Efficient regioselective heterocyclisation leading to fluorescent fused pyrazine derivatives

Article abstract of DOI:10.1016/j.tet.2011.05.048

The regioselective syntheses of substituted pyrrolo[2,3-b]quinoxaline, pyrido[2,3-b]pyrrolo[2,3-e]pyrazine, pyrido[2,3-b]pyrrolo[3,2-e]pyrazine and pyrido[3,4-b]pyrrolo[3,2-e]pyrazine are reported. Differential reactivity between two amino groups in ortho-diaminopyridine can be exploited to obtain new regio-defined unsymmetrical pyridopyrrolopyrazine derivatives. Weak electron-donating methyl or moderately electron-withdrawing carboxylic groups attached to the aromatic ortho-diamines reduce the regioselectivity of obtaining unsymmetrical substituted pyrrolo[2,3-b]quinoxaline. The fluorescence properties of the resultant 1-alkyl pyridopyrrolopyrazine and substituted pyrrolo[2,3-b]quinoxaline derivatives are presented.

Full text of DOI:10.1016/j.tet.2011.05.048

Tetrahedron 67 (2011) 5219e5227
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient regioselective heterocyclisation leading to fluorescent fused pyrazine
derivatives
,
a
a
Katarzyna Ostrowska a , Katarzyna Szymoniak , Magdalena Szczurek ,
*
Krzysztof Jamrozy b, Maria Ra˛pa1a-Kozik c
Department of Organic Chemistry, Jagiellonian University, R. Ingardena 3, PL-30060 Krakow, Poland
Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Niezapominajek 8, PL-30239 Krakow, Poland
Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, PL-30387 Krakow, Poland
a,
_
a
ꢀ
b
c
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
The regioselective syntheses of substituted pyrrolo[2,3-b]quinoxaline, pyrido[2,3-b]pyrrolo[2,3-e]pyr-
azine, pyrido[2,3-b]pyrrolo[3,2-e]pyrazine and pyrido[3,4-b]pyrrolo[3,2-e]pyrazine are reported. Differ-
ential reactivity between two amino groups in ortho-diaminopyridine can be exploited to obtain new
regio-defined unsymmetrical pyridopyrrolopyrazine derivatives. Weak electron-donating methyl or
moderately electron-withdrawing carboxylic groups attached to the aromatic ortho-diamines reduce the
regioselectivity of obtaining unsymmetrical substituted pyrrolo[2,3-b]quinoxaline. The fluorescence
properties of the resultant 1-alkyl pyridopyrrolopyrazine and substituted pyrrolo[2,3-b]quinoxaline
derivatives are presented.
Received 28 December 2010
Received in revised form 19 April 2011
Accepted 10 May 2011
Available online 17 May 2011
Keywords:
ortho-Diaminopyridine
Heterocyclisation
Regioselectivity
Published by Elsevier Ltd.
Pyrrolo[2,3-b]quinoxaline
Pyridopyrrolopyrazine
1. Introduction
2,3-diaminopyridine in the presence of TsOH (pK¼0.7) in the ratio
1:1.3:0.6 proceededwiththedeactivationofthemorebasicC-3 amino
Synthesising analogues of bioactive natural products containing
unsymmetrical units very often requires applying regio-defined
procedures or efforts in the separation of regioisomers. Aromatic
group via formation of a salt. We obtained only one regioisomer,
1-arylpyrido[2,3-b]pyrrolo[2,3-e]pyrazine-2-one, as the product of
the reaction of the more reactive carbonyl group at C-3 of 1 and the
weakest nucleophilic C-2 amino group of 2,3-diaminopyridine.
In this paper, we report the methods to prepare 1-alkyl,1-aryl-
pyrroloquinoxaline 2e6 and regio-defined 1-alkyl,1-aryl-pyr-
idopyrrolopyrazine 7e9 derivatives and their fluorescent properties
(Fig.1). Regioselective heterocyclisationwasachieved byapplyingtwo
procedures. The first procedure was based on the direct condensation
and heteroaromatic ortho-diamines and a-dicarbonyl compounds
are usually used as the building blocks in the synthesis of various
substituted quinoxalines, regioisomeric pyridopyrazine derivatives,
potential DNA intercalators1 and fluorophores.
The different nucleophilicity of amino groups in substituted
aromatic ortho-diamines, including 2,3-diaminopyridine, 3,4-
diaminopyridine, 3,4-diaminotoluene and 3,4-diaminobenzoic acid,
should influence the distribution of products. The presence of the
deactivating group or a nitrogen atom in the aromatic ring differen-
tiates the reactivity and influences the regioselectivity of the re-
actions. According to the chemoselectivity, the most basic amino
group should react with the most reactive carbonyl carbon atom, and
the reaction should lead to the formation of the predominant
regioisomer.2e12 However, the protection of this amino group with
complete control of the regiochemistry should lead to the other
regioisomer. Our previous study13,14 confirmed that condensa-
tion of polycarbonyl N-arylpyrrole 1 (pK¼2.63) derivatives with
of N-alkyl, N-arylpyrrolidinetrione
1 with 3,4-diaminotoluene,
3,4-diaminobenzoic acid and 2,3- or 3,4-diaminopyridine. The second
procedure was a multistep method exploiting the exo-enol tautom-
erism of
1 in CH2Cl2 during the first step, which leads to
3-chloropyrrolinedione.15 Then, the latter was easily substituted with
complete control of the regiochemistry by the more reactive amino
group of ortho-diaminoarene. In the last step, the monosubstituted
3-amino-4-benzoylopyrroline-2,5-dione derivatives were cyclised to
form fused heterocyclic systems.16e18
2. Results and discussion
The inductive effect of the methyl group in 3,4-diaminotoluene
activates the C-4 position in the benzene ring, whereas the same
* Corresponding author. Fax: þ48 12 63 40 515; e-mail address: ostrowsk@
chemia.uj.edu.pl (K. Ostrowska).
