Reformatsky reactions with N-arylpyrrolidine-2-thiones: Synthesis of tricyclic analogues of quinolone antibacterial agents

Article abstract of DOI:10.1016/S0040-4020(01)00964-4

A convenient synthesis of 5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-α]quinoline-4-carboxylic acids, tricylic analogues of the quinolone antibiotics, is described. Key steps in the route are a novel zinc-mediated Reformatsky reaction between diethyl bromomalonate and N-arylpyrrolidine-2-thione 18, and cyclisation of the resulting diethyl pyrrolidinylidenemalonate intermediates 19 in polyphosphoric acid. The products proved to be devoid of biological activity.

Full text of DOI:10.1016/S0040-4020(01)00964-4

TETRAHEDRON
Pergamon
Tetrahedron 57 <2001) 9635±9648
Reformatsky reactions with N-arylpyrrolidine-2-thiones:
synthesis of tricyclic analogues of quinolone antibacterial agents
Joseph P. Michael,p Charles B. de Koning, Gladys D. Hosken and Trevor V. Stanbury
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, P.O. Wits 2050, South Africa
Received 6 July 2001; revised 21 August 2001; accepted 13 September 2001
AbstractÐA convenient synthesis of 5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acids, tricyclic analogues of the quino-
lone antibiotics, is described. Key steps in the route are a novel zinc-mediated Reformatsky reaction between diethyl bromomalonate and
N-arylpyrrolidine-2-thiones 18, and cyclisation of the resulting diethyl pyrrolidinylidenemalonate intermediates 19 in polyphosphoric acid.
The products proved to be devoid of biological activity. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Structure±activity relationships for the quinolone anti-
bacterials, summarised in a classic review by Albrecht,15
and updated several times since then,11,16±18 have high-
lighted, among other factors, the importance of the
carboxylic acid at C-3, as well as a small hydrophobic
substituent on nitrogen <N-1), typically an ethyl or cyclo-
propyl group. Although substituents at C-2 invariably
render the compounds inactive, a short bridge of two or
three atoms between N-1 and C-2 seldom compromises
activity. The bridge may include nitrogen, sulphur or
oxygen.19 The all-carbon bridged pyrrolo[1,2-a]quinolinone
8, a pe¯oxacin analogue, has a minimal inhibitory concen-
tration <MIC) of 0.78 mg ml21 against Staphylococcus
Enaminones,1 the basic structure of which is shown in 1, are
versatile intermediates for the synthesis of heterocycles.2 A
less well recognised property of substructure 1 is its ability
to serve as a pharmacophore.3,4 Examples of biologically
active enaminones include the anticonvulsant 2,4 the
2-alkylideneindole 3, which has anti-in¯ammatory poten-
tial,5 and the fused polycyclic compound 4, a synthetic
analogue of the duocarmycin class of antitumour agents.6
However, the most important chemotherapeutic agents to
contain an embedded enaminone component are without
doubt the quinolone antibacterials.7,8 In particular, the
¯uorinated quinolones, representative examples of which
include cipro¯oxacin <5), nor¯oxacin <6) and pe¯oxacin
<7), are amongst the most effective broad-spectrum oral
antibacterial agents developed to date. Cipro¯oxacin, for
instance, is used worldwide for treating genitourinary,
gastrointestinal, respiratory and skin infections, as well as
sexually transmitted diseases. The ¯uoroquinolones are
especially effective against Gram-negative bacteria, DNA
synthesis in which is inhibited by the drugs' ability to
corrupt the activities of DNA gyrase and topoisomerase
IV, inducing these essential enzymes to kill cells by
generating high levels of double-stranded DNA breaks.9,10
Furthermore, newer compounds are being developed
with promising activity against Gram-positive bacteria,
anaerobes and mycobacteria,11±13 as well as antitumour
activity.14 Even though literally thousands of quinolones
have been synthesised for biological evaluation, the search
for improved quinolone drugs continues, driven by the need
for enhanced performance, broader ef®cacy, novel inter-
ventions and problems with bacterial resistance.
Keywords: thiolactams; Reformatsky reaction; enaminones; quinolones.
Corresponding author. Tel.: 127-11-717-6753; fax: 127-11-339-7967;
e-mail: jmichael@aurum.chem.wits.ac.za
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020<01)00964-4

9636
J. P. Michael et al. / Tetrahedron 57 (2001) 9635±9648
malonates 12. This cyclisation is essentially a modi®cation
of the classical Conrad±Limpach synthesis of 4-quinolones
from anilines and acetoacetic esters.28 Our chosen route to
the tricyclic targets was based on our prior experience with
N-aryl-2-pyrrolidinylideneacetates such as 13,29 which we
had previously prepared either by Eschenmoser sulphide
contraction30 between N-arylpyrrolidine-2-thiones and
ethyl bromoacetate, or, more ef®ciently, by condensation
between substituted anilines and ethyl 6-chloro-3-oxo-
hexanoate. Ready access to these enaminones dictated the
use of the Gould±Jacobs cyclisation for the present work.
Scheme 1. Standard routes to 4-quinolone-3-carboxylates.
Initial model studies on the 2,5-dimethoxyphenyl substrate
13a showed that a purely thermal cyclisation at 2708C
in medicinal paraf®n failed, no doubt because the
<E)-geometry of the precursor did not permit the close
approach of the aryl and ester groups. However, heating
13a in polyphosphoric acid <PPA) at 1508C for 1.25 h
afforded the tricyclic quinolone 14a in 86% yield. Under
the acidic conditions, the somewhat basic vinylogous
urethane presumably undergoes protonation, resulting in
scrambling of the geometry via an intermediate iminium
ion. Similarly, 13b was cyclised to 14b, although only in
48% yield. However, under the same conditions the 2,4,5-
trimethoxyphenyl substrate 13c yielded an approximately
1:2 mixture of the expected product 14c0 and compound
14c00, in which the methoxy substituent peri to the carbonyl
group had been demethylated to give an intramolecularly
hydrogen-bonded phenol.31 Ethyl 1-<2-naphthyl)-2-pyrroli-
dinylideneacetate 13d was cyclised quantitatively to give
only 14d, an interesting product that possesses the nucleus
of a 14-azasteroid.
aureus CMX686B, and 1.56 mg ml21 against Escherichia
coli.20 This compound also includes two structural features
that seem to be obligatory for high biological activity: a
¯uorine substituent at C-6, and a cyclic amine at C-7. A
related compound, 9, has also demonstrated activity against
a wide range of microorganisms.21
As part of our continuing investigations into the use of
enaminones <vinylogous amides, vinylogous urethanes and
related systems) as precursors for alkaloids and other
nitrogen-containing heterocycles,22 we have explored a
new synthetic route to tricyclic analogues of the quinolone
antibacterials. In this paper we describe a ¯exible synthesis
of several 5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-
4-carboxylic acids that allows for easy variation in the
nature, number and position of substituents on the aromatic
ring, as well as providing access to the active compound 8
itself. Some preliminary results were reported in a prior
communication.23
2. Results and discussion
Two principal strategies, both proceeding via enaminone
intermediates, have been reported for the construction of
the quinolin-4-one nucleus of the quinolone antibacterials
<Scheme 1).24 In the route developed by chemists at Bayer
AG,25,26 the quinolone nucleus 10 is formed by base-
induced cyclisation of 2-<2-halobenzoyl)-3-aminoacrylates
11. The alternative route employs a thermal or acid-
catalysed Gould±Jacobs cyclisation27 of anilinomethylene-
Extension of these model studies to the synthesis of tricyclic
quinolones bearing the pharmacologically crucial
carboxylic acid substituent required access to analogues of
vinylogous urethanes 13 with two ester substituents rather
than one. We envisaged making them by sulphide contrac-
tion between diethyl bromomalonate32 and N-arylpyrroli-
dine-2-thiones, which were in turn prepared from
commercially available or easily synthesised anilines 15
in three steps <Scheme 2). Firstly, acylation with 4-chloro-
butyryl chloride yielded intermediate N-aryl-4-chloro-
butanamides 16, which were cyclised without puri®cation
Scheme 2. Reagents: i, Cl<CH2)3COCl, Na2HPO4, CHCl3; ii, NaOEt, EtOH;
iii, P2S5, C6H6, ultrasound.

J. P. Michael et al. / Tetrahedron 57 (2001) 9635±9648
Table 1. Percentage yields for the sequence of conversions 15!17!18!20!22
9637
Entry
Substituents
Lactam 17
Thiolactam 18
Tricyclic ester 20 <over 2 steps)
Tricyclic acid 22
a
b
c
d
e
f
g
h
i
R1ˆR4ˆOMe, R2ˆR3ˆH
R1ˆR2ˆR3ˆR4ˆH
97
80
84
77
94
73
81
92
88
84
69
76
62
73
66
79
92
83
49
61
85
91
R1ˆMe, R2ˆR3ˆR4ˆH
R1ˆR3ˆR4ˆH, R2ˆMe
R1ˆR2ˆR4ˆH, R3ˆMe
R1ˆR2ˆR4ˆH, R3ˆOMe
R1ˆR4ˆH, R2±R3ˆOCH2O
R1ˆBr, R2ˆR3ˆR4ˆH
R1ˆR4ˆH, R2ˆR3ˆF
65
20 <20d)144 <20j)a
96
87 <22d); 89 <22j)a
64
63
59
46
69
92
81
69
100
91
a
20j, 22j: R1ˆR2ˆR3ˆH, R4ˆMe.
to give N-arylpyrrolidin-2-ones 17 by treatment with
sodium ethoxide in ethanol <a modi®cation of the procedure
of Manhas and Jeng33). Thionation of lactams 17 with
phosphorus pentasulphide in benzene was promoted by
sonicating the heterogeneous reaction mixture in an ultra-
sonic cleaning bath.34 The yields for the N-arylpyrrolidin-2-
ones 17a±i and N-arylpyrrolidine-2-thiones 18a±i prepared
in this way are shown in Table 1 <columns 3 and 4).
All compounds gave unexceptional spectra except for
precede the demethylation step. Although this is a poten-
tially useful result in view of our ultimate goal, it proved
more advantageous to ®nd milder conditions for a general
cyclisation protocol. This goal was achieved simply by
lowering the reaction temperature to 85±1008C; under
these conditions, 19a was converted into the tricyclic ester
20a in 75% isolated yield over 45 min.
Sulphide contraction of the remaining eight N-arylpyrro-
lidine-2-thiones 18b±i with diethyl bromomalonate gave
variable results, in line with our prior observation of
capricious sulphide contractions with N-arylated thio-
lactams.29 After fruitless exploration of alternative routes
to enaminones 19 involving condensation of thioiminium
salts with diethyl malonate,36 or reaction of diethyl
diazomalonate with the thiolactams in the presence of
rhodium<II) acetate,37,38 we turned to a unique thiocarbonyl
version of the Reformatsky reaction that we had previously
reported for preparing the vinylogous urethane 13e from
ethyl bromoacetate, N-phenylpyrrolidine-2-thione 18b and
zinc±copper couple.29 We had initially been deterred from
re-exploring this option by the subsequent failure of other
workers to achieve similar reactions with thiocarbonyl
compounds other than thiocarbonates, dithioesters and
thioketones.39 However, when we attempted a zinc-
mediated condensation of diethyl bromomalonate with
pyrrolidine-2-thiones 18b±i, we observed smooth con-
version into the desired products 19b±i provided that four
equivalents each of activated zinc and the bromomalonate
were used, and that iodine <0.2 equiv.) was used as an acti-
vator <Scheme 3).40 While the products were easily isolated
<aqueous work-up and chromatography on silica gel; ca.
65±100% yields) and characterised by NMR spectroscopy,
they could never be obtained entirely free of a malonate-
derived impurity <ca. 10%). They were thus used in the
cyclisation step without rigorous puri®cation. A noteworthy
feature of the NMR spectra for the products, recorded in
1
N-<2-bromophenyl)pyrrolidine-2-thione 18h, the H NMR
spectrum of which showed two distinct sets of resonances
for 5-H, in contrast to the simple triplet observed in all the
other cases. The non-equivalence of the two 5-H protons at
ambient temperature indicates restricted rotation about the
N-aryl bond, a consequence of the bulky, mutually ortho
sulphur and bromine substituents in the system. This
compound apparently shows the same kind of atropisomer-
ism that has been documented for other N-aryl lactams.35
The vinylogous urethane 19a was chosen as a test case for
optimising conditions for Gould±Jacobs cyclisation with a
diester precursor. Its preparation in 85% yield by sulphide
contraction between thiolactam 18a and diethyl bromo-
malonate was straightforward. Under similar conditions to
those used for cyclisation of the monoester analogue 13a
<PPA, 140±1508C), the desired quinolone product 20a was
formed, but in a comparatively poor yield of 40%. It
appeared that competing reactions at other functional
groups were taking their toll, since with careful experimen-
tation, quantities of 21, the product of peri-demethylation
and ester hydrolysis and decarboxylation, could be isolated.
The addition of 19a to pre-heated PPA at 1938C followed by
stirring for only ®ve minutes gave the carboxylic acid 22a in
60% yield, indicating that cyclisation and ester hydrolysis
1
deuteriated chloroform, is that both the H and 13C signals
for the ester groups, particularly those for the methylene
groups, were very broad and poorly resolved at ambient
temperature. Rotation about the N-aryl bond is no doubt
impeded by the introduction of a very bulky substituent at
C-2, so that conformational equilibration is too slow for
resolution of signals on the NMR spectroscopic time scale.
The slightly contaminated vinylogous urethanes 19 were
cyclised by heating in polyphosphoric acid at 1008C to
give the pyrrolo[1,2-a]quinolones 20 in overall yields of
46±69% based on the thiolactams 18 <Table 1, column 5).

