1,3-Dipolar cycloaddition of stabilized azomethine ylides to alkenyl quinolines: An efficient route to polyfunctionalized 3-pyrrolidinylquinoline derivatives

Article abstract of DOI:10.1002/jhet.5570450206

(Chemical Equation Presented) Some new polysubstituted 3- pyrrolidinylquinolinyl derivatives were prepared by 1,3 dipolar cycloadditions of an azomethine ylide, generated in situ from benzylideneimine of methylglycinate and triethylamine in the presence of LiBr, to quinolyl α,β-unsaturated esters.

Full text of DOI:10.1002/jhet.5570450206

Mar-Apr 2008
329
1,3-Dipolar cycloaddition of stabilized azomethine ylides to alkenyl
quinolines: An efficient route to polyfunctionalized
3-pyrrolidinylquinoline derivatives
Abdelmalek Bouraiou1, Abdelmadjid Debache1, Salah Rhouati1, Bertrand Carboni2,
Ali Belfaitah*1
1Laboratoire des Produits Naturels d'Origine Végétale et de Synthèse Organique,
Campus de Chaabat Ersas, Université Mentouri, Constantine, Algérie.
2 Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes 1, Bat 10 A,
Campus de Beaulieu, 35042 Rennes CEDEX, France.
E-mail: Bertrand.Carboni@univ-rennes1.fr
Received January 29, 2007
MeO2C
R1
R1
R1
NH
R2
R3
CHO
Cl
R2
R3
R'
Ph
R2
R3
PhCH=N-CH2CO2Me
LiBr, Et3N, THF
Ph3P=CHCO2R
Or Ph3PCH3+, I-
CO2R
N
N
Cl
N
Cl
R4
R4
R4
Some new polysubstituted 3-pyrrolidinylquinolinyl derivatives were prepared by 1,3 dipolar
cycloadditions of an azomethine ylide, generated in situ from benzylideneimine of methylglycinate and
triethylamine in the presence of LiBr, to quinolyl α,β−unsaturated esters
J. Heterocyclic Chem., 45, 329 (2008).
synthesis and biological evaluation of quinolinyl
derivative [9]. In a continuation of our efforts in this area,
we report here an efficient and straightforward procedure
for the preparation of polysubstituted 3-pyrrolidinylquin-
olines via a 1,3-dipolar cycloaddition of stabilized N-
metallated azomethine ylides to the corresponding
quinolyl α,β-unsaturated esters (Scheme 1) [10].
INTRODUCTION
Quinolines are an important group of heterocyclic
compounds, in which 2-chloro-3-formylquinolines occupy
a prominent position as key intermediates for further
annelation and various functional group interconversion
[1]. In recent years, significant advances were made in
this area, mainly in relation with the biological activities
of quinoline derivatives as antibiotic [2], anti-
inflammatory [3], analgesic [4] and antitumoral [5]. On
the other hand, 1,3-dipolar cycloaddition is one of the
simplest approaches for the construction of five-
membered rings [6]. The ease of generation of these 1,3-
dipoles, coupled with a high regio and stereoselectivity,
led to a number of syntheses which utilize such a reaction
as the key step. In particular, the in situ generated N-
metallated azomethine ylides are high reactive species,
which react with suitably activated dipolarophiles to
afford the corresponding polysubstituted N-H pyrrolidine
derivatives [7]. Asymmetric versions of these [3+2]
cycloadditions have been also recently reported [8]. In
recent years, we have developed a program devoted to the
RESULTS AND DISCUSSION
The syntheses of the starting (E)-quinolinyl α,β-unsatu-
rated ester derivatives 2a-2h were carried out from the
aldehydes 1 via a Horner-Wadsworth-Emmons reaction
using trialkylphosphonoacetates. Higher yields and
purities were obtained compared with those previously
reported with stabilized phosphonium ylides (Scheme 2)
[10,11]. The rapid entry and the high stereoselectivity of
this method demonstrate the utility of this variant, which
has the additional advantage of producing a water-soluble
phosphate salt PO(OR)2ONa as by-product, easily
removed via aqueous extraction [12]. Compounds 2i-2j
were obtained from triphenylmethylene phosphorane by a
modification of the previously reported procedure[13].
