The first entry to pyrrolo[2,3-c]quinoline-2,4(3aH,5H)-diones

Article abstract of DOI:10.1016/j.tet.2008.02.063

Wittig olefination of 3-aminoquinoline-2,4(1H,3H)-diones 1 with ethyl (triphenylphosphoranylidene)acetate (Ph₃P{double bond, long}CHCO₂Et) afforded (E)-3-amino-4-ethoxycarbonylmethylene-1,2,3,4-tetrahydro-2-quinolones (E)-2 and pyrrolo[2,3-c]quinoline-2,4(3aH,5H)-diones 3. An alternative approach for the synthesis of 3 via 3-bromoacetamidoquinoline-2,4(1H,3H)-diones 7, their corresponding triphenylphosphonium salts 8, and ylides A that undergo intramolecular Wittig reaction, was investigated. Under the applied reaction conditions, the phosphonium salts 8 and ylides A are so unstable that they partly decompose to 3-acetamidoquinoline-2,4(1H,3H)-diones 9 during the synthesis of 3.

Full text of DOI:10.1016/j.tet.2008.02.063

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4387e4402
www.elsevier.com/locate/tet
The first entry to pyrrolo[2,3-c]quinoline-2,4(3aH,5H)-diones
a
a
a
Stanislav Kafka a, , Antonın Klasek , Jirı Polis , Veronika Rosenbreierova ,
*
Ctibor Palık , Vladimır Mrkvicka , Janez Kosmrlj
´
´
ˇ´
´
a
a
b,
*
´
´
ˇ
ꢀ
a Department of Chemistry, Faculty of Technology, Tomas Bata University in Zlin, 762 72 Zlin, Czech Republic
b Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia
Received 16 July 2007; received in revised form 5 February 2008; accepted 21 February 2008
Available online 26 February 2008
ˇ
Dedicated to Professor Miha Tisler
Abstract
Wittig olefination of 3-aminoquinoline-2,4(1H,3H)-diones 1 with ethyl (triphenylphosphoranylidene)acetate (Ph3P]CHCO2Et) afforded
(E)-3-amino-4-ethoxycarbonylmethylene-1,2,3,4-tetrahydro-2-quinolones (E)-2 and pyrrolo[2,3-c]quinoline-2,4(3aH,5H)-diones 3. An alterna-
tive approach for the synthesis of 3 via 3-bromoacetamidoquinoline-2,4(1H,3H)-diones 7, their corresponding triphenylphosphonium salts 8,
and ylides A that undergo intramolecular Wittig reaction, was investigated. Under the applied reaction conditions, the phosphonium salts 8
and ylides A are so unstable that they partly decompose to 3-acetamidoquinoline-2,4(1H,3H)-diones 9 during the synthesis of 3.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Pyrrolo[2,3-c]quinolones; Quinolinones; Wittig olefination; Mechanism; NMR
1. Introduction
subsequent lactamization might afford the corresponding
pyrrolo[2,3-c]quinoline-2,4(3aH,5H)-diones.
As a part of our continued interest in the reactivity of quin-
oline-2(1H)-ones,1e5 we have reported their transformations
to several c-fused derivatives of [1,3]thiazolo[5,4-c]quinolin-
In general, very few synthetic procedures leading to pyr-
rolo[2,3-c]quinolones have been reported,6 despite the fact
that this ring system occurs in certain pharmacologically ac-
tive compounds.7 To the best of our knowledge, however, there
are no reports in the literature for pyrrolo[2,3-c]quinoline-
2,4(3aH,5H)-diones.
4(5H)-one,1e
imidazo[4,5-c]quinolin-4(5H)-one,3
furo
[3,4-c]quinoline-3,4(1H,5H)-dione,1h and furo[2,3-c]quinolin-
4(5H)-one1g,4 ring systems. The furo[2,3-c]quinolin-4(5H)-
one skeleton, for example, has been the result of C-4 Wittig
olefination of 3-hydroxyquinoline-2,4(1H,3H)-dione with
ethyl (triphenylphosphoranylidene)acetate (Ph3P]CHCO2Et)
and subsequent lactonization. An alternative approach via
intramolecular Wittig reaction has also been shown.5 The
smooth reactivity of 3-hydroxyquinoline-2,4(1H,3H)-diones
stimulated our interest in further studies on the closely related
3-aminoquinoline-2,4(1H,3H)-diones, for which we expected
that the C-4 Wittig olefination with Ph3P]CHCO2Et and
2. Results and discussion
Starting 3-butylamino and 3-aminoquinoline-2,4(1H,3H)-
diones 1 used in this work were prepared by literature
procedures.2 Wittig reactions of 1 with Ph3P]CHCO2Et
were conducted in boiling xylene (z140 ꢀC). In most cases,
two types of products were formed and were isolated from
the reaction mixtures, the desired pyrrolo[2,3-c]quinoline-
2,4(3aH,5H)-diones 3 and (E)-4-ethoxycarbonylmethylene-
3-amino-1,2,3,4-tetrahydroquinoline-2-ones, (E)-2 (Scheme
1, Table 1). Considerable quantities of starting material 1
remained unconsumed and were recovered. Unfortunately,
* Corresponding authors. Fax: þ420 57 72 10 172 (S.K.); fax: þ386 1 241
9220 (J.K.).
E-mail addresses: kafka@ft.utb.cz (S. Kafka), janez.kosmrlj@fkkt.uni-lj.si
ˇ
(J. Kosmrlj).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.063

4388
S. Kafka et al. / Tetrahedron 64 (2008) 4387e4402
EtO2C
NHR3
R2
N
O
O
R1
NHR3
R2
(E)-2
Ph3P=CHCO2Et
- Ph3PO
(path a)
+
N
O
CO2Et
NHR3
R2
R1
1
N
O
O
N
R1
- EtOH
(Z)-2
R3
R2
O
Ph3P
N
C O
N
R2
R1
O
R3
3
Ph3P=CHCO2Et
- Ph3PO
- EtOH
(path b)
N
O
R1
A
Scheme 1.
attempts to force the transformation forward and to increase
the yields of 3 were rather unsuccessful. Prolonged reaction
times resulted mostly in complex mixtures of products (entries
8 and 9, Table 1), and elevating the reaction temperature by
changing the solvent from xylene to boiling decane
(z174 ꢀC) or cymene (z177 ꢀC) had no desired effect
(compare entries 2e4, Table 1).
reaction of the intermediately formed ylide A (path b) via
transamination cannot be ruled out.
As seen from Table 1, the choice of R3 substituent in
compounds 1 mostly affected the outcome of the reaction
with Ph3P]CHCO2Et. In general, the yields of both 2 and 3
decreased when R3 was changed from H to the bulkier n-butyl
group.
It could be expected that the Wittig olefination of 1 initially
affords both (E)-2 and (Z)-2, and that the latter, under the
applied reaction conditions spontaneously lactamizes to 3
(Scheme 1, path a). Alternatively, an intramolecular Wittig
The transformations of 1 to 3 were accompanied by the
formation of byproducts, and in a few cases we were success-
ful in isolating and identifying these byproducts (Chart 1,
Table 1, entries 7e9).
Moderate yields of the desired pyrrolo[2,3-c]quinoline-
2,4(3aH,5H)-diones 3 obtained from 1 and Ph3P]CHCO2Et
prompted us to search for an alternative approach, via an intra-
molecular Wittig reaction shown in Scheme 2.
Table 1
Reaction of 1aek with Ph3P]CHCO2Et
The bromoacetamide derivatives 7 were obtained in
relatively good yields from amines 1 and bromoacetyl bromide
in benzene by using potassium carbonate as a base (Table 2).
An exception was 1e, which under the above reaction condi-
tions did not react at all. Changing the reaction conditions to
tetrahydrofuran as solvent and triethylamine as base at room
temperature, the bromoacetylation of 1e was extremely slow
(2 days) and was accompanied by the consumption of large
quantities of bromoacetyl bromide and triethylamine (see Sec-
tion 3). Along with bromoacetamide 7e (43% yield, Table 2,
Entry
1
Substituents
Solvent Time Product,
(h)
yielda (%)
1b
14 37 23
R1
R2
R3
H
2
3
Other
1
2
3
4
5
6
7
8
9
a
H
H
n-C4H9
Xylene
5
7
6
7
4
4
6
b
n-C4H9 n-C4H9 Xylene
Decane
Cymene
89
7
3
d
d
67 24
47 14
c
d
e
H
H
H
CH2Ph
CH2Ph
Ph
H
Xylene
n-C4H9 Xylene
Xylene
20 35 32
9 d
11 42
4
9
H
5e (6)
5e (8)
4f (9),
5f (8),
6f (22)
Xylene 36
n-C4H9 Xylene 58
d
d
31
d
d
d
f
H
Ph
OH
Bu
N
R3
N
Ph
Ph
O
Bu
10
11
12
13
14
a
g
h
i
CH3
CH3
Ph
Ph
Ph
H
Xylene
n-C4H9 Xylene
Xylene
4
4
6
29 27 10
21 54 10
N
O
O
Ph
CH3
CH3
H
d
2
29
2
14c
9
10
d
N
H
O
N
O
N
j
Ph
n-C4H9 Xylene 10
n-C4H9 Decane 21
O
H
H
k
CH2Ph Ph
d
5e; R3 = H
4f
6f
5f; R3 = Bu
Yield of isolated and re-crystallized products is given.
Recovered starting material.
Isolated as the hydrochloride salt.
b
c
Chart 1.

S. Kafka et al. / Tetrahedron 64 (2008) 4387e4402
4389
COCH2Br
R3
R2
COCH2PPh3
O
O
-
Br
N
N R3
R2
BrCH2COBr
base/solvent
room temp.
Ph3P
solvent
NaOH
1
3
N
O
N
O
reflux
R1
R1
7
8
Scheme 2.
entry 5), we isolated from the reaction mixture large amounts
of 4-bromobutyl bromoacetate, which was a result of reaction
between tetrahydrofuran and bromoacetyl bromide.8,9 The low
reactivity of amine 1e in tetrahydrofuran is remarkable as other
amines tested (1f and 1i) transformed to the corresponding
bromoacetamides (7f and 7i) much faster, and consequently,
lower excesses of bromoacetyl bromide were required. For the
preparation of 7e from 1e, a dichloromethane/triethylamine
system (Table 2, entry 8) finally gave acceptable results in terms
of both reaction time and yield.
The phosphonium salts 8 were then prepared by heating
bromoacetamides 7 and triphenylphosphine in boiling benzene
(Scheme 2, Table 3). Along with compounds 8, we isolated
substantial amounts of acetamides 9. The fact that during
the isolation workup some phosphonium salts 8 spontaneously
eliminated HBr, accompanied by the formation of 9, indicated
high acidity of the PCH2 methylene protons and facile
formation of ylide A. The addition of a water molecule (ambi-
ent moisture) to A likely gives intermediate B and finally
acetamide 9, as shown in Scheme 3.10
Interestingly, in those instances where R3 was the n-butyl
moiety, the phosphonium salts 8 also formed (vide infra),
but were so reactive that we were unable to isolate them
from the reaction mixtures. Any attempt to isolate 8b,d,h,j
resulted in complete conversion to acetamides 9b,d,h,j. The
exception was 8f. Under the above reaction conditions, com-
pound 7e did not form phosphonium salt 8e. Better results
were obtained when the reaction was conducted in boiling
1,4-dioxane (See Table 3 and Section 3).
Table 2
Synthesis of bromoacetamides 7aej from 1
Entry Product 7 Substituents
Base/solvent
Time (h) Yielda (%)
R1 R2
R3
H
1
a
b
c
H
H
H
H
H
n-C4H9
K2CO3/benzene 2
74
72
86
74
43
69
22
27
53
92
44
36
2
n-C4H9 n-C4H9 K2CO3/benzene 2
CH2Ph H K2CO3/benzene 2
CH2Ph n-C4H9 K2CO3/benzene 2
3
4
d
e
b
5
Ph
H
Et3N/THF
Et3N/CH2Cl2
b
6
7
f
H
Ph
n-C4H9 K2CO3/benzene 2
b
8
Et3N/THF
K2CO3/benzene 2
9
g
h
i
CH3 Ph
CH3 Ph
H
n-C4H9 K2CO3/benzene 2
10
11
12
a
The above discussed reactivity of phosphonium salts 8 was
unexpected as during the synthesis of analogous furo[2,3-c]-
quinoline-2,4(3aH,5H)-diones via intramolecular Wittig reac-
tion of 80, using the same reaction and workup procedures, the
corresponding hydrolytic products 90 were not observed at all.5
In the last step of the transformation, either the isolated
phosphonium salts (8a,c,e,f,g,i) or the in situ formed com-
pounds (8b,d,h,j) were transformed to the ylides in a two-phase
chloroform/aq NaOH system. The ylides spontaneously trans-
formed further to pyrrolo[2,3-c]quinoline-2,4(3aH,5H)-diones
3. The reactions were generally accompanied by the formation
of 9, confirming the mechanism in Scheme 3 (Table 4).
b
Ph CH3
Ph CH3
H Et3N/THF
n-C4H9 K2CO3/benzene 2
j
Yield of isolated and re-crystallized products is given.
For details, see Section 3.
b
Table 3
Synthesis of phosphonium salts 8a,c,eeg,i from 7
Educt 7
Solvent
Time (h)
Product, yielda (%)
8
Other
a
c
e
f
Benzene
Benzene
1,4-Dioxane
Benzene
Benzene
Benzene
6
6
72
48
62
24
52
26
9c (9)
13
4.5
6
1
Analyses of IR, H, and 13C NMR spectra and in some
1
cases NOE, 2D NMR (1He1H COSY, He13C HMQC, and
g
i
9g (22)
9i (29), 3i (3)
8
HMBC), mass spectra, and CHN elemental analyses con-
firmed the structures of compounds under investigation.
a
Yield of isolated and re-crystallized products is given.
-
O
C
H
C
H
Br
PPh3
O H OH
O H
C C PPh3
O
C
H2O
R4
R4
C
C
H
PPh3
R4
R4
CH3
-HBr
O
- Ph3PO
8
A
B
9
O
N
R3
R2
O
R2
8-9: R4 =
8'-9': R4 =
N
O
N
O
R1
R1
Scheme 3.