0040-4020/$ e see front matter Published by Elsevier Ltd.
doi:10.1016/j.tet.2011.05.048

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K. Ostrowska et al. / Tetrahedron 67 (2011) 5219e5227
R
R
R
R
O
R
N
N
N
N
N
N
N
N
N
N
N
R1
O
O
O
O
Ph
O
N
H
N
H
N
H
N
H
N
O
H
O
Ph
Ph
Ph
Ph
O
O
O
O
2 - 6
1
9
8
7
Fig. 1. General structure of heterocycles studied in this paper.
effect of the carboxylic acid group deactivates the C-3 position in
3,4-diaminobenzenecarboxylic acid. Therefore, the more basic
amino group in direct condensation conditions preferentially forms
the acid 1 salts with OH, which enables the nucleophilic attack of
the C-3 amino group in 3,4-diaminotoluene or the C-4 group in 3,4-
diaminobenzoic acid on the nonamide carbonyl carbon atom first.
In both cases, we obtain a mixture of two pairs of regioisomers, 3,4
and 5,6, respectively, with a slight excess of one form, i.e., 4 and 5
(Table 1). We could not manage to separate regioisomers 3, 4 and
5,6 via TLC, but we isolated 3a and 5a during fractional recrystal-
lisation from DMSO and DMF, respectively (Scheme 1).
formation of one product, 2H-pyrido[3,4-b]pyrrolo[3,2-e]pyrazin-
2-one, as a salt for 9ad and non-bonded for 9b (Scheme 2).
The application of the second concept to the synthesis without
separation of intermediate products in the case of the reaction
with 3,4-diaminotoluene and 3,4-diaminobenzoic acid did not
improve the regioselectivity (Scheme 3, Table 1). The presence of
a methyl or carboxylic group in the aromatic ortho-diamine did
not establish differential reactivity between these two amino
groups.
On the contrary, 2,3-diaminopyridine selectively reacted with 3-
chloropyrroline 2,5-dione derivatives to provide the mono-
Table 1
Cyclocondensation of o-diamines with 1
R
Product yield [%]
A
RS [%]
O
N
Ph
O
B
C
D
OH
O
NH2
NH2
1a R¼Bn
2a 90
1b R¼CH2CH2Ph
2b 89
1c R¼C6H3(2,5-OMe)14
2c 8914
NH
1a
1b
1c
3a/4a 70
3b/4b 75
3c/4c 66
34
36
(A) 41:59; (D) 49:51
(A) 42:58; (B) 41:59
(A) 45:55
68
NH
NH
NH
1a
1b
1c
5a/6a 94
5b/6b 96
5c/6c 80
56
32
(A) 55:45; (C) 63:36; (D) 70/30
(A) 71:29
(A) 74:26
HOOC
NH
NH
1a
7a/8a 52
7b/8b 62
7c 6014
32
34
(B) 90:10; (D) 28:72
(B) 85:15; (C) 75:25; (D) 0:100
(B) 100
1b
N
1c14
NH
NH
1a
1b
9a 43
9b 38
9d 43
100
100
100
N
1d R¼C6H4(4-Me)
A: EtOH, AcOH, refluxed; B: AcOH, TsOH (1:1.3:0.6), 70 ꢀC; C: AcOH, refluxed; D: (i) SOCl2; (ii) H2NAr; (iii) EtOH, AcOH, 70 ꢀC; RS: reaction selectivity (ꢁ2%).
Contrary to our previous results, in the reaction of 2,3-
diaminopyridine with N-alkylpyrrolidinetrione 1a,1b with the ad-
dition of TsOH in a ratio of 1.3:1:0.6, we obtained the mixture of
two regioisomers 7a, 8a and 7b, 8b (Table 1), respectively. The
electron-donating influence of the N-alkyl group in 1 probably
activates the amide carbon atom at C-2 to the nucleophilic attack.
Repeating this reaction with 1b without TsOH and in an equimolar
ratio shows that TsOH displaces the weakest acid 1 and favours the
formation of pyrido[2,3-b]pyrrolo[2,3-e]pyrazine 7b (Table 1,
Scheme 1).
substituted intermediate 12ab with complete control of the
regiochemistry (Scheme 4). Cyclisation of the 3-amino-4-benzoyl-
pyrroline-2,5-dione derivative 12ab in EtOH with the addition of
acetic acid allowed us to obtain the regioisomer 8a in excess and
the pure compound 8b.
The formation of two regioisomers in the last step of this pro-
cedure is likely due to the hydrolysis of the enamine bond of C3eN
caused by the water evolved during cyclisation.
The structure of the regioisomers was confirmed by NMR
spectroscopy. We reported that the 1H NMR data of 2 revealed
the solvent effect of DMSO-d6 and CDCl3 on H-5, H-200/600
chemical shifts.14 The proton H-5 was deshielded in DMSO-d6 for
2a at 0.67 ppm and 2b at 0.63 ppm; whereas, the protons H-200/600
were upfield shifted for 2a at 0.21 ppm and 2b at 0.25 ppm. The
3,4-Diaminopyridine is less prone to nucleophilic attack;
therefore, the condensation without TsOH gives very poor yields for
9ab. The addition of 0.6 equiv of the condensing agent and
extending the reaction time to 50 h leads to the regioselective

K. Ostrowska et al. / Tetrahedron 67 (2011) 5219e5227
5221
R
R
R
R
N
N
N
N
COOH
N
N
N
N
O
O
O
+
O
+
N
H
N
H
N
H
N
H
COOH
Ph
Ph
Ph
O
Ph
3a-c
O
O
5a-c
4a-c
O
6a-c
EtOH, AcOH,
reflux
NH2
NH2
HOOC
NH2
NH2
EtOH, AcOH,
reflux
NH2
NH2
NH2
R
N
O
R
, (1.3 equiv)
NH2
R
N
R
EtOH, AcOH,
reflux
N
TsOH (0.6 equiv),
AcOH, 70 C
N
N
N
N
N
N
Ph
O
O
+
O
O
N
H
N
H
N
N
H
OH
1a R = CH2Ph
b R = CH2CH2Ph
c R = C6H3(2,5-OMe)
O
Ph
Ph
Ph
O
O
2a
2b
O
8a
8b
R
N
N
N
O
N
7a
7b
Ph
OH
Scheme 1. Direct condensation of 1 with substituted aromatic ortho-diamines.