Scheme 1
H
MeO2C
N
R1
R1
R1
Ph
R2
R3
R
R2
R3
R2
R3
CHO
Cl
R=CO2R', Cycloaddition
R=H, No product
Wittig
R
Horner-Wadsworth
-Emmons reactions
N
Cl
N
Cl
N
R4
R4
R4
1
2
3
Synthesis of 3-pyrrolidinylquinolines derivatives

330
A. Bouraiou, A. Debache, S. Rhouati, A. Carboni, A. Belfaitah
Vol 45
Scheme 2
confirms the regiochemistry (2, 4-dicarboxylate structure)
and demonstrated the 4, 5-cis configuration relationship.
The relative configurations of the other carbon atoms
were established by 1H1H-COSY and NOESY
experiments. The intensive NOESY cross-peaks proved
the 2, 4, 5 cis configuration of the pyrrolidinyl ring
protons (Scheme 3). The stereochemical course of this
cycloaddition is therefore in agreement with an endo
cycloadduct of the syn form of N-lithiated azomethine
ylide [15, 16].
R1
R4
R1
R4
R1
R2
R3
R2
R3
CHO
Cl
R2
R3
R
ii
i
N
Cl
N
N
Cl
R4
2i-2j
1a-g
2a-2k
Reagents and conditions: (i) (EtO)2POCH2R, NaH, Dimethoxyethane,
1.5h, reflux; (ii) Ph3PCH3+ I-, tert-BuOK, THF, rt.
Table 1
Table 2
Synthesis of alkenyl quinolines derivatives
Synthesis of 3-pyrrolidinylquinolines derivatives
R1
R2
R3
R4
R
Yield
(%)a
74
70
82
71
61
50
79
0
Yield
Entry Pyrrolidine
Entry
Compound
R1
R2
R3
R4
R
(%)a
70
66
74
69
54
93
87
70
74
68
1
2
2a
2b
2c
2d
2e
2f
H
H
H
H
H
Me
H
H
H
CO2Me
CO2Me
CO2Me
CO2Et
CO2Et
CO2Me
CO2Me
CO2Et
H
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
Me
H
H
H
H
H
Me
H
OMe
H
H
H
H
Me
CO2Me
CO2Et
CO2Me
CO2Et
CO2Et
3
H
OMe
H
4
H
OCH2O
H
OCH2O
H
H
Me
H
Me
5
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
6
Me
H
Me CO2Me
7
2g
2h
2i
Me
H
H
H
H
CO2Me
H
H
8
H
H
9
H
H
H
H
0
10
2j
H
Me
H
H
a Yields of isolated products.
a Yields of isolated products.
The configurations of the other quinolyl derivatives 3b-
3g were established by analogy and by comparison of
their 1H NMR spectra with those of 3a.
Having in hand the starting alkenes 2, we then turned our
attention to the synthesis of the cycloadducts. Among the
various routes available to prepare N-metalled azomethine
ylides, we choose an in situ generation from benzylidene-
imine of methyl glycinate [14], lithium bromide as
catalyst and triethylamine as a base (Scheme 3) [15]. The
reaction was conducted at room temperature in dry THF
and afforded new pyrrolidines 3a–3g in good yields as
single diastereoisomer, with no evidence in the crude
In summary, we have reported a practical and efficient
synthesis of 3-pyrrolidinylquinoline derivatives in good
yields. Careful structural analysis confirms an endo
approach during the cycloaddition step. The presence of the
versatile ester and iminochloride functionalities would be of
great help for further annelation processes. Work is
currently being undertaken in our laboratory to explore the
scope and limitation of this route for the construction of new
enantioenriched pyrrolidinylquinolines and derivatives.
