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 191.0 (COCH3), 176.2 (CON), 161.3
(2 × CIV), 144.2 (=CH), 140.1 (CIV), 118.8 (CIV), 107.1 (2 × CAr), 98.9 (CAr),
55.5 (2 × OCH3), 44.2 (CH2), 35.7 (CH2), 35.7 (CH2), 25.1 (CH3).
MS (CI+): m/z = 290 [M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C16H19O4NNa: 312.1206; found:
1H NMR (300 MHz, CDCl3): δ = 8.00–7.95 [m, 4 H, (HAr)p, (HAr)o], 7.67–
7.51 [m, 2 H, (HAr)p, (HAr)o], 7.50–7.47 [m, 4 H, (HAr)p, (HAr)o], 7.16 [t, J =
9.0 Hz, 1 H, (HAr)o], 6.69–6.62 [m, 3 H, (HAr)p, (2 × HAr)o], 6.60 [d, J = 9.0
Hz, 1 H, (HAr)o], 5.48 [d, J = 6.0 Hz, 1 H, (CHN)p], 5.34 [d, J = 6.0 Hz, 1 H,
(CHN)o], 4.52–4.42 [m, 1 H, (CHH′N)o], 4.39–4.32 [m, 1 H, (CHH′N)o],
4.12–3.99 [m, 2 H, (CHCO)p, (CHCO)o], 3.76 [s, 3 H, (OCH3)p], 3.13 [s, 3
H, (OCH3)o], 3.12–2.61 [m, 10 H, (CH2CH2)o,p, (CHH′N)o ,p, (CH2CO)o and p].
13C NMR (75 MHz, CDCl3): δ = 199.2 (COPh)o,p, 170.2 (CON)o, 169.4
(CON)p, 158.5 (CIV)p, 155.9 (CIV)o, 136.5 (CIV)o, 136.0 (CIV)p, 135.8 (CIV)o,
135.2 (CIV)p, 134.2 (CAr)p, 133.4 (CIV)p, 129.1 (2 × CAr)p, 128.9 (2 × CAr)o,
128.7 (2 × CAr)p, 128.3 (2 × CAr)o, 128.0 (CAr)o, 126.2 (CAr)p, 125.4 (CIV)o,
121.8 (CAr)p, 114.0 (CAr)o,p, 108.0 (CAr)o, 57.8 (CHN)o, 57.5 (CHN)p, 55.4
(OCH3)p, 54.2 (OCH3)o, 49.0 (CHCO)p, 45.8 (CHCO)o, 37.8 (CH2)o,p, 37.3
(CH2)o,p, 29.1 (CH2)p, 28.9 (CH2)o.
312.1196.
4-Acetyl-1-[2-(thiophen-2-yl)ethyl]-1,5-dihydro-2H-pyrrol-2-one
(5q)
Following general procedure 1 and after purification by column chro-
matography on silica gel, compound 5q was obtained as an orange oil
in 80% yield (188 mg).
IR: 3070, 2979, 2923, 1717, 1368, 1230, 1175 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.19 (dd, J = 5.6 Hz, J = 0.9 Hz, 1 H,
=CH), 6.97 (t, J = 1.8 Hz, 1 H, =CH), 6.96–6.93 (m, 1 H, =CH), 6.82–6.80
(m, 1 H, =CH), 3.80 (t, J = 6.6 Hz, 2 H, CH2CH2), 3.28 (d, J = 1.8 Hz, 2 H,
CH2N), 3.15 (t, J = 6.6 Hz, 2 H, CH2CH2), 2.14 (s, 3 H, COCH3).
13C NMR (75 MHz, CDCl3): δ = 191.2 (COCH3), 176.2 (CON), 144.0
(=CH), 139.8 (CIV), 127.4 (=CH), 126.4 (=CH), 124.7 (=CH), 118.9 (CIV),
44.6 (CH2), 35.6 (CH2), 29.4 (CH2), 25.1 (CH3).
MS (CI+): m/z = 322 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C20H20O3N: 322.1438; found:
322.1440.
1-Benzoyl-1,5,6,11b-tetrahydro-[1,3]dioxolo[4,5-g]pyrrolo[2,1-
a]isoquinolin-3(2H)-one [(±)-6c]
MS (CI+): m/z = 236 [M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C12H13O2NSNa: 258.0559; found:
Following general procedure 2 and after purification by column chro-
matography on silica gel, compound 6c was obtained as a green oil in
73% yield (73 mg).
258.0548.
IR: 3062, 2902, 1682, 1485, 1247 cm–1
.
1-Benzoylisoquinolinones 6a–n and 1-Acetylisoquinolinones 6o–
q; General Procedure 2
1H NMR (400 MHz, CDCl3): δ = 7.99–7.97 (m, 2 H, HAr), 7.67–7.62 (m,
1 H, HAr), 7.55–7.51 (m, 2 H, HAr), 6.59 (s, 1 H, HAr), 6.35 (s, 1 H, HAr),
5.87 (dd, J = 5.9 Hz, J = 1.3 Hz, 2 H, CH2), 5.49 (d, J = 8.0 Hz, 1 H, CHN),
4.36–4.31 (m, 1 H, CH2CHH′), 4.05–3.97 (m, 1 H, CH), 3.12–3.05 (m, 1
H, CH2CHH′), 2.95–2.86 (m, 2 H, CHH′CO, CHH′N), 2.72–2.60 (m, 2 H,
CHH′CO, CHH′N).
13C NMR (100 MHz, CDCl3): δ = 199.0 (COPh), 169.2 (CON), 146.9 (CIV),
146.8 (CIV), 135.9 (CIV), 134.2 (CAr), 129.5 (CIV), 129.2 (2 × CAr), 128.8
(2 × CAr), 127.1 (CIV), 109.1 (CAr), 105.0 (CAr), 101.1 (CH2), 57.7 (CHN),
49.1 (CH), 37.7 (CH2), 37.5 (CH2N), 28.9 (CH2CO).