9638
J. P. Michael et al. / Tetrahedron 57 (2001) 9635±9648
they showed insigni®cant activity even at concentrations
of 1022 M in DMSO solution. This result, while disappoint-
ing, is in line with the ®ndings of pharmacological tests on
the handful of 5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]-
quinoline-4-carboxylic acids reported in the literature,
apart from 8 and 9; the tetra¯uoro compound 24 was
ineffective against several bacteria <P. aeruginosa, E. coli,
Proteus vulgaris),41 and the chloro compound 25 was
inactive against a range of fungi and bacteria.21
3. Experimental
3.1. General methods
All solvents used for reactions and preparative chroma-
tography were distilled. Chloroform and carbon tetra-
chloride were dried by passage through a short column of
basic alumina. THF and diethyl ether were distilled from
Na/benzophenone, dichloromethane, acetonitrile, DMF and
triethylamine from CaH2, and benzene and toluene from Na.
Commercially available chemicals were used as received.
Melting points, recorded on a Reichert hot-stage microscope
apparatus, are uncorrected. TLC was performed on alu-
minium-backed Alugram Sil G/UV254 plates pre-coated
with 0.25 mm silica gel 60. Column chromatography was
carried out on Macherey±Nagel Kieselgel 60, particle size
0.063±0.200 mm <conventional columns) or Macherey±
Nagel Kieselgel 60, particle size 0.040±0.063 mm <¯ash
columns). FTIR spectra were recorded on Bruker Vector
22 or Bruker IFS 25 spectrometers. NMR spectra were
recorded on Bruker AC-200 <200.13 MHz for 1H,
50.32 MHz for 13C) or Bruker DRX 400 <400.132 MHz
Scheme 3. Reagents: i, BrCH<CO2Et)2 <4 equiv.), Zn <4 equiv.), I2
<0.2 equiv.), THF, re¯ux; ii, PPA, 85±1008C; iii, NaOH, H2O, re¯ux,
then HCl.
With the m-tolyl substrate 19d, Gould±Jacobs cyclisation
occurred both ortho and para to the methyl group to yield
product 20d <20%) and its regioisomer 20j <44%). In two
other cases in which isomers could possibly be formed <19g,
19i), cyclisation was regiospeci®c. The syntheses of the
tricyclic quinolonecarboxylic acids 22 were completed by
hydrolysis of esters 20 with hot aqueous sodium hydroxide
solution, followed by precipitation of the free acids with
concentrated hydrochloric acid. It should be noted that
22g is an analogue of oxolinic acid <23), a clinically
prescribed quinolone antibacterial.
1
for H, 100.625 MHz for 13C) spectrometers. CDCl3 was
used as solvent unless otherwise stated, and TMS as internal
standard. DEPT and CH-correlated spectra were routinely
used for assignment of signals, supplemented where neces-
sary by nOe, decoupling and correlation experiments.
Chemical shifts are reported on the d scale, and J values
are given in Hz. High-resolution mass spectra were recorded
at 70 eV on a VG 70 SEQ mass spectrometer with a
MASPEC II data system.
7,8-Di¯uoro-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quino-
line-4-carboxylic acid <22i) was itself transformed into the
hydrochloride salt of the biologically active pe¯oxacin
analogue 8 by heating with excess N-methylpiperazine
<658C, 48 h), followed by treatment with hydrochloric
acid <27% yield). Compound 22i is thus a potentially
valuable precursor for other amine-substituted pyrrolo-
[1,2-a]quinolinone analogues of clinically useful quinolone
antibiotics.
3.2. General procedure for cyclisation of ethyl 2-.1-aryl-
pyrrolidin-2-ylidene)acetates 13 with PPA
When the quinolonecarboxylic acids 22a±j were
evaluated for biological activity against two fungi
<Aspergillus niger, Candida albicans) and three bacterial
cultures <Pseudomonas aeruginosa, S. aureus, E. coli),
The appropriate ethyl 2-<1-arylpyrrolidin-2-ylidene)acetate
1329 <0.24±0.9 mmol scale) was added to PPA <ca. 20 g per
g of precursor), pre-heated to 1508C, and the mixture was
stirred for 1.25 h before being cooled to room temperature.
H2O was added, the solution was made basic with concen-
trated aq. NH3 solution, and extracted several times with
CH2Cl2. The combined extracted were dried <MgSO4),
®ltered and evaporated in vacuo to yield essentially pure
2,3-dihydropyrrolo[1,2-a]quinolin-5<1H)-ones 14. The
following compounds were prepared in this way.
3.2.1. 6,9-Dimethoxy-2,3-dihydropyrrolo[1,2-a]quinolin-
5.1H)-one .14a). According to the general procedure, 14a
<52 mg, 86%) was obtained from ethyl 2-[1-<2,5-dimethoxy-
phenyl)pyrrolidin-2-ylidene]acetate <13a)29 <71 mg, 0.24
mmol); cream needles, mp 80±828C <from CH2Cl2±
hexane); Rf 0.17 <MeOH±benzene 1:9);
n
max/cm21

J. P. Michael et al. / Tetrahedron 57 (2001) 9635±9648
9639
<CHCl3) 1633 <s), 1595 <s), 1577 <s), 1490 <s), 1263 <s); dH
<200 MHz, CDCl3) 6.99 <1H, d, Jˆ8.9 Hz; 8-H), 6.64 <1H,
d, Jˆ8.9 Hz, 7-H), 6.17 <1H, t, Jˆ0.9 Hz, 4-H), 4.68 <2H, t,
Jˆ7.1 Hz, 1-H), 3.89 <3H, s, OCH3 at C-6; nOe with signal
at d 6.6.4), 3.83 <3H, s, OCH3 at C-9; nOe with signals at d
6.99 and 4.68), 2.95 <2H, td, Jˆ7.8 and 0.9 Hz, 3-H), 2.15
<2H, quintet with ®ne coupling, Jˆca. 7.7 Hz, 2-H); dC
<50 MHz; CDCl3) 178.4 <CvO), 154.8 <C-3a), 154.5
<C-6), 143.3 <C-9), 133.2 <C-9a), 118.5 <C-5a), 113.9
<C-8), 107.7 <C-4), 104.5 <C-7), 56.8 <OCH3 at C-9), 56.7
<OCH3 at C-6), 56.0 <C-1), 30.6 <C-3), 22.2 <C-2). HRMS
Found: M1, 245.1052. C14H15NO3 requires M, 245.1052.
coupling, Jˆ9.5 Hz, 6-H), 7.85 <1H, dd, Jˆ8.0 and
1.6 Hz, 7-H), 7.74 <1H, ddd, Jˆ8.7, 7.0 and 1.6 Hz, 9-H),
7.57 <1H, ddd, Jˆ8.0, 7.0 and 1.2 Hz, 8-H), 7.28 <1H, d,
Jˆ9.5 Hz, 5-H), 6.38 <1H, t, Jˆ0.9 Hz, 12-H), 4.24 <2H, t,
Jˆ7.3 Hz, 3-H), 3.08 <2H, td, Jˆ7.8 and 0.9 Hz, 1-H), 2.30
<2H, br quintet, Jˆca. 7.5 Hz, 2-H); dC <50 MHz; CDCl3)
179.7 <CvO), 151.9 <C-12a), 138.6 <C-4a), 133.3 <C-7),
131.4 and 129.4 <C-6a, C-10a), 128.3 <C-9), 127.8 <C-6),
127.1 <C-10), 125.6 <C-8), 117.9 <C-10b), 115.1 <C-5),
109.2 <C-12), 51.0 <C-3), 30.6 <C-1), 20.5 <C-2). HRMS
Found, M1, 235.0997. C16H13NO requires M, 235.0997.
3.3. General procedure for the preparation of N-aryl-
pyrrolidin-2-ones 17
3.2.2. 7-Methoxy-2,3-dihydropyrrolo[1,2-a]quinolin-5.1H)-
one .14b). According to the general procedure, 14b <94 mg,
48%) was obtained from ethyl 2-[1-<4-methoxyphenyl)-
pyrrolidin-2-ylidene]acetate <13b)29 <238 mg, 0.91 mmol);
beige powder, mp 150±1558C; Rf 0.19 <MeOH±benzene
1:9); nmax/cm21 <CHCl3) 1625 <m), 1608 <s), 1570 <s),
1498 <s); dH <200 MHz; CDCl3) 7.80 <1H, t, Jˆ1.7 Hz,
6-H), 7.23 <2H, d, Jˆ1.7 Hz, 8-H, 9-H), 6.20 <1H, t, Jˆ
0.9 Hz, 4-H), 4.22 <2H, t, Jˆ7.3 Hz, 1-H), 3.92 <3H, s,
OCH3), 3.13. <2H, td, Jˆ7.8 and 0.9 Hz, 3-H), 2.33 <2H,
quintet with ®ne coupling, Jˆca. 7.4 Hz, 2-H); dC <50 MHz;
CDCl3) 177.4 <CvO), 156.0 and 154.4 <C-3a, C-7), 133.2
<C-9a), 126.8 <C-5a), 122.2 and 117.0 <C-8, C-9), 105.8
<C-6), 103.9 <C-4), 55.7 <OCH3), 50.2 <C-1), 31.4 <C-3),
20.8 <C-2). HRMS Found: M1, 215.0942. C13H13NO2
requires M, 215.0946.
The appropriate aniline 15 <24±66 mmol scale) was added
to a stirred suspension of Na2HPO4 <ca. 2 equiv.) in
anhydrous CHCl3 <50±85 cm3). Once the aniline had
dissolved, an equimolar quantity of 4-chlorobutyryl
chloride was added in portions. An exothermic reaction
occurred, with formation of a milky solution. Stirring was
maintained under N2 for 2±22 h. Filtration of the inorganic
solids through a Celitew pad followed by concentration of
the ®ltrate in vacuo afforded the crude intermediate N-aryl-
4-chlorobutyramide 16. This product was added to a
solution of sodium ethoxide in ethanol <prepared from
7.8 equiv. of Na metal per equivalent of substrate; concen-
tration ca. 1 g per 17 cm3 EtOH). The mixture was stirred at
room temperature under N2 for between 35 min and 18 h
and was then acidi®ed with concentrated HCl. Removal of
the solvent under reduced pressure yielded a crude residue.
H2O <100 cm3) was added, and the organic material was
extracted with CH2Cl2 <3£50 cm3). The extracts were
combined, dried <MgSO4) and concentrated in vacuo to
yield the crude product. Column chromatography on silica
gel with 10±50% EtOAc±hexane mixtures gave the desired
N-arylpyrrolidin-2-ones 17. Nine compounds were prepared
by this general procedure <yields in Table 1). The physical
3.2.3. 6,7,9-Trimethoxy-2,3-dihydropyrrolo[1,2-a]quino-
lin-5.1H)-one .14c0) and 6-hydroxy-7,9-dimethoxy-2,3-
dihydropyrrolo[1,2-a]quinolin-5.1H)-one .14c00). Accord-
ing to the general procedure, 14c0 and 14c00 were obtained as
an inseparable mixture <210 mg, ca. 1:2 ratio) from ethyl
2-[1-<2,4,5-trimethoxyphenyl)pyrrolidin-2-ylidene]acetate
<13c)29 <282 mg, 0.88 mmol). NMR spectroscopic signals
ascribable to 14c0: dH <200 MHz; CDCl3) 6.82 <1H, s,
8-H), 6.21 <1H, s, 4-H), 4.68 <2H, t, Jˆ7.0 Hz, 1-H), 3.93,
3.89 and 3.86 <9H, 3£s, 3£OCH3), 2.98 <2H, t, Jˆ7.8 Hz,
3-H), 2.22 <2H, br quintet, Jˆca. 7.6 Hz); dC<50 MHz;
CDCl3) 176.9 <CvO), 155.3 <C-3a), 105.6 <C-4), 103.0
<C-8), 56.3 <C-1), 30.8 <C-3), 22.0 <C-2). NMR spectro-
scopic signals ascribable to 14c00: dH <200 MHz; CDCl3)
14.82 <OH), 6.83 <1H, s, 8-H), 5.98 <1H, s, 4-H), 4.68
<2H, t, Jˆ7.0 Hz, 1-H), 3.92 and 3.84 <6H, 2£s,
2£OCH3), 3.01 <2H, t, Jˆ7.8 Hz, 3-H), 2.22 <2H, br quintet,
Jˆca. 7.6 Hz, 2-H); dC<50 MHz; CDCl3) 182.1 <CvO),
157.4 <C-3a), 105.6 <C-4), 103.0 <C-8), 55.8 <C-1), 31.2
<C-3), 21.6 <C-2). Other signals in the 13C NMR spectrum
of the mixture were at d 148.4, 145.89, 144.9, 141.2, 139.8,
124.7, 114.3 <aromatic C), 57.8, 57.6, 57.2 and 56.6
<OCH3).
1
properties, H and 13C NMR spectroscopic data for the
following six agree with those published in the literature:
N-<2,5-dimethoxyphenyl)pyrrolidin-2-one <17a),42 N-phenyl-
pyrrolidin-2-one <17b),42 N-<2-methylphenyl)pyrrolidin-2-
one <17c),42 N-<3-methylphenyl)pyrrolidin-2-one <17d),42
N-<4-methylphenyl)pyrrolidin-2-one <17e),42 N-<4-methox-
yphenyl)pyrrolidin-2-one <17f).43 Data for the remaining
three compounds are given below.
3.3.1.
N-.3,4-Methylenedioxyphenyl)pyrrolidin-2-one
.17g). According to the general procedure, 17g was
obtained from 3,4-methylenedioxyaniline 15g44 <81% over
2 steps); cream powder, mp 84±868C; Rf 0.37 <EtOAc±
hexane 1:1); nmax/cm21 <KBr) 1686 <s), 1609 <m), 1491
<s), 1375 <s), 1345 <s), 1313 <s), 1265 <s), 1210 <s), 1032
<s), 930 <s), 872 <s), 793 <s); dH <200 MHz; CDCl3) 7.30
<1H, d, Jˆ2.0 Hz, arom 2-H), 6.85 <1H, dd, Jˆ8.4, 2.0 Hz,
arom 6-H), 6.77 <1H, d, Jˆ8.4 Hz, arom 5-H), 5.94 <2H, s,
OCH2O), 3.79 <2H, t, Jˆ7.0 Hz, 5-H), 2.57 <2H, t, Jˆ
7.6 Hz, 3-H), 2.17 <2H, quintet with ®ne coupling, Jˆca.
7.6 Hz, 4-H); dC <50 MHz; CDCl3) 173.9 <CvO), 147.6 and
144.4 <arom C-3, C-4), 133.7 <arom C-1), 113.1, 107.7 and
102.6 <arom C-2, C-5, C-6), 101.2 <OCH2O); 49.4 <C-5),
32.4 <C-3), 17.8 <C-4); m/z <EI) 205 <M1, 34%), 150
3.2.4. 2,3-Dihydrobenzo[f]pyrrolo[1,2-a]quinolin-11.1H)-
one .14d). According to the general procedure, 14d <64 mg,
100%) was obtained from ethyl 2-[1-<2-naphthyl)pyrro-
lidin-2-ylidene]acetate <13d)29 <77 mg, 0.27 mmol); white
powder, mp 260±2628C; Rf 0.25 <MeOH±benzene 1:9);
n
max/cm21 <CHCl3) 1637 <s), 1610 <m), 1560 <s), 1515
<m), 1483 <m), 1466 <s); dH <200 MHz; CDCl3; signals
assigned by extensive decoupling experiments) 10.51 <1H,
dm, Jˆ8.7 and ca. 1.2 Hz, 10-H), 7.92 <1H, d with ®ne