4390
S. Kafka et al. / Tetrahedron 64 (2008) 4387e4402
Table 4
Synthesis of 3 by intramolecular Wittig reaction
Table 5
Independent preparation of acetamides 9 from 1
Entry
Educt
Methodb
Product, yielda (%)
9
Solvent
Temperature
Time (h)
Yielda (%)
3
9
a
b
c
d
e
f
Py
Py
rt
6
6
6
1
83
62
82
78
68
67
96
75
70
70
62
rt
1
2
3
4
5
6
7
8
9
a
8a
7b
8c
7d
8e
8f
A
B
A
B
A
A
A
B
B
52
25
88
39
51
28
62
12
d
10
68
9
Py
Py
rt
60 ꢀC
Reflux then rt
Toluene
Toluene, Py
Py
4 and then 4
b
25
d
d
5
b
g
h
i
60 ꢀC
60 ꢀC
60 ꢀC
b
1
1
Py
Py
8g
7h
7j
1
b
69
60
i
Toluene
Toluene
b
j
rt
Yield of isolated and re-crystallized products is given.
Method A: 8, aq NaOH/CHCl3, 5 min. Method B: 7, Ph3P, benzene, reflux
4 h then NaOH/CHCl3, 5 min (one pot).
a
Yields of isolated and re-crystallized products are given.
For details, see Section 3.
b
b
isocyanate mechanism has been previously suggested for the
rearrangement of furo[2,3-c]quinoline-2,4(3aH,5H)-diones to
furo[3,4-c]quinoline-3,4(1H,5H)-diones.1a,h Another byprod-
uct was isolated from the reaction of 1f (Scheme 1, Table 1),
and the structure of 5f was assigned as the most plausible to it.
Mechanistically, the formation of pyrrolo[3,4-c]quinoline-
3,4(2H,5H)-diones 5 is conceivable by the aerial oxidation of
4, as further depicted in Scheme 5. The easiness with which
the oxidation of 4f takes place is demonstrated by NMR experi-
ment in which during 13C NMR measurement, in 12 h period of
time, approximately 50% of 4f transformed into 5f.
Ring expansion of a 3-aminoquinoline-2,4(1H,3H)-dione
derivative to the corresponding diazepine has previously been
documented by Podesva and co-workers11 and explained by
C-3/C-4 bond cleavage and subsequent lactamization mecha-
nism. An alternative to the latter, which could also account for
the formation of 6f from 1f, is suggested in Scheme 6. The
structure of compound 6f was confirmed by independent synthe-
sis starting from isatoic anhydride as shown in Scheme 7.
In conclusion, we have reported the synthesis of
pyrrolo[2,3-c]quinoline-2,4(3aH,5H)-diones, based on intra-
and intermolecular Wittig olefination of 3-aminoquinoline-
2,4(1H,3H)-diones. The yields of the products are diminished
due to relatively high reactivity of the intermediates employed
in the reaction sequences, as well as the instability of final
pyrrolo[2,3-c]quinoline-2,4(3aH,5H)-diones. The latter, for
example, rearrange to the isomeric pyrrolo[3,4-c]quinoline-
3,4(2H,5H)-diones. The reactivity of pyrrolo[2,3-c]quinoline-
2,4(3aH,5H)-diones will be the subject of forthcoming
investigations.
Pyrrolo[2,3-c]quinoline-2,4(3aH,5H)-diones 3 show char-
acteristic light blue fluorescence at l 254 and l 366 nm. In
their IR spectra, characteristic absorption bands appear at
1660e1707 and 1597e1609 cmꢁ1 (two lactam groups) and
1600e1608 cmꢁ1 (C]C double bonds). Proton resonance
for H-1 appearing at d 5.91e6.63 ppm (d, J 0e1.2 Hz) and
carbon resonance for C-3a at d 64.8e73.9 are characteristic
of compounds 3. In the HMBC spectrum of pyrrolo[2,3-c]-
quinoline-2,4(3aH,5H)-dione 3f, proton H-1 shows correla-
tions to carbon resonances at d 73.9 (C-3a), 118.3 (C-9a),
155.4 (C-9b), 171.1 (C-2) ppm, as well as weak correlations
to resonances at d 137.2 (C-5a) and 135.6 (C-100) ppm, as
shown in Figure 1.
O
2 N
H
1
H H
9b
9a
5a
3a
1''
N
O
H
Figure 1. Selected HMBC correlations for 3f.
The structures of acetamides 9 were confirmed by spectral
analyses, as well as by independent preparation from 1 with
acetic anhydride (Scheme 4, Table 5). The IR spectra of
compounds 9 are very similar to those of bromoacetamido
derivatives 7 and characteristic absorption bands of C]O
groups appear at 1697e1712 cmꢁ1 in both cases.
R3
NH
R3
N
O
O
COCH3
R2
R2
Ac2O
3. Experimental
N
O
N
O
R1
R1
3.1. General considerations
1
9
Scheme 4.
The melting points were determined on a Kofler block or
Gallenkamp apparatus and are uncorrected. The IR spectra
were recorded on a PerkineElmer 421 and 1310 and Mattson
3000 spectrophotometers using samples in potassium bromide
disks. NMR data were collected on a Bruker Avance DPX 300
spectrometer operating at frequencies 300 MHz (1H), 75 MHz
The suggested mechanism for the formation of isomeric pyr-
rolo[3,4-c]quinoline-3,4(2H,5H)-dione 4f, shown in Scheme 5,
comprises of an addition of carbanion to a transiently formed
isocyanate group and subsequent enolization. An analogous

S. Kafka et al. / Tetrahedron 64 (2008) 4387e4402
4391
O
N
O
Bu
Ph
N
N
Bu
via
Bu
O
[O]
enolization
Ph
O
H
O
4f
5f
Ph
C O
H+
N
H
N
H
N
3f
Scheme 5.
H
N
O
HO
HO
O
Bu
Bu
N
Bu
Ph
Bu
Ph
N
N
Ph
Ph
N
O
N
N
N
H
O
H
O
H
O
H
1f
6f
Scheme 6.
O
O
O
Cl
3 PhCHCOCl
CNH(CH2)3CH
CNH(CH2)3CH3
Cl
1-BuNH2
NaH
O
6f
N
H
O
NH2
NHCOCHPh
Scheme 7.
(13C), and 121 MHz (31P) and equipped with a 5-mm
1H/13C/31P/19F-QNP probehead or 5-mm inverse-detection
probe with z-gradient coil for 2D experiments. Spectra were
recorded at 302 K (unless otherwise indicated). Chemical
shifts are given on the d scale (parts per million) and are
Instrument). Solvents and reagents were used as obtained from
the commercial sources. 3-Aminoquinoline-2,4(1H,3H)-diones
(1aek) were prepared according to the literature procedures.2
3.2. Reaction of 3-aminoquinoline-2,4(1H,3H)-diones (1)
with ethyl (triphenylphosphoranylidene)acetate
1
referenced to internal Me4Si (13C and H) and external neat
H3PO4 (31P). Some 13C chemical shifts are referenced to
DMSO-d6. Coupling constants (J) are given in hertz. Multi-
plicities are indicated as follows: s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), or br (broadened). The
numbering used for the assignment of NMR signals is as
follows: quinolinone skeleton (in 2 and 7e9), pyrroloquinoli-
nedione skeleton (in 3, 4f, 5e, and 5f), and benzodiazepine-
dione skeleton (in 6f), simple figures; phenyl ring, primed
figures; phenyl ring of triphenylphosphonium group, double
primed figures. Structural elucidation and complete assign-
ments of proton and carbon resonances of compounds 2i, 3f,
4f, 5e, 6f, 8a, and 9j were performed by 2D NMR (1He1H
gs-COSY, 1He13C gs-HSQC, gs-HMQC, and gs-HMBC)
spectral analyses. In the 1H spectra of other compounds,
proton resonances of the fused benzene ring were tentatively
assigned on the basis with analogy to 2i, 3f, 8a, and 9j, as
well as our previous experiences on quinolinedione derivativ-
es.1e5 The mass spectra and high-resolution mass spectra were
obtained with a VG-Analytical AutospecQ instrument and
Q-TOF Premier instrument. Data are reported as m/z (relative
intensity). Column chromatography was carried out on Silica
gel 60, particle size 0.063e0.2 mm, 70e230 mesh ASTM
(Fluka). The course of separation and also the purity
of substances were monitored by TLC on AlugramR SIL
G/UV254 foils (MachereyeNagel). Elemental analyses (C,
H, N) were performed with an Elemental Analyzer (Fisons
A mixture of the appropriate 3-aminoquinoline-2,4(1H,3H)-
dione 1 (5 mmol) and ethyl (triphenylphosphoranylidene)ace-
tate (1.9 g, 5.5 mmol) was heated in the solvent (8 mL) at reflux
and for the time indicated in Table 1. After cooling, the crude
reaction mixture was column chromatographed using benzene
and then successive mixtures of benzene/ethyl acetate (in ratios
from 99:1 to 8:2) as eluents to give products 2, 3, 4f, 5e,f, 6f, and
unreacted starting material 1 (compound 2k was oily and was
transformed to its hydrochloride with hydrochloric acid). For
the yields see Table 1. For physical and spectroscopic data for
compounds 2, 3, 4f, 5e,f, and 6f see below.
3.3. Physical and spectroscopic data for (E)-4-ethoxycarbo-
nylmethylene-3-amino-1,2,3,4-tetrahydroquinoline-2-ones (2)
3.3.1. (E)-Ethyl 2-(3-amino-3-butyl-2-oxo-2,3-dihydro-
quinolin-4(1H)-ylidene)acetate (2a)
White solid, mp 103e106 ꢀC (cyclohexane); Rf¼0.15 (33%
acetone in hexane); IR 3374, 3265, 3057, 2956, 2928, 2859,
1700, 1682, 1632, 1612, 1588, 1480, 1373, 1334, 1312, 1235,
1114, 1035, 1021, 920, 873, 844, 763, 751, 685 cmꢁ1; dH
(300 MHz, DMSO-d6) 0.72 (3H, t, J 7.1 Hz, CH3), 1.00e1.42
(6H, m), 1.15 (3H, t, J 7.1 Hz, CH3 of ethyl), 2.03 (2H, br s,
NH2), 4.08 (2H, q, J 7.1 Hz, CH2 of ethyl), 6.40 (1H, s,
]CH), 6.92 (1H, d, J 7.6 Hz, H-8), 6.96 (1H, ddd, J 7.6, 7.6,

4392
S. Kafka et al. / Tetrahedron 64 (2008) 4387e4402
0.9 Hz, H-6), 7.30 (1H, ddd, J 7.6, 7.6, 1.3 Hz, H-7), 7.36 (1H,
dd, J 7.7, 0.9 Hz, H-5), 10.40 (1H, br s, NH); dC (75 MHz,
DMSO-d6) 13.7, 13.8, 21.9, 24.8, 38.2, 59.8, 61.7, 115.0,
116.4, 119.7, 121.6, 129.1, 130.4, 136.1, 150.0, 166.4, 173.1.
Anal. Calcd for C17H22N2O3: C, 67.53; H, 7.33; N, 9.26. Found:
C, 67.56; H, 7.28; N, 9.12.
3.3.5. (E)-Ethyl 2-(3-amino-1-methyl-2-oxo-3-phenyl-2,3-
dihydroquinolin-4(1H)-ylidene)acetate (2g)
White solid, mp 96e105 ꢀC (cyclohexane); Rf¼0.55 (10%
ethanol in chloroform); IR 3366, 3043, 2980, 2936, 1720, 1682,
1640, 1601, 1491, 1468, 1448, 1367, 1363, 1256, 1217, 1158,
1040, 854, 834, 754, 702 cmꢁ1; dH (300 MHz, DMSO-d6) 1.17
(3H, t, J 7.1 Hz, CH3 of ethyl), 3.40 (3H, s, CH3), 4.12 (2H, q,
J 7.1 Hz, CH2 of ethyl), 6.78 (1H, s, ]CH), 6.93 (1H, ddd,
J 7.5, 7.5, 0.8 Hz, H-6), 7.02e7.22 (6H, m, C6H5 and H-8), 7.25
(1H, ddd, J 7.6, 7.6, 1.4 Hz, H-7), 7.32 (1H, dd, J 7.6, 1.4 Hz,
H-5); dC (75 MHz, DMSO-d6) 13.8, 30.4, 60.0, 65.8, 114.9,
117.4, 122.29, 122.33, 125.6, 127.5, 128.3, 129.3, 130.3, 137.5,
141.8, 149.3, 166.1, 170.8; FABMS m/z (%) 337 (Mþþ1, 100),
320 (84), 247 (44), 105 (45). Anal. Calcd for C20H20N2O3: C,
71.41; H, 5.99; N, 8.33. Found: C, 71.21; H, 6.15; N, 8.28.
3.3.2. (E)-Ethyl 2-(3-butyl-3-(butylamino)-2-oxo-2,3-dihydro-
quinolin-4(1H)-ylidene)acetate (2b)
White solid, mp 95e99 ꢀC (hexane); Rf¼0.39 (20% EtOAc
in benzene); IR 3357, 3218, 3075, 2957, 2931, 2870, 1720,
1680, 1620, 1587, 1482, 1465, 1374, 1330, 1248, 1201, 1184,
1161, 773, 757, 689, 661 cmꢁ1; dH (300 MHz, DMSO-d6)
0.73 (3H, t, J 7.0 Hz, CH3), 0.87 (3H, t, J 7.1 Hz, CH3), 1.00e
1.55 (11H, m, 5ꢂCH2, NH), 1.16 (3H, t, J 7.1 Hz, CH3 of ethyl),
2.16e2.42 (2H, m), 4.12 (2H, q, J 7.1 Hz, CH2 of ethyl), 6.33
(1H, s, ]CH), 6.84e6.88 (2H, m, H-6 and H-8), 7.28 (1H,
ddd, J 7.7, 7.7, 1.3 Hz, H-7), 7.35 (1H, dd, J 7.8, 0.9 Hz, H-5),
10.40 (1H, br s, NH); dC (75 MHz, DMSO-d6) 13.68, 13.78,
13.82, 19.8, 22.0, 24.4, 32.4, 38.5, 42.2, 60.0, 67.0, 115.1,
118.0, 118.8, 121.6, 129.2, 130.6, 136.2, 145.7, 167.2, 171.4.
Anal. Calcd for C21H30N2O3: C, 70.36; H, 8.44; N, 7.81. Found:
C, 70.14; H, 8.46; N, 8.07.
3.3.6. (E)-Ethyl 2-(3-(butylamino)-1-methyl-2-oxo-3-phenyl-
2,3-dihydroquinolin-4(1H)-ylidene)acetate (2h)
Yellow oil; Rf¼0.40 (33% EtOAc in hexane); IR 3332, 2956,
2928, 2870, 1720, 1677, 1637, 1601, 1493, 1462, 1446, 1359,
1271, 1210, 1161, 1041, 1033, 940, 850, 753, 702 cmꢁ1; dH
(300 MHz, DMSO-d6) 0.81 (3H, t, J 7.2 Hz, CH3), 1.16 (3H, t,
J 7.1 Hz, CH3 of ethyl), 1.27 (2H, m), 1.38 (2H, m), 2.23 (2H,
m), 2.62 (1H, br t, J 7.1 Hz, NH), 3.37 (3H, s, CH3), 4.12 (2H,
q, J 7.1 Hz, CH2 of ethyl), 6.65 (1H, s, ]CH), 6.94 (1H, ddd,
J 7.5, 7.5, 0.5 Hz, H-6), 7.03e7.28 (7H, m), 7.36 (1H, dd,
J 7.6, 1.4 Hz, H-5); dC (75 MHz, DMSO-d6) 13.7, 13.8, 19.7,
30.2, 32.2, 43.2, 60.1, 70.0, 114.9, 118.4, 122.1, 122.4, 126.9,
127.6, 128.2, 129.5, 130.3, 137.2, 138.6, 147.4, 166.2, 169.5;
EIMS m/z (%) 392 (Mþ, 7), 346 (27), 319 (100), 104 (50);
HREI-MS calcd for C24H28N2O3 392.2100, found 392.2089.
3.3.3. (E)-Ethyl 2-(3-amino-3-benzyl-2-oxo-2,3-dihydro-
quinolin-4(1H)-ylidene)acetate (2c)
White solid, mp 202e204 ꢀC (benzene/cyclohexane);
Rf¼0.40 (33% hexane in EtOAc); IR 3377, 3333, 3050,
3031, 2991, 1694, 1686, 1623, 1585, 1482, 1459, 1376,
1312, 1272, 1214, 1178, 1038, 1031, 891, 864, 836, 811,
764, 710, 700, 690, 645 cmꢁ1; dH (300 MHz, DMSO-d6)
1.11 (3H, t, J 7.0 Hz, CH3), 2.00 (2H, br s, NH2), 2.65 and
2.72 (2H, 2d, J 13.0 Hz, CH2 of benzyl), 4.05 (2H, q,
J 7.0 Hz, CH2 of ethyl), 6.12 (1H, s, ]CH), 6.90e7.27 (7H,
m, H-6, H-8 and phenyl), 7.36 (1H, m, H-7), 7.42 (1H, d,
J 7.6 Hz, H-5), 10.58 (1H, br s, NH); dC (75 MHz, DMSO-d6)
13.7, 44.4, 59.8, 62.5, 115.3, 117.3, 119.8, 121.8, 126.6, 127.5,
129.5, 130.2, 130.5, 135.0, 136.1, 148.9, 166.3, 171.9. Anal.
Calcd for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found:
C, 71.52; H, 5.76; N, 8.28.
3.3.7. (E)-Ethyl 2-(3-amino-3-methyl-2-oxo-1-phenyl-2,3-
dihydroquinolin-4(1H)-ylidene)acetate (2i)
Yellowish solid; mp 148e152 ꢀC (cyclohexane); Rf¼0.71
(10% ethanol in chloroform); IR 3369, 3312, 3070, 2986, 2965,
2924, 2901, 2853, 1719, 1686, 1636, 1601, 1498, 1461, 1456,
1376, 1366, 1329, 1303, 1272, 1225, 1201, 1168, 1032, 931,
910, 886, 863, 767, 751, 703, 520, 491 cmꢁ1; dH (300 MHz,
DMSO-d6) 1.19 (3H, t, J 7.1 Hz, CH3 of ethyl), 1.32 (3H, s,
CH3), 2.82 (2H, br s, NH2), 4.13 (2H, q, J 7.1 Hz, CH2), 6.27
(1H, d, J 7.9 Hz, H-8), 6.56 (1H, s, ]CH), 7.05 (1H, ddd,
J 7.5, 7.5, 0.9 Hz, H-6), 7.20e7.26 (3H, m, H-7, H-20, H-60),
7.44e7.52 (2H, m, H-5, H-40), 7.52e7.60 (2H, m, H-30, H-50);
dC (75 MHz, DMSO-d6) 13.8 (CH3CH2), 26.9 (CH3), 59.1 (C-
3), 59.9 (CH2), 115.6 (]CH), 115.9 (C-8), 121.0 (C-4a), 122.4
(C-6), 128.3, 128.7, 129.5 (C-5), 129.9, 130.2, 137.9 (C-10),
138.7(C-8a), 150.5(C-4),166.2(COO), 173.0(C-2). Anal. Calcd
for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found: C, 71.16; H,
6.29; N, 8.25.
3.3.4. (E)-Ethyl 2-(3-amino-2-oxo-3-phenyl-2,3-dihydro-
quinolin-4(1H)-ylidene)acetate (2e)
Off-white solid, mp 155e160 ꢀC (benzene/ethyl acetate);
Rf¼0.51 (5% ethanol in chloroform); IR 3370, 3303, 3284,
3193, 3084, 3058, 2982, 2914, 2869, 1713, 1686, 1648,
1613, 1586, 1577, 1491, 1482, 1450, 1437, 1368, 1339,
1280, 1250, 1221, 1188, 1158, 1106, 1024, 1009, 947, 922,
886, 869, 850, 771, 748, 701, 683, 655 cmꢁ1; dH (300 MHz,
DMSO-d6) 1.17 (3H, t, J 6.9 Hz, CH3), 2.57 (2H, br s,
NH2), 4.12 (2H, q, J 6.9 Hz, CH2), 6.80 (1H, s, ]CH2),
6.80e7.38 (9H, m), 10.71 (1H, br s, H-1); dC (75 MHz,
DMSO-d6) 13.9, 60.1, 65.2, 115.2, 117.9, 120.7, 121.8,
125.8, 127.5, 128.4, 129.2, 130.2, 135.6, 142.0, 149.2,
166.5, 171.4; EIMS m/z (%) 322 (Mþ, 10), 305 (14), 276
(40), 249 (100), 221 (33), 104 (30); HREI-MS calcd for
C19H18N2O3 322.1317, found 322.1320.
3.3.8. (E)-Ethyl 2-(3-(butylamino)-3-methyl-2-oxo-1-phenyl-
2,3-dihydroquinolin-4(1H)-ylidene)acetate (2j)
Yellowish solid; mp 85e91 ꢀC (hexane); Rf¼0.60 (10% eth-
anol in chloroform); IR 3062, 3041, 2967, 2958, 2933, 2871,
1721, 1678, 1638, 1599, 1492, 1456, 1370, 1351, 1322, 1301,
1266, 1253, 1216, 1201, 1182, 1169, 1165, 1147, 1122, 1092,

