Efficient synthesis of 3-pyrrolylquinolines via an 1,3-dipolar cycloaddition/oxidation sequence

Article abstract of DOI:10.1080/00397910500290425

The synthesis of some new functionalized quinolyl derivatives relies on the 1,3-dipolar cycloaddition of an azomethine ylide, generated from sarcosine and paraformaldehyde, to quinolyl α,β-unsaturated esters, followed by oxidation of the pyrrolidinyl moiety to pyrrole with activated MnO₂. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500290425

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Efficient Synthesis of
3
1
‐Pyrrolylquinolines via an
,3‐Dipolar Cycloaddition/
Oxidation Sequence
a
a
a
H. Menasra , A. Kedjadja , A. Debache , S.
a
a
b
Rhouati, , A. Belfaitah & Bertrand Carboni
a
Laboratoire des Produits Naturels d'Origine
Végétalé et de Synthèse Organique, Faculté des
Sciences, Campus de Chaabat Ersas, Université
Mentouri‐Constantine, Algérie
b
Organométalliques et Catalyse, UMR 6509, Institut
de Chimie, Université de Rennes I, Campus de
Beaulieu, Rennes Cedex, France
Version of record first published: 22 Aug 2006.
To cite this article: H. Menasra, A. Kedjadja, A. Debache, S. Rhouati,, A. Belfaitah &
Bertrand Carboni (2005): Efficient Synthesis of 3‐Pyrrolylquinolines via an 1,3‐Dipolar
Cycloaddition/Oxidation Sequence, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 35:21, 2779-2788
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Synthetic Communications , 35: 2779–2788, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500290425
Efficient Synthesis of 3-Pyrrolylquinolines
via an 1,3-Dipolar Cycloaddition/Oxidation
Sequence
H. Menasra, A. Kedjadja, A. Debache, S. Rhouati, and
A. Belfaitah
Laboratoire des Produits Naturels d’Origine V e´ g e´ tal e´ et de Synth e` se
Organique, Facult e´ des Sciences, Campus de Chaabat Ersas, Universit e´
Mentouri-Constantine, Alg e´ rie
Bertrand Carboni
Organom e´ talliques et Catalyse, UMR 6509, Institut de Chimie,
Universit e´ de Rennes I, Campus de Beaulieu, Rennes Cedex, France
Abstract: The synthesis of some new functionalized quinolyl derivatives relies on
the 1,3-dipolar cycloaddition of an azomethine ylide, generated from sarcosine and
paraformaldehyde, to quinolyl a,b-unsaturated esters, followed by oxidation of the
pyrrolidinyl moiety to pyrrole with activated MnO
2
.
Keywords: Dipolar cycloaddition, oxidation, pyrroles, quinolines, Wittig reaction
3
2
-Substituted 2-chloroquinolines and their derivatives, 2-aminoquinolines,
-alkoxyquinolines, and quinolin-2-(1H)-ones, have attracted considerable
[1]
interest because of their important biological activities. This has stimulated
the search for more potent and specific derivatives, and a great variety of
Received in Poland May 24, 2005
Address correspondence to A. Belfaitah, Laboratoire des Produits Naturels
d’Origine V e´ g e´ tal e´ et de Synth e` se Organique, Facult e´ des Sciences, Campus de
Chaabat Ersas, Universit e´ Mentouri-Constantine, Alg e´ rie. Tel./Fax: 213 31 61 46
2
2; E-mail: abelbelfaitah@yahoo.fr
2
779

2780
H. Menasra et al.
Scheme 1.
compounds have been synthesized that incorporated new functional groups
[2]
into these structural cores, heterocycles for example. To the best of our
knowledge, pyrrolidines and pyrroles, which are present in many biologically
[
3]
active molecules, have never been combined with quinoline subunits. In the
course of our ongoing program related to the synthesis and the biological
[
4]
evaluation of quinolyl derivatives, we have elaborated an efficient and
straightforward route for the synthesis of 3-pyrrolidinyl- and 3-pyrrolylquino-
lines using a 1,3-dipolar cycloaddition/oxidation key sequence (Scheme 1).
Starting quinolylcarbaldehyde derivatives 1a–1g were obtained by sub-
jecting the suitable N-phenylacetamide to Vilsmeier reagent (POCl /DMF
3
[
4,5]
in a 7/3 ratio) as previously reported.