1
products of any others by H NMR spectroscopy or by
T.L.C. The presence of the ester group is essential, since
no adducts were detected with the monosubstituted alkene
2h–2i (Table 2).
Table 3
Significant 1H,13C NMR chemical shifts, selected H-H coupling NOE
Scheme 3
and HMBC connectivities for 3a.
δ1H
(m,J)
4.23
(d,8.3)
4.89
(d,8.5)
3.65
(t, .8)
4.51
δ13C
66.7
65.5
58.0
49.6
1H{1H}
n.O.ea
H-5, H-4',
2-CO2Me
H-2, H-6
Ar, H-2Ar
H-2, H-4'
1H,1H
COSY
4.51
1H,13C
HMBC
H
H
MeO2C
H
4'
1
R1
N
R1
H
H-2
H-5
H-4
H-3
2-CO2, C-3', C-4, C-
3
2
3
N
CO2Me
R2
R3
R2
R3
5
R
Ph
H
4
3.65
4-CO2, C-1Ar, C-4,
C-3
H
R
i
N
Cl
N
Cl
R4
4.51,
4.89
4.23,
3.65
4-CO2, C-1Ar, C-3',
C-2, C-5, C-3
2-CO2, 4-CO2, C-2',
C-4', C-3', C-2,
C-5, C-4
R4
3a-3h
syn-endo
2a-2j
H-4'
(t,7.7)
Reagents and conditions: (i) LiBr, Et3N, THF, rt.
a: Obtained by 2D-NOESY spectroscopy.
The structure of compound 3a was elucidated by
1
detailed NMR studies. The H and 13C NMR assignments
Acknowledgements. We thank ANDRS (Agence
National pour le Développement de la Recherche en
Santé) and MESRES (Ministère de l'enseignement
supérieur de la recherche scientifique) for partial financial
support.
were made on the basis of high-field one and two-
dimensional methods (HMBC, HSQC, COSY, and
NOESY H, H). The shielding of the protons of the C-4-
CO2Me (δ= 3.17 ppm) by the adjacent phenyl group

Mar-Apr 2008
1,3-Dipolar cycloaddition of stabilized azomethine ylides to alkenyl quinolines
331
mmol) of potassium tert-butoxide. After 5 minutes, a solution of
2-chloroquinolyl-3-carbaldehyde 1a (192 mg, 1 mmol) in THF
(2ml) was added dropwise. The resulting mixture was stirred at
room temperature for 10 minutes, then diluted with water (10
mL) and extracted with CH2Cl2 (20 mL). The organic layer was
washed twice with water (5 mL), brine (5 mL) and dried over
anhydrous sodium sulfate. The solvent was evaporated in vacuo
to give a residue which was purified by flash chromatography on
silica gel using CH2Cl2 as eluent.
EXPERIMENTAL
THF was freshly distilled from sodium/benzophenone, POCl3
and CH2Cl2 from P2O5, DMF was kept for few hours over CaCl2
and distilled from CaO and dimethoxyethane from NaH. Melting
points were determined on a Electrothermal Digital Melting
Points Apparatus IA 9200 and are uncorrected. IR spectra were
performed on Shimadzu FT IR-8201 PC spectrophotometer and
Perkin Elmer Spectrum One (FT-IR) spectrophotometer with a
universal ATR sampling accessory. NMR spectra were recorded
in CDCl3 on a Brüker Avance DPX250 or Bruker Avance
DMX300 spectrometer. Chemical shifts (δ) are given in ppm
and J values in Hertz (Hz). Flash column chromatography was
performed on Merck silica gel (60, particle size 0.063-0.2 mm)
using CHCl3 or CH2Cl2 as eluent. Thin layer chromatography
(TLC) was carried out on precoated Merck silica gel aluminium
sheets 60 F254. HRMS data were obtained on spectrometer MAT
311 (Centre Régional de Mesures Physiques de l'Ouest). Low
resolution mass spectra were recorded on a Finnigan PolarisQ
ion trap mass spectrometer using electron impact (EI) ionization
mode at 70 eV and a Finnigan LCQ ion trap mass spectrometer
(ESI).