Ph
R
NH
NH
NH
2
R
2
2
O
N
N
N
N
N
N
2 , (1.2 equiv)
, (1.2 equiv)
N
NH
N
N
O
N
Ph
TsOH (0.6 equiv),
AcOH, 70 C
O
TsOH (0.6 equiv),
AcOH, 70 C
1a,b
1d R = C6H5(4-Me)
N
O
OH
O
Ph
OH
Ph
salt 9a : 1a 43%
salt 9d : 1d 43%
OH
9b 38%
Scheme 2. Direct condensation of 1 with 3,4-diaminopyridine.
resolution of the pair of regioisomers, 3 and 4, was based on the
same effect. The signals for H-200/600 were observed at lower field
(for 3b and 4b at 0.27 ppm). Additionally, a different population
for both sets showed the domination of one regioisomer. The
presence of the nuclear Overhauser effect (NOE) for 3a between
distinguishable H-200/600 and H-5 protons definitively assigned the
structure of 3. The 1H NMR data for 5 and 6 gave two sets
of signals with the doublet at 8.82 ppm for benzyl and 2,5-
dimethoxyphenyl derivatives and 8.85 ppm for 2-phenylethyl,
all with a long range constant of 4J 1.8 Hz. According to the
electronic effect of the carboxylic group and the solvent effect of
DMSO-d6, we attributed these signals to the H-5 proton of
regioisomer 6. The structure of compounds 8 and 9 was con-
firmed by 1D and 2D NMR experiments involving HSQC, HMBC
and NOESY (Table 2).
can be applied for labelling amino acids, peptides, proteins, DNA and
other biomolecules; however, we found several papers concerning
the photophysical studies of quinoxaline,19,20 pyridopyrazine,20
pyrrolopyrazine21,22 and pyrrolo[2,3-b]quinoxaline22 systems. Here,
we present the preliminary study of the fluorescent properties of the
1-alkyl pyrrolo[2,3-b]quinoxaline 2aec, 3a, 5b, pyrido[2,3-b]pyrrolo
[2,3-e]pyrazine 7b, pyrido[2,3-b]pyrrolo[3,2-e]pyrazine 8b, and
pyrido[3,4-b]pyrrolo[3,2-e]pyrazine 9b derivatives.
Typical absorption and emission spectra in acetonitrile for the
compounds under study are presented in Fig. 2. The absorption
spectra of compounds 2aec exhibited peaks centred at 392 nm
with a shoulder at 414 nm. The differences in absorption spectra of
the compounds 2a, 3a and 5a, as presented in Table 3, are probably
due to substituents with different electron-donor abilities. For
regioisomers 7b and 8b, no significant differences were observed in
the absorption maxima, with the exception of the blue shift in the
absorption spectrum of compound 9b.
The 1H NMR data of 12a and 12b revealed one set of signals,
which we attributed to the substitution product of the more nu-
cleophilic amino group at C-3 in 2,3-diaminopyridine in accordance
with the structure of the fused compounds 8ab.
The fluorescence emission spectra exhibited features similar to
those of the corresponding absorption spectra. The quantum yields
Fluorescence detection can be used in a wide range of studies
related to life science. Fluorophores based on nitrogen heterocycles
(
Fn) and lifetimes (
sn) for all of the analysed compounds were
determined in acetonitrile at 25 ꢀC upon excitation at selected

5222
K. Ostrowska et al. / Tetrahedron 67 (2011) 5219e5227
Bn
O
Bn
O
N
N
Ph
O
Ph
O
O
OH
OH
O
1a
SOCl2
CH2Cl2, 0 C
Bn
O
N
Bn
Ph
O
O
H N
H N
O
3a
5a
+
4a
6a
EtOH, AcOH,
70 C
N
R
, rt
HN
Ph
O
R1
O
Cl
+
H2N
10a R1 = CH3
11a R1 = COOH
Scheme 3. Three-step method of synthesis of 6- or 7-substituted pyrrolo[2,3-b]quinoxaline derivatives.
R
O
N
R
7a
8b
+
8a
NH2
NH2
Ph
O
SOCl2
CH2Cl2, 0 C
O
N
EtOH, AcOH,
70 C
N
, rt
N
O
HN
1
Ph
O
O
Cl
H2N
12a
12b
Scheme 4. Three-step method of synthesis of regioisomer 8a in excess and 8b.
Table 2
NMR spectral data for 8b and 9b [300.18 MHz, DMSO-d6,
d (ppm)]
Atom
8b
9b
HSQC
13C
HMBC
NOESY
HSQC
13C
HMBC
NOESY
1H
1H
2
3
166.0
94.9
d
166.0
98.15
d
HeCH2N
d
d
3a
4
4a
5
6
7
8
8a
9a
10
10
20/60
30/50
40
CH2N
CH2Ph
100
200/600
300/500
400
139.3
N
d
139.68
N
138.66
114.29
138.32
N
142.86
132.04
151.09
189.13
138.21
128.76
126.38
128.37
40.35
d
13.76
d
H-5
d
124.0
128.2
122.2
145.5
N
145.8
151.3
188.7
138.4
128.7
128.4
126.3
39.5
H-6
d
H-5, H-6
H-6
H-8
8.65
7.62
8.69
d
H-4, H-6
H-7
H-6
8.30
8.68
H-6, H-8
H-5, H-8
9.34
d
H-6
H-5, H-6, H-30/50, HeCH2N, HeCH2Ph
d
H-5, H-7
HeCH2N
H-200/600
H-30/50, HeCH2Ph
HeCH2Ph
H-8
HeCH2N
H-200/600
d
d
d
d
d
d
H-20/60, HeCH2N
HeCH2Ph
H-20/60
7.24
7.28
7.20
4.11
3.04
d
7.26
7.24
7.29
4.09
3.04
d
H-20/60
H-30/50, H-20/60
H-20/60
HeCH2Ph
H-8
H-8, H-300/500
33.5
34.61
H-30/50
138.5
128.7
127.6
131.6
H-300/500
H-200/600
137.76
128.90
127.08
132.37
H-300/500
H-400, H-300/500
7.76
7.47
7.57
H-300/500, H-400
H-200/600
7.75
7.49
7.62
H-8
H-200/600
wavelengths, and the results are presented in Table 3. Incorporation
of the C6H3(2,5-OMe) moiety (compound 2c) in place of (CH2)nPh
(compounds 2a and 2b) resulted in a loss of fluorescence proper-
ties. The fluorescence decay for all the samples was reasonably
fitted to a monoexponential equation, suggesting the emission
originated from the singlet-excited state in each case. The fluo-
rescence quantum yields and lifetimes of compounds 7b and 9b
were significantly lower in comparison to the other analysed
compounds, possibly as a consequence of the nonradiative de-
activation of the singlet state.