Condensation with stabilized phos-
phonium ylides Ph P ¼ CHCO R, (R ¼ Me or Et) in refluxing 1,2-dimethoxy-
3
2
ethane gave the corresponding (E)-quinolyl a,b-unsaturated esters (coupling
constant between the two ethylenic protons, J ¼ 16 Hz) with high stereoselec-
tivity and good yields (Scheme 2, Table 1)
Having in hand the starting activated alkenes 3, we then turned our
attention to the synthesis of the cycloadducts 4. 1,3-Dipolar cycloaddition
reaction of azomethine ylides is one of the most efficient methods for the con-
struction of five-membered heterocycles in a convergent and stereocontrolled
[6]
manner. Among the various routes available to prepare these dipoles, we
chose an in situ generatcon from N-substituted glycine and paraformaldehyde,
[7]
which was reported to give excellent results with electron-deficient alkenes.
The reaction was conducted in refluxing dry toluene and afforded new pyrro-
lidines 4a–4g in good yields as single diastereoisomers with no evidence of
1
any others in the H NMR or TLC of the crude products. These pyrrolidine
derivatives were easily converted into the corresponding pyrroles 5 in
moderate to good yields (59–77%) by oxidation with a fivefold excess of
activated manganese dioxide in refluxing THF during 5 h (Scheme 3,
Scheme 2.

Synthesis of 3-Pyrrolylquinolines
Table 1. Synthesis of quinolyl a,b-unsaturated esters 3
2781
1
2
R
3
4
R
a
Compound
R
R
R
Yield (%)
3
3
3
3
3
3
3
a
b
c
d
e
f
H
H
H
H
Me
Me
66
70
63
63
70
73
64
Me
Me
H
H
H
H
H
Me
H
H
Me Et
OMe
Me
H
H
H
H
Me
H
Me
Me
Et
H
Me Me
2
OCH O
g
H
a
Yields of isolated pure products.
1
13
Table 2). H and C NMR data were in full agreement with the proposed
structures of compounds 4 and 5.
In summary, we have prepared some new 3-pyrrolidinylquinolines by
1,3-dipolar cycloaddition of a symmetrical, unstabilized azomethine ylide to
the corresponding a,b-unsaturated esters. Oxidative dehydrogenation of
these cycloadducts with activated MnO under mild conditions provided the
2
corresponding pyrroles. Efforts to extend this methodology to other substi-
tuted azomethine ylides and to exploit the presence of versatile ester function-
ality are in progress in our laboratory.
EXPERIMENTAL
THF and toluene were freshly distilled from sodium/benzophenone, and
POCl and CHCl from P O DMF was kept for few hours over CaCl and
3
3
2
5
2
distilled from CaO, and DME from NaH. Melting points were determined
on a electrothermal capillary fine-control apparatus and are uncorrected. All
IR spectra were performed on Shimadzu FT-IR-8201 PC spectrophotometer
1
13
and only significant absorption-band frequency is cited. H NMR and
NMR spectra were recorded in deuterochloroform on a Br u¨ ker Avance
C
1
3
DPX 250 spectrometer at 250 MHz for proton and at 62.9 MHz for C.
Chemical shifts are given in ppm and J values in Hertz (Hz). High-resolution
mass spectra were obtained on a Varian MAT 311 (electron impact) or
Scheme 3.

2782
H. Menasra et al.
Table 2. Synthesis of 3-pyrrohdinyl- and 3-pyrrolylquinolines 4 and 5
1
R
2
3
4
a
Compound Yield (%) Compound Yield (%)
a
R
R
R
R
H
H
H
H
H
H
H
Me
Me
4a
4b
4c
4d
4e
4f
71
62
86
75
88
68
77
5a
5b
5c
5d
5e
—
—
71
59
77
65
74
—
—
Me
Me
H
Me
H
H
Me Et
OMe
H
H
H
H
Me
H
Me Me
Me
OCH
Me
Me
Et
H
H
H
2
O
4g
a
Yields of isolated pure product.
Micromass ZABSpec TOF [LSIMS or electrospray (CH CN, H O)], spec-
3
2
trometers by the “Centre R e´ gional de Mesures Physiques,” Universit e´ de
Rennes 1, France. Flash column chromatography was performed on Merck
silica gel (60, particle size 0.063–0.2 mm) using CHCl as eluent. Thin-
3
layer chromatography (TLC) was carried out on precoated Merck silica-gel
aluminium sheets 60 F254
Substituted 2-chloroquinolyl-3-carbaldehydes 2a–2f have been syn-
.
[4]
thesized in accordance with established methods. Spectroscopic results
and physical properties are in agreement with literature reports.