2-Chloro-3-vinylquinoline (2i). mp 60°C; IR (KBr): 1616,
1
1566, 918, 987 cm-1; H nmr (250 MHz, CDCl3) δ 8.25 (1H, s,
Ar), 8.02 (1H, d, J = 8.4, Ar), 7.80 (1H, d, J = 7.2, Ar), 7.69
(1H, ddd, J = 8.4, 7.2, 1.5, Ar), 7.58 (1H, ddd, J = 8.5, 7.2, 1.5,
Ar), 7.18 (1H, dd, J = 17.6, 11, CH=), 5.80 (1H, d, J = 17.3,
=CH), 5.50 (1H, d, J = 11.2, =CH); 13C nmr (62.5 MHz, CDCl3):
δ 149.8 (C), 146.9 (C), 138.8 (CH), 134.2 (CH), 132.3 (CH),
128.1 (C), 127.5 (CH), 127.3 (CH), 127.1 (CH), 122.3 (C),
118.6 (CH2). HRMS (EI): m/z [M+] Calcd. for C12H10N35Cl:
189.0345; found: 189.0342; MS: m/z (EI) (rel. intensity %) =
191 (32), 190 (12), 189 (100), 155 (10), 154 (88), 153 (25), 152
(10), 128 (13), 127 (52), 126 (21), 101 (12), 99 (5), 95 (5), 77
(29), 76 (19), 75 (15), 64 (13), 63 (25), 51 (17), 50 (11). Calcd
for C11H8NCl: C, 69.67; H, 4.25; N, 7.39. Found: C, 69.72; H,
4.68; N, 7.03.
Substituted 2-chloroquinolyl-3-carbaldehydes 1a-1g have
been synthesized according to reported methods[9].
2-Chloro-6-methyl-3-vinylquinoline (2j). mp 120°C °C; IR
1
Preparation of quinolinyl α,β-unsaturated esters 2a-2h
via Horner-Wadsworth-Emmons reactions. To a suspension
of 50 % sodium hydride dispersion in mineral oil (26 mg, 1.1
mmol) placed in 20 mL of 1, 2-dimethoxyethane, was added, at
0°C through the pressure-equalizing dropping funnel and over a
20 minutes period, (231 mg, 1.1 mmol) of methyldiethyl-
phosphonoacetate. The ice bath was then removed, and the
contents were allowed to cool to room temperature. The reaction
mixture was kept, under stirring at room temperature, for 30
minutes and (192 mg, 1 mmol) of 2-chloro-3-formylquinoline 1a
was added in one portion. The mixture was refluxed for 1.5
hours. After cooling, water was added and the residue was
extracted threefold with CH2Cl2 (40 mL). The organic layers
were separated and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure to afford the desired α,β-
unsaturated ester derivative.
Spectroscopic results and physical properties of 2a-2e and 2g-
2h are in full agreement with those previously described [9, 10].
Methyl (E)-3-(2-chloro-5, 8-dimethylquinolin-3-yl)acrylate
(2f). 150 mg (0.54 mmol) of compound 2f was prepared
according to the general procedure and obtained as white solid;
mp 122°C; ir (KBr): 1710 cm-1 (C=O, ester); 1H nmr (250 MHz,
CDCl3): δ 8.51 (1H, s, Ar), 8.19 (1H, d, J = 16.0, β-H), 7.52
(1H, d, J = 8.9, Ar), 7.30 (1H, d, J = 8.5, Ar), 6.62 (1H, d, J =
16.0, -H), 3.96 (3H, s, OCH3), 2.75 (3H, s, CH3), 2.72 (3H, s,
CH3); 13C nmr (75.4 MHz, CDCl3): δ 166.4 (CO), 148.4 (C),
147.5 (C), 140.1 (CH), 136.6 (C), 134.5 (C), 132.9 (CH), 132.7
(C), 131.4 (CH), 127.8 (CH), 121.7 (CH), 126.2 (C), 52.0 (CH3),
18.5 (CH3), 17.6 (CH3). HRMS (EI): m/z [M+] Calcd. for
C15H14NO235Cl: 275.0713; found: 275.0711. MS m/z (EI) (rel.