K. Ostrowska et al. / Tetrahedron 67 (2011) 5219e5227
5223
a
regioselective manner, whereas
a
moderately electron-
withdrawing carboxylic acid group favours the formation of the
7-carboxylic acid of pyrrolo[2,3-b]quinoxaline independent of the
1.0
0.5
0.0
1.0
0.5
0.0
method used. The presence of
a nitrogen atom in 2,3-
diaminopyridine and 3,4-diaminopyridine diverts more of the nu-
cleophilicity of the ortho-diamino groups than the carboxylic
group. We also showed that 1-alkyl pyrrolo[2,3-b]quinoxaline,
pyrido[2,3-b]pyrrolo[2,3-e]pyrazine,
pyrido[2,3-b]pyrrolo[3,2-e]
pyrazine and pyrido[3,4-b]pyrrolo[3,2-e]pyrazine had weak
fluorescence properties. The presence of the aryl group at the
N-1 position for pyrrolo[2,3-b]quinoxaline resulted in a loss of
fluorescence emission. The position of the nitrogen atom in
the pyridine of the fused heterocyclic system affects the fluores-
cence intensity, which is higher for pyrido[2,3-b]pyrrolo[3,2-e]
pyrazine 8b.
250 300 350 400 450 500 550 600
wavelenght (nm)
Fig. 2. Normalised absorption (bold line) and emission (fine line) spectra of compound
2a in acetonitrile.
Table 3
4. Experimental section
4.1. General
Photophysical properties of the analysed compounds dissolved in acetonitrile
(Mꢂ1 cmꢂ1
)
lem (nm) Fn
snb (ns)
a,b
Compound labs (nm)
3
2a
2b
2c
3a
5a
7b
8b
9b
392
392
392
398
394
392
392
381
22,350
24,900
25,500
21,450
19,500
20,800
21,800
19,900
447
447
d
0.132ꢁ0.021 0.585ꢁ0.003
0.128ꢁ0.020 0.569ꢁ0.002
Phenylenediamine, 3,4-diaminotoluene, 3,4-diaminobenzoic
acid, 2,3- and 3,4-diaminepyridine were commercial products
(Aldrich). The melting points were determined on a Boetius PHMK
05 melting point apparatus. The IR spectra were measured on
a Bruker IFS 48 in KBr pellets or Nujol. The 1H NMR, 13C NMR, COSY,
NOESY, HSQC and HMBC spectra were recorded with a Bruker
d
d
455
452
447
452
441
0.189ꢁ0.027 0.675ꢁ0.002
0.153ꢁ0.028 0.621ꢁ0.005
0.092ꢁ0.016 0.393ꢁ0.003
0.202ꢁ0.028 0.770ꢁ0.002
0.046ꢁ0.015 0.280ꢁ0.005
a
Avance II 300 spectrometer at 300 K. The chemical shifts (
reported in parts per million (ppm) on a scale downfield from
TMS. The 1H NMR spectra were referenced internally to the residual
proton resonance in CDCl3 7.26 ppm) or DMSO-d6 2.50 ppm).
The 13C NMR spectra were referenced to CDCl3
77.0 ppm) or
DMSO-d6 ( 39.5 ppm). The coupling constants (J) were reported in
d) were
The fluorescence quantum yields (Fn) were estimated from the corrected
fluorescence spectra using 9,10-diphenylanthracene in cyclohexane (Fs¼0.90) as
a standard.
d
b
Average of five measurements.
(d
(d
(d
d
The changes in the fluorescence properties of compound 2b in
different solvents are summarised in Table 4. Compound 2b, dis-
solved in protic solvents, showed a bathochromic shift in the
fluorescence emission maximum of the fluorescence spectra. The
shift was accompanied by a lowering of the fluorescence quantum
yield and lifetime due to the polar interactions participating in
nonradiative deactivation.
Hertz (Hz). The mass spectra were measured on a Finnigan Mat 95
(EI, 70 eV) and ESI. The microanalyses were performed with a Euro
EA 3000 Elemental Analyser; the results agreed satisfactorily with
calculated values. The 13C NMR spectra were not taken for 3a, 3c, 4a
and 4c because of their extremely low solubility.
All the solvents for the UV and fluorescence spectra were
obtained from SigmaeAldrich or Merck and were of spectroscopic
purity. The analysed compounds were dissolved in acetonitrile to
prepare 20 mM stock solutions for determination of their photo-
Table 4
Solvent effect on the spectral properties of compound 2b
physical properties. The effect of solvent polarity was examined by
measuring the absorbance and fluorescence of the compounds di-
luted in selected solvents using 1 mM stock solution prepared in
N,N-dimethylformamide (DMF).
The absorption spectra were recorded with a Power WaveX-
Select spectrophotometer (Bio-Tek Instruments) in 1-cm cells.