[4,5]
Preparation of Substituted Quinolyl a,b-Unsaturated Esters 3a–3g
Substituted 2-chloroquinolyl-3-carbaldehyde derivative 2 (10 mmol) was
added, under magnetic stirring, to 1.1 eq. (11 mmol) of stabilized phos-
phonium ylide dissolved in an appropriate quantity of dry DME (50 ml–
2
1
2
.10 M solution). The reaction mixture was refluxed for 4–5 h (the
progress of the reaction was monitored by TLC until disappearance of
starting materials). The oil bath was then removed, and the contents were
allowed to cool to room temperature. The solvent was evaporated in
vacuum and the residue was washed with a mixture of pentan6/ether
(50/50). The precipitate (OPPh ) was filtered off, and the filtrate was con-
centrated under reduced pressure to give a residue, which was subjected to
3
flash column chromatography (silica gel, eluent: CHCl ) to afford pure
3
crystalline product.
[
8]
Methyl (2E)-3-(2-chloroquinolin-3-yl)acrylate 3a:
1
R ¼ 0.5, mp 162–
f
1
638C. IR (nmax, KBr) ¼ 1711 (C 55 O, ester). H NMR (d ppm, J Hz): 8.30
(
s, 1H), 8.05 (d, J ¼ 15.9, 1H), 7.90 (dd, J ¼ 8.4, 2.4 1H), 7.78 (dd,
J ¼ 8.4, 2.4, 1H), 7.70 (dd, J ¼ 8.6, 2.4, 1H), 7.54 (d, J ¼ 8.6, 2.4, 1H),
1
3
6
.50 (d, J ¼ 15.9, 1H), 3.80 (s, 3H). C NMR (d ppm): 165.3 (CO), 148.9

Synthesis of 3-Pyrrolylquinolines
2783
(
C), 146.9 (C), 138.5 (CH), 135.0 (CH), 130.5 (CH), 127.4 (C), 126.9 (CH),
26.6 (CH), 126.3 (CH), 125.9 (C), 121.2 (CH), 52.2 (CH3).
1
Methyl (2E)-3-(2-chloro-5,7-dimethylquinolin-3-yl)]acrylate 3b: R ¼ 0.75,
f
1
mp 167–1688C. IR(n , KBr) ¼ 1716 (C 55 O, ester). H NMR (d PPm,
max
J Hz): 8.46 (s, 1H), 8.14 (d, J ¼ 15.9, 1H), 7.64 (s, 1H), 7.28 (s, 1H), 6.58
1
3
(
ppm): 167.0 (CO), 149.5 (C), 148.3 (C), 142.5 (C), 140.0 (CH), 138.0 (C),
d, J ¼ 15.9, 1H), 3.88 (s, 3H), 2.66 (s, 3H), 2.44 (s, 3H). C NMR (d
1
5
35.4 (CH), 132.9 (CH), 130.1 (C), 126.3 (CH), 125.1 (CH), 121.9 (C),
þ.
2.0 (CH ), 22.0 (CH ), 18.6 (CH ). HRMS (E.I) [M]
3
calcd for
3
3
C H ClNO ¼ 275.0713; found 275.0738.
1
5
14
2
Ethyl (2E)-3-(2-chloro-5,8-dimethylquinolin-3-y1)]acrylate 3c: R ¼ 0.77, mp
f
1
1
8
1
1
1
20–1218C. IR (nmax, KBr) ¼ 1705 (C 55 O, ester). H NMR (d ppm, J Hz):
.48 (s, 1H), 8.15 (d, J ¼ 16.0, 1H), 7.48 (d, J ¼ 7.2, 1H), 7.29 (d, J ¼ 7.2,
H), 6.53 (d, J ¼ 16.0, 1H), 4.35 (q, J ¼ 7.1, 2H), 2.72 (s, 3H), 2.67 (s, 3H),
1
3
.40 (t, J ¼ 7.1, 3H) C NMR (d ppm): 166.7 (CO), 149.7 (C), 147.5 (C),
40.1 (CH), 135.3 (CH), 133.1 (C), 132.5 (C), 130.7 (CH), 127.1 (C), 125.8
(CH), 122.5 (C), 121.7 (CH), 60.9 (CH ), 18.5 (CH ), 14.3 (CH ).