9640
J. P. Michael et al. / Tetrahedron 57 (2001) 9635±9648
<100). HRMS Found: M1, 205.0752. C11H11NO3 requires
M, 205.0739.
cm21 <KBr) 1638 <m), 1617 <m), 1489 <s), 1458 <m), 1435
<m), 1415 <m), 1301 <s), 1147 <m), 1113 <m), 770 <s); dH
<200 MHz; CDCl3) 7.31±7.23 <3H, m, arom H), 7.18±7.08
<1H, m, arom H), 3.93 <2H, t, Jˆ7.2 Hz, 5-H), 3.17 <2H, t,
Jˆ7.9 Hz, 3-H), 2.24 <2H, quintet with ®ne coupling, Jˆca.
7.4 Hz, 4-H), 2.22 <3H, s, CH3); dC <50 MHz; CDCl3) 202.5
<CvS), 139.1 and 134.4 <arom C-1, C-2), 130.9, 128.4,
126.9, 125.8 <arom C-3, C-4, C-5, C-6), 58.1 <C-5), 44.8
<C-3), 20.8 <C-4), 17.2 <CH3). Anal. Found: C, 68.96; H,
6.85; N, 7.36. C11H13NS requires C, 69.07; H, 6.85; N, 7.32%.
3.3.2.
N-.2-Bromophenyl)pyrrolidin-2-one
.17h).
According to the general procedure, 17h was obtained
from 2-bromoaniline 15h <92% over 2 steps); off-white
powder, mp 55±568C <lit.33 54.5±558C); Rf 0.29 <EtOAc±
hexane 1:1); dH <200 MHz; CDCl3) 7.65 <1H, dd, Jˆ7.9 and
1.5 Hz, arom 3-H), 7.41±7.16 <3H, m, arom H), 3.77 <2H, t,
Jˆ6.9 Hz, 5-H), 2.58 <2H, t, Jˆ7.9 Hz, 3-H), 2.24 <2H,
quintet with ®ne coupling, Jˆca. 7.3 Hz, 4-H); dC
<50 MHz; CDCl3) 174.8 <CvO), 137.9 <arom C-1), 133.6,
129.6, 129.4 and 128.5 <arom C-3, C-4, C-5, C-6), 122.2
<arom C-2), 50.0 <C-5), 31.0 <C-3), 19.1 <C-4).
3.4.2. N-.3-Methylphenyl)pyrrolidine-2-thione .18d).
According to the general procedure, 18d <2.23 g, 62%)
was obtained from N-<3-methylphenyl)pyrrolidin-2-one
<17d) <3.28 g, 18.7 mmol); pale yellow solid, mp 97±988C
3.3.3. N-.3,4-Di¯uorophenyl)pyrrolidin-2-one .17i).
According to the general procedure, 17i was obtained
from 3,4-di¯uoroaniline 15i <88% over 2 steps); off-white
<from EtOAc±hexane); Rf 0.67 <EtOAc±hexane 1:1); nmax
/
cm21 <KBr) 1638 <m), 1610 <m), 1589 <m), 1485 <s), 1464
<m), 1444 <m), 1416 <m), 1327 <m), 1298 <s), 1267 <m),
1136 <m), 804 <s), 696 <s); dH <200 MHz; CDCl3) 7.33±
7.27 <3H, m, arom H), 7.15±7.10 <1H, m, arom H), 4.07
<2H, t, Jˆ7.2 Hz, 5-H), 3.20 <2H, t, Jˆ7.9 Hz, 3-H), 2.37
<3H, s, CH3), 2.19 <2H, quintet with ®ne coupling, Jˆca.
7.6 Hz, 4-H); dC <50 MHz; CDCl3) 202.4 <CvS), 140.3 and
138.8 <arom C-1, C-3), 128.7, 128.3, 125.3 and 121.9 <arom
C-2, C-4, C-5, C-6), 58.7 <C-5), 46.0 <C-3), 21.1 <CH3), 20.4
<C-4). Anal. Found: C, 68.96; H, 6.80; N, 7.36. C11H13NS
requires C, 69.07; H, 6.85; N, 7.32%.
powder, mp 53.5±558C; Rf 0.40 <EtOAc±hexane 1:1); nmax
/
cm21 <KBr) 1686 <s), 1518 <s), 1396 <s), 1335 <m), 1277
<m), 1213 <m), 1181 <m), 1130 <m), 869 <m), 819 <m), 781
<m); dH <200 MHz; CDCl3) 7.69 <1H, ddd, Jˆ2.5, 7.5 and
12.7 Hz, arom 6-H), 7.27±7.03 <2H, m, arom 2-H, 5-H),
3.80 <2H, t, Jˆ7.0 Hz, 5-H), 2.59 <2H, t, Jˆ7.9 Hz, 3-H);
2.16 <2H, quintet with ®ne coupling, Jˆca. 7.5 Hz, 4-H); dC
2
<50 MHz; CDCl3) 174.2 <CvO), 149.8 <dd, JCFˆ13.3 Hz,
1JCFˆ246.8 Hz, arom C-3 or C-4), 146.8 <dd, 2JCFˆ12.9 Hz,
4
1JCFˆ245.8 Hz, arom C-3 or C-4), 136.0 <d, JCFˆca.
2
3.6 Hz, arom C-1), 116.0 <d, JCFˆ17.4 Hz, arom C-2 or
3.4.3. N-.4-Methylphenyl)pyrrolidine-2-thione .18e).
According to the general procedure, 18e <3.20 g, 73%)
was obtained from N-<4-methylphenyl)pyrrolidin-2-one
<17e) <4.00 g, 22.8 mmol); pale yellow solid, mp 88±
918C; Rf 0.76 <EtOAc±hexane 1:1); nmax/cm21 <KBr)
1638 <m), 1617 <m), 1514 <s), 1482 <s), 1464 <s), 1447 <s),
1418 <m), 1408 <m), 1312 <s), 1295 <s) 1260 <s), 1140 <s),
1107 <m), 1044 <m), 1020 <m), 835 <s), 560 <s); dH
<200 MHz; CDCl3) 7.38 <2H, d, Jˆ8.4 Hz, arom H), 7.22
<2H, d, Jˆ8.4 Hz, arom H), 4.05 <2H, t, Jˆ7.2 Hz, 5-H),
3.18 <2H, t, Jˆ7.9 Hz, 3-H), 2.35 <3H, s, CH3), 2.18 <2H,
quintet with ®ne coupling, Jˆ7.6 Hz, 4-H); dC <50 MHz;
CDCl3) 202.1 <CvS), 137.6 and 137.2 <arom C-1, C-4),
129.3 and 124.4 <arom C-2, C-3, C-5, C-6), 58.5 <C-5),
45.9 <C-3), 20.8 <CH3), 20.2 <C-4). HRMS Found: M1,
191.0765. C11H13NS requires M, 191.0769.
4
3
C-5), 115.0 <dd, JCFˆ3.6 Hz, JCFˆ5.8 Hz, arom C-6),
2
109.3 <d, JCFˆ21.9 Hz, arom C-2 or C-5), 48.6 <C-5),
32.5 <C-3), 17.6 <C-4); m/z <EI) 197 <M1, 47%), 142
<100), 113 <13). HRMS Found: M1, 197.0660. C10H9NO
requires M, 197.0652.
3.4. General procedure for the preparation of N-aryl-
pyrrolidine-2-thiones 18
The appropriate N-arylpyrrolidin-2-one 17 <9±23 mmol
scale) was dissolved in benzene <concentration ca. 1 g per
10 cm3) with the aid of an ultrasonic cleaning bath.
Phosphorus pentasulphide <ca. 0.6 equiv.) was added in
portions to the mixture, and ultrasonic irradiation was
maintained for 2±22 h. The reaction was monitored by
TLC until the starting material had been consumed. The
reaction mixture was ®ltered, and the residue was copiously
washed with boiling benzene <200 cm3). The combined
organic phases were evaporated under reduced pressure,
and the crude product was puri®ed by chromatography on
silica gel with EtOAc±hexane mixtures. Nine N-arylpyrro-
lidine-2-thiones 18 were obtained <yields in Table 1). The
physical properties, 1H and 13C NMR spectroscopic data for
the following three agree with those published in the litera-
ture: N-<2,5-dimethoxyphenyl)pyrrolidine-2-thione <18a),29
N-phenylpyrrolidine-2-thione <18b),29 N-<4-methoxy-
phenyl)pyrrolidine-2-thione <18f).29 Data for the remaining
six compounds are given below.
3.4.4. N-.3,4-Methylenedioxyphenyl)pyrrolidine-2-thione
.18g). According to the general procedure, 18g <1.57 g,
79%) was obtained from N-<3,4-methylenedioxyphenyl)-
pyrrolidin-2-one <17g) <1.84 g, 9.0 mmol); colourless
spars, mp 143±1448C <from CHCl3±hexane); Rf 0.68
<EtOAc±hexane 1:1); nmax/cm21 <KBr) 1506 <s), 1492 <s),
1301 <s), 1256 <s), 1039 <s), 932 <s), 830 <s); dH <200 MHz;
CDCl3) 7.00±6.99 <1H, m, arom H), 6.86±6.85 <2H, m,
arom H), 6.01 <2H, s, OCH2O), 4.05 <2H, t, Jˆ7.3 Hz,
5-H), 3.21 <2H, t, Jˆ7.9 Hz, 3-H), 2.22 <2H, quintet with
®ne coupling, Jˆca. 7.6 Hz, 4-H); dC <50 MHz; CDCl3)
202.8 <CvS), 147.8 and 146.8 <arom C-3, C-4), 134.3
<arom C-1) 118.4, 108.2 and 106.6 <arom C-2, C-5, C-6),
101.6 <OCH2O), 59.1 <C-5), 45.9 <C-3), 20.5 <C-4); m/z <EI)
221 <M1, 66%), 220 <100). HRMS Found: M1, 221.0495.
C11H11NO2S requires M, 221.0511.
3.4.1. N-.2-Methylphenyl)pyrrolidine-2-thione .18c).
According to the general procedure, 18c <3.34 g, 76%)
was obtained from N-<2-methylphenyl)pyrrolidin-2-one
<17c) <4.00 g, 22.8 mmol); colourless solid, mp 115±
3.4.5. N-.2-Bromophenyl)pyrrolidine-2-thione .18h).
1168C <from EtOAc); Rf 0.59 <EtOAc±hexane 1:1); nmax
/