TFA (2.5 equiv) was added under an Ar atm to compound 5 (0.3 mmol,
1 equiv) and the reaction mixture was stirred at r.t. until TLC indicat-
ed no remaining starting material. The reaction was then diluted with
CH2Cl2 and washed with sat. NaHCO3. The organic layer was dried
over MgSO4 and the solvent was removed in vacuo. The crude product
was purified by flash column chromatography on silica gel (CH2Cl2–
Et2O, 95:5) to give the desired product 6.
1-Benzoyl-8,9-dimethoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]iso-
quinolin-3(2H)-one [(±)-6a]
MS (CI+): m/z = 336 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C20H18O4N: 336.1230; found:
Following general procedure 2 and after purification by column chro-
matography on silica gel, compound 6a was obtained as an orange
solid in 78% yield (91 mg).
336.1231.
1-Benzoyl-8,10-dimethoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]iso-
quinolin-3(2H)-one [(±)-6d]
IR: 3059, 2935, 1718, 1684, 1514, 1263 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.00–7.97 (m, 2 H, HAr), 7.67–7.62 (m,
1 H, HAr), 7.54–7.50 (m, 2 H, HAr), 6.61 (s, 1 H, HAr), 6.28 (s, 1 H, HAr),
5.38 (d, J = 8.4 Hz, 1 H, CHN), 4.44–4.39 (m, 1 H, CH2CHH′), 4.09–4.02
(m, 1 H, CH), 3.84 (s, 3 H, OCH3), 3.45 (s, 3 H, OCH3), 3.10–3.03 (m, 1 H,
CH2CHH′), 2.97–2.67 (m, 4 H, COCH2, CH2CH2).
Following general procedure 2 and after purification by column chro-
matography on silica gel, compound 6d was obtained as a green oil in
78% yield (82 mg).
IR: 3057, 2925, 1679, 1592, 1246 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.97–7.94 (m, 2 H, HAr), 7.63–7.57 (m,
1 H, HAr), 7.52–7.46 (m, 2 H, HAr), 6.28 (d, J = 6.0 Hz, 1 H, HAr), 6.19 (d,
J = 6.0 Hz, 1 H, HAr), 5.26 (d, J = 8.0 Hz, 1 H, CHN), 4.50–4.40 (m, 1 H,
CH2CHH′), 4.08–3.99 (m, 1 H, CH), 3.77 (s, 3 H, OCH3), 3.11 (s, 3 H,
OCH3), 3.00–2.91 (m, 2H, CH2CHH′, CHH′CO), 2.80–2.61 (m, 2 H, CH2N,
CHH′CO).
13C NMR (100 MHz, CDCl3): δ = 200.0 (COPh), 169.6 (CON), 148.1
(2 × CIV), 136.3 (CIV), 134.2 (CAr), 129.2 (2 × CAr), 128.7 (2 × CAr), 128.0
(CIV), 125.8 (CIV), 111.9 (CAr), 107.9 (CAr), 58.6 (CH), 55.6 (OCH3), 53.5
(OCH3), 49.2 (CH), 37.9 (CH2), 37.4 (CH2N), 28.4 (CH2CO).
MS (CI+): m/z = 352 [M + H]+.
HRMS (MALDI-DHB-PEG400): m/z [M + H]+ calcd for C21H22O4N:
352.1543; found: 352.1528.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1502–1517

1514
K. Jebali et al.
Paper
Synthesis
13C NMR (75 MHz, CDCl3): δ = 199.3 (COPh), 170.2 (CON), 159.7 (CIV),
157.0 (CIV), 136.6 (CIV), 136.4 (CIV), 133.4 (CAr), 128.9 (2 × CAr), 128.3
(2 × CAr), 118.0 (CIV), 104.9 (CAr), 96.7 (CAr), 57.6 (CHN), 55.5 (OCH3),
54.2 (OCH3), 46.2 (CH), 37.4 (CH2N), 37.4 (CH2CO), 29.4 (CH2).
MS (CI+): m/z = 352 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C21H22O4N: 352.1543; found:
H, CHN), 4.58–4.48 (m, 2 H, CH, CHH′CO), 2.98–2.87 (m, 2 H, CHH′CO,
CH2CHH′), 2.85–2.80 (m,
2 × CH2CHH′).
1 H, CH2CHH′), 2.72–2.55 (m, 2 H,
13C NMR (100 MHz, CDCl3): δ = 197.9 (COPh), 173.3 (CON), 150.0 (CIV),
141.3 (CH=CH), 137.3 (CIV), 133.7 (CAr), 129.1 (2 × CAr), 128.4 (2 × CAr),
114.1 (CIV), 107.7 (CH=CH), 57.3 (CHN), 42.2 (CH), 37.5 (CH2N), 34.5
(CH2CO), 23.1 (CH2).
352.1541.
MS (CI+): m/z = 282 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C17H16O3N: 282.1125; found:
1-Benzoyl-8-methoxy-6,6-dimethyl-1,5,6,10b-tetrahydropyrro-
lo[2,1-a]isoquinolin-3(2H)-one [(±)-6f]
282.1127.
Following general procedure 2 and after purification by column chro-
matography on silica gel, compound 6f was obtained as a green oil in
67% yield (70 mg).
9-Benzoyl-4,8,9,9a-tetrahydrothieno[2,3-g]indolizin-7(5H)-one
[(±)-6i]
IR: 3059, 2962, 1684, 1448, 1291 cm–1
.
Following general procedure 2 and after purification by column chro-
matography on silica gel, compound 6i was obtained as a yellow oil in
93% yield (24 mg).