2 3 3
Methyl (2E)-3-(-2-chloro-7-methoxyquinolin-3-yl)]acrylate 3d: R ¼ 0.80,
f
1
mp 142–1458C. IR (n , KBr) ¼ 1712 (C 55 O, ester). H NMR (d ppm,
max
J Hz): 8.26 (s, 1H), 8.09 (d, J ¼ 15.9, 1H), 7.70 (d, J ¼ 8.9, 1H), 7.50
(
(
(
(
d, J ¼ 8.9, 2.4, 1H), 7.29 (d, J ¼ 2.4, 1H), 6.50 (d, J ¼ 15.9, 1H), 3.94
1
3
s, 3H), 3.85 (s, 3H). C NMR (d ppm): 169.8 (CO), 161.1 (C), 151.8
C), 149.2 (C), 141.3 (CH), 136.8 (CH), 133.6 (CH), 129.4 (C), 125.4
CH), 123.1 (C), 121.0 (CH), 106.6 (CH), 56.0 (CH ), 51.5 (CH ).
3
3
þ.
HRMS (E.I) [M] calcd. for C H ClNO ¼ 227.05057; found 227.0511.
1
4
12
3
Methyl (2E)-3-(2-chloro-7-methylquinolin-3-yl)acrylate 3e: R ¼ 0.50, mp
f
1
1
428C. IR (n , KBr) ¼ 1713 (C 55 O, ester). H NMR (d ppm, J Hz): 8.60
max
(
s, 1H), 8.24 (d, J ¼ 15.9, 1H), 7.80 (d, J ¼ 8.8, 1H), 7.80 (s, 1H), 7.42
1
3
(
NMR (d ppm): 162.7 (CO), 148.5 (C), 146.7 (C), 138.0 (CH), 134.8 (CH),
d, J ¼ 8.8, 1H), 6.58 (d, J ¼ 15.9, 1H), 3.88 (s, 3H), 2.55 (s, 3H).
C
1
1
30.6 (CH), 127.2 (C), 126.7 (CH), 126.3 (CH), 121.3 (C), 120.3 (CH),
.
16.3 (C), 52.0 (CH ), 23.0 (CH ). HRMS (E.I) [M-Cl ] calcd. for
þ
3
3
C H C1NO ¼ 226.08680; found 226.0873.
1
4
12
2
Methyl (2E)-3-(2-chloro-6,7-dimethylquinolin 3-yl) acrylate 3f: R ¼ 0.53,
a
f
1
mp 1538C. IR (n , KBr) ¼ 1716 (C 55 O, ester). H NMR (d ppm, J Hz):
max
8
.15 (s, 1H), 8.11 (d, J ¼ 16.0, 1H), 7.78 (s, 1H), 7.57 (s, 1H), 6.53
1
3
(
d, J ¼ 6.0, 1H), 3.87 (s, 3H), 2.66 (s, 3H), 2.44 (s, 3H). C NMR (d ppm):
1
66.5 (CO), 149.0 (C), 146.5 (C), 143.8 (C), 140.0 (CH), 138.3 (C), 135.4
(
(
CH), 127.8 (CH), 127.3 (C), 126.2 (CH), 125.4 (CH), 121.3 (C), 52.0
CH ), 20.7 (CH ), 20.6 (CH ).
3
3
3

2784
H. Menasra et al.
Ethyl (2E)-3-(2-chloro-6,7-deoxymethylquinolin-3-yl)acrylate 3g: R ¼ 0.8,
f
1
mp 168–1708C. IR (n , KBr) ¼ 1709 (C 55 O, ester). H NMR (d ppm,
max
J Hz): 8.01 (s, 1H), 7.94 (d, J ¼ 16.0, 1H), 7.14 (s, 1H), 6.92 (s, 1H),
6
3
1
1
.38 (d, J ¼ 16.0, 1H), 6.06 (s, 2H), 4.21 (q, J ¼ 2H), 1.28 (t, J ¼ 7.1,
1
3
H). C NMR (d ppm): 165.0 (CO), 151.4 (C), 147.6 (C), 146.9 (C),
45.5 (C), 138.2 (CH), 133.4 (CH), 124.0 (C), 123.0 (C), 120.4 (CH),
04.0 (CH), 101.6 (CH), 101.3 (CH ), 59.8 (CH ), 13.2 (CH ).
2
2
3
Synthesis of Quinolyl Pyrrolidine Derivatives 4a–4g
To a mixture of a substituted quinolyl a,b-unsaturated ester derivative
(
(
10 mmol) and sarcosine (2 eq., 20 mmol) dissolved in dry toluene
22
4.10 M) was added, under magnetic stirring, CH O (5 eq., 50 mmol),
2
portion by portion, of over 2 hours. The reaction mixture was refluxed for
8–72 h and water was removed by means of a Dean Stark trap (the
4
progress of the reaction was monitored by TLC). The oil bath was removed,
and the mixture was then allowed to cool to room temperature. The precipitate
was filtered off, and the filtrate was concentrated under, reduced pressure. The
residue was subjected to column chromatography (silica gel, eluent: CHCl ) to
3
afford pure product.