J. P. Michael et al. / Tetrahedron 57 (2001) 9635±9648
9641
According to the general procedure, 18h <2.94 g, 92%) was
obtained from N-<2-bromophenyl)pyrrolidin-2-one <17h)
<3.00 g, 12.5 mmol); colourless needles, mp 122±1238C
<from EtOAc±hexane); nmax/cm21 <KBr) 1638 <m), 1617
<m), 1486 <s), 1435 <s), 1420 <s), 1327 <s), 1292 <s), 1265
<s), 1142 <s), 1061 <m), 1029 <m), 760 <s), 714 <m); Rf 0.63
<EtOAc±hexane 1:1); dH <200 MHz; CDCl3) 7.73±7.66
<1H, m, arom H), 7.48±7.23 <3H, m, arom H), 4.30±3.80
<2H, br m, 5-H), 3.21 <2H, t, Jˆ7.8 Hz, 3-H), 2.32 <2H,
quintet with ®ne coupling, Jˆca. 7.6 Hz, 4-H); dC
<50 MHz; CDCl3) 204.3 <CvS), 139.6 <arom C-1), 133.7,
130.1, 129.0 and 128.7 <arom C-3, C-4, C-5, C-6), 121.0
<arom C-2), 57.5 <C-5), 44.9 <C-3), 21.3 <C-4). Anal. Found:
C, 47.07; H, 3.90; N, 5.55. C10H10BrNS requires C, 46.89;
H, 3.93; N, 5.47%.
<2£CvO), 153.2 and149.1 <arom C-2, C-5), 130.3 <arom
C-1), 114.0, 113.2 and 112.9 <arom C-3, C-4, C-6), 92.7
<N±CvC), 59.6 <br s, 2£CO2CH2CH3), 56.1 and 55.7
<C-5, OCH3); 34.3 <C-3), 21.5 <C-4), 14.0 <br s, 2£
CO2CH2CH3). HRMS Found: M1, 363.1701, C19H25NO6
requires M, 363.1682. Anal. Found: C, 62.71; H, 7.08; N,
3.85. C19H25NO6 requires C, 62.80; H, 6.93; N, 3.85%.
3.6. Cyclisation of diethyl N-[1-.2,5-dimethoxyphenyl)-
pyrrolidin-2-ylidene]malonate .19a) in polyphosphoric
acid
3.6.1. 6-Hydroxy-9-methoxy-1,2,3,5-tetrahydropyrrolo-
[1,2-a]quinolin-5-one .21). Diethyl [1-<2,5-dimethoxy-
phenyl)pyrrolidin-2-ylidene]malonate <19a) <105 mg, 0.29
mmol) was added to PPA <10 g) pre-heated to 1608C.
After 75 min of stirring, the mixture was allowed to cool
and diluted with H2O <20 cm3) and diethyl ether <50 cm3).
The organic material was extracted with diethyl ether
<2£20 cm3), dried <Na2SO4), and the solvent was removed
under reduced pressure, yielding a crude solid <0.04 g).
Recrystallisation gave the title compound 21 <11 mg,
17%) as a yellow powder, mp 196±1978C <from EtOH±
hexane); Rf 0.49 <MeOH±EtOAc 1:3); nmax/cm21 <KBr)
3416 <br, OH), 1638 <s), 1580 <m), 1559 <m), 1506 <s),
1485 <m), 1267 <s), 1071 <m), 1158 <m), 841 <s); dH
<200 MHz; CDCl3) 14.62 <1H, s, Ar OH) 6.94 <1H, d,
Jˆ8.8 Hz, 7-H or 8-H), 6.53 <1H, d, Jˆ8.8 Hz, 7-H or
8-H), 6.02 <1H, s, 4-H), 4.68 <2H, t, Jˆ7.3 Hz, 1-H), 3.78
<3H, s, OCH3), 3.00 <2H, t, J2ˆ7.9 Hz, 3-H), 2.20 <2H,
quintet with ®ne coupling, Jˆca. 7.6 Hz, 2-H); dC
<50 MHz; CDCl3) 181.8 <CvO), 157.7 and 155.7 <C-3a,
C-9), 140.4 and 130.6 <C-5a, C-9a), 116.8, 108.2 and
103.6 <C-4, C-7, C-8), 114.0 <C-6), 57.2 and 55.9 <C-1,
OCH3), 31.1 <C-3), 21.6 <C-2); m/z <EI) 231 <M1, 32%),
217 <17), 216 <100, M12CH3). HRMS Found: M1,
231.0894. C13H13NO3 requires M, 231.0895.
3.4.6. N-.3,4-Di¯uorophenyl)pyrrolidine-2-thione .18i).
According to the general procedure, 18i <2.71 g, 83%) was
obtained from N-<3,4-di¯uorophenyl)pyrrolidin-2-one <17i)
<3.02 g, 15.3 mmol); colourless powder, mp 95±978C <from
CHCl3±hexane); Rf 0.59 <EtOAc±hexane 1:1); nmax/cm21
<KBr) 1609 <s), 1560 <s), 1512 <s), 1430 <s), 1304 <s),
1280 <s), 1137 <s), 1111 <s), 882 <m), 828 <m), 772 <s); dH
<200 MHz; CDCl3) 7.57±7.46 <1H, m, arom 6-H), 7.29±
7.15 <2H, m, arom 2-H, 5-H), 4.10 <2H, t, Jˆ7.3 Hz, 5-H),
3.21 <2H, t, Jˆ7.9 Hz, 3-H), 2.24 <2H, quintet with ®ne
coupling, Jˆca. 7.5 Hz, 4-H); dC <50 MHz; CDCl3) 203.4
<CvS), 149.7 <dd, 2JCFˆ13.4 Hz, 1JCFˆ249.4 Hz, arom C-3
or C-4), 148.9 <dd, 2JCFˆ12.4 Hz, 1JCFˆ249.7 Hz, arom C-3
4
3
or C-4), 136.5 <dd, JCFˆ3.5 Hz, JCFˆ7.8 Hz, arom C-1),
121.1 <dd, 4JCFˆ3.8 Hz, 3JCFˆ6.3 Hz, arom C-6), 117.3 <d,
2
2JCFˆ18.1 Hz, arom C-2 or C-5), 114.7 <d, JCFˆ19.8 Hz,
arom C-2 or C-5), 58.4 <C-5), 46.1 <C-3), 20.3 <C-4); m/z
<EI) 213 <M1, 63%), 212 <100), 142 <22), 113 <18). HRMS
Found: M1, 213.0419. C10H9F2NS requires M, 213.0424.
3.5. Diethyl [1-.2,5-dimethoxyphenyl)pyrrolidin-2-
ylidene]malonate .19a)
3.6.2. 6,9-Dimethoxy-5-oxo-1,2,3,5-tetrahydropyrrolo-
[1,2-a]quinoline-4-carboxylic acid .22a). Diethyl [1-<2,5-
dimethoxyphenyl)pyrrolidin-2-ylidene]malonate <19a) <199
mg, 0.55 mmol) was added to PPA <4.00 g) pre-heated to
1938C. After 5 min of stirring the mixture was allowed to
cool for 5 min. H2O <5 cm3) was added dropwise over
10 min, and the solution was neutralized with aqueous
NH3 <36%). A white precipitate formed. The mixture was
extracted with CH2Cl2 <3£50 cm3), and the combined
extracts were washed with water <3£50 cm3). The organic
phase was dried <Na2SO4) and the solvent removed in vacuo
to yield the carboxylic acid 22a <0.047 g, 60%) as a yellow
amorphous solid <vide infra for characterisation).
A solution of N-<2,5-dimethoxyphenyl)pyrrolidine-2-thione
<18a) <314 mg, 1.32 mmol) and diethyl bromomalonate
<374 mg, 1.57 mmol) in CH2Cl2 <5 cm3) was stirred at rt
for 47 h, at which time TLC indicated complete salt
formation. Triphenylphosphine <410 mg, 1.56 mmol) was
added, forming an orange solution. After 10 min, triethyl-
amine <0.33 cm3, 2.33 mmol, 1.8 equiv.) was added, and
stirring was continued for a further 68 h. The solvent was
removed from the dark red solution in vacuo, and the crude
orange-brown solid <1.03 g) was puri®ed by column
chromatography on silica gel, eluting with CH2Cl2 followed
by EtOAc±hexane <7:3). The title compound 19a <407 mg,
85%) was obtained as a pale yellow solid, mp 119±1208C
<from EtOAc±hexane); Rf 0.43 <EtOAc±hexane 1:1); nmax
/
3.7. General procedure for the preparation of diethyl
.1-arylpyrrolidin-2-ylidene)malonates 19 by
Reformatsky reaction
cm21 <KBr) 1712 <s), 1674 <s), 1551 <s), 1515 <s), 1446 <m),
1323 <m), 1285 <s), 1228 <s), 1104 <s), 1050 <m), 807 <m);
dH <200 MHz; CDCl3) 6.88±6.74 <2H, m, arom 3-H, 4-H),
6.69 <1H, d, Jˆ2.6 Hz, arom 6-H), 4.20±3.90 and 4.05±3.90
<4H, overlapping v br s and dt, Jˆ9.7 and 6.9 Hz,
CO2CH2CH3 and 5-H), 3.83 <3H, s, OCH3), 3.74 <3H, s,
OCH3), 3.60±3.20 and 3.55±3.25 <4H, overlapping v br s
and m, CO2CH2CH3 and 3-H), 2.10 <2H, quintet with ®ne
coupling, Jˆca. 7.6 Hz, 4-H), 1.25±1.00 <6H, v br s,
2£CO2CH2CH3); dC <50 MHz; CDCl3) 167.3 <C-2), 163.8
A solution of diethyl bromomalonate32 <4 equiv.) in dry
THF <5±10 cm3) was added in portions over 30 min to a
mixture of Zn powder <4 equiv., dried beforehand by
heating at 1508C for at least 1 h) and I2 <ca. 0.2 equiv.) in
boiling THF <5±10 cm3) under an atmosphere of dry N2 gas.
The appropriate N-arylpyrrolidine-2-thione 18 <1±6.8 mmol
scale) was added as a solid in one portion, and an additional