The fluorescence measurements were performed using a HITACHI
F-4500 spectrofluorometer. All the spectra were recorded at 25 ꢀC
with an excitation slit width of 5 nm, an emission slit of 10 nm and
700 V of PMT voltage.
Solvent
labs (nm)
lem (nm)
Fn
sn (ns)
CHCl3
THF
Acetone
EtOH
MeOH
MeCN
395
394
389
392
392
392
450
449
449
455
455
447
0.113ꢁ0.022
0.119ꢁ0.020
0.101ꢁ0.020
0.038ꢁ0.005
0.028ꢁ0.007
0.128ꢁ0.023
0.484ꢁ0.005
0.539ꢁ0.003
0.566ꢁ0.003
0.397ꢁ0.003
0.252ꢁ0.002
0.569ꢁ0.005
3. Conclusions
The fluorescence quantum yields of the analysed compounds
were determined using 9,10-diphenylanthracene (
F
s¼0.90 in cy-
In conclusion, we have shown that the differential reacti-
vity between two amino groups in ortho-diaminopyridine
can be exploited to obtain regio-defined unsymmetrical pyr-
idopyrrolopyrazine derivatives. When the most nucleophilic amino
group is involved in the formation of a salt in direct condensation
with the presence of TsOH (method B), pyrido[2,3-b]pyrrolo[2,3-e]
pyrazine 7 and pyrido[3,4-b]pyrrolo[3,2-e]pyrazine 9 are obtained
with control of the regiochemistry. When the most nucleophilic
amino group of 2,3-diaminopyridine substitutes a chlorine atom in
the three-step procedure (method D), the reaction predominantly
leads to the formation of pyrido[2,3-b]pyrrolo[3,2-e]pyrazine 8.
A weak electron-donating methyl group attached to the ortho-
diaminobenzene reduced the ability to construct compounds in
clohexane) as a standard. The fluorescence lifetimes were de-
termined using a time-correlated single photon counting system
based on the Horiba Jobin Yvon IBH lifetime spectrofluorometer
system components, which consisted of a picosecond single-
photon detection TBX-04 module, integrated with a fast photo-
multiplier, high-voltage power supply, GHz preamplifier and
picosecond-timing discriminator. A picosecond pulsed laser diode
(NanoLED-11, Horiba Jobin, Yvon) was used as a light source. The
specimens were excited at 372 nm with 1 MHz repetition. The
fluorescence decays were observed through a cut-off filter of
475 nm (Andover Corporation Optical Filter). To avoid pulse pile-
up, the power of the diode was adjusted to the appropriate low
level by a neutral gradient filter. The excitation pulse diode laser

5224
K. Ostrowska et al. / Tetrahedron 67 (2011) 5219e5227
profile, required for the deconvolution analysis, was measured on
a diluted glycogen suspension without using a filter. For the data
acquisition and decay analysis, the Jobin Yvon IBH data station and
DAS6 software were used. All the measurements were performed at
25 ꢀC, and each recorded lifetime was averaged from five in-
dependent decay measurements.
3-Benzoyl-1-benzyl-1,4-dihydropyrrolo[2,3-b]quinoxalin-2(4H)-
one (2a). Yellow needles, yield: 1.06 g (90%); mp: 275e277 ꢀC; IR
(KBr):
n
¼3490 (OH), 3264 (NH), 3060, 3026 (CH, Ar), 2916 (CH,
CH2), 1708 (C]O), 1653 (C]N), 1616 (C]C) cmꢂ1
;
1H NMR
(300.13 MHz, DMSO-d6):
d
5.08 (s, 2H, CH2), 7.24 (dd, 1H, 3J¼7.4,
4J¼1.1, H-40), 7.31 (dddd, 2H, 3J¼7.9, 3J¼7.4, 4J¼1.4, J¼0.7, H-30/50),
5
7.34 (dddd, 2H, 3J¼7.9, 4J¼2.0, 4J¼1.1, J¼0.7, H-20/60), 7.48 (dddd,
5
5
4.2. General procedure for preparing N-aryl-, Nalkylpyrro
lidine-2,3,5-trione 1
2H, 3J¼7.7, 3J¼7.5, 4J¼1.4, J¼0.6, H-300/500), 7.50 (dd, 1H, 3J¼8.1,
3J¼7.2, 4J¼1.4, H-7), 7.54 (dd, 1H, 3J¼8.3, 3J¼7.2, 4J¼1.4, H-6), 7.56
(dd, 1H, 3J¼7.5, 4J¼1.2, H-400), 7.83 (m, 3J¼8.1, 4J¼1.4, 5J¼0.2, 1H, H-
5
A solution of amine (0.2 mol) in xylene (100 mL) with pyridine
8), 7.86 (dddd, 2H, 3J¼7.7, 4J¼1.7, 4J¼1.2, J¼0.6, H-200/600), 8.25 (m,
(1 mL) was added gradually to
a
solution of 3-oxo-3-
3J¼8.3, 4J¼1.4, 5J¼0.2, 1H, H-5), 13.77 (br, 1H, NH); 13C NMR
phenylpropionic acid ethyl ester (40 g, 0.2 mol) in boiling xylene
(200 mL). The rate of addition of the amine was the same as the rate
of distillation of xylene with pyridine. The distillate (120 mL) was
again added gradually to the reaction mixture. This procedure was
repeated three times. The distillation ended when the boiling flask
contained one-thirtieth of the original reaction mixture. The crude
product precipitated from the reaction mixture was collected and
crystallised.23
(75.47 MHz, DMSO-d6): d 41.4 (CH2), 94.6 (C-3), 118.9 (C-5), 125.9
(C-7), 127.1 (C-6), 127.1 (C-40), 127.2 (C-300/500), 127.4 (C-8), 127.5 (C-
30/50), 127.7 (C-4a), 128.4 (C-20/60), 128.7 (C-200/600), 131.4 (C-400),
135.6 (C-8a), 137.2 (C-10), 138.9 (C-100), 139.2 (C-3a), 148.2 (C-9a),
166.1 (C-2), 188.8 (C-10); MS-EI: 379 (Mþ), 105 (PhCO), 91 (PhCH2).