1H NMR (300 MHz, CDCl3): δ = 8.00–7.96 (m, 2 H, HAr), 7.67–7.62 (m,
1 H, HAr), 7.55–7.50 (m, 2 H, HAr), 6.87–6.62 (m, 3 H, HAr), 5.52 (d, J =
8.1 Hz, 1 H, CHN), 4.12–3.66 [m, 3 H, CH, CH2C(CH3)2], 3.76 (s, 3 H,
OCH3), 2.97–2.63 (m, 2 H, CH2CO), 1.38 (s, 3 H, CH3), 1.27 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 199.4 (COPh), 169.6 (CON), 158.9 (CIV),
144.8 (CIV), 136.1 (CIV), 134.2 (CAr), 129.1 (2 × CAr), 128.9 (2 × CAr),
128.8 (CIV), 128.3 (CIV), 127.6 (CIV), 126.1 (CAr), 112.4 (CAr), 111.7 (CAr),
58.2 (CHN), 55.4 (OCH3), 49.5 (CH), 37.8 (CH2CO), 35.5 (CH2), 30.8
(CH3), 26.4 (CH3).
IR: 2925, 1733, 1456, 1255 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.97–7.95 (m, 2 H, HAr), 7.66–7.62 (m,
1 H, HAr), 7.54–7.50 (m, 2 H, HAr), 7.09 (d, J = 5.2 Hz, 1 H, =CHS), 6.57
(d, J = 5.2 Hz, 1 H, =CH), 5.40–5.37 (m, 1 H, CHN), 4.57–4.52 (m, 1 H,
CH2CHH′), 4.00–3.93 (m, 1 H, CH), 3.12–3.05 (m, 1 H, CH2CHH′), 3.01–
2.85 (m, 3 H, CH2CH2, CHH′CO), 2.73–2.66 (m, 1 H, CHH′CO).
13C NMR (100 MHz, CDCl3): δ = 198.6 (COPh), 169.7 (CON), 136.0 (CIV),
134.8 (CIV), 134.1 (CAr), 133.7 (CIV), 129.1 (2 × CAr), 128.7 (2 × CAr),
124.4 (CH=CH), 123.9 (CH=CH), 57.5 (CHN), 48.3 (CH), 37.5 (2 × CH2),
24.9 (CH2).
MS (CI+): m/z = 350 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C22H24O3N: 350.1751; found:
350.1752.
MS (CI+): m/z = 298 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C17H16O2NS: 298.0896; found:
298.0895.
1-Benzoyl-1,5,6,10b-tetrahydrodipyrrolo[1,2-a:2′,1′-c]pyrazin-
3(2H)-one [(±)-6g]
Following general procedure 2 and after purification by column chro-
matography on silica gel, compound 6g was obtained as a brown oil in
86% yield (86 mg).
1-Benzoyl-1,2,5,6,7,11c-hexahydro-3H-indolizino[7,8-b]indol-3-
one [(±)-6j]
IR: 3061, 2923, 2853, 1679, 1296 cm–1
.
Following general procedure 2 and after purification by column chro-
matography on silica gel, compound 6j was obtained as a yellow oil in
85% yield (84 mg).
1H NMR (400 MHz, CDCl3): δ = 7.99–7.97 (m, 2 H, HAr), 7.66–7.62 (m,
1 H, HAr), 7.55–7.50 (m, 2 H, HAr), 6.58–6.57 (m, 1 H, =CH), 6.12 (t, J =
2.8 Hz, 1 H, =CH), 5.75 (d, J = 8.0 Hz, 1 H, =CH), 5.42 (d, J = 7.6 Hz, 1 H,
CHN), 4.46–4.41 (m, 1 H, CH), 4.20–4.14 (m, 1 H, CH), 4.06–3.95 (m, 2
H, CH2CH2), 3.37–3.29 (m, 1 H, CH2CHH′), 2.89–2.68 (m, 2 H, CH2CO).
13C NMR (100 MHz, CDCl3): δ = 198.3 (COPh), 170.2 (CON), 136.0 (CIV),
134.1 (CAr), 129.1 (2 × CAr), 128.8 (2 × CAr), 127.9 (CIV), 119.8 (CH=CH),
108.8 (CH=CH), 103.7 (CH=CH), 55.4 (CHN), 48.2 (CH), 44.2 (CH2CO),
37.5 (CH2N), 36.7 (CH2).
IR: 3400, 1670, 1447, 1259, 730, 660 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.26 (m, 1 H, NH), 7.93–7.90 (m, 2 H,
HAr), 7.68–7.62 (m, 1 H, HAr), 7.55–7.50 (m, 3 H, HAr), 7.30–7.27 (m, 1
H, HAr), 7.20–7.09 (m, 2 H, HAr), 5.46–5.43 (m, 1 H, CHN), 4.60–4.54
(m, 1 H, CH2CHH′), 3.92–3.82 (m, 1 H, CH), 3.11–2.66 (m, 5 H, 2 × CH2,
CH2CHH′).
13C NMR (75 MHz, CDCl3): δ = 200.1 (COPh), 169.7 (CON), 136.2 (CIV),
135.7 (CIV), 134.4 (CAr), 131.8 (CIV), 129.2 (2 × CAr), 128.6 (2 × CAr),
126.8 (CIV), 122.5 (CAr), 119.9 (CAr), 118.5 (CAr), 111.3 (CAr), 108.5 (CIV),
55.0 (CHN), 50.3 (CH), 37.8 (CH2), 37.2 (CH2N), 21.3 (CH2CO).
MS (CI+): m/z = 281 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C17H17N2O2: 281.1205; found:
281.1209.
MS (CI+): m/z = 331 [M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C21H18N2O2Na: 353.1266; found:
9-Benzoyl-4,8,9,9a-tetrahydrofuro[2,3-g]indolizin-7(5H)-one [(±)-
6h]
353.1268.
Following general procedure 2 and after purification by column chro-
matography on silica gel, compound 6h was obtained as a yellow solid
in 85% yield (71 mg).