9642
J. P. Michael et al. / Tetrahedron 57 (2001) 9635±9648
quantity of THF <5±10 cm3) was used to ensure quantitative
transfer. The mixture was heated under re¯ux for 1±1.5 h.
After cooling, aqueous K2CO3 solution <50%, 20±40 cm3)
was added, and stirring was maintained for up to 2 h. The
aqueous phase was extracted with diethyl ether, and the
extracts were copiously washed with aqueous KI solution
<10%). The organic phase was dried <MgSO4) and evapo-
rated in vacuo. The crude residue was puri®ed by chroma-
tography on silica gel using CH2Cl2 as eluant followed by
EtOAc±hexane mixtures <1:9±1:1). The diethyl <1-aryl-
pyrrolidin-2-ylidene)malonates 19, obtained as orange oils
or semi-solids after chromatography, retained an insepar-
able malonate-derived contaminant <1H NMR spectroscopic
signals at d 4.4±4.1 and 1.4±1.2 ppm). The products were
therefore used in the next reaction without further puri®-
cation, but their NMR spectra were recorded, as detailed
below. The following nine compounds were prepared by
this procedure:
17.6 <Ar±CH3), 13.9 <v br s, 2£CO2CH2CH3). HRMS
Found: M1, 317.1625. C18H23NO4 requires M, 317.1627.
3.7.4. Diethyl [1-.3-methylphenyl)pyrrolidin-2-ylidene]-
malonate .19d). According to the general procedure, 19d
<1.89 g, impure) was obtained from N-<3-methylphenyl)-
pyrrolidine-2-thione <18d) <1.31 g, 6.82 mmol) and diethyl
bromomalonate <6.53 g, 27.3 mmol); Rf 0.33 <EtOAc±
hexane 3:7); dH <200 MHz; CDCl3) 7.18±7.28 <1H, m,
arom 6-H), 7.02±6.97 <3H, m, arom 2-H, 3-H, 4-H),
4.35±4.00 <2H, v br s, CO2CH2CH3), 3.81 <2H, t, Jˆ
7.1 Hz, 5-H), 3.60±3.25 and 3.35 <4H, overlapping v br s
and t, Jˆ7.6 Hz, CO2CH2CH3 and 3-H), 2.33 <3H, s, Ar±
CH3), 2.17±2.04 <2H, m, 4-H), 1.25±1.00 <6H, v br s,
2£CO2CH2CH3); dC <50 MHz; CDCl3) 167.3 <C-2) 163.5
<2£CvO), 142.2 <arom C-1), 138.9 <arom C-3), 128.9,
127.1, 125.2 and 121.7 <arom C), 93.2 <N±CvC); 59.7
<br s, 2£CO2CH2CH3), 57.8 <C-5), 34.8 <C-3), 21.2 and
20.9 <C-4 and Ar±CH3), 14.0 <br s, 2£CO2CH2CH3).
HRMS Found: M1, 317.1634. C18H23NO4 requires M,
317.1627.
3.7.1. Diethyl [1-.2,5-dimethoxyphenyl)pyrrolidin-2-yl-
idene]malonate .19a). According to the general procedure,
19a <1.16 g, impure) was obtained from N-<2,5-dimethoxy-
phenyl)pyrrolidine-2-thione <18a) <1.00 g, 4.21 mmol) and
diethyl bromomalonate <4.03 g, 16.9 mmol); characteri-
sation as described above.
3.7.5. Diethyl [1-.4-methylphenyl)pyrrolidin-2-ylidene]-
malonate .19e). According to the general procedure, 19e
<840 mg, impure) was obtained from N-<4-methylphenyl)-
pyrrolidine-2-thione <18e) <497 mg, 2.60 mmol) and diethyl
bromomalonate <2.50 g, 10.5 mmol); Rf 0.29 <EtOAc±
hexane 3:7); dH <200 MHz; CDCl3) 7.17±7.04 <4H, m,
arom 2H), 4.35±4.10 <2H, v br m, CO2CH2CH3), 3.95±
3.70 and 3.79 <4H, overlapping v br m and t, Jˆ7.1 Hz,
CO2CH2CH3 and 5-H), 3.35 <2H, t, Jˆ7.8 Hz, 3-H), 2.32
<3H, s, Ar±CH3), 2.10 <2H, quintet with ®ne coupling, Jˆ
ca. 7.5 Hz, 4-H), 1.20±1.05 <6H, br m, 2£CO2CH2CH3).
3.7.2. Diethyl .1-phenylpyrrolidin-2-ylidene)malonate
.19b). According to the general procedure, 19b <392 mg,
impure) was obtained from N-phenylpyrrolidine-2-thione
<18b) <247 mg, 1.39 mmol) and diethyl bromomalonate
<1.33 g, 5.56 mmol); Rf 0.64 <EtOAc±hexane 1:1); dH
<200 MHz; CDCl3) 7.39±7.15 <5H, m, arom H), 4.30±
3.95 <2H, v br s, CO2CH2CH3), 3.82 <2H, t, Jˆ7.2 Hz,
5-H), 3.60±3.25 and 3.36 <4H, overlapping br s and t,
Jˆ7.9 Hz, CO2CH2CH3 and 3-H), 2.12 <2H, quintet with
®ne coupling, Jˆ7.5 Hz, 4-H), 1.35±0.95 <6H, v br s,
2£CO2CH2CH3); dC <50 MHz; CDCl3) 167.3 <C-2), 163.7
<2£CvO), 142.3 <arom C-1), 129.1, 126.5 and 124.8
<arom C), 89.0 <N±CvC), 59.7 <br s, 2£CO2CH2CH3),
57.9 <C-5), 34.8 <C-3), 21.0 <C-4), 14.1 <br s, 2£
CO2CH2CH3). HRMS Found: M1, 303.1479. C17H21NO4
requires M, 303.1471.
3.7.6. Diethyl [1-.4-methoxyphenyl)pyrrolidin-2-ylidene]-
malonate .19f). According to the general procedure, 19f
<1.48 g, impure) was obtained from N-<4-methoxyphenyl)-
pyrrolidine-2-thione <18f) <1.00 g, 4.82 mmol) and diethyl
bromomalonate <4.61 g, 19.3 mmol); Rf 0.35 <EtOAc±
hexane 1:1); dH <200 MHz; CDCl3) 7.12 <2H, d, Jˆ
8.9 Hz, arom 2-H, 6-H), 6.89 <2H, d, Jˆ8.9 Hz, arom 3-H,
5-H), 4.35±4.15 <2H, v br s, CO2CH2CH3), 3.95±3.60, 3.79
and 3.76 <7H, overlapping v br s, s and t, Jˆ7.2 Hz,
CO2CH2CH3, OCH3 and 5-H), 3.34 <2H, t, Jˆ7.8 Hz,
3-H), 2.10 <2H, quintet with ®ne coupling, Jˆca. 7.5 Hz,
4-H), 1.13 <6H, br t, Jˆca. 6.9 Hz, 2£CO2CH2CH3); dC
<50 MHz; CDCl3) 167.1 <C-2), 163.8 <2£CvO), 157.8
<arom C-4), 134.7 <arom C-1), 126.4 <arom C-2, C-6),
114.0 <arom C-3, C-5), 92.1 <N±CvC), 59.5 <br s,
2£CO2CH2CH3); 58.2 and 55.2 <C-5, OCH3), 34.6 <C-3)
20.9 <C-4), 13.9 <br s, 2£CO2CH2CH3). HRMS Found:
M1, 333.1566. C18H23NO5 requires M, 333.1576.
3.7.3. Diethyl [1-.2-methylphenyl)pyrrolidin-2-ylidene]-
malonate .19c). According to the general procedure, 19c
<1.68 g, impure) was obtained from N-<2-methylphenyl)pyr-
rolidine-2-thione <18c) <1.00 g, 5.22 mmol) and diethyl
bromomalonate <5.00 g, 20.9 mmol); Rf 0.41 <EtOAc±hex-
ane 1:1); dH <200 MHz; CDCl3) 7.24±7.09 <4H, m, arom H),
4.25±3.90 <2H, v br s, CO2CH2CH3), 3.75±3.53 <2H, m,
5-H); 3.45±3.20 and 3.37 <4H, overlapping v br s and t,
Jˆ7.6 Hz, CO2CH2CH3 and 3-H), 2.23 <3H, s, Ar±CH3);
2.23±2.07 <2H, m, 4-H); 1.35±0.95 <6H, v br s, 2£
CO2CH2CH3); dH <200 MHz; toluene-d8) 7.10±6.85 <4H,
m, arom H), 4.20±4.05 <2H, br m, CO2CH2CH3), 3.45±
3.25 and 3.23 <4H, overlapping br m and td, Jˆ7.9 and
1.1 Hz, CO2CH2CH3 and 3-H), 3.15 <2H, m, 5-H), 1.46
<2H, quintet with ®ne coupling, Jˆca. 7.5 Hz, 4-H), 1.05
<3H, t, Jˆ7.1 Hz, CO2CH2CH3), 0.92 <3H, t, Jˆ7.1 Hz,
CO2CH2CH3); dC <50 MHz; CDCl3) 167.0 <C-2), 163.2
<2£CvO), 139.6 and 135.9 <arom C-1, C-2), 130.8,
127.9, 127.6 and 126.6 <arom C), 92.5 <N±CvC), 59.5 <v
b r s, 2£CO2CH2CH3), 57.1 <C-5), 34.2 <C-3), 21.6 <C-4),
3.7.7. Diethyl [1-.3,4-methylenedioxyphenyl)pyrrolidin-
2-ylidene]malonate .19g). According to the general pro-
cedure, 19g <735 mg, impure) was obtained from N-<3,4-
methylenedioxyphenyl)pyrrolidine-2-thione <18g) <491 mg,
2.22 mmol) and diethyl bromomalonate <2.16 g, 9.04
mmol); Rf 0.79 <EtOAc); dH <200 MHz; CDCl3) 6.78±
6.62 <3H, m, arom H), 5.97 <2H, s, OCH2O), 4.39±3.42
and 3.74 <6H, overlapping v br s and t, Jˆ7.1 Hz, 2£
CO2CH2CH3 and 5-H), 3.32 <2H, t, Jˆ7.8 Hz, 3-H), 2.09
<2H, quintet with ®ne coupling, Jˆca. 7.5 Hz, 4-H), 1.16

J. P. Michael et al. / Tetrahedron 57 (2001) 9635±9648
9643
<6H, br t, Jˆca. 7.0 Hz, CO2CH2CH3); dC <50 MHz; CDCl3)
167.2 <C-2), 163.6 <2£CvO), 147.8 and 146.0 <arom C-3,
C-4), 136.1 <arom C-1), 118.7, 108.0 and 106.6 <arom C-2,
C-5, C-6), 111.9 <N±CvC), 101.5 <OCH2O), 59.7 <br s,
2£CO2CH2CH3), 58.4 <C-5), 34.7 <C-3), 21.0 <C-4), 14.0
<br s, 2£CO2CH2CH3). HRMS Found: M1, 347.1361.
C18H21NO6 requires M, 347.1369.
<1H, d, Jˆ9.0 Hz, 7-H or 8-H), 4.69 <2H, t, Jˆ7.3 Hz, 1-H),
4.35 <2H, q, Jˆ7.1 Hz, CO2CH2CH3), 3.88 <3H, s, OCH3),
3.83 <3H, s, OCH3), 3.23 <2H, t, Jˆ7.9 Hz, 3-H), 2.16 <2H,
quintet with ®ne coupling, Jˆca. 7.6 Hz, 2-H), 1.37 <3H, t,
Jˆ7.1 Hz, CO2CH2CH3); dC <50 MHz; CDCl3) 174.7
<quinolone CvO), 166.9 <ester CvO), 157.6, 154.6,
143.0, 131.8, 119.1, 114.9, 111.9 and 106.3 <arom C),
60.4 <CO2CH2CH3), 56.8, 56.7 and 56.4 <C-1 and
2£OCH3), 31.1 <C-3), 21.8 <C-2), 14.2 <CO2CH2CH3); m/z
<EI) 317 <M1, 30%), 288 <13), 272 <17, M12OCH2CH3),
270 <31), 256 <43), 244 <17, M12CO2CH2CH3), 243 <100),
242 <18), 215 <18), 214 <14), 200 <10), 185 <10), 115 <14).
HRMS Found: M1, 317.1250. C17H19NO5 requires M,
317.1263. The yield of the same product prepared via
malonate-contaminated diethyl [1-<2,5-dimethoxyphenyl)-
pyrrolidin-2-ylidene]malonate <19a) was 49% over 2 steps
from thiolactam 18a.
3.7.8. Diethyl [1-.2-bromophenyl)pyrrolidin-2-ylidene]-
malonate .19h). According to the general procedure, 19h
<244 mg, impure) was obtained from N-<2-bromophenyl)-
pyrrolidine-2-thione <18h) <253 mg, 0.99 mmol) and diethyl
bromomalonate <930 mg, 3.89 mmol); Rf 0.69 <EtOAc±
hexane 1:1); dH <200 MHz; CDCl3) 7.62 <1H, dd, Jˆ1.4
and 7.9 Hz, arom 3-H), 7.37±7.12 <3H, m, arom H),
4.19±4.00 and 3.97 <3H, overlapping v br m and dt, Jˆ
9.6 and Jˆ6.5 Hz, CO2CH2CH3 and NCHaHb), 3.56±3.24,
3.40 and 3.36 <5H, overlapping v br m, dt, Jˆ7.6 and 9.6 Hz,
and t with ®ne coupling, Jˆca. 7.7 Hz, CO2CH2CH3,
NCHaHb and 3-H), 2.15 <2H, quintet with ®ne coupling,
Jˆca. 7.4 Hz, 4-H), 1.18 and 1.05 <6H, overlapping br t
and br t, Jˆca. 6.3 and 6.4 Hz, 2£CO2CH2CH3).
3.8.2. Ethyl 5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quino-
line-4-carboxylate .20b). According to the general pro-
cedure, 20b <218 mg) was obtained from malonate
contaminated diethyl <1-phenylpyrrolidin-2-ylidene)malo-
nate <19b) <392 mg); 61% over 2 steps from N-phenyl-
pyrrolidine-2-thione <18b); colourless spars, mp 141±
1428C <from CHCl3±hexane) <lit.45 140±1428C); Rf 0.18
<EtOAc); nmax/cm21 <KBr) 1692 <s), 1621 <s), 1599 <s),
1535 <s), 1502 <m), 1488 <m), 1462 <m), 1204 <m), 1151
<s), 1082 <m), 1035 <m), 767 <s); dH <200 MHz; CDCl3) 8.30
<1H, dd, Jˆ1.6 and Jˆ8.1 Hz, 6-H), 7.52 <1H, td, Jˆ1.6 and
7.2 Hz, 8-H), 7.27 <1H, td, Jˆ0.9 and 7.6 Hz, 7-H),
7.16 <1H, d, Jˆ8.4 Hz, 9-H), 4.34 <2H, q, Jˆ7.1 Hz,
CO2CH2CH3), 4.17 <2H, t, Jˆ7.5 Hz, 1-H), 3.36 <2H, t,
Jˆ7.9 Hz, 3-H), 2.28 <2H, quintet with ®ne coupling,
Jˆca. 7.7 Hz, 2-H), 1.39 <3H, t, Jˆ7.1 Hz, CO2CH2CH3);
dC <50 MHz; CDCl3) 174.4 <quinolone CvO), 166.1 <ester
CvO), 159.5 <C-3a), 137.3 <C-9a), 131.9 <C-8), 126.7
<C-6), 126.5 <C-5a), 124.0 <C-7), 115.6 <C-9), 108.8 <C-4),
60.1 <CO2CH2CH3), 50.5 <C-1), 33.0 <C-3), 20.0 <C-2), 14.2
<CO2CH2CH3); m/z <EI) 257 <M1, 16%), 212 <32, M12
OCH2CH3), 186 <14), 185 <100, M12CO2C2H4). HRMS
Found: M1, 257.1040. C15H15NO3 requires M, 257.1052.
3.7.9. Diethyl [1-.3,4-di¯uorophenyl)pyrrolidin-2-yl-
idene]malonate .19i). According to the general procedure,
19i <1.26 g, impure) was obtained from N-<3,4-di¯uoro-
phenyl)pyrrolidine-2-thione <18i) <0.99 g, 4.65 mmol) and
diethyl bromomalonate <4.44 g, 18.6 mmol); dH <200
MHz; CDCl3) 7.20±6.92 <3H, m, arom H), 4.36±3.96
<2H, v br s, CO2CH2CH3), 3.79 <2H, t, Jˆ7.1 Hz, 5-H),
3.70±3.49 <2H, v br s, CO2CH2CH3), 3.33 <2H, t, Jˆ
7.8 Hz, 3-H), 2.13 <2H, quintet with ®ne coupling, Jˆca.
7.5 Hz, 4-H), 1.37±0.93 <6H, v br s, 2£CO2CH2CH3).
3.8. General procedure for PPA-induced cyclisation of
diethyl .1-arylpyrrolidin-2-ylidene)malonates 19 to ethyl
5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carb-
oxylates 20
The malonate-contaminated diethyl <1-arylpyrrolidin-2-
ylidene)malonates 19 were dissolved in diethyl ether
<3±4 cm3) and added to PPA <ca. 10 g per g of crude 19).
The stirred mixture was heated at 85±1008C for 1±1.5 h,
after which ice and H2O <ca. 30 cm3) was added. Stirring
was maintained for 0.75 h before the solution was extracted
with CH2Cl2 <4£40 cm3). The extracts were dried <MgSO4)
before removal of the solvent in vacuo. The crude residue
was puri®ed by chromatography on silica gel with hexane±
EtOAc mixtures to yield the ten pyrrolo[1,2-a]quinolinones
20 described below. Other than in the case of 20a, the yields
cited are over 2 steps, and are based on the amount of
N-arylpyrrolidine-2-thione 18 used in the previous reaction.
3.8.3. Ethyl 9-methyl-5-oxo-1,2,3,5-tetrahydropyrrolo-
[1,2-a]quinoline-4-carboxylate .20c). According to the
general procedure, 20c <0.917 g) was obtained from malo-
nate contaminated diethyl [1-<2-methylphenyl)pyrrolidin-2-
ylidene]malonate <19c) <1.679 g); 65% over 2 steps from
thiolactam 18c; cream needles, mp 137±1388C <from
CHCl3±hexane); Rf 0.25 <EtOAc); nmax/cm21 <KBr) 1715
<m), 1699 <s), 1616 <s), 1586 <s), 1549 <m), 1489 <m), 1421
<m), 1146 <s), 1106 <m), 1035 <m), 771 <m), 747 <m); dH
<200 MHz; CDCl3) 8.33 <1H, dd, Jˆ1.7 and 7.8 Hz, 6-H),
7.36±7.31 <1H, m, 8-H), 7.18 <1H, t, Jˆ7.8 Hz, 7-H),
4.65 <2H, t, Jˆ7.3 Hz, 1-H), 4.38 <2H, q, Jˆ7.2 Hz,
CO2CH2CH3), 3.34 <2H, t, Jˆ7.9 Hz, 3-H), 2.76 <3H, s,
Ar±CH3), 2.23 <2H, quintet with ®ne coupling, Jˆca.
7.6 Hz, 2-H), 1.40 <3H, t, Jˆ7.2 Hz, CO2CH2CH3); dC
<50 MHz; CDCl3) 174.5 <quinolone CvO), 166.7 <ester
CvO), 160.5 <C-3a), 138.3 <C-9a), 136.7 <C-8), 128.7
<C-9), 126.1 <C-6), 125.5 <C-5a), 124.3 <C-7), 109.5 <C-4),
60.6 <CO2CH2CH3), 55.8 <C-1), 32.1 <C-3), 23.7 <Ar±
CH3), 21.9 <C-2), 14.4 <CO2CH2CH3); m/z <EI) 271 <M1,
18%), 226 <28, M12OCH2CH3), 200 <15), 199 <100,
3.8.1. Ethyl 6,9-dimethoxy-5-oxo-1,2,3,5-tetrahydro-
pyrrolo[1,2-a]quinoline-4-carboxylate .20a). According
to the general procedure, 20a <130 mg, 75%) was obtained
from pure diethyl [1-<2,5-dimethoxyphenyl)pyrrolidin-2-
ylidene]malonate <19a) <prepared by sulphide contraction;
199 mg, 0.55 mmol); waxy solid, mp 129±1328C; Rf 0.49
<MeOH±EtOAc 1:3); nmax/cm21 <KBr) 1699 <s), 1630 <s),
1590 <s), 1535 <s), 1366 <m), 1341 <m), 1315 <s), 1258 <s),
1142 <s), 1076 <m), 1022 <m), 960 <m), 827 <m), 810 <m); dH
<200 MHz; CDCl3) 7.02 <1H, d, Jˆ9.0 Hz, 7-H or 8-H), 6.69