Anal. Calcd for C24H17N3O2: C, 75.97; H, 4.52; N, 11.07. Found: C,
76.11; H, 4.44; N, 11.04.
3-Benzoyl-1-(2-phenylethyl)-1,4-dihydropyrrolo[2,3-b]quinoxalin-
2(4H)-one (2b). Yellow needles, yield: 1.08 g (89%); mp: 245 ꢀC; IR
3-Oxo-3-phenyl-N-(benzyl)propanamide.24 Light yellow needles
(EtOH), yield: 23.83 g (45%); mp: 89 ꢀC (lit.24 mp: 91e92 ꢀC).
3-Oxo-3-phenyl-N-(2-phenylethyl)propanamide.25 This com-
pound was obtained as light yellow needles (EtOAc), yield: 24.5 g
(KBr):
n
¼3486 (OH), 3182 (NH), 3061, 3026 (CH, Ar), 2936 (CH, CH2),
1703 (C]O), 1653 (C]N), 1620 (C]C) cmꢂ1; 1H NMR (300.13 MHz,
DMSO-d6):
d 3.02 (m, 2H, CH2Ph), 4.09 (m, 2H, CH2N), 7.18 (dd, 1H,
(44%); mp: 87 ꢀC (lit.25 mp: 83e85 ꢀC); IR (KBr):
1694, 1663 (CO) cmꢂ1
n
¼3303 (NH),
3J¼7.5, J¼1.2, H-40), 7.21 (dddd, 2H, 3J¼7.7, 4J¼1.8, 4J¼1.2, 5J¼0.5,
4
5
;
1H NMR (300.13 MHz, CDCl3):
d
2.83 (t, 2H,
H-20/60), 7.26 (dddd, 2H, 3J¼7.7, 3J¼7.5, 4J¼1.4, J¼0.5, H-30/50), 7.45
2-H0, J¼7), 3.56 (q, 2H, 1-H0, J¼7), 3.90 (s, 2H, 2-H, J¼7), 7.02 (s, 1H,
NH), 7.18 (d, 2H, 2-HeAr00, J¼7), 7.22 (t, 1H, 4-HeAr00, J¼7), 7.27 (t,
2H, 3-HeAr00, J¼7), 7.48 (t, 2H, 3-HeAr0, J¼8), 7.61 (t, 1H, 4-HeAr0,
(dddd, 2H, 3J¼7.7, 3J¼7.5, 4J¼1.4, 5J¼0.6, H-300/500), 7.50 (dd,1H, 3J¼8.2,
3J¼7.3, 4J¼1.4, H-6), 7.52 (dd,1H, 3J¼8.2, 3J¼7.3, 4J¼1.3, H-7), 7.55 (dd,
1H, 3J¼7.5, 4J¼1.2, H-400), 7.77 (dddd, 2H, 3J¼7.7, 4J¼1.7, 4J¼1.2, 5J¼0.6,
H-200/600), 7.84 (m, 3J¼8.2, 4J¼1.4, 5J¼ꢂ0.4, 1H, H-8), 8.21 (m, 3J¼8.2,
4J¼1.3, 5J¼ꢂ0.4, 1H, H-5), 13.66 (br, 1H, NH); 13C NMR (75.47 MHz,
J¼8), 7.98 (d, 2H, 2-HeAr0, J¼8); 13C NMR (CDCl3):
d
35.86 2-C0, 41.17
1-C0, 45.86 2-C, 126.73e138.98 CeAr, 165.83 1-C, 196.18 3-C; MS-EI:
m/z 267 (Mþ), 176 (MþꢂPhCH2), 147 (MþꢂPhCH2CH2NH), 104
(PhCNH), 91 (PhCH2), 77. Anal. Calcd for C17H17NO2: C, 76.38; H,
6.41; N, 5.24. Found: C, 76.46; H, 6.63; N, 5.32.
DMSO-d6): d 33.6 (CH2Ph), 39.4 (CH2N), 94.5 (C-3), 118.7 (C-5), 125.8
(C-6), 126.3 (C-40), 126.9 (C-7), 127.3 (C-8), 127.4 (C-4a), 127.5 (C-300/
500), 128.3 (C-30/50), 128.7 (C-20/60), 128.7 (C-200/600), 131.4 (C-400), 135.5
(C-8a),138.5(C-10),138.7(C-100),138.8(C-3a),148.1 (C-9a),166.0(C-2),
188.8 (C-10); MS-EI: 393 (Mþ), 302 (MþꢂPhCH2), 289
(MþꢂPhCH2CH2),105 (PhCO). Anal. Calcd for C25H19N3O2: C, 76.32; H,
4.86; N, 10.68. Found: C, 76.33; H, 4.87; N, 10.72.
3-Oxo-3-phenyl-N-(2,5-dimethoxyphyl)propanamide.26
Light
yellow needles (MeOH), yield: 31.09 (50%); mp: 77 ꢀC (lit.26 mp:
76e78 ꢀC).
Oxalyl chloride (3 mL, 34 mmol) was added dropwise at rt to
a
stirred solution of 3-oxo-3-phenyl-N-(2-phenylethyl)prop-
anamide (8.01 g, 30 mmol) in dry toluene (150 mL). The solution
was stirred at 60 ꢀC for 20 h. The crude product precipitated from
the reaction mixture was collected and crystallised from acetic acid.
1-Benzyl-4-(phenylhydroxymethylidene)pyrrolidine-2,3,5-trione
(1a).15 Light yellow plates (AcOH), yield: 8.50 g (96%); mp:
125e6 ꢀC (lit.15 mp: 96 ꢀC).
4.4. Procedure for the reaction with 3,4-diaminotoluene, 3,4-
diaminobenzoic acid
Method A. Aromatic ortho-diamine (3.4 mmol) was added to a so-
lution of 1 (3.1 mmol) in EtOH (50 mL) with addition of glacial acetic
acid (2 mL). The solution was refluxed for 3 h and left overnight. The
precipitate was filtered off and crystallised from chlorobenzene.