1-Benzoyl-9,10-dimethoxy-1,2,5,6,7,11b-hexahydro-3H-ben-
zo[c]pyrrolo[1,2-a]azepin-3-one [(±)-6l]
IR: 1676, 1418, 1256, 730, 697 cm–1
.
Following general procedure 2 and after purification by column chro-
matography on silica gel, compound 6l was obtained as a yellow oil in
47% yield (51 mg).
1H NMR (400 MHz, CDCl3): δ = 7.93–7.90 (m, 2 H, HAr), 7.62–7.58 (m,
1 H, HAr), 7.51–7.47 (m, 2 H, HAr), 6.99 (dd, J = 1.3 Hz, J = 0.7 Hz, 1 H,
=CHO), 5.54 (d, J = 2.0 Hz, 1 H, CH=CH), 5.15 (dt, J = 7.0 Hz, J = 2.0 Hz, 1
IR: 2936, 1678, 1516, 1260 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1502–1517

1515
K. Jebali et al.
Paper
Synthesis
1H NMR (300 MHz, CDCl3): δ = 7.82–7.79 (m, 2 H, HAr), 7.59–7.54 (m,
1 H, HAr), 7.45–7.40 (m, 2 H, HAr), 6.62 (s, 1 H, HAr), 6.49 (s, 1 H, HAr),
5.27 (d, J = 8.0 Hz, 1 H, CHN), 4.26–4.17 (m, 1 H, CH), 4.13–4.06 (m, 1
H, COCHH′), 3.85 (s, 3 H, OCH3), 3.59 (s, 3 H, OCH3), 3.08–2.87 (m, 2 H,
CH2CHH′, COCHH′), 2.84–2.81 (m, 2 H, CH2), 2.55–2.48 (m, 1 H,
CH2CHH′), 2.29–2.15 (m, 1 H, CH2CHH′), 1.77–1.64 (m, 1 H, CH2CHH′).
13C NMR (75 MHz, CDCl3): δ = 198.6 (COPh), 171.2 (CON), 148.4 (CIV),
147.4 (CIV), 136.2 (CIV), 134.0 (CAr), 130.2 (CIV), 129.1 (CIV), 128.9
(2 × CAr), 128.7 (2 × CAr), 114.1 (CAr), 111.5 (CAr), 66.4 (CH), 56.0 (OCH3),
55.9 (OCH3), 49.2 (CHN), 38.4 (CH2N), 36.3 (CH2CO), 30.0 (CH2), 25.4
(CH2).
1-Acetyl-8,9-dimethoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]iso-
quinolin-3(2H)-one [(±)-6o]
Following general procedure 2 and after purification by column chro-
matography on silica gel, compound 6o was obtained as an orange oil
in 54% yield (46 mg).
IR: 1720, 1590, 1141, 697, 658 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.59 (s, 1 H, HAr), 6.51 (s, 1 H, HAr), 5.17
(d, J = 8.0 Hz, 1 H, CHN), 4.37–4.32 (m, 1 H, CH), 3.85 (s, 3 H, OCH3),
3.79 (s, 3 H, OCH3), 3.23–3.16 (m, 1 H, COCHH′), 3.03–2.96 (m, 1 H,
CH2CHH′), 2.92–2.57 (m, 4 H, CH2CHH′, COCHH′, CH2CH2), 2.32 (s, 3 H,
CH3).
13C NMR (100 MHz, CDCl3): δ = 207.3 (COCH3), 169.3 (CON), 148.4
(CIV), 148.3 (CIV), 128.3 (CIV), 126.0 (CIV), 112.0 (CAr), 108.1 (CAr), 56.9
(CHN), 56.1 (OCH3), 56.0 (OCH3), 54.2 (CH), 37.4 (CH2N), 35.7 (CH2CO),
29.8 (CH3), 28.4 (CH2).
MS (CI+): m/z = 366 [M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C22H23O4NNa: 388.1519; found:
388.1506.
12-Benzoyl-6-methoxy-7,8,12,12a-tetrahydronaphtho[1,8-cd]pyr-
rolo[1,2-a]azepin-10(11H)-one [(±)-6m]
MS (CI+): m/z = 290 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C16H19O4N: 290.1441; found:
Following general procedure 2 and after purification by column chro-
matography on silica gel, compound 6m was obtained as a brown oil
in 47% yield (55 mg).
290.1445.
1-Acetyl-8,10-dimethoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]iso-
quinolin-3(2H)-one [(±)-6p]
IR: 3056, 2935, 1680, 1255 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.05–8.02 (m, 2 H, HAr), 7.76–7.70 (m,
2 H, HAr), 7.67–7.61 (m, 1 H, HAr), 7.55–7.50 (m, 2 H, HAr), 7.33–7.18
(m, 3 H, HAr), 6.06 (d, J = 5.7 Hz, 1 H, CHN), 4.79–4.72 (m, 1 H, CH),
4.25–4.18 (m, 1 H, CH2CHH′), 3.95 (s, 3 H, OCH3), 3.93–3.86 (m, 1 H,
CH2CHH′), 3.41–3.17 (m, 2 H, 2 × CH2CHH′), 3.03–2.73 (m, 2 H,
CH2CO).
13C NMR (75 MHz, CDCl3): δ = 197.7 (COPh), 170.6 (CON), 155.1 (CIV),
135.3 (CIV), 134.0 (CAr), 134.0 (CIV), 132.9 (CIV), 130.6 (CIV), 129.8 (CAr),
129.2 (2 × CAr), 129.0 (CIV), 128.6 (2 × CAr), 123.3 (CIV), 123.3 (CAr),
122.8 (CAr), 113.4 (CAr), 59.8 (CHN), 56.8 (OCH3), 43.5 (CH), 43.1 (CH2),
35.7 (CH2N), 23.8 (CH2CO).