S. Kafka et al. / Tetrahedron 64 (2008) 4387e4402
4393
1073, 1027, 974, 943, 871, 835, 775, 766, 759, 751, 699, 684,
666, 631, 542, 524, 513, 506, 482, 459, 416 cmꢁ1; dH
(300 MHz, DMSO-d6) 0.84 (3H, t, J 7.0 Hz, CH3), 1.19 (3H, t,
J 7.0 Hz, CH3 of ethyl), 1.22e1.39 (4H, m), 1.39 (3H, s, CH3),
2.37e2.50 (3H, m, NHCH2), 4.15 (2H, q, J 7.0 Hz, CH2 of
ethyl), 6.22 (1H, d, J 8.14 Hz, H-8), 6.44 (1H, s, ]CH), 7.02
(1H, dd, J 7.5, 7.5 Hz), 7.18e7.26 (3H, m), 7.45e7.60 (4H,
m); dC (75 MHz, DMSO-d6) 13.78, 13.80, 19.7, 24.9, 32.3,
42.3, 60.1, 63.8, 115.7, 117.1, 120.2, 122.3, 128.3, 128.9,
129.7, 129.9, 130.3, 137.8, 138.7, 147.8, 166.7, 170.8; EIMS
m/z (%) 392 (Mþ, 3), 346 (31), 319 (100). Anal. Calcd for
C24H28N2O3: C, 73.44; H, 7.19; N, 7.14. Found: C, 73.10; H,
6.91; N, 7.18.
2956, 2930, 2870, 1707, 1661, 1608, 1478, 1468, 1399, 1363,
1344, 1298, 1128, 1032, 867, 851, 760, 750, 6471 cmꢁ1; dH
(300 MHz, DMSO-d6) 0.71 (3H, t, J 7.5 Hz, CH3), 0.70e0.84
(2H, m), 0.93 (3H, t, J 7.4 Hz, CH3), 1.04e1.20 (2H, m),
1.28e1.40 (2H, m), 1.54e1.83 (3H, m), 2.03e2.17 (1H, m),
3.25e3.55 (2H, m), 6.38 (1H, s, H-1), 7.05 (1H, d, J 8.0 Hz,
H-8), 7.12 (1H, dd, J 7.5, 7.5 Hz, H-6), 7.40 (1H, dd, J 7.1,
7.1 Hz, H-7), 7.63 (1H, d, J 7.1 Hz, H-5), 10.49 (1H, br s,
NH); dC (75 MHz, DMSO-d6) 13.6, 13.8, 20.0, 21.3, 23.4,
30.6, 33.9, 41.2, 70.4, 115.7, 116.4, 119.8, 123.1, 126.2,
131.4, 136.7, 153.6, 169.6, 170.4; EIMS m/z (%) 312 (Mþ,
89), 296 (100), 266 (97), 213 (97), 199 (51), 185 (59); HREI-MS
calcd for C19H24N2O2 312.1838, found 312.1846.
3.3.9. (E)-Ethyl 2-(1-benzyl-3-(butylamino)-2-oxo-3-phenyl-
2,3-dihydroquinolin-4(1H)-ylidene)acetate hydrochloride
(2k$HCl)
3.4.3. 3a-Benzyl-3,3a-dihydro-2H-pyrrolo[2,3-c]quinoline-
2,4(5H)-dione (3c)
White solid; mp 315e322 ꢀC (AcOH); Rf¼0.48 (10% etha-
nol in chloroform); IR 3257, 3058, 2977, 2909, 2872, 1692,
1667, 1622, 1606, 1585, 1481, 1437, 1370, 1244, 1228, 1144,
1112, 1036, 969, 871, 779, 745, 683, 636 cmꢁ1; dH (300 MHz,
DMSO-d6) 2.84 and 3.10 (2H, 2d, J 13.1 Hz, CH2), 5.91 (1H,
d, J 1.0 Hz, H-1), 6.88e6.95 (2H, m), 7.09 (1H, d, J 7.9 Hz,
H-6), 7.15e7.22 (4H, m), 7.45 (1H, ddd, J 7.5, 7.5, 1.2 Hz,
H-7), 7.53 (1H, dd, J 7.5, 1.2 Hz, H-9), 8.81 (1H, br s, NH),
10.59 (1H, br s, NH); dC (75 MHz, DMSO-d6) 42.5, 68.2,
116.0, 116.9, 120.6, 123.3, 126.3, 126.9, 127.4, 130.4, 131.4,
132.8, 137.0. Anal. Calcd for C18H14N2O2: C, 74.47; H, 4.86;
N, 9.65. Found: C, 74.27; H, 4.77; N, 9.43.
White solid; mp 172e178 ꢀC (ethanol); IR 3432 (br), 3060,
3032, 2962, 2935, 2873, 2460e2830, 2533, 2421, 2384, 1728,
1686, 1639, 1602, 1495, 1466, 1450, 1382, 1312, 1275, 1225,
1186, 1100, 1029, 992, 862, 771, 725, 695, 609, 548 cmꢁ1; dH
(300 MHz, DMSO-d6) 0.83 (3H, t, J 7.1 Hz), 1.13 (3H, t,
J 7.0 Hz), 1.19e1.33 (2H, m), 1.76 (2H, m), 3.04 (1H, br s), 3.70
(1H, br s), 4.13 (2H, m), 5.33 (2H, m), 6.93e7.40 (15H, m),
10.09 (1H, br s), 11.11 (1H, br s). Anal. Calcd for C30H33ClN2O3:
C, 71.34; H, 6.59; N, 5.55. Found: C, 71.73; H, 6.73; N, 5.58.
Because of low solubility of 2k$HCl, the compound was for
13C NMR measurement freebased by extraction from saturated
aqueous solution of NaHCO3 into dichloromethane. Compound
2k: dC (75 MHz, CDCl3) 13.95, 14.04, 20.3, 32.8, 43.7, 47.9,
60.5, 70.5, 115.4, 119.9, 122.8, 123.6, 126.3, 127.1, 127.8,
128.03, 128.11, 129.0, 129.9, 130.1, 136.6, 137.2, 138.1,
148.0, 167.0, 170.5.
3.4.4. 3a-Benzyl-3-butyl-3,3a-dihydro-2H-pyrrolo[2,3-c]-
quinoline-2,4(5H)-dione (3d)
White solid; mp 220e223 ꢀC (benzene/cyclohexane);
Rf¼0.70 (10% ethanol in chloroform); IR 3028, 2965, 2924,
2862, 1693, 1656, 1605, 1495, 1479, 1358, 1344, 1295,
1157, 1104, 1031, 879, 852, 759, 699, 635 cmꢁ1; dH
(300 MHz, DMSO-d6) 0.95 (3H, t, J 7.3 Hz, CH3), 1.30e
1.45 (2H, m), 1.69e1.86 (2H, m), 2.87 and 3.45 (2H, 2d,
J 13.6 Hz, CH2Ph), 3.40e3.51 and 3.55e3.68 (2H, 2m),
6.12 (1H, s, H-1), 6.76e6.83 (2H, m), 7.10 (1H, d, J 8.0 Hz,
H-6), 7.15e7.23 (4H, m), 7.44 (1H, ddd, J 7.5, 7.5, 0.9 Hz,
H-7), 7.58 (1H, dd, J 7.2, 0.5 Hz, H-9), 10.62 (1H, br s,
NH); dC (75 MHz, DMSO-d6) 13.8, 20.0, 31.1, 42.0, 71.2,
115.9, 116.7, 120.3, 123.3, 126.1, 127.1, 127.6, 128.2,
129.8, 131.4, 132.4, 136.7, 152.8, 168.8, 169.6. Anal. Calcd
for C22H22N2O2: C, 76.28; H, 6.40; N, 8.09. Found: C,
76.41; H, 6.37; N, 7.91.
3.4. Physical and spectroscopic data for pyrrolo[2,3-c]-
quinoline-2,4(5H)-diones 3
3.4.1. 3a-Butyl-3,3a-dihydro-2H-pyrrolo[2,3-c]quinoline-
2,4(5H)-dione (3a)
White solid; mp 265e269 ꢀC (diethyl ether); Rf¼0.50 (10%
ethanol in chloroform); IR 3265, 3144, 3082, 2957, 2932,
1746, 1692, 1676, 1607, 1526, 1477, 1456, 1360, 1300,
1289, 1248, 1172, 962, 872, 823, 760, 744, 642 cmꢁ1; dH
(300 MHz, DMSO-d6) 0.75 (3H, t, J 6.8 Hz, CH3), 1.00e
1.20 (4H, m), 1.40e1.52 and 1.77e1.88 (2H, 2m), 6.21 (1H,
d, J 1.2 Hz, H-1), 7.03 (1H, d, J 8.0 Hz, H-8), 7.11 (1H,
ddd, J 7.5, 7.5, 0.6 Hz, H-6), 7.39 (1H, ddd, J 7.8, 7.8,
1.3 Hz, H-7), 7.62 (1H, dd, J 7.6, 1.0 Hz, H-5), 8.72 (1H, br
s, NH), 10.44 (1H, br s, NH); dC (75 MHz, DMSO-d6) 13.6,
21.7, 24.3, 37.1, 67.8, 115.7, 116.5, 119.5, 122.9, 126.3,
131.4, 137.1, 155.8, 169.5, 171.8; HRESI-MS calcd for
C15H17N2O2 [Mþ1]þ 257.1290, found 257.1295.
3.4.5. 3a-Phenyl-3,3a-dihydro-2H-pyrrolo[2,3-c]quinoline-
2,4(5H)-dione (3e)
White solid; mp 268e278 ꢀC (acetic acid); Rf¼0.67 (10%
ethanol in chloroform); IR 3282, 3147, 3085, 3056, 2988,
2973, 2926, 2909, 2871, 1703, 1697, 1693, 1671, 1668, 1627,
1608, 1479, 1450, 1357, 1301, 1244, 1229, 1158, 1107, 1088,
1033, 975, 946, 915, 869, 833, 782, 751, 714, 695, 683, 643,
567, 494, 464, 431 cmꢁ1; dH (300 MHz, DMSO-d6) 6.44 (1H,
d, J 1.0 Hz, H-1), 6.95 (1H, d, J 8.0 Hz, H-6), 7.08 (1H, ddd,
J 7.5, 7.5, 0.7 Hz, H-8), 7.20e7.39 (6H, m), 7.66 (1H, dd, J 7.5,
3.4.2. 3,3a-Dibutyl-3,3a-dihydro-2H-pyrrolo[2,3-c]-
quinoline-2,4(5H)-dione (3b)
White solid; mp 186e190 ꢀC (benzene/cyclohexane);
Rf¼0.51 (20% EtOAc in benzene); IR 3225, 3126, 3081,