Methyl 4-(2-chloroquinolin-3-yl)-l-methylpyrrolidine-3-carboxylate 4a:
1
R ¼ 0.40. IR (n , KBr) ¼ 1736 (C 55 O, ester). H NMR (d ppm, J Hz):
f
max
8
1
3
2
1
1
4
.30 (s, 1H), 7.95 (d, J ¼ 8.4, 1H), 7.80 (dd, J ¼ 8.4, 1H), 7.68 (td, J ¼ 8.4,
.0, 1H), 7.60 (td, J ¼ 8.4, 1.1 H), 4.24 (td, J ¼ 8.1, 5.1, 1H), 3.70 (s, 3H),
.33–3.24 (m, 2H), 3.02 (dd, J ¼ 8.5, 8.1, 1H), 2.90 (dd, J ¼ 9.5, 8.1, 1H),
1
3
.84–2.73 (m, 1H), 2.50 (s, 3H). C NMR (d ppm): 173.6 (CO), 150.7 (C),
46.4 (C), 136.4 (CH), 134.9 (CH), 130.2 (CH), 128.0 (C), 127.4 (CH),
27.1 (CH), 126.7 (C), 62.5 (CH ), 59.3 (CH ), 52.0 (CH ), 50.5 (CH),
2
2
3
þ.
3.9
(CH),
41.7
(CH3).
HRMS
(E.I)
[M]
calcd.
for
C H C1N O ¼ 318.11351; found 318.1147.
1
7
19
2 2
Methyl 4-(2-chloro-5,7-dimethylquinolin-3-yl)-1-methylpyrrolidine-3-carbo-
xylate 4b: R ¼ 0.35, mp. 77–788C. IR(n , KBr) ¼ 1736 (C 55 O, ester).
f
max
1
H NMR (d ppm, J Hz): 8.27 (s, 1H), 7.52 (s, 1H), 7.10 (s, 1H), 4.17 (dt,
J ¼ 8.1, 5.1, 1H), 3.64 (s, 3H), 3.26–3.11 (m, 2H), 3.02 (dd, J ¼ 9.4, 8.3,
1
3
1
H), 2.87–2.78 (m, 2H), 2.57 (s, 3H), 2.40 (s, 3H), 2.39 (s, 3H). C NMR
d ppm): 173.9 (CO), 150.3 (C), 147.0 (C), 140.2 (C), 133.9 (C), 133.5 (C),
(
1
32.7 (CH), 129.8 (CH), 125.1 (CH), 124.8 (C), 62.8 (CH ), 59.4 (CH ),
2 2
5
2.1 (CH ), 50.6 (CH), 44.2 (CH), 41.7 (CH ), 21.7 (CH ), 18.5 (CH ).
3
3
3
3
þ.
HRMS (E.I) [M] calcd. for C H C1N O ¼ 332.12916; found 332.1286.
1
8
21
2 2
Ethyl 4-(2-chloro-5,8-dimethylquinolin-3-yl) -1-methylpyrrolidine-3-carbox-
1
ylate 4c: R ¼ 0.38, oil. IR (n , KBr) ¼ 1730 (C 55 O, ester). H NMR
f
max
(d ppm, J Hz): 8.37 (s, 1H), 7.39 (d, J ¼ 7.2, 1H), 7.22 (d, J ¼ 7.2, 1H),

Synthesis of 3-Pyrrolylquinolines
2785
4
3
2
.27 (dt, J ¼ 8.2, 5.8, 1H), 4.23–4.18 (m, 2H), 3.29 (dd, J ¼ 8.1, 6.4, 1H),
.22 (dd, J ¼ 8.1, 7.3, 1H), 3.12 (dd, J ¼ 8.2, 7.2, 1H), 2.94–2.86 (m, 2H),
1
3
.69 (s, 3H), 2.64 (s, 3H), 2.46 (s, 3H), 1.25 (t, J ¼ 7.2, 3H). C NMR (d
ppm): 173.6 (CO), 149.4 (C), 146.0 (C), 134.3 (C), 134.0 (C), 133.1 (CH),
31.9 (C), 129.8 (CH), 127.2 (CH), 126.8 (C), 62.9 (CH ), 61.0 (CH ), 59.5
1
2
2
(
CH ), 50.8 (CH), 44.3 (CH), 41.8 (CH ), 18.6 (CH ), 17.7 (CH ), 14.2 (CH ).