intensity %) 275 (M+, 15), 244 (5), 241 (16), 240 (100), 225
(12), 224 (6), 212 (13), 197 (7), 180 (10), 154 (5), 153 (9), 152
(13), 151 (6), 127 (7), 115 (6), 101 (6), 90 (13), 89 (11), 77 (12),
76 (15), 75 (6), 63 (6). Calcd for C15H14NO2Cl: C, 65.34; H,
5.12; N, 5.08. Found: C, 65.08; H, 5.51; N, 4.80.
(KBr): 1724, 1694, 1654, 1691, 1521, 1173, 783 cm-1; H nmr
(250 MHz, CDCl3 δ 8.20 (1H, s, Ar), 7.80 (1H, d, J = 8.4, Ar),
7.60-7.50 (2H, m, Ar), 7.20 (1H, dd, J = 17.6, 11.1, HC=), 5.83
(1H, d, J = 17.1, =CH), 5.50 (1H, d, J = 11.2, =CH), 2.55 (3H, s,
CH3); 13C nmr (62.5 MHz, CDCl3): δ 148.9 (C), 145.6 (C), 137.1
(CH), 133.6 (C), 132.5 (CH), 132.4 (C), 130.3 (CH), 127.8
(CH), 127.4 (CH), 126.3 (C), 118.2 (CH2), 21.5 (CH3). Calcd for
C12H10NCl: C, 70.77; H, 4.95; N, 6.88. Found: C, 71.28; H,
5.22; N, 6.71.
Synthesis of quinolinyl pyrrolidine derivatives 3a-3h. To
lithium bromide (130 mg, 1.5 mmol) dissolved in dry THF (20
mL) were added, under stirring at room temperature, benzyl-
ideneimine of methyl glycinate (177 mg, 1 mmol) [14], freshly
distilled Et3N (101 mg, 1.2 mmol) and alkenylquinoline 2 (1
mmol). The reaction mixture was kept, under stirring at room
temperature, for 48 hours (the progress of the reaction was
monitored by TLC). Ether (15 mL) was added followed by 10
mL of saturated aqueous solution of NH4Cl. The organic layer
was separated and dried over anhydrous MgSO4. The solvent
was removed under reduced pressure and the residue was
purified by flash chromatography on silica gel using CHCl3 as
eluent.
Dimethyl (2S*,3R*,4S*,5R*) 3-(2-chloro-7-methylquinolin-
3-yl)-5-phenylpyrrolidine-2,4-dicarboxylate (3a). mp 159 °C;
IR (ATR): 1718, 1710, 1627, 1494, 1433, 1251, 1194, 1038, 734
cm-1; 1H nmr (300 MHz, CDCl3): δ 8.16 (1H, s, Ar), 7.79 (1H, s,
Ar), 7.72 (1H, d, J = 8.5, Ar), 7.28-7.42 (6H, m, Ar), 4.89 (1H,
d, J = 8.5, 5-H), 4.51 (1H, t, J = 7.7, 3-H), 4.23 (1H, d, J = 8.3,
2-H), 3.75 (3H, s, OCH3), 3.65 (1H, t, J = 7.8, 4-H), 3.17 (3H, s,
OCH3), 3.17 (1H, br s, NH), 2.65 (3H, s, CH3); 13C nmr (75.4
MHz, CDCl3): δ 173.1 (C, 2-CO2), 172.2 (C, 4-CO2), 151.1 (C,
C-2'), 147.3 (C, C-9'), 141.5 (C, C-7'), 139.2 (C, C-1Ar), 137.0