Method B. Compound 1 (3.1 mmol) was added to a solution of
aromatic o-diamine (4.03 mmol) and TsOH (0.32 g, 1.86 mmol) in
AcOH (25 mL). The solution was refluxed for 3 h and left overnight.
The precipitate was filtered off and crystallised from chlorobenzene.
Method C. Aromatic ortho-diamine (3.4 mmol) was added to
a solution of 1 (3.1 mmol) in AcOH (50 mL). The solution was
refluxed for 3 h and left overnight. The precipitate was filtered off
and crystallised from chlorobenzene.
Method D. SOCl2 (212 mg, 0.13 mL, 1.78 mmol) was added to an
ice-cooled stirred solution of 1 (1.7 mmol) in CH2Cl2 (30 mL) at 0 ꢀC.
After 1 h, the mixture was warmed to rt and stirred for 24 h; then
H2O (100 mL) was added to the stirred mixture. The CH2Cl2 phase
was separated and dried (MgSO4). Aromatic o-diamine (1.7 mmol)
was added to the CH2Cl2 phase. The mixture was stirred for 5 days.
The solvent was removed, and the residue was dissolved in EtOH
(50 mL) with AcOH (0.5 mL) and stirred at 70 ꢀC for 5 days. The
precipitate was filtered off and crystallised.
1-(2-Phenylethyl)-4-(phenylhydroxymethylidene)pyrrolidine-
2,3,5-trione (1b). Light yellow plates, yield: 5.95 g (62%); mp:
134e5 ꢀC; IR (KBr):
n
¼3439 (OH), 3082, 3060, 3028 (]CH, Ar),
2987, 2950 (CH2), 1776, 1739, 1656 (C]O) cmꢂ1 1H NMR
(300.13 MHz, CDCl3): 3.02 (m, 2H, CH2Ph), 3.97 (m, 2H, CH2N),
7.24e7.68 (m, 8H, HeAr), 8.20 (d, 2H, HeAr); 13C NMR (75.47 MHz,
CDCl3): 33.70 (CH2Ph), 39.43 (CH2N), 126.69, 128.45, 128.52,
;
d
d
129.75, 130.07, 130.48, 134.74, 136.98 (AreC), 160.97 (C-2), 174.49
(C-3), 184.57 (C-6); MS-EI: 321 (Mþ), 105 (PhCO), 91 (PhCH2). Anal.
Calcd for C19H15NO4: C, 71.02; H, 4.70; N, 4.35. Found: C, 71.08; H,
4.66; N, 4.38.
1-(2,5-Dimethoxyphenyl)-4-(phenylhydroxylmethylidene)pyrroli-
dine-2,3,5-trione (1c).14
4.3. Procedure for the reaction with o-phenylenediamine
Method A. Aromatic ortho-diamine (3.4 mmol) was added to
a solution of 1 (3.1 mmol) in EtOH (50 mL) with the addition of
glacial acetic acid (2 mL). The solution was refluxed for 3 h and left
overnight. The precipitate was filtered off and crystallised from
chlorobenzene.
3-Benzoyl-1-benzyl-7-methyl-1,4-dihydropyrrolo[2,3-b]quinoxalin-
2(4H)-one (3a), 3-benzoyl-1-benzyl-6-methyl-1,4-dihydropyrrolo[2,3-
b]quinoxalin-2(4H)-one (4a). Yellow needles, yield: (A) 853 mg

K. Ostrowska et al. / Tetrahedron 67 (2011) 5219e5227
5225
(70%), (D) 227 mg (34%); mp: 263 ꢀC; IR (KBr):
3180 (NH), 3085, 3062, 3029 (CH, Ar), 2920 (CH, CH2), 1700
(C]O), 1652 (C]N), 1624, 1611, 1587 (C]C) cmꢂ1 1H NMR
(300.13 MHz, DMSO-d6): 2.43 (s, 3H, 7-CH3 for 3a), 2.45(s, 3H, 6-CH3
for 4a), 5.05 (s, 4H, CH2Ph for 3a and 4a), 7.24e7.55 (m, 18H, HeAr, 3a
and 4a), 7.63 (s,1H, H-8, 3a), 7.64 (d, 1H, 3J¼8.3, H-8, 4a), 7.78 (m, 4H,
3J¼7.3, H-200/600, 3a and 4a), 8.03 (s, 1H, H-5, 4a), 8.13 (d, 3J¼8.4, 1H,
H-5, 3a),13.7 (s, 2H, NH, 3a and 4a); MS-ESI: 394 (Mþþ1). Anal. Calcd
for C25H18N3O2: C, 76.32; H, 4.87; N, 10.68. Found: C, 76.31; H, 4.81;
N, 10.71.
n
¼3455 (OH),
(20) [PhCO], 91 (27) [PhCH2]. Anal. Calcd for C25H17N3O4: C, 70.91;
H, 4.05; N, 9.92. Found: C, 70.83; H, 4.10; N, 9.87.