Following general procedure 2 and after purification by column chro-
matography on silica gel, compound 6p was obtained as a green oil in
43% yield (37 mg).
IR: 2936, 1683, 1606, 1437, 1170 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 6.31 (d, J = 2.3 Hz, 1 H, HAr), 6.26 (d, J =
2.3 Hz, 1 H, HAr), 5.06 (d, J = 7.5 Hz, 1 H, CHN), 4.42–4.32 (m, 1 H,
CH2CHH′), 3.78 (s, 3 H, OCH3), 3.69 (s, 3 H, OCH3), 3.21–3.12 (m, 1 H,
CH), 2.98–2.81 (m, 2 H, 2 × CH2CHH′), 2.73–2.59 (m, 2 H, CH2CHH′,
COCHH′), 2.56–2.46 (m, 1 H, COCHH′), 2.27 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 207.1 (COCH3), 170.1 (CON), 159.7 (CIV),
157.0 (CIV), 136.4 (CIV), 117.6 (CIV), 105.1 (CAr), 97.0 (CAr), 56.7 (CHN),
55.5 (OCH3), 54.6 (OCH3), 51.8 (CH), 37.3 (CH2N), 35.9 (CH2CO), 29.7
(CH3), 29.3 (CH2).
MS (CI+): m/z = 372 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C24H22O3N: 372.1594; found:
372.1596.
MS (CI+): m/z = 290 [M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C16H19O4NNa: 312.1206; found:
312.1195.
12-Benzoyl-1,6-dimethoxy-7,8,12,12a-tetrahydronaphtho[1,8-
cd]pyrrolo[1,2-a]azepin-10(11H)-one [(±)-6n]
Following general procedure 2 and after purification by column chro-
matography on silica gel, compound 6n was obtained as a brown oil
in 88% yield (105 mg).
9-Acetyl-4,8,9,9a-tetrahydrothieno[2,3-g]indolizin-7(5H)-one [(±)-
6q]
Following general procedure 2 and after purification by column chro-
matography on silica gel, compound 6q was obtained as a brown oil in
47% yield (51 mg).
IR: 3059, 2959, 1680, 1256 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.88–7.85 (m, 2 H, HAr), 7.68–7.65 (m,
2 H, HAr), 7.61–7.55 (m, 1 H, HAr), 7.49–7.43 (m, 2 H, HAr), 7.13 (d, J =
9.0 Hz, 1 H, HAr), 6.96 (d, J = 9.0 Hz, 1 H, HAr), 6.00 (d, J = 4.4 Hz, 1 H,
CHN), 4.28–4.19 (m, 1 H, CH2CHH′), 4.06–3.99 (m, 1 H, CH), 3.93 (s, 3
H, OCH3), 3.70–3.50 (m, 2 H, 2 × CH2CHH′), 3.44 (s, 3 H, OCH3), 3.04–
2.93 (m, 1 H, CH2CHH′), 2.72–2.39 (AB system, 2 H, CH2).
13C NMR (75 MHz, CDCl3): δ = 198.7 (COPh), 172.1 (CON), 155.9 (CIV),
155.2 (CIV), 135.8 (CIV), 134.1 (CIV), 133.3 (CAr), 129.9 (CAr), 128.9
(2 × CAr), 128.5 (CAr), 128.4 (2 × CAr), 125.5 (CIV), 123.2 (CIV), 119.8 (CIV),
111.1 (CAr), 109.9 (CAr), 61.7 (CHN), 56.5 (OCH3), 55.3 (OCH3), 47.9
(CH), 41.7 (CH2N), 35.0 (CH2CO), 27.2 (CH2).
IR: 2960, 1683, 1418, 1236, 1174 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.14 (d, J = 5.2 Hz, 1 H, =CH), 6.71 (d, J =
5.2 Hz, 1 H, =CH), 5.09 (dt, J = 8.0 Hz, J = 1.8 Hz, 1 H, CHN), 4.50–4.45
(m, 1 H, CH2CHH′), 3.15–3.08 (m, 1 H, CH), 3.04–2.96 (m, 1 H,
CH2CHH′), 2.96–2.78 (m, 3 H, CH2CHH′, CH2CO), 2.64–2.57 (m, 1 H,
CH2CHH′), 2.29 (s, 3 H, COCH3).
13C NMR (100 MHz, CDCl3): δ = 206.3 (COCH3), 169.6 (CON), 134.8
(CIV), 133.7 (CIV), 124.3 (=CH), 124.0 (=CH), 56.6 (CHN), 53.0 (CH), 37.4
(CH2N), 35.3 (CH2CO), 29.6 (CH3), 24.8 (CH2).
MS (CI+): m/z = 236 [M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C12H13O2NNaS: 258.0559; found:
MS (CI+): m/z = 402 [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C25H24O4N: 402.1705; found:
258.0550.
402.1711.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1502–1517

1516
K. Jebali et al.
Paper
Synthesis
N-Allyl-N-(3,4-dimethoxyphenethyl)acrylamide (7)
over MgSO4 and the solvent was removed in vacuo. The crude residue
was purified by flash column chromatography on silica gel (CH2Cl2–
Et2O, 90:10) to give the desired product as a brown oil (90%, 139 mg).
1H NMR (300 MHz, CDCl3): δ = 6.61 (s, 1 H, HAr), 6.56 (s, 1 H, HAr), 4.72
(t, J = 7.4 Hz, 1 H, CHN), 4.30 (ddd, J = 12.4 Hz, J = 5.8 Hz, J = 2.5 Hz, 1
H, CHCHH′), 3.87 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 3.06–2.83 (m, 2 H,
CHH′N, CHCHH′), 2.71–2.42 (m, 3 H, CHH′N, CH2CH2), 1.90–1.75 (m, 2
H, CH2CO).