4394
S. Kafka et al. / Tetrahedron 64 (2008) 4387e4402
1.0 Hz, H-9), 9.25 (1H, br s, NH), 10.73 (1H, br s, NH); dC
(75 MHz, DMSO-d6) 70.0, 115.8, 117.5, 120.9, 123.2, 125.5,
126.4, 128.6, 128.9, 131.5, 136.8, 137.3, 155.7, 168.0, 171.6.
Anal. Calcd for C17H12N2O2: C, 73.90; H, 4.38; N, 10.14.
Found: C, 74.18; H, 4.62; N, 9.90.
131.4, 134.6, 137.9, 153.7, 167.2, 170.2; HRESI-MS calcd
for C22H23N2O2 [Mþ1]þ 347.1760, found 347.1771.
3.4.9. 3a-Methyl-5-phenyl-3,3a-dihydro-2H-pyrrolo[2,3-c]-
quinoline-2,4(5H)-dione (3i)
White solid; mp 297e299 ꢀC (AcOH); Rf¼0.56 (10% eth-
anol in chloroform); IR 3339, 3259, 3089, 3065, 2984, 1701,
1692, 1632, 1597, 1492, 1479, 1459, 1370, 1342, 1314,
1279, 1204, 1160, 1135, 970, 931, 858, 765, 754, 740, 709,
642, 585, 504, 444 cmꢁ1; dH (300 MHz, DMSO-d6) 1.56
(3H, s, CH3), 6.32 (1H, d, J 8.9 Hz, H-6), 6.33 (1H, s, H-1),
7.20 (2H, dd, J 7.4, 7.2 Hz), 7.29e7.37 (2H, m), 7.47e7.58
(3H, m), 7.76 (1H, dd, J 6.5, 0.9 Hz, H-9), 8.92 (1H, br s,
NH); dC (75 MHz, DMSO-d6) 25.9, 64.8, 116.6, 117.3,
119.0, 123.5, 126.9, 128.7, 129.1 (br), 130.1 (br), 131.3,
137.6, 139.6, 156.4, 169.2, 171.3. Anal. Calcd for
C18H14N2O2: C, 74.47; H, 4.86; N, 9.65. Found: C, 74.32;
H, 5.08; N, 9.60.
3.4.6. 3-Butyl-3a-phenyl-3,3a-dihydro-2H-pyrrolo[2,3-c]-
quinoline-2,4(5H)-dione (3f)
White solid; mp 195e202 ꢀC (xylene); Rf¼0.46 (10% etha-
nol in chloroform); IR 3211, 3183, 3168, 3117, 3072, 3029,
2963, 2918, 2872, 2858, 1703, 1660, 1609, 1587, 1478, 1447,
1392, 1362, 1339, 1287, 1233, 1190, 1109, 1092, 1077, 1034,
1003, 944, 923, 899, 886, 784, 753, 714, 696, 640, 590, 570,
542, 524, 493, 469, 450 cmꢁ1; dH (300 MHz, DMSO-d6) 0.72
(3H, t, J 7.2 Hz, CH3), 0.95e1.14 (2H, m, CH3CH2),
0.95e1.14 and 1.35e1.50 (2H, m, CH3CH2CH2), 3.05e3.15
and 3.30e3.40 (2H, m, CH3CH2CH2CH2), 6.60 (1H, s, H-1),
6.93 (1H, d, J 7.8 Hz, H-6), 7.04 (1H, dd, J 7.8, 7.8 Hz, H-8),
7.18e7.23 (2H, m, H-20, H-60), 7.29 (1H, dd, J 7.8, 7.8 Hz,
H-7), 7.30e7.42 (3H, m, H-30, H-40, H-5’), 7.61 (1H, d,
J 7.8 Hz, H-9), 10.83 (1H, br s, NH); dC (75 MHz, DMSO-d6)
14.5 (CH3), 20.6 (CH3CH2), 30.8 (CH3CH2CH2), 42.8
(CH3CH2CH2CH2), 73.9 (C-3a), 116.6 (C-6), 118.3 (C-9a),
121.6 (C-1), 124.1 (C-8), 127.0 (C-2’, C-60), 127.3 (C-9),
130.07 (C-40), 130.14 (C-30, C-50), 132.3 (C-7), 135.6 (C-10),
137.2 (C-5a), 155.4 (C-9b), 168.9 (C-4), 171.1 (C-2); EIMS
m/z (%) 332 (Mþ, 100), 289 (62), 261 (39), 233 (29), 204
(23), 91 (36). Anal. Calcd for C21H20N2O2: C, 75.88; H, 6.06;
N, 8.43. Found: C, 75.84; H, 5.90; N, 8.43.
3.4.10. 3-Butyl-3a-methyl-5-phenyl-3,3a-dihydro-2H-
pyrrolo[2,3-c]quinoline-2,4(5H)-dione (3j)
White solid; mp 145e147 ꢀC (benzene/cyclohexane);
Rf¼0.26 (20% EtOAc in benzene); IR 3068, 3048, 2991,
2974, 2957, 2934, 2908, 2870, 2854, 1698, 1687, 1635,
1600, 1492, 1481, 1459, 1430, 1392, 1367, 1358, 1339,
1315, 1290, 1281, 1260, 1247, 1207, 1186, 1159, 1146,
1134, 1120, 1100, 1071, 1042, 1025, 1001, 976, 967, 948,
914, 858, 764, 732, 707, 678, 640, 633, 593, 507, 481,
433 cmꢁ1; dH (300 MHz, DMSO-d6) 0.90 (3H, t, J 6.8 Hz,
CH3), 1.23e1.38 (2H, m), 1.63 (3H, s, CH3), 1.63e1.80
(2H, m), 3.36e3.63 (2H, m), 6.32 (1H, d, J 7.9 Hz, H-6),
6.49 (1H, s, H-1), 7.26e7.30 (2H, m), 7.30e7.46 (2H, m),
7.46e7.63 (3H, m), 7.77 (1H, d, J 7.0 Hz, H-9); dC
(75 MHz, DMSO-d6) 13.7, 19.9, 24.0, 30.7, 41.3, 67.4,
116.6, 117.2, 118.9, 123.6, 126.7, 128.7, 129.4 (br), 130.0
(br), 131.2, 137.4, 139.2, 154.9, 169.1, 169.7; dC (75 MHz,
DMSO-d6, 343 K) 13.6, 20.0, 24.0, 30.7, 41.4, 67.5, 116.6,
117.4, 118.9, 123.6, 126.7, 128.6, 129.0, 130.0, 131.2,
137.5, 139.3, 155.0, 169.2, 169.7; EIMS m/z (%) 346 (Mþ,
100), 303 (59), 289 (45), 275 (35), 77 (19). Anal. Calcd for
C22H22N2O2: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.11;
H, 6.29; N, 8.06.
3.4.7. 5-Methyl-3a-phenyl-3,3a-dihydro-2H-pyrrolo[2,3-c]-
quinoline-2,4(5H)-dione (3g)
White solid; mp 250e255 ꢀC (benzene); Rf¼0.30 (33%
hexane in EtOAc); IR 3168, 3079, 3058, 2971, 2800, 1688,
1663, 1648, 1603, 1490, 1468, 1447, 1352, 1308, 1279,
1177, 1132, 1093, 1043, 949, 882, 760, 748, 698, 688,
650 cmꢁ1; dH (300 MHz, DMSO-d6) 3.38 (3H, s, CH3), 6.46
(1H, s, H-1), 7.05e7.35 (7H, m), 7.43 (1H, dd, J 7.5,
7.5 Hz, H-7), 7.69 (1H, d, J 7.2 Hz, H-9), 9.32 (1H, br s,
NH); dC (75 MHz, DMSO-d6) 30.0, 69.8, 115.8, 118.8,
120.6, 123.5, 125.4, 126.4, 128.6, 128.8, 131.5, 137.0,
138.3, 154.9, 167.3, 171.4. Anal. Calcd for C18H14N2O2: C,
74.47; H, 4.86; N, 9.65. Found: C, 74.11; H, 4.84; N, 9.36.
3.4.11. 2-Butyl-1-phenyl-1H-pyrrolo[3,4-c]quinoline-3,4-
(2H,5H)-dione (4f)
3.4.8. 3-Butyl-5-methyl-3a-phenyl-3,3a-dihydro-2H-
pyrrolo[2,3-c]quinoline-2,4(5H)-dione (3h)
White solid; mp 252e260 ꢀC; Rf¼0.45 (10% ethanol in
chloroform); IR 3404 (br), 3143, 3100, 3066, 3027, 3008,
2952, 2931, 2872, 1703, 1648, 1621, 1604, 1562, 1511,
1480, 1455, 1438, 1415, 1393, 1366, 1325, 1313, 1279,
1269, 1253, 1220, 1196, 1188, 1156, 1079, 1032, 953, 895,
859, 803, 774, 757, 714, 699, 649, 644, 595, 557, 530, 518,
495, 462, 433 cmꢁ1; dH (300 MHz, DMSO-d6) 0.82 (3H, t,
J 7.3 Hz, CH3), 1.12e1.25 (2H, m, CH3CH2), 1.33e1.46 (2H,
m, CH3CH2CH2), 2.58e2.70 and 3.55e3.66 (2H, 2m,
CH3CH2CH2CH2), 6.08 (1H, s, H-1), 7.05 (1H, ddd, J 8.1,
8.1, 1.0 Hz, H-8), 7.32 (1H, dd, J 8.1, 1.0 Hz, H-9),
7.33e7.44 (6H, m, H-6, Ph), 7.52 (1H, ddd, J 7.1, 8.1,
White solid; mp 142e144 ꢀC (cyclohexane); Rf¼0.70 (33%
hexane in EtOAc); IR 3084, 2956, 2932, 2870, 1692, 1647,
1601, 1582, 1491, 1467, 1453, 1353, 1324, 1279, 1134,
1098, 1045, 960, 916, 857, 849, 748, 698, 635 cmꢁ1; dH
(300 MHz, DMSO-d6) 0.72 (3H, t, J 7.0 Hz, CH3), 0.97e
1.17 (3H, m), 1.38e1.55 (1H, m), 3.03e3.18 and 3.27e3.42
(2H, 2m), 3.41 (3H, s, NCH3), 6.63 (1H, s, H-1), 7.05e7.17
(3H, m), 7.21 (1H, d, J 8.2 Hz, H-6), 7.28e7.37 (3H, m),
7.40 (1H, ddd, J 7.8, 7.8, 1.3 Hz, H-7), 7.65 (1H, dd, J 7.5,
1.1 Hz, H-9); dC (75 MHz, DMSO-d6) 13.5, 19.7, 29.9, 41.9,
73.0, 115.8, 118.6, 120.3, 123.5, 125.9, 126.4, 129.1, 129.2,

S. Kafka et al. / Tetrahedron 64 (2008) 4387e4402
4395
1.0 Hz, H-7), 11.96 (1H, br s, NH); dC (75 MHz, DMSO-d6)
13.4 (CH3), 19.2 (CH3CH2), 29.6 (CH3CH2CH2), 38.9
(CH3CH2CH2CH2), 61.1 (C-1), 114.2 (C-9a), 115.9 (C-6),
120.4 (C-3a), 121.8 (C-8), 124.6 (C-9), 127.9 (Ph), 128.8
(Ph), 129.2 (Ph), 132.1 (C-7), 136.0 (C-10), 140.7 (C-5a),
156.9 (C-4), 159.3 (C-9b), 164.9 (C-3); EIMS m/z (%) 332
(Mþ, 46), 289 (24), 261 (39), 95 (100); HRESI-MS calcd
for C21H21N2O2 [Mþ1]þ 333.1603, found 333.1612.
H-20, H-60), 7.02e7.09 (1H, m, H-40), 7.10e7.18 (2H, m,
H-30, H-50), 7.19 (1H, dd, J 8.0, 8.0 Hz, H-8), 7.47 (1H, dd,
J 7.8, 1.6 Hz, H-6), 10.67 (1H, br s, NH); dC (75 MHz,
DMSO-d6) 13.6 (CH3), 19.3 (CH3CH2), 29.8 (CH3CH2CH2),
49.6 (CH3CH2CH2CH2), 66.0 (C-3), 119.8 (C-9), 123.4
(C-7), 124.1 (C-20, C-60), 127.17 and 127.19 (C-5a and
C-40), 128.2 (C-30, C-50), 130.1 (C-6), 131.5 (C-8), 134.4
(C-10), 135.0 (C-9a), 166.0 (C-5), 170.7 (C-2); EIMS m/z
(%) 308 (Mþ, 70), 251 (27), 208 (32), 203 (100), 147 (60),
119 (52), 91 (47). Anal. Calcd for C19H20N2O2: C, 74.00; H,
6.54; N, 9.08. Found: C, 74.21; H, 6.74; N, 8.98.
3.4.12. 1-Hydroxy-1-phenyl-1H-pyrrolo[3,4-c]quinoline-
3,4(2H,5H)-dione (5e)
Yellow solid; mp 298e302 ꢀC (acetic acid); Rf¼0.13 (10%
ethanol in chloroform); IR 3404, 3301, 3189, 3096, 3067,
2919, 2850, 1754, 1728, 1682, 1650, 1619, 1561, 1468,
1452, 1434, 1410, 1385, 1332, 1267, 1200, 1176, 1157,
1137, 1068, 1033, 1006, 946, 931, 894, 846, 810, 779, 760,
748, 724, 699, 602, 556, 532, 516, 491, 462 cmꢁ1; dH
(300 MHz, DMSO-d6) 7.06 (1H, dd, J 7.5, 7.5 Hz, H-8),
7.26 (1H, br s, OH), 7.28e7.41 (4H, m, H-6, H-30, H-40,
H-50), 7.47e7.57 (4H, m, H-7, H-9, H-20, H-60), 9.11 (1H,
br s, H-2), 11.97 (1H, br s, H-5); dC (75 MHz, DMSO-d6)
85.7, 113.5 (C-9a), 115.9 (C-6), 119.0 (C-3a), 121.8 (C-8),
125.4, 125.7, 128.1, 128.4, 132.3, 140.4, 141.7, 157.2,
162.1, 166.0; EIMS m/z (%) 292 (Mþ, 50), 263 (62), 215
(75), 105 (75), 77 (100); HREI-MS calcd for C17H12N2O3
292.0848, found 292.0846.
3.4.15. Independent synthesis of 6f
2-Amino-N-butylbenzamide was prepared from isatoic
anhydride and butyl amine as described in the literature.12
To a vigorously stirred ice-cold mixture of 2-amino-N-bu-
tylbenzamide (384 mg, 2.0 mmol), dichloromethane (20 mL),
and saturated aqueous solution of NaHCO3 (20 mL), a solution
of 2-chloro-2-phenylacetyl chloride (90%, 416 mg, 2.0 mmol)
in dichloromethane (5 mL) was added dropwise. The reaction
mixture was then stirred at room temperature for 45 min. The
layers were separated and the water layer was extracted with
dichloromethane (5 mL). The combined organic layers were
dried over Na2SO4 and evaporated to dryness to give N-bu-
tyl-2-(2-chloro-2-phenylacetamido)benzamide (659 mg, 95%)
as brown solid. For analyses, the product was crystallized
from acetonitrile to give white needles. Mp 123e124 ꢀC
(acetonitrile); IR 3303, 2958, 2934, 1676, 1627, 1593, 1551,
1515, 1447, 1296, 1226, 754, 725, 699 cmꢁ1; dH (300 MHz,
DMSO-d6) 0.91 (3H, t, J 7.3 Hz), 1.28e1.42 (2H, m),
1.47e1.59 (2H, m), 3.28 (2H, br q, J 7.3 Hz), 5.94 (1H, s),
7.21 (1H, ddd, J 7.6, 7.6, 0.9 Hz), 7.35e7.58 (6H, m), 7.75
(1H, dd, J 7.9, 1.3 Hz), 8.35 (1H, d, J 7.8 Hz), 8.75 (1H, br
t, J 5.3 Hz), 12.12 (1H, br s); dC (75 MHz, DMSO-d6) 13.7,
19.6, 30.9, 38.8, 61.2, 120.5, 121.9, 123.5, 127.9, 128.0,
128.7, 128.9, 131.7, 137.3, 137.8, 165.8, 167.8. Anal. Calcd
for C19H21ClN2O2: C, 66.18; H, 6.14; N, 8.12. Found: C,
66.13; H, 5.98; N, 8.11.
A mixture of N-butyl-2-(2-chloro-2-phenylacetamido)benz-
amide (82 mg, 0.24 mmol) and NaH (60% dispersion in min-
eral oil, 80 mg, 2.0 mmol) in DMF (3 mL) was stirred at room
temperature for 2 h. Ammonium chloride solution (5 mL, satd
aq) was added and the product was extracted with ethyl
acetate/hexane (3:5, 10 mL). The organic layer was separated,
dried over Na2SO4, concentrated in vacuo, and subjected to
column chromatography using ethyl acetate/hexane (3:5) as
eluant to give 6f (33 mg, 45%) as white solid, mp 158e
159 ꢀC (benzene/hexane). IR and NMR spectra are in agree-
ment with those for 6f obtained from 1f, as described above.
3.4.13. 2-Butyl-1-hydroxy-1-phenyl-1H-pyrrolo[3,4-c]-
quinoline-3,4(2H,5H)-dione (5f)
White solid; mp 212e220 ꢀC (benzene/hexane); Rf¼0.15
(10% ethanol in chloroform); IR 3148, 3059, 2960, 2931,
2871, 1721, 1650, 1566, 1484, 1439, 1415, 1371, 1312,
1190, 1120, 1045, 927, 862, 807, 759, 752, 722, 698, 606,
542 cmꢁ1; dH (300 MHz, DMSO-d6) 0.73 (3H, t, J 7.0 Hz,
CH3), 1.06e1.33 (4H, m), 2.83e2.92 and 3.17e3.28 (2H,
2m), 7.05 (1H, ddd, J 7.7, 7.6, 1.0 Hz, H-8), 7.30e7.47
(8H, m), 7.52 (1H, ddd, J 8.2, 7.3, 1.4 Hz, H-7), 12.04
(1H, br s, OH); dC (75 MHz, DMSO-d6) 13.4, 19.5, 30.3,
37.7, 88.5, 113.2, 115.9, 119.0, 121.9, 125.4, 125.5, 128.4,
128.6, 132.2, 138.6, 141.5, 156.8, 160.4, 164.9; EIMS m/z
(%) 348 (Mþ, 27), 221 (100), 77 (52). Anal. Calcd for
C21H20N2O3: C, 72.40; H, 5.79; N, 8.04. Found: C, 72.39;
H, 5.80; N, 8.05.
3.4.14. 4-Butyl-3-phenyl-3,4-dihydro-1H-benzo[e][1,4]-
diazepine-2,5-dione (6f)
White solid; mp 159e163 ꢀC (benzene/hexane); Rf¼0.79
(10% ethanol in chloroform); IR 3206, 3085, 2956, 2926,
2869, 2860, 1676, 1633, 1606, 1583, 1496, 1484, 1462,
1450, 1434, 1416, 1401, 1364, 1317, 1304, 1295, 1278,
1250, 1221, 1196, 1155, 1113, 1079, 1046, 1032, 966, 882,
868, 843, 818, 795, 765, 735, 693, 648, 587, 540, 493, 472,
418 cmꢁ1; dH (300 MHz, DMSO-d6) 0.93 (3H, t, J 7.3 Hz,
CH3), 1.27e1.42 (2H, m, CH3CH2), 1.55e1.74 (2H, m,
CH3CH2CH2), 3.45e3.60 and 4.04e4.20 (2H, 2m,
CH3CH2CH2CH2), 5.46 (1H, s, H-3), 6.83 (1H, d, J 8.0 Hz,
H-9), 6.90 (1H, dd, J 7.6, 7.6 Hz, H-7), 6.94e7.01 (2H, m,
3.5. General procedure for the synthesis of
3-bromoacetamidoquinoline-2,4(1H,3H)-diones 7aed,feh,j
in benzene with K2CO3 as a base
To a solution of 3-aminoquinoline-2,4(1H,3H)-dione 1
(aed,feh,j) (10 mmol) in benzene (60 mL), powdered potas-
sium carbonate (4.15 g, 30 mmol) and bromoacetyl bromide