9644
J. P. Michael et al. / Tetrahedron 57 (2001) 9635±9648
M12CO2C2H4). HRMS Found: M1, 271.1200. C16H17NO3
requires M, 271.1208.
115.6 <C-9), 108.5 <C-4), 60.1 <CO2CH2CH3), 50.6 <C-1),
33.0 <C-3), 20.8 <C-2), 20.0 <Ar±CH3), 14.2 <CO2CH2CH3);
m/z <EI) 271 <M1, 18%), 226 <26, M12OCH2CH3), 200
<15), 199 <100). HRMS Found: M1, 271.1198. C16H17NO3
requires M, 271.1208.
3.8.4. Ethyl 8-methyl-5-oxo-1,2,3,5-tetrahydropyrrolo-
[1,2-a]quinoline-4-carboxylate .20d) and ethyl 6-methyl-
5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carb-
oxylate .20j). According to the general procedure, 20d
<373 mg) and 20j <808 mg) were obtained from malonate-
contaminated diethyl [1-<3-methylphenyl)pyrrolidin-2-
ylidine]malonate <19d) <1.888 g); 20 and 44% yields,
respectively, over 2 steps from thiolactam 18d. Compound
20j: colourless needles, mp 148±1498C <from CHCl3±hex-
ane); Rf 0.33 <acetone±CH2Cl2 1:9); nmax/cm21 <KBr) 1717
<s), 1599 <s), 1540 <s), 1497 <s), 1439 <m), 1419 <m), 1367
<m), 1283 <m), 1204 <s), 1134 <s), 1024 <m), 814 <m), 786
<m), 758 <s), 755 <m); dH <200 MHz; CDCl3) 7.46 <1H, t,
Jˆ7.9 Hz, 8-H), 7.14±7.09 <2H, m, 7-H, 9-H), 4.39 <2H, q,
Jˆ7.1 Hz, CO2CH2CH3), 4.22 <2H, t, Jˆ7.5 Hz, 1-H), 3.45
<2H, t, Jˆ7.9 Hz, 3-H), 2.96 <3H, s, Ar±CH3), 2.33 <2H,
quintet with ®ne coupling, Jˆca. 7.7 Hz, 2-H), 1.40 <3H,
t, Jˆ7.1 Hz, CO2CH2CH3), dC <50 MHz; CDCl3) 177.5
<quinolone CvO), 166.8 <ester CvO), 157.8 <C-3a),
142.6 <C-6), 139.5 <C-9a), 131.3 <C-8), 127.7 <C-7), 125.3
<C-5a), 113.6 <C-9), 111.0 <C-4), 60.6 <CO2CH2CH3), 51.3
<C-1), 32.8 <C-3), 24.0 <Ar±CH3), 20.4 <C-2), 14.5
<CO2CH2CH3); m/z 271 <M1, 34%), 226 <14, M12
OCH2CH3), 198 <17), 197 <100, M12CO2C2H4), 169 <11).
HRMS Found: M1, 271.1205. C16H17NO3 requires M,
271.1208. Compound 20d: light brown powder, mp 165±
1688C; Rf 0.15 <acetone±CH2Cl2 1:9); nmax/cm21 <KBr)
1707 <s), 1686 <s), 1604 <s), 1560 <m), 1528 <s), 1476 <m),
1221 <m), 1193 <m), 1150 <m), 1091 <m), 1033 <m), 803 <s);
dH <200 MHz; CDCl3) 8.21 <1H, d, Jˆ8.2 Hz, 6-H), 7.10
<1H, dd, Jˆ0.8 and 8.2 Hz, 7-H), 6.96 <1H, s, 9-H), 4.35
<2H, q, Jˆ7.1 Hz, CO2CH2CH3), 4.19 <2H, t, Jˆ7.5 Hz,
1-H), 3.39 <2H, t, Jˆ7.9 Hz, 3-H), 2.43 <3H, s, Ar±CH3),
2.29 <2H, quintet with ®ne coupling, Jˆca. 7.7 Hz, 2-H),
1.39 <3H, t, Jˆ7.1 Hz, CO2CH2CH3), dC <50 MHz; CDCl3)
174.6 <quinolone CvO), 166.4 <ester CvO), 159.5 <C-3a),
143.0, 137.6 and 124.6 <C-5a, C-8, C-9a), 126.9 and 125.7
<C-6, C-7), 115.5 <C-9), 108.8 <C-4), 60.3 <CO2CH2CH3),
50.6 <C-1), 33.1 <C-3), 21.8 <C-2), 20.1 <Ar±CH3), 14.3
<CO2CH2CH3); m/z <EI) 271 <M1, 14%), 226 <26, M12
OCH2CH3), 200 <17), 199 <100). HRMS Found: M1,
271.1201. C16H17NO3 requires M, 271.1208.
3.8.6. Ethyl 7-methoxy-5-oxo-1,2,3,5-tetrahydropyrrolo-
[1,2-a]quinoline-4-carboxylate .20f). According to the
general procedure, 20f <0.878 g) was obtained from malo-
nate-contaminated diethyl [1-<4-methoxyphenyl)pyrrolidin-
2-ylidene]malonate <19f) <1.475 g); 63% over 2 steps from
thiolactam 18f; pale yellow amorphous solid, mp 175±
176.58C; Rf 0.12 <EtOAc); nmax/cm21 <KBr) 2976 <m),
1717 <s), 1600 <s), 1582 <s), 1540 <s), 1506 <s), 1427 <m),
1387 <m), 1347 <m), 1266 <m), 1204 <s), 1151 <s), 1044 <s),
1026 <s), 815 <s), 625 <m); dH <200 MHz; CDCl3) 7.75 <1H,
s, 6-H), 7.15 <2H, d, Jˆ1.3 Hz, 8-H, 9-H), 4.36 <2H, q,
Jˆ7.1 Hz, CO2CH2CH3), 4.20 <2H, t, Jˆ7.5 Hz, 1-H),
3.87 <3H, s, OCH3), 3.42 <2H, t, Jˆ7.9 Hz, 3-H), 2.30
<2H, quintet with ®ne coupling, Jˆca. 7.6 Hz, 2-H), 1.40
<3H, t, Jˆ7.1 Hz, CO2CH2CH3); dC <50 MHz; CDCl3) 174.1
<quinolone CvO), 166.5 <ester CvO), 158.4 and 156.6
<C-3a, C-7), 132.0 and 128.1 <C-5a, C-9a), 122.0, 117.3
and 106.9 <C-6, C-8, C-9), 108.0 <C-4), 60.2 <CO2CH2CH3),
55.5 <OCH3), 50.9 <C-1), 32.1 <C-3), 20.1 <C-2), 14.3
<CO2CH2CH3); m/z <EI) 287 <M1, 35%), 242 <26, M12
OCH2CH3), 241 <12), 242 <12), 216 <17), 215 <100, M12
CO2C2H4), 214 <21, M12CO2CH2CH3). HRMS Found:
M1, 287.1169. C16H17NO4 requires M, 287.1158.
3.8.7. Ethyl 7,8-methylenedioxy-5-oxo-1,2,3,5-tetrahydro-
pyrrolo[1,2-a]quinoline-4-carboxylate .20g). According
to the general procedure, 20g <395 mg) was obtained from
malonate-contaminated diethyl [1-<3,4-methylenedioxy-
phenyl)pyrrolidin-2-ylidene]malonate <19g) <735 mg);
59% over 2 steps from thiolactam 18g; beige powder, mp
242±2468C; Rf 0.12 <EtOAc); nmax/cm21 <KBr) 1686 <s),
1628 <m), 1584 <s), 1539 <s), 1506 <s), 1467 <s), 1242 <s),
1191 <m), 1098 <m), 1081 <m), 1036 <m), 932 <m), 806 <m);
dH <200 MHz; CDCl3) 7.67 <1H, br s, 6-H), 6.64 <1H, br s,
9-H), 6.08 <2H, br s, OCH2O), 4.36 <2H, br q, Jˆ7.0 Hz,
CO2CH2CH3), 4.18 <2H, br t, Jˆ7.1 Hz, 1-H), 3.44 <2H, br t,
Jˆ7.6 Hz, 3-H), 2.32 <2H, br quintet, Jˆca. 7.4 Hz, 2-H),
1.40 <3H, br t, Jˆ7.0 Hz, CO2CH2CH3); dC <50 MHz;
CDCl3) 173.5 <quinolone CvO), 166.7 <ester CvO),
158.1 <C-3a), 151.9 and 145.8 <C-7, C-8), 134.7 <C-9a),
122.7 <C-5a), 108.6 <C-4), 104.2 and 102.1 <C-6, C-9),
95.4 <OCH2O), 60.5 <CO2CH2CH3), 51.4 <C-1), 33.1
<C-3), 20.3 <C-2), 14.4 <CO2CH2CH3); m/z <EI) 301 <M1,
21%), 256 <26, M12OCH2CH3), 230 <15), 229 <100, M12
CO2C2H4). HRMS Found: M1, 301.0936. C16H15NO5
requires M, 301.0950.
3.8.5. Ethyl 7-methyl-5-oxo-1,2,3,5-tetrahydropyrrolo-
[1,2-a]quinoline-4-carboxylate .20e). According to the
general procedure, 20e <454 mg) was obtained from
malonate-contaminated diethyl [1-<4-methylphenyl)pyrro-
lidin-2-ylidene]malonate <19e) <840 mg); 64% over 2
steps from thiolactam 18e; pale yellow amorphous solid,
mp 175±1798C; Rf 0.23 <EtOAc); nmax/cm21 <KBr) 1703
<s), 1629 <s), 1603 <s), 1506 <s), 1186 <s), 1167 <s), 1098
<s), 1033 <m), 806 <s); dH <400 MHz; CDCl3) 8.17 <1H, d,
Jˆ1.4 Hz, 6-H), 7.40 <1H, dd, Jˆ1.4 and 8.5 Hz, 8-H), 7.15
<1H, d, Jˆ8.5 Hz, 9-H), 4.37 <2H, q, Jˆ7.1 Hz,
CO2CH2CH3), 4.22 <2H, t, Jˆ7.5 Hz, 1-H), 3.45 <2H, t,
Jˆ7.9 Hz, 3-H), 2.43 <3H, s, Ar±CH3), 2.34 <2H, quintet
with ®ne coupling, Jˆca. 7.7 Hz, 2-H), 1.40 <3H, t, Jˆ
7.1 Hz, CO2CH2CH3); dC <100 MHz; CDCl3) 174.4 <quino-
lone CvO), 166.3 <ester CvO), 159.0 <C-3a), 135.4, 137.6
and 126.5 <C-5a, C-7, C-9a), 133.2 and 126.3 <C-6, C-8),
3.8.8. Ethyl 9-bromo-5-oxo-1,2,3,5-tetrahydropyrrolo-
[1,2-a]quinoline-4-carboxylate .20h). According to the
general procedure, 20h <153 mg) was obtained from
malonate-contaminated diethyl [1-<2-bromophenyl)pyrro-
lidin-2-ylidene]malonate <19h) <244 mg); 46% over 2
steps from thiolactam 18h; light brown amorphous solid,
mp 175±1788C; Rf 0.43 <EtOAc); nmax/cm21 <KBr) 1699
<s), 1622 <s), 1585 <m), 1535 <m), 1481 <m), 1421 <m),
1218 <m), 1147 <m), 1077 <m), 1039 <m); dH <200 MHz;
CDCl3) 8.40 <1H, dd, Jˆ1.6 and 7.9 Hz, 6-H), 7.80 <1H,