13C NMR (75 MHz, CDCl3): δ = 173.3 (CON), 148.2 (CIV), 148.0 (CIV),
129.4 (CIV), 125.6 (CIV), 111.8 (CAr), 107.7 (CAr), 56.7 (CH), 56.2 (OCH3),
56.0 (OCH3), 37.2 (CH2N), 31.9 (CH2CH2), 28.2 (CH2CO), 27.9 (CHCH2).
MS (CI+): m/z = 248 [M + H]+.
HRMS (MALDI-DHB-PEG400): m/z [M + H]+ calcd for C14H18O3N:
To a solution of dimethoxyphenylethylamine 4a (12 mmol, 3 equiv) in
THF, K2CO3 (12 mmol, 3 equiv) and allylbromide (4 mmol, 1 equiv)
were added at 0 °C. The mixture was then stirred at room tempera-
ture for 24 h. The reaction mixture was filtered through a pad of
Celite®, the residue was washed with CH2Cl2 and the filtrate was then
concentrated in vacuo. The crude product (2.8 mmol, 1 equiv) was di-
luted in CH2Cl2 and, under an N2 atm at 0 °C, Et3N (2.8 mmol, 1 equiv)
and acryloyl chloride (2.8 mmol, 1 equiv) were added to the solution.
The mixture was stirred at r.t. and complete conversion of the starting
material was monitored by TLC. The solution was then quenched with
H2O. The aq phase was extracted with and the organic phase was
washed with brine, dried over MgSO4 and concentrated in vacuo. The
crude residue was purified by column chromatography on silica gel
(CH2Cl2–Et2O, 90:10) to give compound 7 as a yellow oil (68%, 523
mg).
248.1281; found: 248.1274.
1H NMR (300 MHz, DMSO-d6): δ = 6.87–6.57 (m, 4 H, 3 × HAr, =CHCO),
6.10 (ddd, J = 25.6 Hz, J = 16.8 Hz, J = 2.2 Hz, 1 H, COCH=CHH′), 5.88–
5.70 (m, 1 H, CH2=CH), 5.36 (ddd, J = 25.6 Hz, J = 16.8 Hz, J = 2.2 Hz, 1
H, COCH=CHH′), 5.18–5.05 (m, 2 H, =CH2), 3.98–3.94 (m, 2 H, CH2CH),
3.73 (s, 3 H, OCH3), 3.71 (s, 3 H, OCH3), 3.54–3.44 (m, 2 H, CH2N), 2.76–
2.69 (m, 2 H, CH2CH2).
13C NMR (75 MHz, DMSO-d6): δ = 165.2/164.9 (CIV rotamers), 148.6
(CIV rotamers), 147.4/147.2 (CIV rotamers), 134.5/133.9 (=CH rotam-
ers), 131.5/130.8 (CIV rotamers), 128.5/128.3 (=CH rotamers),
127.2/127.0 (=CH2 rotamers), 120.8/120.4 (CAr rotamers), 116.8/115.9
(=CH2 rotamers), 112.8/112.4 (CAr rotamers), 111.8 (CAr rotamers),
55.4/55.3 (2 × OCH3 rotamers), 48.0 (CH2 rotamers), 47.7 (CH2 rotam-
ers), 34.4/33.0 (CH2 rotamers).
4-Benzoyl-5-(furan-2-yl)-1-phenethylpyrrolidin-2-one [(±)-10]
To a solution of α,β-unsaturated lactam 5e (0.4 mmol, 1 equiv) in DCE
(10 mL), furan (10 equiv) and TFA (2.5 equiv) were added at r.t. The
mixture was stirred until TLC indicated no remaining starting materi-
al. The mixture was then diluted with CH2Cl2 and the organic phase
was washed with sat. NaHCO3, dried over MgSO4 and concentrated in
vacuo. The desired product was obtained, after purification of the res-
idue by column chromatography on silica gel (CH2Cl2–Et2O, 95:5), as a
yellow oil (32%, 21 mg).
IR: 1679, 1596, 1448, 1240, 746, 700 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.85–7.82 (m, 2 H, HAr), 7.60–7.56 (m,
1 H, HAr), 7.47–7.43 (m, 3 H, 2 × HAr, =CH), 7.25–7.20 (m, 2 H, HAr),
7.17–7.10 (m, 3 H, HAr), 6.35 (dd, J = 3.2 Hz, J = 1.9 Hz, 1 H, =CH), 6.25
(dd, J = 3.2 Hz, J = 0.7 Hz, 1 H, =CH), 4.93 (d, J = 4.9 Hz, 1 H, CHN), 4.27–
4.21 (m, 1 H, CHCO), 3.78–3.70 (m, 1 H, CHCHH′), 3.01–2.93 (m, 2 H,
CHCHH′, CH2CHH′N), 2.87–2.79 (m, 1 H, CH2CHH′), 2.75 (dd, J = 16.8
Hz, J = 6.3 Hz, 1 H, CHCHH′), 2.61–2.54 (m, 1 H, CH2CHH′).
MS (CI+): m/z = 276 [M + H]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C16H21O3NNa: 298.1419; found:
298.1421.
13C NMR (100 MHz, CDCl3): δ = 197.3 (COPh), 171.9 (CON), 151.1 (CIV),
143.5 (CAr), 138.8 (CIV), 135.1 (CIV), 133.9 (CAr), 128.9 (2 × CAr), 128.8
(2 × CAr), 128.7 (2 × CAr), 128.6 (2 × CAr), 126.5 (=CH), 110.6 (=CH),
109.9 (=CH), 57.4 (CHN), 44.5 (CHCO), 42.8 (CH2CON), 34.2 (CH2CH2),
33.8 (CH2CH2).