4396
S. Kafka et al. / Tetrahedron 64 (2008) 4387e4402
(1 mL, 11.45 mmol) were added with stirring, at room temper-
ature. The reaction mixture was stirred for 2 h, methanol
(1 mL) was added, and the solids were filtered off. The filtrate
was diluted with benzene (30 mL) and consecutively washed
with 3% hydrochloric acid (30 mL), water, 5% solution of
potassium carbonate (30 mL), and again water (30 mL). The
benzene layer was dried with anhydrous sodium sulfate,
filtered, and evaporated to dryness to give crude 7 (aed,fe
h,j), which was crystallized from the solvent given below.
For yields of analytically pure products, see Table 2. For phys-
ical and spectroscopic data, see below.
3.5.4. N-(3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-
yl)-2-bromo-N-butylacetamide (7d)
White solid; mp 175e177 ꢀC (hexane); IR 3236, 3196, 3122,
3087, 3032, 2996, 2931, 2871, 1706, 1671, 1639, 1614, 1599,
1487, 1455, 1440, 1366, 1284, 1256, 1232, 1199, 1156, 1097,
930, 761, 700, 665, 628 cmꢁ1; dH (300 MHz, DMSO-d6) 0.99
(3H, t, J 7.3 Hz, CH3), 1.35e1.49 (2H, m), 1.82e2.01 (2H,
m), 3.26 and 3.33 (2H, 2d, J 12.4 Hz, CH2Ph), 3.72 (2H, br t,
J 8.2 Hz), 4.24 (2H, s, CH2Br), 6.62 (1H, d, J 8.0 Hz, H-8),
6.88 (1H, dd, J 7.5, 7.5 Hz, H-6), 6.88e7.00 (5H, m), 7.27
(1H, ddd, J 7.7, 7.7, 1.4 Hz, H-7), 7.55 (1H, dd, J 7.8, 1.1 Hz,
H-5), 10.67 (1H, br s, NH); dC (75 MHz, DMSO-d6) 13.6,
19.4, 28.2, 33.3, 41.0, 44.7, 71.5, 115.6, 120.5, 121.5, 125.5,
127.17, 127.24, 130.3, 130.8, 134.8, 140.8, 166.6, 170.2,
193.4. Anal. Calcd for C22H23BrN2O3: C, 59.60; H, 5.23; N,
6.32. Found: C, 59.32; H, 5.20; N, 6.33.
3.5.1. 2-Bromo-N-(3-butyl-2,4-dioxo-1,2,3,4-tetrahydro-
quinolin-3-yl)acetamide (7a)
White solid; mp 195e197 ꢀC (ethyl acetate); IR 3351, 3189,
3058, 2960, 2927, 2863, 1706, 1671, 1633, 1611, 1531, 1485,
1433, 1385, 1357, 1296, 1223, 1165, 953, 810, 761,
665 cmꢁ1; dH (300 MHz, DMSO-d6) 0.77 (3H, t, J 6.9 Hz,
CH3), 1.10e1.29 (4H, m), 1.72e1.82 (2H, m), 3.93 (2H, s,
CH2Br), 7.09e7.16 (2H, m), 7.62 (1H, ddd, J 7.8, 7.8, 1.5 Hz,
H-6), 7.76 (1H, dd, J 7.8, 1.3 Hz, H-5), 9.24 (1H, br s, NH),
10.92 (1H, br s, NH); dC (75 MHz, DMSO-d6) 13.5, 21.9,
24.4, 27.8, 35.9, 67.3, 116.3, 118.7, 122.4, 126.8, 136.0,
141.5, 165.7, 170.2, 192.6. Anal. Calcd for C15H17BrN2O3: C,
51.01; H, 4.85; N, 7.93. Found: C, 50.85; H, 4.79; N, 7.72.
3.5.5. 2-Bromo-N-butyl-N-(2,4-dioxo-3-phenyl-1,2,3,4-
tetrahydroquinolin-3-yl)acetamide (7f)
White solid; mp 115e122 ꢀC (benzene); IR 3238, 3191,
3163, 3066, 2997, 2960, 2929, 2872, 1715, 1680, 1665, 1642,
1617, 1596, 1488, 1449, 1435, 1354, 1323, 1251, 1228, 1208,
1158, 1122, 1100, 1039, 888, 780, 756, 700, 682, 667, 634,
588, 559, 534, 524, 509, 439 cmꢁ1; dH (300 MHz, DMSO-d6)
0.53 (3H, t, J 7.3 Hz, CH3), 0.87 (2H, tq, J 7.3, 7.3 Hz),
1.35e1.46 (2H, m), 3.12 (2H, t, J 8.2 Hz), 4.27 and 4.33 (2H,
2d, J 12.3 Hz, CH2Br), 7.03 (1H, d, J 8.5 Hz, H-8), 7.07 (1H,
dd, J 8.5, 7.6 Hz, H-7), 7.37 (1H, br s, NH), 7.46 (5H, br s,
Ph), 7.53 (1H, ddd, J 7.8, 7.6, 1.2 Hz, H-7), 7.80 (1H, dd,
J 7.8, 0.8 Hz, H-5); dC (75 MHz, DMSO-d6) 12.9, 18.9, 28.3,
31.2, 45.8, 77.4, 116.0, 119.3, 122.3, 127.4, 128.2, 129.2,
130.1, 130.3, 135.8, 140.6, 166.9, 168.5, 189.4. Anal. Calcd
for C21H21BrN2O3: C, 58.75; H, 4.93; N, 6.53. Found: C,
59.03; H, 4.82; N, 6.25.
3.5.2. 2-Bromo-N-butyl-N-(3-butyl-2,4-dioxo-1,2,3,4-tetra-
hydroquinolin-3-yl)acetamide (7b)
White solid; mp 174e176 ꢀC (benzene); IR 3279, 3201,
2958, 2931, 2871, 1710, 1692, 1676, 1662, 1641, 1611, 1599,
1486, 1438, 1361, 1317, 1265, 1251, 1231, 1197, 1096, 928,
882, 764, 690, 666, 640, 618 cmꢁ1; dH (300 MHz, DMSO-d6)
0.73 (3H, t, J 7.1 Hz, CH3), 0.95 (3H, t, J 7.3 Hz, CH3),
0.92e1.12 (1H, m), 1.13e1.27 (3H, m), 1.30e1.42 (2H, m),
1.71e2.02 (4H, m), 3.56 (2H, t, J 8.2 Hz), 4.21 (2H, s,
CH2Br), 7.14e7.17 (2H, m), 7.59 (1H, ddd, J 7.7, 7.7, 1.4 Hz,
H-7), 7.74 (1H, d, J 7.8 Hz, H-5), 10.94 (1H, br s, NH); dC
(75 MHz, DMSO-d6) 13.3, 13.5, 19.4, 22.2, 24.4, 28.1, 33.0,
34.1, 44.5, 71.4, 116.2, 120.0, 122.1, 126.2, 135.5, 141.4,
166.7, 170.7, 193.1. Anal. Calcd for C19H25BrN2O3: C, 55.75;
H, 6.16; N, 6.84. Found: C, 55.62; H, 6.17; N, 6.79.
3.5.6. 2-Bromo-N-(1-methyl-2,4-dioxo-3-phenyl-1,2,3,4-
tetrahydroquinolin-3-yl)acetamide (7g)
White solid; mp 216e217 ꢀC (benzene); IR 3329, 3023,
2963, 1712, 1679, 1661, 1602, 1515, 1492, 1474, 1448, 1361,
1301, 1210, 1109, 1037, 896, 780, 766, 731, 697, 687 cmꢁ1
;
dH (300 MHz, DMSO-d6) 3.53 (3H, s, CH3), 4.00 and 4.05
(2H, 2d, J 11.3 Hz, CH2Br), 7.20 (1H, dd, J 7.5, 7.5 Hz, H-6),
7.28e7.34 (2H, m), 7.34e7.44 (4H, m), 7.72 (1H, ddd, J 7.8,
7.8, 1.6 Hz, H-7), 7.83 (1H, dd, J 7.7, 1.5 Hz, H-5), 9.71 (1H,
br s, NH); dC (75 MHz, DMSO-d6) 27.8, 30.1, 71.5, 115.9,
119.8, 123.1, 127.2, 127.7, 129.1, 129.5, 132.8, 136.5, 142.0,
166.3, 168.5, 189.3. Anal. Calcd for C18H15BrN2O3: C, 55.83;
H, 3.90; N, 7.23. Found: C, 55.64; H, 4.12; N, 7.04.
3.5.3. N-(3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-
yl)-2-bromoacetamide (7c)
White solid; mp 120e125 ꢀC (benzene); IR 3254, 3062,
2999, 2928, 2861, 1709, 1667, 1613, 1596, 1486, 1455,
1439, 1385, 1298, 1237, 1212, 1158, 1106, 1031, 960, 942,
765, 748, 701, 684, 666, 636 cmꢁ1; dH (300 MHz, DMSO-
d6) 3.11 and 3.18 (2H, 2d, J 12.5 Hz, CH2Ph), 3.95 (2H, s,
CH2Br), 6.76 (1H, d, J 8.0 Hz, H-8), 6.91e6.98 (3H, m),
7.02e7.18 (3H, m), 7.38 (1H, ddd, J 7.7, 7.7, 1.5 Hz, H-7),
7.60 (1H, dd, J 7.8, 1.3 Hz, H-5), 9.51 (1H, br s, NH), 10.78
(1H, br s, NH); dC (75 MHz, DMSO-d6) 27.8, 43.2, 67.4,
115.8, 119.6, 122.0, 126.0, 127.3, 127.6, 129.8, 131.7,
135.6, 141.2, 165.6, 169.8, 193.2. Anal. Calcd for
C18H15BrN2O3: C, 55.83; H, 3.90; N, 7.23. Found: C, 55.96;
H, 3.97; N, 7.17.
3.5.7. 2-Bromo-N-butyl-N-(1-methyl-2,4-dioxo-3-phenyl-
1,2,3,4-tetrahydroquinolin-3-yl)acetamide (7h)
White solid; mp 153e156 ꢀC (benzene/cyclohexane); IR
3072, 3038, 2963, 2932, 2877, 1701, 1667, 1625, 1600, 1492,
1472, 1417, 1348, 1302, 1238, 1215, 1143, 1073, 1026, 993,
887, 768, 751, 705, 663 cmꢁ1; dH (300 MHz, DMSO-d6) 0.53
(3H, t, J 7.3 Hz, CH3), 0.79e0.96 (2H, m), 1.32e1.50 (2H,
m), 3.13 (2H, t, J 8.7 Hz), 3.48 (3H, s, NCH3), 4.28 and 4.33