2 3 3 3 3
Methyl 4-(2-chloro-7-methoxyquinolin-3-yl)-1-methylpyrrolidine-3-carboxy-
1
late 4d: R ¼ 0.6, oil. IR (n , KBr) ¼ 1735 (C 55 O, ester). H NMR (d ppm,
f
max
J Hz): 8.14 (s, 1H), 7.63 (d, J ¼ 8.8, 1H), 7.24 (d, J ¼ 2.5, 1H), 7.12
(
dd, J ¼ 8.8, 2.5, 1H), 4.20 (dd, J ¼ 8.1, 5.2, 1H), 3.86 (s, 3H), 3.66
(
s, 3H), 3.22–3.14 (m, 2H), 2.99 (dd, J ¼ 9.5, 8.2, 1H), 2.85 (dd, J ¼ 9.7,
1
3
.1, 1H), 2.81–2.73 (m, 1H), 2.40 (s, 3H). C NMR (d ppm): 174.0 (CO),
5
1
61.1 (C), 151.0 (C), 148.1 (C), 135.9 (CH), 132.8 (CH), 128.3 (C), 122.6
(
(
C), 120.1 (CH), 106.1 (CH), 62.8 (CH ), 59.5 (CH ), 55.4 (CH ), 52.1
2 2 3
þ.
CO CH ), 50.7 (CH), 43.8 (CH), 41.7 (CH ). HRMS (E.I) [M] calcd. for
2
3
3
C H C1N O ¼ 334.10842; found 334.1070.
1
7
19
2 3
Methyl
4-(2-chloro-7-methylquinolin-3-yl)-1-methylpyrrolidine-3-carbo-
xylate 4e: R ¼ 0.35, mp 65–668C. IR (n , KBr) ¼ 1719 (C 55 O, ester).
f
max
1
H NMR (d ppm, J Hz): 8.25 (s, 1H), 7.75 (d, J ¼ 8.4, 1H), 7.48 (s, 1H),
7
.40 (d, J ¼ 8.4, 1H), 4.23 (dd, J ¼ 8.1, 5.0, 1H), 3.71 (s, 3H), 3.26–3.18
(
(
(
m, 2H), 3.03 (dd, J ¼ 9.5, 8.1, 1H), 2.89 (dd, J ¼ 9.5, 5.0, 1H), 2.83–2.75
1
3
m, H), 2.54 (s, 3H), 2.48 (s, 3H). C NMR (d ppm): 173.9 (CO), 150.7
C), 146.5 (C), 140.6 (CH), 134.2 (CH), 131.9 (CH), 128.6 (CH), 127.0 (C),
25.5 (C), 124.8 (C), 62.7 (CH ), 59.4 (CH ), 52.2 (CH ), 50.6 (CH), 43.9
2 2 3
1
þ.
(
CH), 41.8 (CH3), 21.9 (CH3). HRMS (E.I) [M]
cacld. for
C H C1N O ¼ 304.09786; found 304.0975.
1
6
17
2 2
Methyl 4-(2-chloro-6,7-dimethylquinolin-3-yl)-1-methylpyrrolidine-3-carbox-
1
ylate 4f: R ¼ 0.40, oil. IR (n , KBr) ¼ 1742 (C 55 O, ester). H NMR
f
max
(
d ppm, J Hz): 8.20 (s, 1H), 7.73 (s, 1H), 7.56 (s, 1H), 4.24 (dd, J ¼ 8.2, 5.5
1
H), 3.70 (s, 3H), 3.34–3.24 (m, 2H), 3.11 (d, J ¼ 9.6, 8.3, 1H), 3.01
(
(
d, J ¼ 9.5, 5.4, 1H), 2.97–2.85 (m, 2H), 2.51 (s, 3H), 2.44 (s, 3H), 2.44
1
3
s, 3H). C NMR (d ppm): 173.9 (CO), 149.7 (C), 145.5 (C), 140.5 (C),
37.0 (C), 135.2 (C), 134.0 (CH), 127.3 (C), 126.5 (CH), 126.0 (CH), 62.6
1
(
CH ), 59.4 (CH ), 52.1 (CH ), 50.6 (CH), 43.9 (CH), 41.7 (CH ), 20.4 (CH ),
2
2
3
3
3
1
9.9 (CH3).