MS (CI+): m/z = 382 [M + Na]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C23H21O3NNa: 382.1419; found:
1-(3,4-Dimethoxyphenethyl)-1,5-dihydro-2H-pyrrol-2-one (8)
Under an N2 atm, compound 7 (275 mg, 1 mmol) was dissolved in tol-
uene and Grubbs’ 2nd generation catalyst (10 mol%) was added in
small portions and the reaction was heated at 40 °C for 10 h. The re-
action mixture was then concentrated in vacuo and the crude product
was purified by column chromatography on silica gel (CH2Cl2–Et2O,
90:10) to afford the lactam 8 as an orange oil (63%, 155 mg).
1H NMR (300 MHz, CDCl3): δ = 9.97 (dt, J = 5.9 Hz, J = 1.7 Hz, 1 H,
=CHCO), 6.80–6.71 (m, 3 H, HAr), 6.16 (dt, J = 5.9 Hz, J = 1.8 Hz, 1 H,
HC=CH), 3.85 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 3.75 (dd, J = 2.3 Hz, J =
1.6 Hz, 2 H, CH2), 3.67 (t, J = 7.2 Hz, 2 H, CH2N), 2.84 (t, J = 7.2 Hz, 2 H,
CH2CH2).
382.1427.
Acknowledgment
13C NMR (75 MHz, CDCl3): δ = 171.5 (CON), 149.0 (CIV), 147.7 (CIV),
142.7 (=CH), 131.4 (CIV), 128.3 (=CH), 120.7 (CAr), 111.9 (CAr), 111.4
(CAr), 56.0 (2 × OCH3), 53.7 (CH2N), 43.9 (CH2CH2), 34.6 (CH2CH2).
MS (CI+): m/z = 248 [M + H]+.
HRMS (MALDI-DHB-PEG400): m/z [M + H]+ calcd for C14H18O3N:
The authors are deeply indebted to the Ministère de l’Enseignement
Supérieur et de la Recherche, the Centre National de la Recherche Sci-
entifique (CNRS), Université de Nantes and Université de Tunis El
Manar for their constant support. K.J. wishes to acknowledge the
Ministère Français des Affaires Etrangères et du Développement In-
ternational (Eiffel Scholarship program) and the Ministère Tunisien
de l’Enseignement Supérieur et de la Recherche Scientifique.
248.1281; found: 248.1276.
8,9-Dimethoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-
3(2H)-one [(±)-9]
Supporting Information
TFA (2.5 equiv) was added under an Ar atm to compound 8 (15 mg,
0.06 mmol) and the mixture was stirred at 50 °C until TLC indicated
no remaining starting material. The reaction was then diluted with
CH2Cl2 and washed with sat. NaHCO3. The organic layer was dried
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561398.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1502–1517

1517
K. Jebali et al.
Paper
Synthesis
References
2009, 513. (d) Martinez-Estibalez, U.; Gomez-SanJuan, A.;
Garcia-Calvo, O.; Aranzamendi, E.; Lete, E.; Sotomayor, N. Eur. J.
Org. Chem. 2011, 3610; and cited literature.
(1) For a review of the chemistry of pyrrolo[2,1-a]isoquinolines,
see: Mikhailovskii, A. G.; Shklyaev, V. S. Chem. Heterocycl.
Compd. 1997, 33, 243.
(2) (a) King, F. D.; Aliev, A. E.; Caddick, S.; Copley, R. C. B. Org.
Biomol. Chem. 2009, 7, 3561. (b) King, F. D.; Aliev, A. E.; Caddick,
S.; Tocher, D. A. Org. Biomol. Chem. 2011, 9, 1547; and cited lit-
erature.
(14) For selected examples of Brønsted acid promoted cyclization of
N-acyliminium ions on π-nucleophilic aromatic rings, see:
(a) Tanis, S. P.; Deaton, M. V.; Dixon, L. A.; McMills, M. C.;
Raggon, J. W.; Collins, M. A. J. Org. Chem. 1998, 63, 6914.
(b) Kałuża, Z.; Mostowicz, D. Tetrahedron: Asymmetry 2003, 14,
225. (c) Rose, M. D.; Cassidy, M. P.; Rashatasakhon, P.; Padwa, A.
J. Org. Chem. 2007, 72, 538. (d) Allin, S. M.; Gaskell, S. N.; Towler,
J. M. R.; Page, P. C. B.; Saha, B.; McKenzie, M. J.; Martin, W. P.
J. Org. Chem. 2007, 72, 8972. (e) Grigg, R.; Sridharan, V.; Sykes,
D. A. Tetrahedron 2008, 64, 8952. (f) Shengule, S. R.; Ryder, G.;
Willis, A. C.; Pyne, S. G. Tetrahedron 2012, 68, 10280.
(g) Stepakov, A. V.; Ledovskaya, M. S.; Boitsov, V. M.; Molchanov,
A. P.; Kostikov, R. R.; Gurzhiy, V. V.; Starova, G. L. Tetrahedron
Lett. 2012, 53, 5414. (h) Goff, D. A. Tetrahedron 2013, 69, 242.
(i) Ledovskaya, M. S.; Molchanov, A. P.; Boitsov, V. M.; Kostikov,
R. R.; Stepakov, A. V. Tetrahedron 2015, 71, 1952.
(3) For a recent synthesis, see: Kawai, N.; Matsuda, M.; Uenishi, J.
Tetrahedron 2011, 67, 8648.
(4) Moreno, L.; Párraga, J.; Galán, A.; Cabedo, N.; Primo, J.; Cortes, D.
Bioorg. Med. Chem. 2012, 20, 6589; and cited literature.
(5) Liu, D.; Shen, T.; Xiang, L. Helv. Chim. Acta 2001, 94, 497.
(6) Li, Q.; Jiang, J.; Fan, A.; Cui, Y.; Jia, X. Org. Lett. 2011, 13, 312; and
cited literature.
(7) (a) Khiati, S.; Seol, Y.; Agama, K.; Rosa, I. D.; Agrawal, S.; Fesen,
K.; Zhang, H.; Neuman, K. C.; Pommier, Y. Mol. Pharm. 2014, 86,
193. (b) Shen, L.; Xie, N.; Yang, B.; Hu, Y.; Zhang, Y. Eur. J. Med.