S. Kafka et al. / Tetrahedron 64 (2008) 4387e4402
4397
(2H, 2d, J 12.3 Hz, CH2Br), 7.18 (1H, dd, J 7.4, 7.4 Hz, H-6),
3.6.1. 2-Bromo-N-(2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-
7.31 (1H, d, J 8.5 Hz, H-8), 7.32e7.39 (2H, m), 7.41e7.49
(3H, m), 7.65 (1H, ddd, J 7.8, 7.8, 1.5 Hz, H-7), 7.91 (1H, dd,
J 7.7, 1.5 Hz, H-5); dC (75 MHz, DMSO-d6) 12.9, 19.0, 26.3,
28.3, 30.1, 31.2, 45.9, 77.5, 115.6, 120.4, 122.8, 127.8, 128.2,
129.3, 130.1, 136.0, 141.6, 166.9, 168.1, 188.5. Anal. Calcd
for C22H23BrN2O3: C, 59.60; H, 5.23; N, 6.32. Found: C,
59.37; H, 5.24; N, 6.17.
quinolin-3-yl)acetamide (7e)
White solid; mp 242e243 ꢀC (ethanol); IR 3520, 3426,
3214, 3184, 3031, 2926, 2856, 1699, 1666, 1613, 1594,
1540, 1485, 1449, 1434, 1371, 1319, 1231, 1210, 1203,
1158, 1115, 1039, 1001, 946, 885, 781, 767, 739, 695, 671,
640, 579, 527, 507, 453, 442 cmꢁ1; dH (300 MHz, DMSO-
d6) 4.00 and 4.05 (2H, 2d, J 11.2 Hz, CH2), 7.07e7.16 (2H,
m), 7.40 (5H, m, Ph), 7.61 (1H, ddd, J 7.7, 7.7, 1.3 Hz,
H-6), 7.74 (1H, dd, J 7.7, 0.9 Hz, H-5), 9.64 (1H, br s, NH),
11.21 (1H, br s, NH); dC (75 MHz, DMSO-d6) 27.9, 71.3,
116.4, 118.7, 122.7, 127.2, 127.4, 129.1, 129.4, 132.9,
136.3, 141.1, 166.4, 168.9, 190.4; HRESI-MS calcd for
C17H1479BrN2O3 [M(79Br)þ1]þ 373.0188, found 373.0197.
Crude 4-bromobutyl bromoacetate obtained as above was
purified by chromatography on a silica gel column using
benzene. The collected fractions were evaporated and dried
under vacuum for 1 h at 100 ꢀC and then in an evacuated
desiccator over SicapentÒ for 2 days to give pure product as
a colorless liquid. IR 2962, 1738, 1436, 1284, 1164, 1111,
1029, 559 cmꢁ1; dH (300 MHz, CDCl3) 1.80e1.90 (2H, m),
1.90e2.02 (2H, m), 3.45 (2H, t, J 6.4 Hz), 3.83 (2H, s), 4.22
(2H, t, J 6.2 Hz); dC (75 MHz, CDCl3) 25.2, 26.6, 28.6,
32.4, 64.8, 164.8. The NMR data are in good agreement
with those reported in the literature.9
3.5.8. 2-Bromo-N-butyl-N-(3-methyl-2,4-dioxo-1-phenyl-
1,2,3,4-tetrahydroquinolin-3-yl)acetamide (7j)
White solid; mp 151e156 ꢀC (benzene/cyclohexane); IR
3150e3660, 2952, 2925, 2867, 1709, 1677, 1634, 1602,
1494, 1464, 1367, 1337, 1307, 1258, 1232, 1201, 1162,
1104, 981, 917, 894, 786, 757, 710, 663, 658, 626, 539,
448, 428 cmꢁ1; dH (300 MHz, DMSO-d6) 0.94 (3H, t,
J 7.3 Hz, CH3), 1.37 (2H, m), 1.66 (3H, s, CH3), 1.65e1.85
(2H, m), 3.61 (2H, t, J 8.0 Hz), 4.22 and 4.29 (2H, 2d,
J 12.2 Hz, CH2Br), 6.40 (1H, d, J 8.4 Hz, H-8), 7.11 (1H,
m), 7.21 (1H, dd, J 7.5, 7.5 Hz, H-7), 7.42 (1H, m), 7.50e7.67
(4H, m), 7.94 (1H, dd, J 6.8, 0.7 Hz, H-5); dC (75 MHz,
DMSO-d6) 13.6, 19.4, 19.6, 27.8, 32.9, 44.9, 69.9, 116.5,
118.7, 122.8, 127.7, 128.8, 129.1 (br), 130.1 (br), 135.7,
137.3, 143.3, 166.7, 170.7, 191.7. Anal. Calcd for
C22H23BrN2O3: C, 59.60; H, 5.23; N, 6.32. Found: C, 59.43;
H, 5.24; N, 6.31.
3.7. Synthesis of 2-bromo-N-(2,4-dioxo-3-phenyl-1,2,3,4-
tetrahydroquinolin-3-yl)acetamide (7e) in CH2Cl2 with
triethylamine as a base
3.6. Synthesis of 2-bromo-N-(2,4-dioxo-3-phenyl-1,2,3,4-
tetrahydroquinolin-3-yl)acetamide (7e) in THF with
triethylamine as a base
To a stirred solution of amine 1e (0.875 g, 3.47 mmol) in
dichloromethane (70 mL), a solution of bromoacetyl bromide
(2.22 g, 10.8 mmol) in dichloromethane (5 mL) and subse-
quently a solution of triethylamine (0.53 g, 5.2 mmol) in
dichloromethane (5 mL) were added. The resulting reaction
mixture was sealed with a CaCl2 drying tube, stirred at room
temperature, and monitored by TLC. After 5 h, additional
portions of bromoacetyl bromide (1.43 g, 6.94 mmol) and tri-
ethylamine (0.36 g, 3.5 mmol) were added, and then stirring
was continued for an additional 14 h. Then 6% aqueous sodium
bicarbonate (10 mL) was added and the resulting mixture was
stirred for 2 min. The solid material was filtered off, washed
with water (20 mL), and crystallized from ethanol to give 7e
(891 mg, 69%). For physical and spectral data, see above.
To a stirred solution of amine 1e (1.20 g, 4.76 mmol) in tet-
rahydrofuran (70 mL), bromoacetyl bromide (1.27 mL, 2.94 g,
14.3 mmol) and then triethylamine (1.46 mL, 1.06 g,
10.4 mmol) were added. The resulting reaction mixture was
sealed with a CaCl2 drying tube, stirred at room temperature,
and monitored by TLC. Starting 1e was not consumed until
two additional portions of bromoacetyl bromide (1.27 mL,
2.94 g, 14.3 mmol) and triethylamine (0.73 mL, 0.53 g,
5.2 mmol) were added in a 12 h period, and then stirring
continued for additional 12 h. The volatile compounds were
evaporated on a rotary evaporator at 50 ꢀC. The residue was
suspended in chloroform (70 mL) and the suspension was
shaken with 2% hydrochloric acid (20 mL). The insoluble
material was filtered off, air-dried, and crystallized from etha-
nol affording 7e (679 mg, 38% yield). The organic layer of the
filtrate was separated, washed with 2% hydrochloric acid
(20 mL) and water (2ꢂ20 mL), dried over anhydrous sodium
sulfate, and evaporated to dryness. The liquid residue was
subjected to column chromatography on silica gel using chlo-
roform (to give 5.65 g of 4-bromobutyl bromoacetate as an
orange liquid) and subsequently using a mixture of chloro-
form/ethanol (19:1) as eluting systems to give another crop
of impure 7e (339 mg). Crystallization of the latter from
ethanol afforded the second crop of pure 7e (83 mg, 5%;
43% overall yield, Table 2).
3.8. Preparation of 3-bromoacetamidoquinoline-2,4(1H,3H)-
diones 7f and 7i in THF with triethylamine as a base
To an ice-cold stirred solution of the appropriate 3-aminoqui-
noline-2,4(1H,3H)-dione1(5 mmol)intetrahydrofuran(15 mL)
was added bromoacetyl bromide (1.33 mL, 15 mmol). Then a
solution of triethylamine (0.55 g, 5.4 mmol) in tetrahydrofuran
(5 mL) was added dropwise for 15 min. The reaction mixture
was stirred for 30 min in the ice bath and then for another
30 min at room temperature. The solvents were removed on a
rotary evaporator at 80 ꢀC. The residue was dissolved in chloro-
form (100 mL) and the resulting solution was washed with 2%

4398
S. Kafka et al. / Tetrahedron 64 (2008) 4387e4402
hydrochloric acid (3ꢂ20 mL) and water (3ꢂ20 mL). The
chloroform layer was dried over anhydrous sodium sulfate,
filtered, and evaporated to dryness. The crude products 7 were
purified by crystallization. The yields of analytically pure prod-
ucts are given in Table 2. Physical and spectroscopic data of
compounds 7f and 7i are listed above and below, respectively.
C-600 or C-300, C-500), 133.6 (d, JCP 10.7 Hz, C-300, C-500 or
4
C-200, C-600), 134.8 (d, JCP 2.7 Hz, C-400), 136.2 (C-7), 141.3
2
(C-8a), 162.8 (d, JCP 5.0 Hz, CONH), 169.6 (C-2), 191.9
(C-4); dP (121 MHz, DMSO-d6) 25.0. Anal. Calcd for
C33H32BrN2O3P: C, 64.40; H, 5.24; N, 4.55. Found: C, 64.14;
H, 5.19; N, 4.25.
3.8.1. 2-Bromo-N-(3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-
tetrahydroquinolin-3-yl)acetamide (7i)
3.9.2. (2-(3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-
ylamino)-2-oxoethyl)triphenylphosphonium bromide (8c)
White solid; mp 251e254 ꢀC (ethanol/ethyl acetate); IR
3181, 3083, 2990, 2868, 1713, 1678, 1665, 1611, 1596, 1585,
1524, 1484, 1438, 1372, 1356, 1335, 1323, 1246, 1111, 1029,
997, 945, 768, 748, 719, 687 cmꢁ1; dH (300 MHz, DMSO-d6)
White solid; mp 234e236 ꢀC (benzene); IR 3302, 3069,
2982, 2927, 2852, 1728, 1717, 1692, 1682, 1660, 1600, 1582,
1552, 1492, 1464, 1385, 1378, 1343, 1313, 1303, 1272, 1254,
1208, 1182, 1160, 1135, 1108, 1073, 992, 965, 789, 767, 760,
710, 691, 663, 626, 561, 544, 519, 489, 444 cmꢁ1; dH
(300 MHz, DMSO-d6) 1.58 (3H, s, CH3), 3.95 (2H, s, CH2),
6.40 (1H, d, J 8.3 Hz, H-8), 7.10e7.20 (1H, br s), 7.22 (1H,
ddd, J 8.3, 6.7, 0.6 Hz, H-7), 7.35e7.48 (1H, br s), 7.50e7.65
(4H, m), 7.94 (1H, dd, J 7.8, 1.6 Hz, H-5), 9.55 (1H, br s,
NH); dC (75 MHz, DMSO-d6) 22.7, 28.1, 64.9, 117.0, 119.0,
123.4, 128.1, 129.3, 129.5 (br), 130.6 (br), 136.5, 137.7,
143.9, 166.3, 170.9, 192.6. Anal. Calcd for C18H15BrN2O3: C,
55.83; H, 3.90; N, 7.23. Found: C, 56.13; H, 4.10; N, 7.24.
2
3.17 (2H, 2d, J 12.7 Hz, CH2Ph), 5.15 (2H, d, JPH 15.0 Hz,
CH2P), 6.73 (1H, d, J 8.0 Hz, H-8), 6.92e7.09 (6H, m, H-6,
H-20, H-30, H-40, H-50, H-60), 7.37 (1H, ddd, J 7.7, 7.7, 1.4 Hz,
H-7), 7.57 (1H, dd, J 7.7, 1.0 Hz, H-5), 7.65e7.78 (12H, m,
3ꢂ(H-200, H-300, H-500, H-600)), 7.82e7.92 (3H, m, 3ꢂH-400),
9.79 (1H, br s, CONH), 10.83 (1H, br s, H-1); dC (75 MHz,
1
DMSO-d6) 29.9 (d, JCP 59.0 Hz, CH2P), 43.2, 68.1 (C-3),
1
115.9, 118.4 (d, JCP 88.9 Hz, C-100), 119.3, 122.2, 126.2,
127.3, 127.6, 129.8, 129.9 (d, JCP 13.0 Hz, C-200, C-600 or
C-300, C-500), 131.4, 133.6 (d, JCP 10.8 Hz, C-300, C-500 or C-200,
C-600), 134.8 (d, 4JCP 2.7 Hz, C-400), 135.9 (C-7), 141.0 (C-8a),
3.9. General procedure for the synthesis of triphenyl-
phosphonium bromides 8a,c,f,g
2
162.7 (d, JCP 4.9 Hz, CONH), 169.3, 192.5; dP (121 MHz,
DMSO-d6) 25.0. Anal. Calcd for C36H30BrN2O3P: C, 66.57;
H, 4.66; N, 4.31. Found: C, 66.59; H, 4.73; N, 4.22.
A suspension of the appropriate bromoacetamide 7
(1.3 mmol) and triphenylphosphine (375 mg, 1.43 mmol) in
benzene (10 mL) was heated at reflux for the time given in Table
3. After cooling, the precipitated phosphonium bromide 8 was
suction filtered and washed with benzene. Products 8a,c,f were
purified by crystallization from the solvents given below and
8g was used for further transformations without purification. In
the cases of 8c and 8g, the mother liquors after filtration were
combined, evaporated to dryness, and the residues were column
chromatographed on silica gel using benzene and then using suc-
cessive mixtures of benzene/ethyl acetate (in ratios from 99:1 to
8:2) as eluents to give 3-acetamidoquinoline-2,4(1H,3H)-diones
9c and 9g. The yields of the products are given in Table 3 and the
spectral and analytical data are given below.
3.9.3. (2-(Butyl(2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-
quinolin-3-yl)amino)-2-oxoethyl)triphenylphosphonium
bromide (8f)
Yellowish solid; mp 177e183 ꢀC (ethanol/ethyl acetate); IR
3270e3680, 3058, 2962, 2908, 2870, 2856, 1713, 1680, 1632,
1613, 1596, 1485, 1438, 1428, 1366, 1346, 1321, 1250, 1225,
1198, 1160, 1109, 1039, 1029, 888, 865, 852, 794, 766, 749,
720, 701, 687, 660, 588, 544, 511, 498, 480, 440 cmꢁ1; dH
(300 MHz, DMSO-d6) 0.55 (3H, t, J 7.4 Hz, CH3), 0.88 (2H,
2
m), 1.55 (2H, m), 3.27 (2H, m), 5.62 (2H, d, JPH 14.2 Hz,
CH2P), 6.93 (1H, d, J 8.1 Hz), 7.03 (1H, dd, J 7.4, 7.4 Hz),
7.37e7.90 (22H, m), 11.18 (1H, br s, H-1); dC (75 MHz,
DMSO-d6) 12.8 (CH3), 19.0 (CH3CH2), 30.3 (d, 1JCP 65.7 Hz,
CH2P), 30.5 (CH3CH2CH2), 46.3 (CH3CH2CH2CH2), 78.0
(C-3), 116.1, 119.2, 119.3 (d, 1JCP 89.8 Hz, C-100), 122.5, 127.4,
128.0, 129.6 (d, JCP 12.9 Hz, C-200, C-600 or C-300, C-500), 133.6
3.9.1. (2-(3-Butyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-yl-
amino)-2-oxoethyl)triphenylphosphonium bromide (8a)
White solid; mp 252e262 ꢀC (ethyl acetate); IR 3180, 3127,
3051, 3022, 2958, 2870, 1712, 1673, 1612, 1540, 1484, 1437,
4
(d, JCP 10.5 Hz, C-300, C-500 or C-200, C-600), 134.3 (d, JCP
2
1360, 1244, 1111, 1043, 997, 946, 815, 749, 720, 688 cmꢁ1
;
2.7 Hz, C-400), 135.9 (C-7), 140.2 (C-8a), 165.4 (d, JCP
dH (300 MHz, DMSO-d6) 0.78 (3H, t, J 7.0 Hz, CH3),
1.13e1.22 (4H, m, CH3CH2CH2), 1.70e1.81 (2H, m,
CH3CH2CH2CH2), 5.14 (2H, d, JPH 15.1 Hz, CH2P), 7.09
4.1 Hz, CONH), 167.9 (C-2), 189.2 (C-4); dP (121 MHz,
DMSO-d6) 25.2; HRESI-MS calcd for C39H36N2O3P [MꢁBr]þ
611.2464, found 611.2460.
2
(1H, d, J 7.7 Hz, H-8), 7.10 (1H, dd, J 7.7, 7.7 Hz, H-6), 7.60
(1H, ddd, J 7.7, 7.7, 1.6 Hz, H-7), 7.69e7.77 (13H, m, H-5,
3ꢂ(H-200, H-300, H-500, H-600)), 7.83e7.92 (3H, m, 3ꢂH-400),
9.56 (1H, br s, NHCO), 10.97 (1H, br s, H-1); dC (75 MHz,
DMSO-d6) 13.5 (CH3), 21.8 (CH3CH2), 24.5 (CH3CH2CH2),
3.9.4. (2-(1-Methyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-
quinolin-3-ylamino)-2-oxoethyl)triphenylphosphonium
bromide (8g)
White solid; mp 229e233 ꢀC; IR 3171, 3054, 2990, 2842,
1713, 1676, 1601, 1513, 1490, 1472, 1437, 1354, 1298, 1111,
997, 859, 781, 772, 750, 721, 691, 641 cmꢁ1; dH (300 MHz,
DMSO-d6) 3.49 (3H, s, CH3), 5.11 (2H, m, CH2P), 7.18
1
29.6 (d, JCP 58.2 Hz, CH2P), 35.7 (CH3CH2CH2CH2), 68.2
1
(C-3), 116.3 (C-8), 118.36 (C-4a), 118.43 (d, JCP 88.8 Hz,
C-100), 122.5 (C-6), 126.9 (C-5), 129.9 (d, JCP 13.0 Hz, C-200,