J. P. Michael et al. / Tetrahedron 57 (2001) 9635±9648
9645
dd, Jˆ1.7 and 7.6 Hz, 8-H), 7.12 <1H, t, Jˆ7.8 Hz, 7-H),
4.92 <2H, t, Jˆ7.3 Hz, 1-H), 4.37 <2H, q, Jˆ7.1 Hz,
CO2CH2CH3), 3.36 <2H, t, Jˆ7.9 Hz, 3-H), 2.25 <2H,
quintet with ®ne coupling, Jˆca. 7.5 Hz, 2-H), 1.40 <3H,
t, Jˆ7.1 Hz, CO2CH2CH3); dC <50 MHz; CDCl3) 173.2
<quinolone CvO), 165.9 <ester CvO), 161.1 <C-3a),
139.2 <C-8), 136.8, 129.9, 110.2 and 108.0 <C-4, C-5a,
C-9, C-9a), 127.3 and 124.9 <C-6, C-7), 60.6 <CO2CH2CH3),
56.4 <C-1), 32.0 <C-3), 21.8 <C-2), 14.2 <CO2CH2CH3); m/z
<EI) 335 <M1, 12%), 292 <19), 290 <M12OCH2CH3, 20),
271 <19), 266 <10), 265 <77), 264 <15), 263 <79), 226 <26),
200 <14), 199 <100), 154 <18). HRMS Found: M1, 335.0143.
C15H14BrNO3 requires M, 335.0157.
the general procedure, 22a <180 mg, 85%) was obtained
from ethyl 6,9-dimethoxy-5-oxo-1,2,3,5-tetrahydropyrrolo-
[1,2-a]quinoline-4-carboxylate <20a) <232 mg, 0.73 mmol);
colourless needles, mp 257±2598C decomp. <from DMF);
n
max/cm21 <KBr) 3412 <br, OH), 1699 <s), 1612 <m), 1546
<s), 1419 <m), 1314 <m), 1266 <m), 1150 <m), 1084 <m), 820
<m); dH <200 MHz; CDCl3) 16.38 <1H, s, CO2H), 7.20 <1H,
d, Jˆ9.1 Hz, 7-H or 8-H), 6.86 <1H, d, Jˆ9.1 Hz, 7-H or
8-H), 4.88 <2H, t, Jˆ7.6 Hz, 1-H), 3.97 <3H, s, OCH3), 3.92
<3H, s, OCH3), 3.71 <2H, t, Jˆ8.1 Hz, 3-H), 2.25 <2H,
quintet with ®ne coupling, Jˆca. 7.7 Hz, 2-H); dC <50
MHz; CDCl3) 179.6 <quinolone CvO), 170.5 <CO2H),
167.6, 163.5, 154.5, 143.3, 131.1, 116.5 <C-7 or C-8),
107.3 <C-7 or C-8), 106.2, 57.8, 57.0 and 56.7 <C-1, 2£
OCH3), 33.2 <C-3), 21.5 <C-2). Anal. Found: C, 62.00; H,
5.20; N, 4.81. C15H15NO5 requires C, 62.28; H, 5.23; N,
4.84%.
3.8.9. Ethyl 7,8-di¯uoro-5-oxo-1,2,3,5-tetrahydropyrrolo-
[1,2-a]quinoline-4-carboxylate .20i). According to the
general procedure, 20i <0.944 g) was obtained from malo-
nate-contaminated diethyl [1-<3,4-di¯uorophenyl)pyrro-
lidin-2-ylidene]malonate <19i) <1.258 g); 69% over 2 steps
from thiolactam 18i; colourless needles, mp 184±1858C
<from EtOAc±hexane); Rf 0.34 <EtOAc); nmax/cm21 <KBr)
1717 <s), 1710 <s), 1610 <s), 1545 <m), 1491 <s), 1303 <m),
1191 <m), 1095 <m), 1083 <s); dH <400 MHz; CDCl3) 8.11
3.9.2. 5-Oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-
4-carboxylic acid .22b). According to the general pro-
cedure, 22b <195 mg, 91%) was obtained from ethyl
5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxyl-
ate <20b) <240 mg, 0.93 mmol); white powder, mp 258±
3
2
2598C decomp. <from DMF) <lit.45 252±2548C); nmax
/
<1H, dd, J6,Fˆ8.7 Hz and J6,Fˆ10.5 Hz, 6-H), 7.10 <1H,
3
2
cm21 <KBr) 3411 <br, OH), 1708 <s), 1598 <s), 1535 <s),
1458 <s), 1173 <m), 1282 <m), 972 <m), 777 <s); dH <400
MHz; D2O/NaOD) 7.99 <1H, d, Jˆ8.1 Hz, 6-H), 7.46 <1H, t,
Jˆca. 7.7 Hz, 8-H), 7.26 <1H, t, Jˆca. 7.6 Hz, 7-H), 7.10
<1H, d, Jˆ8.4 Hz, 9-H), 4.04 <2H, t, Jˆ7.3 Hz, 1-H), 3.23
<2H, t, Jˆ7.8 Hz, 3-H), 2.25 <2H, quintet with ®ne coupling,
Jˆca. 7.5 Hz, 2-H); dC <100 MHz; D2O/NaOD) 175.7 and
174.6 <2£CvO), 156.4 <C-3a), 138.2 <C-9a), 133.1, 125.9,
125.6 <C-5a), 125.0, 119.0 <C-4), 117.4, 52.2 <C-1), 32.6
<C-3), 21.0 <C-2). Anal. Found: C, 68.05; H, 4.89; N,
6.12. C13H11NO3 requires C, 68.11; H, 4.84; N, 6.11%.
dd, J8,Fˆ6.2 Hz and J8,Fˆ10.6 Hz, 8-H), 4.37 <2H, q, Jˆ
7.1 Hz, CO2CH2CH3), 4.23 <2H, t, Jˆ7.5 Hz, 1-H), 3.49
<2H, t, Jˆ7.9 Hz, 3-H), 2.38 <2H, quintet with ®ne coupling,
Jˆca. 7.7 Hz, 2-H), 1.39 <3H, t, Jˆ7.1 Hz, CO2CH2CH3);
dC <100 MHz; CDCl3) 173.2 <quinolone CvO), 166.0 <ester
2
1
CvO), 160.2 <C-3a), 153.3 <dd, JCFˆ15.2 Hz and JCFˆ
2
1
256.1 Hz, C-7 or C-8), 148.1 <dd, JCFˆ13.3 Hz and JCFˆ
250.0 Hz, C-7 or C-8), 134.6 <d, 3JCFˆ9.5 Hz, C-9a), 124.0
2
<C-5a), 115.1 <d, JCFˆ18.7 Hz, C-6 or C-9), 109.3 <C-4),
2
104.6 <d, JCFˆ21.9 Hz, C-6 or C-9), 60.7 <CO2CH2CH3),
51.3 <C-1), 33.2 <C-3), 20.4 <C-2), 14.3 <CO2CH2CH3); m/z
<EI) 293 <M1, 15%), 248 <M12OCH2CH3, 33), 222 <15),
221 <100), 220 <M12CO2CH2CH3, 10), 69 <18), 41 <11), 28
<23). HRMS Found: M1, 293.0858. C15H13F2NO3 requires
M, 293.0863.
3.9.3. 9-Methyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]-
quinoline-4-carboxylic acid .22c). According to the
general procedure, 22c <344 mg, 96%) was obtained from
ethyl 9-methyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quino-
line-4-carboxylate <20c) <399 mg, 1.47 mmol); colourless
needles, mp 297±2988C <from DMF); nmax/cm21 <KBr)
3413 <br, OH), 1711 <s), 1599 <s), 1542 <s), 1514 <m),
1488 <s), 1463 <m), 1416 <m), 1276 <w), 1110 <w), 976
<2), 796 <m); dH <200 MHz; D2O/NaOD) 7.98 <1H, d, Jˆ
7.7 Hz, 6-H), 7.26±7.10 <2H, m, 7-H, 8-H), 4.57 <2H, br t,
Jˆ7.1 Hz, 1-H), 3.18 <2H, t, Jˆ7.8 Hz, 3-H), 2.49 <3H, s,
Ar±CH3), 2.22 <2H, quintet with ®ne coupling, Jˆca.
7.4 Hz, 2-H); dC <50 MHz; D2O/NaOD) 177.0 and 176.0
<2£CvO), 166.4, 159.2, 140.9, 138.9, 129.8, 129.2,
126.7, 126.5, 121.1, 59.2 <C-1), 33.7 <C-3), 25.4 <Ar±
CH3), 24.3 <C-2); m/z <EI) 243 <M1, 28%), 224 <10), 200
<15), 199 <100, M12CO2), 198 <10), 171 <14), 170 <13).
HRMS Found: M1, 243.0911. C14H13NO3 requires M,
243.0895. Anal. Found: C, 68.87; H, 5.43; N, 5.59.
C14H13NO3 requires C, 69.12; H, 5.39; N, 5.76%.
3.9. General procedure for the preparation of 5-oxo-
1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic
acids 22 from esters 20
A mixture of the appropriate ethyl 5-oxo-1,2,3,5-tetrahydro-
pyrrolo[1,2-a]quinoline-4-carboxylate 20 <0.15±1.50 mmol
scale) and aqueous 1M NaOH solution <10±20 cm3) was
heated to 80±1008C, and maintained in this temperature
range for 1 h. The reaction mixture was allowed to cool,
and then acidi®ed to pH ca. 4 with concentrated HCl. The
precipitate that formed was ®ltered and washed with
copious quantities of with water. Drying in a desiccator
yielded essentially pure 5-oxo-1,2,3,5-tetrahydropyrrolo-
[1,2-a]quinoline-4-carboxylic acids 22. The products
could be recrystallised from DMF for microanalysis, but
owing to their generally poor solubility in other organic
solvents, NMR spectra were recorded on the sodium salts
<prepared in situ in NaOD/D2O solution) in all cases other
than 22a. The following 10 compounds were prepared by
the general procedure.
3.9.4. 8-Methyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]-
quinoline-4-carboxylic acid .22d). According to the
general procedure, 22d <104 mg, 87%) was obtained from
ethyl 8-methyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quino-
line-4-carboxylate <20d) <133 mg, 0.49 mmol); beige
powder, mp 272±2738C decomp. <from DMF); nmax/cm21
3.9.1. 6,9-Dimethoxy-5-oxo-1,2,3,5-tetrahydropyrrolo-
[1,2-a]quinoline-4-carboxylic acid .22a). According to