Chem. 2014, 85, 807.
(8) (a) Pérard-Viret, J.; Souquet, F.; Manisse, M.-L.; Royer, J. Tetrahe-
dron Lett. 2010, 51, 96. (b) Zubkov, F. I.; Ershova, J. D.; Zaytsev, V.
P.; Obushak, M. D.; Matiychuk, V. S.; Sokolova, E. A.; Khrustalev,
V. N.; Varlamov, A. V. Tetrahedron Lett. 2010, 51, 6822.
(9) (a) Tietze, L. F.; Tolle, N.; Kratzert, D.; Stalke, D. Org. Lett. 2009,
11, 5230. (b) Paladino, M.; Zaifman, J.; Ciufolini, M. A. Org. Lett.
2015, 17, 3422; and cited literature.
(15) For selected examples of Brønsted acid promoted cyclization of
imide carbonyl groups on π-nucleophilic aromatic rings, see:
(a) Selvakumar, J.; Ramanathan, C. R. Org. Biomol. Chem. 2011, 9,
7643. (b) Selvakumar, J.; Rao, R. S.; Srinivasapriyan, V.;
Marutheeswaran, S.; Ramanathan, C. R. Eur. J. Org. Chem. 2015,
2175.
(16) Ben Othman, R.; Affani, R.; Tranchant, M.-J.; Antoniotti, S.; Dalla,
V.; Duñach, E. Angew. Chem. Int. Ed. 2010, 49, 776.
(10) Suyavaran, A.; Ramamurthy, C.; Mareeswaran, R.; Shanthi, Y. V.;
Selvakumar, J.; Mangalaraj, S.; Kumar, M. S.; Ramanathan, C. R.;
Thirunavukkarasu, C. Bioorg. Med. Chem. 2015, 23, 488.
(11) For selected syntheses of these frameworks, see: (a) Ishihara, Y.;
Kiyota, Y.; Goto, G. Chem. Pharm. Bull. 1990, 38, 3024.
(b) Katritzky, A. R.; Maimait, R.; Xu, Y.-J.; Akhmedova, R. G. Syn-
thesis 2002, 601. (c) Moreau, A.; Couture, A.; Deniau, E.;
Grandclaudon, P.; Lebrun, S. Tetrahedron 2004, 60, 6169.
(d) Chowdappa, N.; Sherigara, B. S.; Augustine, J. K.; Areppa, K.;
Mandal, A. B. Synthesis 2010, 2949. (e) Gurram, M.; Gyimóthy,
B.; Wang, R.; Lam, S. Q.; Ahmed, F.; Herr, R. J. J. Org. Chem. 2011,
76, 1605. (f) Louafi, F.; Moreau, J.; Shahane, S.; Golhen, S.;
Roisnel, T.; Sinbandhit, S.; Hurvois, J.-P. J. Org. Chem. 2011, 76,
9720. (g) Iza, A.; Ugarriza, I.; Uria, U.; Reyes, E.; Carrillo, L.;
Vicario, J. L. Tetrahedron 2013, 69, 8878. (h) Min, J.-Y.; Kim, G.
J. Org. Chem. 2014, 79, 1444. (i) Islas-Jácome, A.; Gutiérrez-Car-
rillo, A.; García-Garibay, M. A.; González-Zamora, E. Synlett
2014, 25, 403.
(17) For an example of Brønsted acid promoted intramolecular
Friedel–Crafts-type Michael addition of a δ-tethered π-nucleop-
hilic aromatic ring α,β-unsaturated δ-lactam, see: Fang, B.;
Zheng, H.; Zhao, C.; Jing, P.; Li, H.; Xie, X.; She, X. J. Org. Chem.
2012, 77, 8367.
(18) For an example of Brønsted acid promoted intramolecular
Friedel–Crafts-type Michael addition of δ-tethered π-nucleop-
hilic aromatic ring α,β-unsaturated δ-lactones, see: Sun, Y.; Yu,
B.; Wang, X.; Tang, S.; She, X.; Pan, X. J. Org. Chem. 2010, 75,
4224.
(19) Jebali, K.; Arfaoui, A.; Saadi, F.; Lebreton, J.; Amri, H. Synth.
Commun. 2014, 44, 3400.
(20) Hamon, M.; Dickinson, N.; Devineau, A.; Bolien, D.; Tranchant,
M.-J.; Taillier, C.; Jabin, I.; Harrowven, D. C.; Whitby, R. J.;
Ganesan, A.; Dalla, V. J. Org. Chem. 2014, 79, 1900.
(21) See ref. 20 for a discussion of the mechanism and also: Ascic, E.;
Jensen, J. F.; Nielsen, T. E. Angew. Chem. Int. Ed. 2011, 50, 5188.
(22) The structure of racemic compound 6h was established by
single X-ray diffraction analysis. The ORTEP diagram of com-
pound 6h is shown in the Supporting Information.
(23) Langlois, M.; Bremont, B.; Shen, S.; Poncet, A.; Andrieux, J.;
Sicsic, S.; Serraz, I.; Mathe-Allainmat, M.; Renard, P.;
Delagrange, P. J. Med. Chem. 1995, 38, 2050.
(12) For selected reviews, see: (a) Speckamp, W. N.; Hiemstra, H. Tet-
rahedron 1985, 41, 4367. (b) Speckamp, W. N.; Moolenaar, M. J.
Tetrahedron 2000, 56, 3817; and cited literature.
(13) For selected reviews of reactions involving N-acyliminium ions,
see: (a) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. Rev. 2004, 104, 1431. (b) Yazici, A.; Pyne,
S. G. Synthesis 2009, 339. (c) Yazici, A.; Pyne, S. G. Synthesis
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1502–1517