S. Kafka et al. / Tetrahedron 64 (2008) 4387e4402
4399
(1H, dd, J 7.3, 7.3 Hz), 7.22e7.96 (23H, m), 9.83 (1H, s, NH);
Compound 8i: white solid; mp 179e186 ꢀC (ethanol/ethyl
acetate); IR 3100e3680 (br), 3169, 3010, 2994, 2870, 1709,
1674, 1650, 1599, 1491, 1464, 1439, 1375, 1335, 1262,
1141, 1111, 997, 862, 755, 745, 732, 707, 690, 514,
503 cmꢁ1; dH (300 MHz, DMSO-d6) 1.62 (3H, s, CH3), 5.11
(2H, m, CH2P), 6.36 (1H, d, J 8.4 Hz, H-8), 6.92 (1H, br s),
7.20 (1H, dd, J 7.5, 7.5 Hz, H-6), 7.43 (1H, br s), 7.50e7.92
(20H, m), 9.89 (1H, br s, H-1); dC (75 MHz, DMSO-d6)
1
dC (75 MHz, DMSO-d6) 29.6 (d, JCP 57.2 Hz, CH2P), 30.2
1
(CH3), 72.0 (C-3), 116.0, 118.3 (d, JCP 88.6 Hz, C-100),
119.5, 123.3, 127.0, 127.7, 129.3, 129.7, 130.0 (d, JCP
12.9 Hz, C-200, C-600 or C-300, C-500), 132.5, 133.7 (d, JCP
4
10.7 Hz, C-300, C-500 or C-200, C-600), 134.8 (d, JCP 2.8 Hz,
2
C-400), 136.7 (C-7), 141.8 (C-8a), 163.1 (d, JCP 5.2 Hz,
CONH), 167.9, 188.9; dP (121 MHz, DMSO-d6) 25.1; FABMS
m/z (%) 569 ([MꢁBr]þ, 100), 303 (30); HRESI-MS calcd for
C36H30N2O3P [MꢁBr]þ 569.1994, found 569.2001.
1
22.5 (CH3), 29.8 (d, JCP 59.8 Hz, CH2P), 65.0 (C-3), 116.6
1
(C-8), 118.4 (C-4a), 118.5 (d, JCP 88.8 Hz, C-100), 123.2
(C-6), 127.8 (C-5), 128.8 (br), 129.0, 129.9 (d, JCP 12.9 Hz,
C-200, C-600 or C-300, C-500), 130.2, 133.7 (d, JCP 10.6 Hz,
3.9.5. (2-(2,4-Dioxo-3-phenyl-1,2,3,4-tetrahydroquinolin-3-
ylamino)-2-oxoethyl)triphenylphosphonium bromide (8e)
A mixture of bromoacetamide 7e (716 mg, 1.92 mmol) and
triphenylphosphine (577 mg, 2.20 mmol) in 1,4-dioxane
(16 mL) was refluxed (KOHdseal) for 13 h. The reaction
mixture was allowed to cool to room temperature and the solid
material was filtered. The filter cake was washed with 1,4-
dioxane (1.5 mL) and air-dried at room temperature to a con-
stant mass yielding 8e (792 mg, 62%).
4
C-300, C-500 or C-200, C-600), 134.8 (d, JCP 2.7 Hz, C-400),
2
136.3 (C-7), 137.0, 143.3, 163.1 (d, JCP 5.0 Hz, CONH),
170.2 (C-2), 191.6 (C-4); dP (121 MHz, DMSO-d6) 25.1;
HRESI-MS calcd for C36H30N2O3P [MꢁBr]þ 569.1994,
found 569.2017.
3.10. Transformation of 3-bromoacetamidoquinoline-
2,4(1H,3H)diones (7b,d,h,j; R3¼n-butyl) to pyrrolo[2,3-c]-
quinoline-2,4(3aH,5H)-diones 3b,d,h and
Compound 8e: white solid; mp 256e263 ꢀC; IR 3181,
3145, 3124, 3079, 3058, 3012, 2977, 2965, 2928, 2912,
2900, 2872, 2859, 2768, 1716, 1678, 1673, 1611, 1585,
1529, 1485, 1439, 1393, 1351, 1328, 1248, 1229, 1160,
1112, 997, 943, 867, 749, 721, 689, 571, 515, 497 cmꢁ1; dH
(300 MHz, DMSO-d6) 5.11 (2H, m, CH2P), 7.05e7.11 (2H,
m), 7.32e7.43 (5H, m), 7.59 (1H, ddd, J 8.0, 8.0, 1.5 Hz,
H-7), 7.68 (1H, dd, J 8.0, 1.5 Hz, H-5), 7.72e7.82 (12H, m,
3ꢂ(H-200, H-300, H-500, H-600)), 7.85e7.93 (3H, m, 3ꢂH-400),
9.78 (1H, br s, NHCO), 11.27 (1H, br s, H-1); dC (75 MHz,
3-acetamidoquinolinediones 9b,d,h,j
A solution of the appropriate 3-bromoacetamidoquinoline-
2,4(1H,3H)-dione
7
(4 mmol) and triphenylphosphine
(1.154 g, 4.4 mmol) in benzene (30 mL) was heated at reflux
for 4 h. The reaction mixture was evaporated to dryness, redis-
solved in chloroform (30 mL), and extensively shaken with
aqueous sodium hydroxide (0.5 M, 10 mL) for 5 min. The
layers were separated and the chloroform layer was washed
with water (2ꢂ10 mL). Organic layer was dried over anhy-
drous sodium sulfate, filtered, and evaporated to dryness.
The residue was subjected to column chromatography on silica
gel using benzene and then using successive mixtures of
benzene/ethyl acetate (in ratios from 99:1 to 8:2) as eluents
to give pyrrolo[2,3-c]quinoline-2,4(3aH,5H)-diones 3b,d,h
and 3-acetamidoquinolinediones 9b,d,h. Using this procedure,
compound 7j only afforded the corresponding 3-acetamido-
quinolinediones 9j. The yields of the products are given in
Table 4.
1
DMSO-d6) 29.6 (d, JCP 57.1 Hz, CH2P), 71.8 (C-3), 116.4,
1
118.3 (d, JCP 88.7 Hz, C-100), 118.4, 122.9, 127.0, 127.4,
129.2, 129.7, 129.9 (d, JCP 13.0 Hz, C-200, C-600 or C-300,
C-500), 132.5, 133.7 (d, JCP 10.7 Hz, C-300, C-500 or C-200,
4
C-600), 134.8 (d, JCP 2.8 Hz, C-400), 136.5 (C-7), 140.8
2
(C-8a), 163.1 (d, JCP 5.1 Hz, CONH), 168.3 (C-2), 189.9
(C-4); dP (121 MHz, DMSO-d6) 25.0; HRESI-MS calcd for
C35H28N2O3P [MꢁBr]þ 555.1838, found 555.1820.
3.9.6. (2-(3-Methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydro-
quinolin-3-ylamino)-2-oxoethyl)triphenylphosphonium
bromide (8i)
3.11. General procedure for the preparation of pyrrolo-
[2,3-c]quinoline-2,4-(3aH,5H)-diones 3a,c,e,g from
phosphonium salts 8a,c,e,g
A mixture of bromoacetamide 7i (548 mg, 1.42 mmol), tri-
phenylphoshine (427 mg, 1.63 mmol), and benzene (7 mL)
was heated at reflux (KOHdseal) for 8 h. Two layers were
formed after cooling. The upper less-viscous layer was re-
moved and the bottom oily layer was extracted with benzene
(2ꢂ4 mL). Repeated crystallization of the refined oily layer
from ethanol/ethyl acetate mixture of solvents afforded 8i
(243 mg, 26%). Collected mother liquors after crystallizations
were evaporated in vacuo and subjected to column chromatog-
raphy on silica gel using chloroform and then successive mix-
tures of chloroform/ethanol in ratios 99:1 and 98:2 to give
crude compounds 9i and 3i in sequence. Crystallization of
these two crude products gave pure compounds 9i (125 mg,
29%) and 3i (11 mg, 2.5%).
A solution of the corresponding phosphonium salt 8
(0.18 mmol) in chloroform (10 mL) was extensively shaken
with aqueous sodium hydroxide (0.5 M, 8 mL) for 5 min.
The precipitated product 3 was suction filtered, washed with
chloroform, and crystallized from the solvent given below.
In the case of 3f, which after the above procedure remained
dissolved in chloroform, the organic layer was separated, dried
over Na2SO4, and evaporated to dryness. The oily residue was
triturated consecutively with hexane, cyclohexane, and diethyl
ether affording crystalline 3f.
The yields of the products are given in Table 3. For the
physical and spectroscopic data see above.

4400
S. Kafka et al. / Tetrahedron 64 (2008) 4387e4402
3.12. Independent synthesis of 3-acetamidoquinoline-
2,4(1H,3H)diones 9 from 3-aminoquinoline-2,4(1H,3H)-
diones 1
3.12.1.4. N-(3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-
yl)-N-butylacetamide (9d). White solid; mp 270e273 ꢀC
(methanol); IR 3224, 3158, 2996, 2929, 1703, 1670, 1613,
1599, 1486, 1431, 1370, 1285, 1257, 1206, 1154, 1077,
1011, 929, 822, 763, 699, 666 cmꢁ1; dH (300 MHz, DMSO-
d6) 0.99 (3H, t, J 7.3 Hz, CH3), 1.34e1.48 (2H, m),
1.77e1.82 (2H, m), 2.04 (3H, s, COCH3), 3.21 and 3.28
(2H, 2d, J 11.6 Hz, CH2), 3.60e3.70 (2H, m), 6.60 (1H, d,
J 8.0 Hz, H-8), 6.85 (1H, ddd, J 7.5, 7.5, 0.8 Hz, H-6), 6.88e
6.99 (5H, m), 7.24 (1H, ddd, J 7.6, 7.6, 1.4 Hz, H-7), 7.53
(1H, dd, J 7.8, 1.3 Hz, H-5), 10.58 (1H, br s, NH); dC
(75 MHz, DMSO-d6) 13.7, 19.5, 21.1, 33.2, 41.1, 44.8, 70.9,
115.5, 120.6, 121.3, 125.4, 127.1, 127.2, 130.2, 131.1,
134.5, 140.7, 170.4, 170.9, 193.8. Anal. Calcd for
C22H24N2O3: C, 72.51; H, 6.64; N, 7.69. Found: C, 72.54;
H, 6.69; N, 7.49.
3.12.1. General procedure for the preparation of 9aed,gei
To a solution of 3-aminoquinoline-2,4(1H,3H)-dione 1
(0.31 mmol) in pyridine (3 mL), acetic anhydride (98%,
0.5 mL, 5 mmol) was added. The reaction mixture was stirred
at room temperature for 6 h (9aec) or heated at 60 ꢀC for 1 h
(9d,gei), the volatile compounds were evaporated to dryness
in vacuo, and the residue was crystallized from the solvents
indicated below. The yields are listed in Table 5.
3.12.1.1. N-(3-Butyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-
yl)acetamide (9a). White solid; mp 242e245 ꢀC (benzene);
IR 3354, 3163, 3060, 2927, 1705, 1667, 1644, 1611, 1541,
1485, 1438, 1368, 1357, 1296, 1254, 1163, 1037, 949, 760,
666 cmꢁ1; dH (300 MHz, DMSO-d6) 0.76 (3H, t, J 6.7 Hz,
CH3), 1.07e1.28 (4H, m), 1.74 (2H, t, J 7.7 Hz), 1.85 (3H,
s, COCH3), 7.10 (1H, dd, J 7.2, 7.2 Hz, H-7), 7.11 (1H, d, J
7.7 Hz, H-8), 7.59 (1H, dd, J 7.5, 7.5 Hz, H-6), 7.75 (1H, d,
J 7.4 Hz, H-5), 8.82 (1H, br s, NH), 10.86 (1H, br s, NH);
dC (75 MHz, DMSO-d6) 13.5, 21.2, 22.0, 24.4, 35.9, 67.0,
116.2, 119.0, 122.2, 126.7, 135.8, 141.6, 169.1, 171.0,
193.3. Anal. Calcd for C15H18N2O3: C 65.68; H, 6.61; N,
10.21. Found: C, 65.60; H, 6.69; N, 9.99.
3.12.1.5. N-Butyl-N-(2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-
quinolin-3-yl)acetamide (9f). White solid; mp 222e224 ꢀC
(ethanol/ethyl acetate); IR 3229, 3165, 3139, 3121, 3100,
3065, 2995, 2964, 2927, 2859, 1713, 1676, 1613, 1604,
1508, 1496, 1486, 1464, 1450, 1433, 1347, 1322, 1307,
1255, 1241, 1226, 1211, 1176, 1156, 1124, 1077, 1036, 942,
880, 771, 758, 750, 699, 686, 669, 622, 590, 539, 525, 510,
438 cmꢁ1; dH (300 MHz, DMSO-d6) 0.57 (3H, t, J 7.3 Hz,
CH3), 0.80e0.97 (2H, m), 1.25e1.45 (2H, m), 2.11 (3H, s,
CH3), 3.00e3.12 (2H, m), 6.98e7.10 (2H, m), 7.38e7.55
(6H, m), 7.78 (1H, d, J 7.3 Hz), 11.1 (1H, br s, NH); dC
(75 MHz, DMSO-d6) 13.9, 20.0, 22.3, 32.2, 46.9, 77.9,
116.9, 120.3, 123.1, 128.3, 129.9, 130.1, 130.8, 131.2,
136.5, 141.6, 170.1, 171.7, 190.9; HRESI-MS calcd for
C21H23N2O3 [Mþ1]þ 351.1709, found 351.1720.
3.12.1.2. N-Butyl-N-(3-butyl-2,4-dioxo-1,2,3,4-tetrahydroqui-
nolin-3-yl)acetamide (9b). White solid; mp 114e116 ꢀC (benz-
ene/cyclohexane); IR 3195, 3070, 2959, 2929, 2867, 1697,
1666, 1632, 1614, 1487, 1431, 1414, 1369, 1362, 1255,
1208, 1157, 1029, 908, 807, 757, 692, 666 cmꢁ1; dH
(300 MHz, DMSO-d6) 0.72 (3H, t, J 7.0 Hz), 0.91e1.05
(4H, m), 1.12e1.27 (3H, m), 1.30e1.42 (2H, m), 1.68e1.98
(4H, m), 2.01 (3H, s, COCH3), 3.50 (2H, t, J 8.1 Hz), 7.07
(1H, dd, J 7.5, 7.5 Hz, H-6), 7.10 (1H, d, J 8.1 Hz, H-8),
7.56 (1H, ddd, J 7.7, 7.7, 1.5 Hz, H-7), 7.73 (1H, dd, J 7.8,
1.0 Hz, H-5), 10.87 (1H, br s, NH); dC (75 MHz, DMSO-d6)
13.4, 13.6, 19.5, 21.1, 22.3, 24.4, 33.0, 34.2, 44.6, 70.7,
116.2, 120.2, 121.9, 126.1, 135.3, 141.4, 170.5, 171.4,
193.6; HRESI-MS calcd for C19H27N2O3 [Mþ1]þ 331.2022,
found 331.2011.
3.12.1.6. N-(1-Methyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-
quinolin-3-yl)acetamide (9g). White solid; mp 225e229 ꢀC
(benzene); IR 3329, 3272, 3035, 1706, 1657, 1645, 1474,
1449, 1361, 1291, 1252, 1126, 1039, 996, 894, 769, 760,
704, 675 cmꢁ1; dH (300 MHz, DMSO-d6) 1.92 (3H, s,
COCH3), 3.51 (3H, s, NCH3), 7.18 (1H, dd, J 7.4, 7.4 Hz,
H-6), 7.27e7.38 (5H, m), 7.40 (1H, d, J 8.5 Hz, H-8), 7.71
(1H, ddd, J 7.8, 7.8, 1.3 Hz, H-7), 7.81 (1H, dd, J 7.6,
1.1 Hz, H-5), 9.31 (1H, s, NH); dC (75 MHz, DMSO-d6)
21.2, 30.0, 71.3, 115.8, 119.9, 122.9, 127.2, 127.6, 128.9,
129.2, 133.2, 136.2, 142.1, 169.3, 169.9, 189.9. Anal. Calcd
for C18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C,
69.84; H, 5.11; N, 9.03.
3.12.1.3. N-(3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-
yl)acetamide (9c). White solid; mp 232e236 ꢀC (methanol);
IR 3379, 3227, 3180, 3060, 2930, 1707, 1660, 1640, 1611,
1509, 1485, 1434, 1380, 1366, 1298, 1282, 1235, 1163,
1110, 1037, 940, 825, 774, 738, 698, 666 cmꢁ1; dH
(300 MHz, DMSO-d6) 1.86 (3H, s, COCH3), 3.07 and 3.14
(2H, 2d, J 12.5 Hz, CH2), 6.74 (1H, d, J 8.0 Hz, H-8),
6.89e6.98 (3H, m), 6.98e7.06 (3H, m), 7.35 (1H, ddd,
J 7.6, 7.6, 1.5 Hz, H-7), 7.59 (1H, dd, J 7.8, 1.3 Hz, H-5),
9.09 (1H, br s, NH), 10.69 (1H, br s, NH); dC (75 MHz,
DMSO-d6) 21.2, 43.2, 67.2, 115.7, 119.7, 121.8, 125.9,
127.1, 127.5, 129.7, 132.0, 135.4, 141.2, 169.0, 170.5,
193.9. Anal. Calcd for C18H16N2O3: C, 70.12; H, 5.23; N,
9.09. Found: C, 69.68; H, 5.22; N, 8.94.
3.12.1.7. N-Butyl-N-(1-methyl-2,4-dioxo-3-phenyl-1,2,3,4-tetra-
hydroquinolin-3-yl)acetamide
(9h). White
solid;
mp
167e169 ꢀC (cyclohexane); IR 3070, 2964, 2932, 1701,
1667, 1625, 1600, 1493, 1472, 1417, 1404, 1348, 1302,
1238, 1215, 1144, 1073, 1026, 993, 930, 887, 768, 751, 706,
663 cmꢁ1; dH (300 MHz, DMSO-d6) 0.56 (3H, t, J 7.3 Hz,
CH3), 0.83e0.97 (2H, m), 1.28e1.48 (2H, m), 2.10 (3H, s,
COCH3), 3.01e3.12 (2H, m), 3.46 (3H, s, NCH3), 7.16 (1H,
ddd, J 7.5, 7.5, 0.6 Hz, H-6), 7.29 (1H, d, J 8.3 Hz, H-8),
7.32e7.48 (5H, m), 7.63 (1H, ddd, J 7.8, 7.8, 1.2 Hz, H-7),