(CH, C-4'), 131.2 (C, C-3'), 130.0 (CH, C-6'), 128.7 (2xCH, C-3
Ar, C-5 Ar), 128.5 (CH, C-4 Ar), 128.3 (CH, C-8'), 127.6 (CH,
C-5'), 127.3 (2xCH, C-2 Ar, C-6 Ar), 125.7 (C, C-10'), 66.7
(CH, C-2), 65.5 (CH, C-5), 58.0 (CH, C-4), 52.9 (2-OCH3), 51.9
(4-OCH3), 49.6 (CH, C-3), 22.3 (CH3); HRMS (EI): m/z [M+]
General procedure for preparation of vinylquinolines 2i-
2j. To a suspension of methyltriphenylphosphonium iodide
(1.010 g, 2.5 mmol) in dry THF (5 mL) was added (561 mg, 5

332
A. Bouraiou, A. Debache, S. Rhouati, A. Carboni, A. Belfaitah
Vol 45
Calcd. for C24H23N2O435Cl: 438.1346; found: 438.1358. MS
(ESI): m/z 439.1 (MH+, 100), 407 (31), 379 (64), 347 (17), 319
(43), 283 (8), 230 (5), 178 (4), 121 (46). Calcd for
C24H23N2O4Cl: C, 65.68; H, 5.28; N, 6.38. Found: C, 65.41; H,
5.44; N, 6.05.
(C), 131.9 (C), 130.9 (CH), 128.8 (2xCH), 128.3 (CH), 127.7
(C), 127.5 (2xCH), 127.5 (CH), 125.6 (CH), 66.6 (CH, C-2),
65.5 (CH, C-5), 61.1 (CH2), 58.1 (CH, C-4), 53.0 (OCH3), 49.6
(CH, C-3), 18.1 (CH3), 13.9 (CH3); HRMS (EI): m/z [M+] Calcd.
for C25H25N2O435Cl: 452.1502; found: 452.1514. MS (ESI): m/z
453.4 (MH+, 100%), 407 (41), 393 (39), 379 (15), 347 (18),
319(39), 283 (6), 230 (3), 178 (3), 121 (44), 91 (1). Calcd for
C25H25N2O4Cl: C, 66.30; H, 5.56; N, 6.18. Found: C, 66.36; H,
5.70; N, 6.36.
4-Ethyl-2-methyl (2S*,3R*,4S*,5R*) 3-(2-chloroquinolin-3-
yl)-5-phenylpyrrolidine -2,4-dicarboxylate (3b). mp 95°C; IR
(ATR): 1740, 1712, 1563, 1489, 1364, 1172, 1028, 746 cm-1 ; 1H
.
nmr (300 MHz, CDCl3): δ 8.23 (1H, s, Ar), 8.03 (1H, d, J = 8.1,
Ar), 7.85 (1H, d, J = 7.3, Ar), 7.74 (1H, td, J = 7.7, 1.5, Ar),
7.59 (1H, td, J =7.7, 1.1, Ar), 7.28-7.44 (5H, m, Ar), 4.91 (1H,
d, J = 8.5, 5-H), 4.55 (1H, t, J = 7.9, 3-H), 4.24 (1H, d, J = 8.3,
2-H), 3.76 (3H, s, OCH3), 3.61-3.67 (3H, m, -CH2-, 4-H), 3.10
(1H, br s, NH), 0.78 (3H, t, J = 7.1, CH3); 13C nmr (75.4 MHz,
CDCl3): δ 173.0 (C=O), 171.6 (C=O), 151.3 (C), 147.1 (C),
139.2 (C), 137.3 (CH), 132.4 (C), 130.9 (CH), 128.7 (2xCH),
128.3 (CH), 127.8 (2xCH), 127.7 (C),127.5 (CH), 127.4
(2xCH), 66.7 (CH, C-2), 65.5 (CH, C-5), 61.1 (CH2), 58.1 (CH,
C-4), 52.9 (OCH3), 51.9 (CH3), 49.6 (CH, C-3), 13.9 (CH3).