Ethyl
3
4-(2-chloro-6,7-deoxymethylquinolin-3-yl)-1-methylpyrrolidine-
-carboxylate 4g: R ¼ 0.62, yellow crystals, mp 224–2258C. IR (nmax,
f
1
KBr) ¼ 1735 (C 55 O, ester). H NMR (d ppm, J Hz): 8.35 (s, 1H), 7.28
(
s, 1H), 7.13 (s, 1H), 6.14 (s, 2H), 4.35–4.14 (m, 3H), 3.57–3.31 (m, 2H),
.25 (dd, J ¼ 9.4, 8.2, 1H), 2.97 (dd, J ¼ 9.4, 5.1, 1H), 2.84–2.75 (m, 1H),
3
1
3
2
.52 (s, 3H). 1.35 (t, J ¼ 7.1, 3H). C NMR (d ppm): 172.4 (CO), 151.4
(
C), 148.3 (C), 148.1 (C), 144.9 (C), 134.4 (CH), 131.7 (C), 124.9 (C),

2786
H. Menasra et al.
1
5
04.9 (CH), 102.6 (CH), 102.0 (CH ), 62.0 (CH ), 61.4 (CH ), 58.9 (CH ),
2
2
2
2
þ.
1.7 (CH), 43.3 (CH), 41.7 (CH ), 14.0 (CH ). HRMS (E.I) [M] calcd. for
3
3
C H C1N O ¼ 362.10334; found 362.1032.
1
8
19
2 4
Synthesis of Quinolyl Pyrrole Derivatives 5
To a 0.1 M solution of 4 (1.5mmol, in 15ml of dry THF) was added, at one time,
2
portion of activated MnO was then added, and the reflux was continued for
.5 equiv of activated MnO . The mixture was refluxed for 2.5 h. The same
2
2
an additional 2.5 h. After cooling, the mixture was diluted with THF (5 ml)
and filtered through celite. Celite was washed with THF (5 ꢀ 5 ml), and the
filtrate was concentrated under reduced pressure, diluted with CH Cl , and
2
2
washed with aqueous 1 N hydrochloric acid (2 ꢀ 5 m1). The organic layers
were separated and dried over anhydrous MgSO . The filtrate was concentrated
4
and the residue purified by flash chromatography on silica gel using CHCl as
3
eluent to afford pure corresponding pyrrole derivatives.
Methyl 4-(2-chloroquinolin-3-yl)-l-methyl-1H-pyrrole-3-carboxylate 5a:
1
R ¼ 0.77, mp ¼ 115–1168C. IR(n , KBr) ¼ 1712 (C 55 O, ester)
H
f
max
NMR (d ppm, J Hz): 8.11 (s, 1H), 8.05 (dd, J ¼ 8.4, 1H), 7.80 (dd, J ¼ 8.4,
1
1
1
H) 7.70 (td, J ¼ 8.4, 1.1 1H), 7.52 (td, J ¼ 8.4, 1.1 1H), 7.41 (d, J ¼ 2.4,
1
3
H), 6.72 (d, J ¼ 2.4, 1H), 3.78 (s, 3H), 3.67 (s, 3H). C NMR (d ppm):
64.6 (C), 151.5 (C), 146.6 (C), 138.7 (CH), 129.9 (CH), 128.8 (C), 128.3
(
(
CH), 127.9 (CH), 127.3 (C), 127.0 (CH), 126.8 (C), 123.2 (CH), 121.8
þ.
CH), 115.0 (C), 50.9 (CH ), 36.8 (CH ). HRMS (E.I) [M] calcd. for
3
3
C H C1N O ¼ 300.06656; found 300.0661.
1
6
13
2 2
Methyl 4-(2-chloro-5,7-dimethylquinolin-3-yl)-1-methyl-1H-pyrrole-3-car-
2
1
1
boxylate 5b: R ¼ 0.8, IR (KBr): n (cm ) ¼ 1712 (C 55 O, ester). H NMR
f
(
(
(
d ppm, J Hz): 8.20 (s, 1H), 7.73 (s, 1H), 7.40 (d, J ¼ 2.4, 1H), 7.23
s, 1H), 6.72 (d, J ¼ 2.4, 1H), 3.78 (s, 3H), 3.66 (s, 3H), 2.63 (s, 3H), 2.53
1
s, 3H). C NMR (d ppm): 166.9 (CO), 150.9 (C), 146.4 (C), 139.4 (C),
3
1
1
36.2 (CH), 133.5 (C), 129.4 (C), 127.8 (C), 127.0 (C), 125.7 (CH),
24.1 (CH), 122.9 (CH), 121.7 (CH), 110.7 (C), 51.6 (CH ), 41.7
3
þ.