9646
J. P. Michael et al. / Tetrahedron 57 (2001) 9635±9648
<KBr) 3443 <br, OH), 1693 <s), 1622 <m), 1601 <s), 1520 <s),
1438 <s), 1286 <m), 1097 <m), 960 <w), 809 <s); dH
<400 MHz; D2O/NaOD) 8.02 <1H, d, Jˆ8.4 Hz, 6-H), 7.23
<1H, d, Jˆ8.4 Hz, 7-H), 7.18 <1H, s, 9-H), 4.23 <2H, t, Jˆ
7.4 Hz, 1-H), 3.28 <2H, t, Jˆ7.8 Hz, 3-H), 2.40 <3H, s,
Ar±CH3), 2.33 <2H, quintet with ®ne coupling, Jˆca.
7.7 Hz, 2-H); dC <50 MHz; D2O/NaOD) 177.3 and 176.6
<2£CvO), 167.6, 157.9, 146.6, 140.5, 128.7, 127.7,
125.3, 120.6, 118.8, 54.0 <C-1), 34.3 <C-3), 23.6 and 22.9
<Ar±CH3, C-2); m/z <EI) 243 <M1, 14%), 200 <15), 199
<100, M12CO2), 198 <13), 170 <12). HRMS Found: M1,
243.0890. C14H13NO3 requires M, 243.0895.
254 <12), 229 <100, M12CO2), 228 <M12CO2H), 114 <11).
HRMS Found: M1, 273.0642. C14H11NO5 requires M,
273.0637. Anal. Found: C, 61.43; H, 4.03; N, 4.78.
C14H11NO5 requires C, 61.54; H, 4.06; N, 5.13%.
3.9.8. 9-Bromo-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]-
quinoline-4-carboxylic acid .22h). According to the
general procedure, 22h <45 mg, 100%) was obtained from
ethyl 9-bromo-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quino-
line-4-carboxylate <20h) <49 mg, 0.15 mmol); colourless
needles, mp 265±2668C decomp. <from DMF); nmax/cm21
<KBr) 3413 <br, OH), 1714 <s), 1580 <m), 1528 <m), 1514
<m), 1481 <m), 1458 <m), 1440 <s), 1414 <m), 1094 <m), 784
<m), 745 <w); dH <200 MHz; D2O/NaOD) 8.00 <1H, dd,
Jˆ8.1 and 1.2 Hz, 8-H), 7.70 <1H, dd, Jˆ7.6 and 1.2 Hz,
6-H), 7.00 <1H, t, Jˆca. 7.9 Hz, 7-H), 5.05±4.50 <m, over-
lapping 1-H and H2O), 3.14 <2H, t, Jˆ7.8 Hz, 3-H), 2.18
<2H, quintet with ®ne coupling, Jˆca. 7.4 Hz, 2-H); dC
<50 MHz; D2O/NaOD) 176.7 and 176.2 <2£CvO), 169.3,
160.2, 142.1, 139.4, 130.7, 128.4, 127.4, 121.9, 111.2, 60.1
<C-1), 33.8 <C-3), 24.4 <C-2). Anal. Found: C, 50.39; H,
3.03; N, 4.56: C13H10NO3Br requires C, 50.67; H, 3.27; N,
4.55%.
3.9.5. 7-Methyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]-
quinoline-4-carboxylic acid .22e). According to the
general procedure, 22e <165 mg, 92%) was obtained from
ethyl 7-methyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quino-
line-4-carboxylate <20e) <199 mg, 0.73 mmol); off-white
powder, mp 244±2458C; nmax/cm21 <KBr) 3413 <br, OH),
1718 <s), 1600 <s), 1536 <s), 1463 <s), 1287 <m), 812 <m); dH
<400 MHz; D2O/NaOD) 7.90 <1H, s with ®ne coupling,
6-H), 7.45 <1H, dd, Jˆ1.7 and 8.6 Hz, 8-H), 7.24 <1H, d,
Jˆ8.6 Hz, 9-H), 4.20 <2H, t, Jˆ7.5 Hz, 1-H), 3.26 <2H, t,
Jˆ7.9 Hz, 3-H), 2.41 <3H, s, Ar±CH3), 2.31 <2H, quintet
with ®ne coupling, Jˆca. 7.7 Hz, 2-H); dC <100 MHz; D2O/
NaOD) 175.3 and 174.9 <2£CO), 167.0, 155.9, 136.7, 135.6,
134.8, 125.7, 125.3, 119.0, 117.5, 52.3 <C-1), 32.6 <C-3), 21.2
and 21.1 <Ar±CH3, C-2). Anal. Found: C, 69.43; H, 5.51; N,
5.84. C14H13NO3 requires C, 69.12; H, 5.39; N, 5.76%.
3.9.9. 7,8-Di¯uoro-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]-
quinoline-4-carboxylic acid .22i). According to the
general procedure, <359 mg, 91%) was obtained from
ethyl 7,8-di¯uoro-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]-
quinoline-4-carboxylate <20i) <439 mg, 1.50 mmol); pale
yellow powder, mp 269±2708C decomp. <from DMF);
3.9.6. 7-Methoxy-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]-
quinoline-4-carboxylic acid .22f). According to the
general procedure, 22f <160 mg, 81%) was obtained from
ethyl 7-methoxy-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]-
quinoline-4-carboxylate <20f) <219 mg, 0.76 mmol); white
powder, mp 225±2278C <from DMF); nmax/cm21 <KBr)
3423 <br, OH), 1712 <s), 1601 <s), 1537 <s), 1481 <s), 1459
<s), 1282 <s), 1234 <m), 1024 <m), 814 <m); dH <400 MHz;
D2O/NaOD) 7.40 <1H, d, Jˆ2.6 Hz, 6-H), 7.22 <1H, d,
Jˆ9.2 Hz, 9-H), 7.12 <1H, dd, Jˆ2.6 and 8.6 Hz, 8-H),
4.18 <2H, t, Jˆ7.4 Hz, 1-H), 3.83 <3H, s, OCH3), 3.25
<2H, t, Jˆ7.8 Hz, 3-H), 2.29 <2H, quintet with ®ne coupling,
Jˆca. 7.6 Hz, 2-H); dC <50 MHz; D2O/NaOD) 176.5 and
176.4 <2£CvO), 169.5, 158.2, 157.0, 135.2, 128.6, 124.6,
121.1, 120.1, 107.7, 58.2 <OCH3), 54.2 <C-1), 34.3 <C-3),
22.8 <C-2). Anal. Found: C, 64.93; H, 5.05; N, 5.44.
C14H13NO4 requires C, 64.86; H, 5.06; N, 5.40%.
n
max/cm21 <KBr) 3450 <br, OH), 1716 <s), 1608 <s), 1505
<s), 1491 <s), 1480 <s), 1285 <s), 1246 <s), 1104 <m), 973 <m),
930 <m), 813 <m), 786 <s), 606 <m); dH <400 MHz; D2O/
NaOD) 7.87 <1H, dd, J6,7-Fˆ11.0 Hz and J6,8-Fˆ8.6 Hz,
6-H), 7.87 <1H, dd, J9,8-Fˆ11.5 Hz and J9,7-Fˆ6.7 Hz,
9-H), 4.27 <2H, t, Jˆ7.5 Hz, 1-H), 3.31 <2H, t, Jˆ7.9 Hz,
3-H), 2.37 <2H, quintet with ®ne coupling, Jˆca. 7.5 Hz,
2-H). Anal. Found: C, 58.76; H, 3.46; N, 5.30: C13H9F2NO3
requires C, 58.87; H, 3.42; N, 5.28%.
3.9.10. 6-Methyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]-
quinoline-4-carboxylic acid .22j). According to the
general procedure, 22j <193 mg, 89%) was obtained from
ethyl 6-methyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quino-
line-4-carboxylate <20j) <242 mg, 0.89 mmol); white
powder, mp 263±2648C decomp. <from DMF); nmax/cm21
<KBr) 3414 <br, OH), 1714 <s), 1599 <s), 1540 <s), 1455 <s),
1277 <s), 1251 <m), 1157 <m), 994 <m), 820 <m), 791 <m),
767 <m); dH <400 MHz; D2O/NaOD) 7.43 <1H, t, Jˆca.
7.9 Hz, 8-H), 7.15 <1H, d, Jˆ7.6 Hz, 7-H or 9-H), 7.07
<1H, d, Jˆ8.4 Hz, 7-H or 9-H), 4.17 <2H, t, Jˆ7.4 Hz,
1-H), 3.22 <2H, t, Jˆ7.9 Hz, 3-H), 2.81 <3H, s, Ar±CH3),
2.30 <2H, quintet with ®ne coupling, Jˆca. 7.6 Hz, 2-H); dC
<100 MHz; D2O/NaOD) 178.6 and 175.4 <2£CvO), 166.6,
154.2, 141.2, 140.2, 132.3, 127.7, 124.5, 120.8, 115.5, 52.6
<C-1), 32.0 <C-3), 24.0 <Ar±CH3), 21.0 <C-2). Anal. Found:
C, 69.25; H, 5.37; N, 5.81. C14H13NO3 requires C, 69.12; H,
5.39; N, 5.76%.
3.9.7.
7,8-Methylenedioxy-5-oxo-1,2,3,5-tetrahydro-
pyrrolo[1,2-a]quinoline-4-carboxylic acid .22g). Accord-
ing to the general procedure, 22g <82 mg, 69%) was
obtained from ethyl 7,8-methylenedioxy-5-oxo-1,2,3,5-
tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acid <20g)
<132 mg, 0.44 mmol); white powder, mp .3158C <from
DMF); nmax/cm21 <KBr) 3462 <br, OH), 1702 <s), 1626
<s), 1551 <s), 1498 <s), 1438 <s), 1279 <s), 1243 <s), 1105
<m), 1028 <s), 927 <m), 812 <m); dH <400 MHz; D2O/NaOD)
7.46 <1H, s, 6-H), 6.91 <1H, s, 9-H), 6.09 <2H, s, OCH2O),
4.28 <2H, t, Jˆ7.4 Hz, 1-H), 3.27 <2H, t, Jˆ7.8 Hz, 3-H),
2.35 <2H, quintet with ®ne coupling, Jˆca. 7.6 Hz, 2-H); dC
<100 MHz; D2O/NaOD) 175.0 and 174.3 <2£CvO), 167.8,
154.4, 153.0, 146.8, 136.5, 121.6, 118.8, 103.5, 102.9, 96.8,
53.1 <C-1), 32.4 <C-3), 21.3 <C-2); m/z <EI) 273 <M1, 31%),
3.9.11. 7-Fluoro-8-.4-methylpiperazin-1-yl)-5-oxo-1,2,3,5-
tetrahydropyrrolo[1,2-a]quinoline-3-carboxylic acid .8).
A mixture of 7,8-di¯uoro-5-oxo-1,2,3,5-tetrahydropyrrolo-
[1,2-a]quinoline-4-carboxylic acid <22i) <87 mg, 0.33

J. P. Michael et al. / Tetrahedron 57 (2001) 9635±9648
9647
mmol) and N-methylpiperazine <2 cm3) was stirred under
a N2 atmosphere at ca. 658C for 48 h. Excess N-methyl-
piperazine was removed under reduced pressure to leave a
solid yellow residue, to which was added aqueous HCl
<0.1 M; 6 cm3). The solid precipitate was ®ltered, washed
with H2O <10 cm3) and dried in a desiccator to yield the
hydrochloride salt of the title compound 8 <34 mg, 27%)
as a yellow powder, mp .2508C <lit.20 .2508C); dH
<200 MHz; CF3CO2H) 8.29 <1H, d, J6,Fˆ12.4 Hz, 6-H),
7.35 <1H, d, J9,Fˆ6.5 Hz, 9-H), 4.93 <2H, br t, Jˆca.
7.4 Hz, 1-H), 4.27±4.18 <2H, m, NCH2), 4.11 <2H, br t,
Jˆca. 7.6 Hz, 3-H), 3.96±3.90 <2H, m, NCH2), 3.75±3.50
<4H, m, NCH2), 2.11 <2H, br quintet, Jˆca. 7.3 Hz, 2-H).
The NMR spectroscopic data agree with those reported in
the literature.20
17. Chu, D. T. W.; Fernandes, P. B. Adv. Drug Res. 1991, 21, 39±
144.
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Acknowledgements
23. Michael, J. P.; de Koning, C. B.; Stanbury, T. V. Tetrahedron
Lett. 1996, 37, 9403±9406.
We thank the National Research Foundation, Pretoria, the
University of the Witwatersrand, and the UK/RSA Science
and Technology Fund for providing the funding for
this research. We are grateful to Dr P. R. Boshoff <Cape
Technikon) and Mrs S. Heiss <University of the Witwaters-
rand) for mass spectra and NMR spectra, respectively, and
to Professor I. Moodley and his staff <Department of
Pharmacy, University of the Witwatersrand) for the anti-
microbial testing.
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