Calcd for C24H23N2O4Cl: C, 65.68; H, 5.28; N, 6.38. Found: C,
65.36; H, 5.35; N, 6.25.
Dimethyl (2S*,3R*,4S*,5R*) 3-(2-chloro-7-methoxyquinol-
in-3-yl)-5-phenylpyrrolidine-2,4-dicarboxylate (3c). mp 124-
125°C; IR (ATR): 3413 (NH), 1739 and 1717 (CO, esters) cm-1;
1H nmr (300 MHz, CDCl3): δ 8.40 (1H, s, Ar), 7.72 (1H, d, J =
8.9, Ar), 7.60 (1H, d, J = 2.5, Ar), 7.48-7.23 (5H, m, Ar), 7.20
(1H, dd, J = 8.9, 2.5, Ar), 5.00 (1H, d, J = 8.4, 5-H), 4,50 (1H,
m, 3-H), 4.36 (1H, d, J = 8.2, 2-H), 3,94 (1H, br s, NH), 3.94
(3H, s, OCH3) 3.75 (3H, s, OCH3), 3,80 (1H, m, 4-H), 3.25 (3H,
s, OCH3); 13C nmr (75.4 MHz, CDCl3): δ 173.2 (C=O), 171.0
(C=O), 151.2 (C), 148.9 (C), 146.7 (C), 141.4 (C), 136.7 (CH),
131.9 (CH), 130.1 (C), 129.7 (C), 128.6 (2xCH), 128.4 (CH),
127.2 (2xCH), 125.2 (CH), 106.2 ( CH), 65.5 (CH), 64.4 (CH),
56.7 (CH), 55.5 (OCH3), 52.7 (OCH3), 51.8 (OCH3), 48.4 (CH);
HRMS (EI): m/z [M+] Calcd. for C24H23N2O535Cl: 454.1295;
found: 454.1305. Calcd for C24H23N2O5Cl: C, 63.37; H, 5.10; N,
6.16. Found: C, 63.02; H, 5.58; N, 5.85.
Dimethyl-(2S*,3R*,4S*,5R*)-3-(2-chloro-5,8-dimethyl-
quinolin-3-yl)-5-phenylpyrrolidine-2,4-dicarboxylate (3f). mp
126°C; IR (ATR): 1741, 1713, 1584, 1431, 1378, 1169, 1093,
1
828, 757, 701 cm-1; H nmr (300MHz, CDCl3): δ 8.31 (1H, s,
Ar), 7.28-7.45 (7H, m, Ar), 4.95 (1H, d, J = 8.5, 5-H), 4.54 (1H,
t, J = 8.1, 3-H), 4.32 (1H, d, J = 8.6, 2-H), 3.77 (3H, s, OCH3),
3.76 (1H, t, J = 8.1, 4-H), 3.19 (3H, s, OCH3), 3.15 (1H, br s,
NH), 2.74 (3H, s, CH3), 2.68 (3H, s, CH3); 13C nmr (75.4 MHz,
CDCl3): δ 173.1 (C=O), 172.1 (C=O), 149.6 (C), 146.7 (C),
139.3 (C), 134.7 (C), 132.3 (C), 131.0 (C), 130.7 (CH), 128.8
(2xCH), 128.4 (CH), 128.0 (CH), 127.6 (CH), 127.4 (2xCH),
127.1 (C), 66.7 (CH, C-2), 65.5 (CH, C-5), 58.1 (CH, C-4), 52.9
(OCH3), 51.9 (OCH3), 49.9 (CH, C-3), 19.0 (CH3), 18.1 (CH3);
HRMS (EI): m/z [M+] Calcd. for C25H25N2O435Cl: 452.1502;
found: 452.1514. MS (ESI): m/z 453.3 (MH+, 100%), 421 (39),
393 (62), 361 (20), 333 (34), 297(7), 244(3), 178(2), 121 (43),
91 (1). C25H25N2O4Cl: C, 66.30; H, 5.56; N, 6.18. Found: C,
66.17; H, 5.71; N, 6.03.