(CH3), 21.7 (CH3), 18.5 (CH3). HRMS (E.I) [M]
cacld. for
C H C1N O ¼ 328.09786; found 328.0985.
1
8
17
2 2
Ethyl 4-(2-chloro-5,8-dimethylquinolin-3-yl)-1-methyl-1H-pyrrole-3-carbo-
2
1
xylate 5c: Yd ¼ 65%. R ¼ 0.7. IR (KBr): n(cm ) ¼ 1708 (C 55 O, ester).
f
1
H NMR (d ppm, J Hz): 8.18 (s, 1H), 7.45 (d, J ¼ 7.2, 1H), 7.40 (d, J ¼ 2.4,
1
H), 7.26 (d, J ¼ 7.2, 1H), 6.72 (d, J ¼ 2.4 1H), 4.14 (q, J ¼ 7.1, 2H), 3.78
1
3
(
s, 3H), 2.76 (s, 3H), 2.68 (s, 3H), 1.09 (t, J ¼ 7.1, 3H). C NMR (d ppm):
67.6 (C), 150.7 (C), 146.7 (C), 139.8 (C), 134.2 (CH), 133.8 (C), 129.7
CH), 128.8 (C), 128.2 (C), 125.8 (CH), 124.7 (CH), 123.1 (C), 115.4 (C),
1.0 (CH ) 41.8 (CH ) 18.6 (CH ) 17.7 (CH ), 14.2 (CH ).
1
(
6
2
3
3
3
3

Synthesis of 3-Pyrrolylquinolines
2787
Methyl 4-(2-chloro-7-methoxyquinolin-3-yl)-1 methyl-1H-pyrrole-3-carbox-
ylate 5d: R ¼ 0.75, mp ¼ 115–117 8C. IR(n , KBr) ¼ 1710 (C 55 O,
f
max
1
ester). H NMR (d ppm, J Hz): 8.13 (s, 1H), 7.71 (d, J ¼ 8.9, 1H), 7.34–
7
3
1
1
5
.36 (m, 2H), 7.17 (dd, J ¼ 8.9, 2.2, 1H), 6.70 (d, J ¼ 2.4, 1H), 3.96 (s, 3H),
1
.75 (s, 3H), 3.67 (s, 3H). C NMR (d ppm): 167.1 (C), 161.3 (C),
3
51.1 (C), 148.9 (C), 135.9 (CH), 131.1 (CH), 128.7 (C), 125.6 (C),
24.2 (CH), 123.0 (C), 122.7 (C), 121.0 (CH), 115.1 (C), 106.6 (CH),
þ.
6.1 (CH ), 51.6 (CH ), 41.7 (CH ). HRMS (E.I) [M]
3
calcd. for
3
3
C H C1N O ¼ 330.07712; found 330.0781.
1
7
15
2 3
Methyl 4-(2-chloro-7-methylquinolin-3-yl)-1-methyl-1H-pyrrole-3-carboxy-
late 5e: R ¼ 0.7, mp ¼ 177–178 8C. IR(n , KBr) ¼ 1716 (C 55 O, ester).
f
max
l
H NMR (d ppm, J Hz): 8.04 (s, 1H), 7.84 (d, J ¼ 2.2, 1H), 7.74 (d, J ¼ 8.2,
1
H), 7.40 (d, J ¼ 2.4, 1H), 7.39 (J ¼ 2.4, 1H), 6.73 (d, J ¼ 2.4, 1H), 3.77
1
s, 3H), 3.65 (s, 3H), 2.19 (s, 3H). C NMR (d ppm): 169.2 (C), 146.9 (C),
3
(
1
1
40.3 (C), 138.4 (CH), 130.8 (CH), 129.0 (CH), 128.7 (CH), 127.8 (C),
27.3 (C), 126.9 (C), 125.8 (C), 123.2 (CH), 121.7 (CH), 115.2 (C), 51.2
þ.
(
CH3), 36.7 (CH3), 21.8 (CH3). HRMS (E.I) [M]
calcd. for
C H C1N O ¼ 314.08221; found 314.0816.
1
7
15
2 2
ACKNOWLEDGMENTS
We thank ANDRS (Agence Nationale pour le D e´ veloppement de la Recherche
en Sant e´ ) and MESRES (Minist e` re de 1’Enseignement Sup e´ rieur et de la
Recherche Scientifique) for partial financial support.
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