S. Kafka et al. / Tetrahedron 64 (2008) 4387e4402
4401
7.89 (1H, dd, J 7.7, 1.6 Hz, H-5); dC (75 MHz, DMSO-d6)
3.12.4. Preparation of N-(3-methyl-2,4-dioxo-1-phenyl-
13.0, 19.0, 21.4, 30.0, 31.2, 46.0, 77.1, 115.5, 120.5, 122.7,
127.7, 129.0, 129.2, 129.9, 130.0, 135.8, 141.6, 168.7,
170.8, 189.0. Anal. Calcd for C22H24N2O3: C, 72.50; H,
6.64; N, 7.69. Found: C, 72.40; H, 6.61; N, 7.79.
1,2,3,4-tetrahydroquinolin-3-yl)acetamide (9i) in toluene
To a stirred solution of 1i (370 mg, 1.39 mmol) in toluene
(35 mL) at 27 ꢀC, acetic anhydride (98%, 0.19 mL, 2.0 mmol)
was added and then stirring was continued for 1 h. The reaction
mixture was left at 10 ꢀC overnight and the resulting precipitate
was filtered off to give crude 9i (329.5 mg). The filtrate was con-
centrated invacuo to approximately 5 mL and the second crop of
crude 9i (62.7 mg) was obtained by filtration. Crystallization of
the combined crops (both being pure according to TLC analysis)
afforded 9i (301 mg, 70%).
3.12.1.8. N-(3-Methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydro-
quinolin-3-yl)acetamide (9i). White solid; mp 245e247 ꢀC
(benzene); IR 3297, 3065, 2984, 1721, 1686, 1651, 1601,
1543, 1492, 1463, 1377, 1341, 1301, 1253, 1209, 1181,
1159, 1138, 1109, 1072, 1024, 989, 853, 788, 760, 711, 691,
664, 614, 586, 523, 499, 448 cmꢁ1; dH (300 MHz, DMSO-
d6) 1.53 (3H, s, CH3), 1.87 (3H, s, COCH3), 6.37 (1H, d,
J 8.3 Hz, H-8), 7.03e7.23 (1H, br s), 7.20 (1H, dd, J 8.3,
6.4 Hz, H-7), 7.34e7.48 (1H, br s), 7.50e7.68 (4H, m), 7.93
(1H, dd, J 7.8, 1.5 Hz, H-5), 9.13 (1H, br s, NH); dC
(75 MHz, DMSO-d6) 21.6, 22.5, 64.5, 116.9, 119.1, 123.3,
128.1, 128.7, 129.2 (br), 130.6 (br), 136.3, 137.8, 144.0,
169.7, 171.7, 193.2. Anal. Calcd for C18H16N2O3: C, 70.12;
H, 5.23; N, 9.09. Found: C, 70.27; H, 5.52; N, 9.07.
3.12.5. N-Butyl-N-(3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-
tetrahydroquinolin-3-yl)acetamide (9j)
A solution of 1j (484 mg, 1.5 mmol) and acetic anhydride
(98%, 0.22 mL, 2.3 mmol) in toluene (35 mL) was stirred at
room temperature for 3 days. The second portion of acetic anhy-
dride (2.10 mL, 22 mmol) was added. The next day, pyridine
(0.32 mL, 4.0 mmol) was added in two equal portions at 9 h
interval. After stirring the reaction mixture overnight, the
solvent was evaporated in vacuo to give an oily residue from
which a solid precipitated upon workup with hexane (10 ꢀC).
Filtration and crystallization afforded 9j (339 mg, 62%).
3.12.2. Preparation of N-(2,4-dioxo-3-phenyl-1,2,3,4-
tetrahydroquinolin-3-yl)acetamide (9e)
A suspension of 1e (505 mg, 2.00 mmol) in toluene (70 mL)
and 98% acetic anhydride (0.6 mL, 6 mmol) wasstirred and heated
at reflux for 4 h and then stirring was continued at room tempera-
ture for an additional 4 h. The solids were filtered off and dried to
give pure 9e (512 mg, 87%), which for analyses was re-crystallized
from propan-2-ol (68% overall yield, see Table 5).
Compound 9e: white solid; mp 286e289 ꢀC (propan-2-ol);
IR 2820e3670, 3384, 3363, 3184, 3168, 3135, 3094, 3060,
3040, 2994, 2925, 2864, 1709, 1671, 1644, 1613, 1594, 1516,
1486, 1450, 1438, 1429, 1358, 1325, 1290, 1254, 1231, 1183,
1165, 1116, 1108, 1040, 1003, 943, 876, 818, 785, 767, 735,
696, 667, 574, 526, 507, 460, 438 cmꢁ1; dH (300 MHz,
DMSO-d6) 1.93 (3H, s, CH3), 7.05e7.13 (2H, m), 7.34e7.41
(5H, m), 7.58 (1H, ddd, J 7.6, 7.6, 1.2 Hz, H-7), 7.72 (1H, dd,
J 7.7, 1.2 Hz, H-5), 9.24 (1H, br s, NH), 11.13 (1H, br s, NH);
dC (75 MHz, DMSO-d6) 21.3, 71.1, 116.3, 118.7, 122.5,
127.2, 127.3, 128.9, 129.1, 133.2, 136.0, 141.1, 169.6, 169.9,
191.0. Anal. Calcd for C17H14N2O3: C, 69.38; H, 4.80; N,
9.52. Found: C, 69.16; H, 4.88; N, 9.57.
3.12.6. N-Butyl-N-(3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-
tetrahydroquinolin-3-yl)acetamide (9j)
White solid; mp 144e148 ꢀC (cyclohexane); IR 3061, 3036,
3008, 2986, 2967, 2952, 2933, 2871, 1703, 1671, 1631, 1601,
1496, 1483, 1464, 1423, 1379, 1370, 1359, 1342, 1308, 1266,
1242, 1217, 1199, 1163, 1199, 1163, 1103, 1018, 1001, 984,
894, 758, 749, 709, 692, 661, 608, 541, 446 cmꢁ1; dH
(300 MHz, DMSO-d6) 0.95 (3H, t, J 7.3 Hz, CH3CH2),
1.31e1.41 (2H, m, CH3CH2), 1.61 (3H, s, CH3e(C-3)), 1.64e
1.74 (2H, m, CH3CH2CH2), 2.06 (3H, s, COCH3), 3.55 (2H,
br t, J 8.1 Hz, CH3CH2CH2CH2), 6.38 (1H, d, J 8.3 Hz, H-8),
7.11 (1H, br d, J 6.7 Hz, H-20 (H-60)), 7.19 (1H, dd, J 7.5,
7.5 Hz, H-6), 7.40 (1H, br d, J 6.5 Hz, H-60 (H-20)), 7.52 (2H,
m, H-7, H-40), 7.56e7.66 (2H, m, H-30, H-50), 7.93 (1H, dd,
J 7.7, 1.4 Hz, H-5); dC (75 MHz, DMSO-d6) 13.7 (CH3CH2),
19.4 and 19.5 (CH3CH2 and CH3-(C-3)), 20.9 (CH3CO), 32.8
(CH3CH2CH2), 44.9 (CH3CH2CH2CH2), 69.1 (C-3), 116.3
(C-8), 118.8 (C-4a), 122.6 (C-6), 127.6 (C-5), 128.7 (C-40),
129.0 (br, C-20, C-60), 130.0 (br, C-30, C-50), 135.4 (C-7),
137.5 (C-10), 143.2 (C-8a), 170.5 (COCH3), 171.3 (C-2),
192.2 (C-4); dC (75 MHz, DMSO-d6, 373 K) 13.5, 19.5, 19.8,
20.9, 33.0, 45.2, 69.4, 116.4, 119.3, 122.6, 127.7, 128.6,
129.1, 129.9, 135.2, 137.9, 143.5, 170.6, 171.4, 192.1. Anal.
Calcd for C22H24N2O3: C, 72.51; H, 6.64; N, 7.69. Found: C,
72.30; H, 6.80; N, 7.62.
3.12.3. N-Butyl-N-(2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-
quinolin-3-yl)acetamide (9f)
Pyridine (0.95 mL, 12 mmol) and acetic anhydride (98%,
1.52 mL, 15.8 mmol) were added to a solution of 1f (1.213 g,
3.93 mmol) in toluene (80 mL). The mixture was stirred at
60 ꢀC for 1 h, followed by the addition of a second aliquot of
pyridine (0.95 mL, 12 mmol). The homogeneous mixture was
stirred at 65e75 ꢀC for 4 h. Then stirring was continued without
heating overnight. The resulting precipitate was filtered off to
give crude 9f (1.096 g). The filtrate was concentrated in vacuo
to approximately 10 mL, from which the second crop of crude
9f (310 mg) was filtered off. Crystallization of the combined
crops (both being pure according to TLC analysis) afforded 9f
(929 mg, 67%).
Acknowledgements
This study was supported by the Czech Science Foundation
(Grant No. 203/07/0320), by the Ministry of Education, Youth
and Sports of the Czech Republic (Project MSM7088352101
and Joint Project Nr 9-06-3 of Programme KONTAKT), and
the Slovenian Research Agency (Projects P1-0230-0103 and

4402
S. Kafka et al. / Tetrahedron 64 (2008) 4387e4402
6. (a) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Paladino, G.; Zoni, C.
Eur. J. Org. Chem. 2005, 2091e2096; (b) Bergman, J.; Rehn, S.
Tetrahedron 2002, 58, 9179e9185 and references cited therein.
Joint Project BI-CZ/07-08-018). The authors thank Dr. Bogdan
ˇ
ˇ
ꢀ
Kralj and Dr. Dusan Zigon (Mass Spectrometry Center, Jozef
Stefan Institute, Ljubljana, Slovenia) for mass spectral measure-
ments, Professors Slovenko Polanc and Mahesh Lakshman for
helpful discussions during the preparation of the manuscript,
7. (a) Fryer, I. R.; Ning, R. Y.-F.; Sternbach, L. H.; Walser, A.
(HoffmanneLa Roche, Inc., USA) U.S. Patent 4,014,883, 1977; Chem.
Abstr. 1977, 87, 39450; (b) Thal, C.; Boye, O.; Guenard, D.; Potier, P.
(Centre National de la Recherche Scientifique, Fr.) Patent No. WO
9002733, 1990; Chem. Abstr. 1990, 113, 115077; (c) Alazard, J.-P.;
´
and Mrs. Hana Gerzova for technical assistance.
ꢀ
´
Millet-Paillusson, C.; Guenard, D.; Thal, C. Bull. Soc. Chim. Fr. 1996,
References and notes
133, 251e266; (d) Gorlitzer, K.; Fabian, J.; Frohberg, P.; Drutkowski,
G. Pharmazie 2002, 57, 243e247; (e) Pfefferkorn, J. A.; Song, Y.; Trivedi,
B. K. (WarnereLambert Company LLC, USA), Patent No. WO
2006059210, 2006; Chem. Abstr. 2006, 145, 45964; (f) Nakahira, H.;
Kimura, H.; Hochigai, H. (Dainippon Simitomo Pharma Co., Ltd, Japan)
Patent No. WO 2006112331, 2006; Chem. Abstr. 2006, 145, 454996; (g)
Bienayme, H.; Dumoulin, A.; Grisoni, S.; Kaloun, El B.; Poigny, S.; Rabot
R.; Rahali, R.; Tam, E. (Pierre Fabre Medicament, Fr.) Patent No. FR
2887881, 2007; Chem. Abstr. 2007, 146, 121944.
´
ˇ
1. (a) Klasek, A.; Koristek, K.; Polis, J.; Kosmrlj, J. Heterocycles 1998, 48,
2309e2326; (b) Klasek, A.; Koristek, K.; Polis, J.; Kosmrlj, J. Tetra-
ˇ
´
ˇ
ˇ
´
hedron 2000, 56, 1551e1560; (c) Klasek, A.; Polis, J.; Mrkvicka, V.;
ꢀ
ˇ
´
Kosmrlj, J. J. Heterocycl. Chem. 2002, 39, 1315e1320; (d) Klasek, A.;
Koristek, K.; Kafka, S.; Kosmrlj, J. Heterocycles 2003, 60, 1811e1820;
ˇ
ˇ
´
ꢀ
ˇ
(e) Klasek, A.; Mrkvicka, V.; Pevec, A.; Kosmrlj, J. J. Org. Chem.
ˇ
2004, 69, 5646e5651; (f) Kosmrlj, J.; Kafka, S.; Leban, I.; Grad, M.
8. It has been reported that bromoacetamides can be prepared from amines
and bromoacetyl bromide in THF as a solvent, see, for example: (a)
Suzuki, T.; Nagano, Y.; Matsuura, A.; Kohara, A.; Ninomiya, S.; Kohda,
K.; Miyata, N. Bioorg. Med. Chem. Lett. 2003, 13, 4321e4326; (b)
Torres-Murro, J.; Quintero, L.; Sartillo-Piscil, F. Tetrahedron Lett. 2005,
46, 7691e7694.
´ꢀ
ꢀ
Magn. Reson. Chem. 2007, 45, 700e704; (g) Pomeisl, K.; Kvıcala, J.;
´
´
ꢀ
Paleta, O.; Klasek, A.; Kafka, S.; Kubelka, V.; Havlıcek, J.; Cejka, J.
ˇ
´
Tetrahedron 2007, 63, 10549e10561; (h) Kafka, S.; Kosmrlj, J.; Klasek,
A.; Pevec, A. Tetrahedron Lett. 2008, 49, 90e93.
´
2. Kafka, S.; Klasek, A.; Polis, J.; Kosmrlj, J. Heterocycles 2002, 57,
ˇ
1659e1682.
9. After our experiments in THF were completed, we came across with the
work of Schneider and Viljoen who demonstrated how THF reacts with
bromoacetyl bromide to afford 4-bromobutyl bromoacetate, see:
Schneider, D. F.; Viljoen, M. S. Synth. Commun. 2002, 32, 721e728.
10. Bestmann, H. J. Angew. Chem. 1965, 77, 609e613.
´
3. (a) Klasek, A.; Lycka, A.; Holcapek, M.; Hoza, I. Tetrahedron 2004, 60,
ꢀ
ꢀ
´
9953e9961; (b) Klasek, A.; Koristek, K.; Lycka, A.; Holcapek, M.
Tetrahedron 2003, 59, 5279e5288; (c) Klasek, A.; Lycka, A.; Holcapek,
ˇ
ꢀ
ꢀ
´
ꢀ
ꢀ
M.; Hoza, I. J. Heterocycl. Chem. 2006, 43, 1251e1260.
´ˇ
4. Kafka, S.; Kovar, M.; Klasek, A.; Kappe, T. J. Heterocycl. Chem. 1996,
´
11. Podesva, C.; Vagi, K.; Solomon, C. Can. J. Chem. 1968, 46, 2263e2269.
12. Bonne, D.; Dekhane, M.; Zhu, J. Org. Lett. 2005, 7, 5285e5288.
33, 1977e1982.
´
5. Klasek, A.; Kafka, S. J. Heterocycl. Chem. 1998, 35, 307e311.