Dimethyl-(2S*,3R*,4S*,5R*)-3-(2-chloro-6-methylquinol-
in-3-yl)-5-phenylpyrrolid-ine-2,4-dicarboxylate (3g). mp
50°C; IR (ATR): 1740, 1727, 1592, 1434, 1166, 1042, 823, 760,
1
694 cm-1; H nmr (300 MHz, CDCl3): δ 8.13 (1H, s, Ar), 7.92
(1H, d, J = 8.5, Ar), 7.58 (2H, m, Ar), 7.35 (5H, m, Ar), 4.90
(1H, d, J = 8.5, 5-H), 4.52 (1H, t, J = 7.3, 3-H), 4.25 (1H, d, J =
8.3, 2-H), 3.76 (3H, s, OCH3), 3.66 (1H, dd, J = 8.4, 7.1, 4-H),
3.18 (3H, s, OCH3), 2.98 (1H, br s, NH), 2.55 (3H, s, CH3); 13C
nmr (75.4 MHz, CDCl3) δ 173.1 (C=O), 172.1 (C=O), 150.2 (C),
145.7 (C), 139.2 (C), 137.8 (C), 136.7 (CH), 133.2 (CH), 132.1
(C), 128.8 (2xCH), 128.4 (CH), 128.3 (CH), 127.7 (C), 127.3
(2xCH), 126.6 (CH), 66.6 (CH, C-2), 65.5 (CH, C-5), 58.0 (CH,
C-4), 52.9 (OCH3), 51.9 (OCH3), 49.6 (CH, C-3), 22.0 (CH3).
Calcd for C24H23N2O4Cl: C, 65.68; H, 5.28; N, 6.38. Found: C,
66.05; H, 5.58; N, 6.13.
4-Ethyl 2-methyl-(2S*,3R*,4S*,5R*)-3-(6-chloro[1,3]dioxolo-
[4,5-g]quinolin-7-yl)-5-phenylpyrrolidine-2,4-dicarbox-ylate
(3d). mp 134-136°C; IR (ATR): 1739, 1714, 1457, 1172, 1040,
1
952, 745, 696 cm-1; H nmr (300 MHz, CDCl3) δ 7.99 (1H, s,
Ar), 7.28-7.35 (6H, m, Ar), 7.06 (1H, s, Ar), 6.13 (2H, s,
O-CH2-O), 4.89 (1H, d, J = 8.5, 5-H), 4.46 (1H, t, J = 7.9, 3-H),
4.20 (1H, d, J = 8.5, 2-H), 3.75 (3H, s, OCH3), 3.60-3.66 (3H,
m, O-CH2-, 4-H), 2.85 (1H, br s, NH), 0.77 (3H, t, J = 7.1, CH3);
13C nmr (75.4 MHz, CDCl3) : δ 173.1 (C=O), 171.7 (C=O),
151.9 (C), 148.9 (C), 145.4 (C), 139.3 (C), 136.1 (C), 130.1 (C),
128.7 (2xCH), 128.3 (CH), 127.5 (2xCH), 124.8 (C), 105.3
(CH), 102.7 (CH), 102.4 (CH), 101.2 (CH2), 66.6 (CH, C-2),
65.8 (CH, C-5), 61.1 (CH2), 57.9 (CH, C-4), 52.9 (OCH3), 49.6
(CH, C-3), 13.9 (CH3).Calcd for C25H23N2O6Cl: C, 62.18; H,
4.80; N, 5.80. Found: C, 62.38; H, 4.92; N, 5.65.
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654 cm-1; H nmr (300 MHz, CDCl3): δ 8.20 (1H, s, Ar),7.68
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Mar-Apr 2008
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