3-Benzoyl-1-(2-phenylethyl)-2-oxo-2,4-dihydro-1H-pyrrolo[2,3-
b]quinoxaline-7-carboxylic acid (5b), 3-benzoyl-(2-phenylethyl)-
2-oxo-2,4-dihydro-1H-pyrrolo[2,3-b]quinoxaline-6-carboxylic acid
(6b). Yellow needles, yield: (A): 1.3 g (96%); mp: 305e323 ꢀC; IR
;
d
(KBr): 3505, 3303, 3028, 2922, 2852, 1699, 1653, 1618, 1584 cmꢂ1
;
1H NMR (300.13 MHz, DMSO-d6):
d
3.03 (t, 3J¼7, 4H, CH2Ph, 5b, 6b),
4.09 (t, 3J¼7, 4H, NCH2, 5b, 6b), 7.19e7.31 (m, 12H, AreH, 5b, 6b),
7.47 (t, 3J¼7.5, 2H, AreH, 5b), 7.59 (t, 2H, AreH, 6b), 7.77 (dd, 3J¼7.5,
4J¼1.4, 4H, H-200, 600, 5b, 6b), 7.87 (d, 3J¼8.5, 1H, H-8, 6b), 7.98 (dd,
3J¼8.5, 4J¼1.6, 1H, H-7, 6b), 8.0 (dd, 3J¼8.5, 4J¼1.6, 1H, H-6, 5b), 8.23
(d, 3J¼8.5, 1H, H-5, 5b), 8.31 (d, 4J¼1.6, 1H, H-8, 5b), 8.86 (d, 4J¼1.8,
1H, H-5, 6b), 13.17 (s, 2H, COOH, 5b, 6b), 13.78 (s, 2H, NH, 5b, 6b);
3-Benzoyl-1-benzyl-7-methyl-1,4-dihydropyrrolo[2,3-b]quinox-
alin-2(4H)-one (3a). Yellow needles, yield: (A): 28 mg (2%); mp:
265 ꢀC; IR (KBr):
n
¼3476 (OH), 3185 (NH), 3085, 3062, 3029 (CH,
Ar), 2954, 2920 (CH, CH2), 1700 (C]O), 1653 (C]N), 1625, 1609,
1584 (C]C) cmꢂ1 1H NMR (300.13 MHz, DMSO-d6):
2.37 (s, 3H,
;
d
13C NMR (75.47 MHz, DMSO-d6):
d 34.11, 41.49, 95.14, 95.86, 116.82,
7-CH3), 5.05 (s, 4H, CH2Ph), 7.24e7.55 (m, 9H, HeAr), 7.63 (s, 1H,
119.27, 121.04, 126.80, 127.57, 128.06, 128.85, 129.06, 129.29, 131.09,
132.11, 135.35, 138.74, 138.96, 139.03, 139.12, 139.53, 139.81, 149.28,
149.98, 163.58, 166.48, 167.09, 189.21, 189.40; MS (EI, 70 eV): m/z
437 (70) [Mþ], 346 (26) [MþꢂPhCH2], 333 (100) [MþꢂPhCH2CH2],
105 (89) [PhCO]. Anal. Calcd for C26H19N3O4: C, 71.38; H, 4.38; N,
9.60. Found: C, 71.25; H, 4.47; N, 9.51.
3
H-8), 7.78 (m, 2H, J¼6.8, H-200/600), 8.13 (d, 3J¼8.4, 1H, H-5), 13.67
(s, 1H, NH); MS-ESI: 394 (Mþþ1).
3-Benzoyl-7-methyl-1-(2-phenylethyl)-1,4-dihydropyrrolo[2,3-b]
quinoxalin-2(4H)-one (3b), 3-benzoyl-6-methyl-1-(2-phenylethyl)-
1,4-dihydropyrrolo[2,3-b]quinoxalin-2(4H)-one (4b). Yellow needles,
yield: (A): 0.95 g (75%), (B): 0.86 g (68%); mp: 243 ꢀC; IR (KBr):
3-Benzoyl-1-(2,5-dimethoxyphenyl)-2-oxo-2,4-dihydro-1H-pyr-
rolo[2,3-b]quinoxaline-7-carboxylic acid (5c), 3-benzoyl-(2,5-
dimethoxyphenyl)-2-oxo-2,4-dihydro-1H-pyrrolo[2,3-b]quinoxaline-
6-carboxylic acid (6c). Yellow needles, yield: (A): 1.16 g (80%); mp:
280e305 ꢀC; IR (KBr): 3429, 3118, 3001, 2943, 2836, 1698, 1649,
n
¼3447 (OH), 3184 (NH), 3087, 3061, 3027 (CH, Ar), 2978, 2940 (CH,
CH2), 1700, 1697 (C]O), 1651 (C]N), 1622, 1603 (C]C) cmꢂ1 1H
NMR (300.13 MHz, DMSO-d6): 2.44 (s, 6H, 6-CH3 (4b), 7-CH3,
;
d
(3b)), 2.99 (t, 4H, CH2Ph), 4.06 (t, 4H, CH2N), 7.17e7.55 (m, 18H,
HeAr, 3b and 4b), 7.65 (s, 1H, H-8, 3b), 7.72 (d, 1H, 3J¼8.3, H-8, 4b),
7.76 (m, 4H, 3J¼6.9, H-200/600, 3b and 4b), 7.99 (s, 1H, H-5, 4b), 8.09
(d, 1H, H-5, 3b), 13.6 (s, 2H, NH, 3b and 4b); 1H NMR (300.13 MHz,
1619, 1602 cmꢂ1 1H NMR (300.13 MHz, DMSO-d6):
; d 3.64 (s, 6H,
OCH3, 5c, 6c), 3.73 (s, 6H, OCH3, 5c, 6c), 7.01e7.16 (m, 6H, AreH, 5c,
6c), 7.42e7.56 (m, 6H, AreH, 5c, 6c), 7.75 (d, 2H, H-8, 6c), 7.83
(d, 4H, H-200, 600, 5c, 6c), 7.90 (d, 2H, H-7, 6c), 7.99 (d, 1H, H-6, 5c),
8.14 (s, 1H, H-8, 5c), 8.20 (d, 1H, H-5, 5c), 8.82 (s, 1H, H-5, 6c), 12.60
(s, 2H, COOH, 5c, 6c), 13.99 (s, 2H, NH, 5c, 6c); 13C NMR (75.47 MHz,
CDCl3):
d 2.51 (s, 3H, 6-CH3 (4b)), 2.55 (s, 3H, 7-CH3, (3b)), 3.17
(m, 4H, CH2Ph), 4.27 (m, 4H, CH2N), 7.20e7.55 (m, 20H, HeAr, 3b
and 4b), 7.81 (s, 1H, H-5, 4b), 7.87 (d, 1H, 3J¼8.6, H-5, 3b), 8.01 (m,
3
4H, J¼6.9, H-200/600, 3b and 4b); 13C NMR (75.47 MHz, DMSO-d6):
DMSO-d6): d 56.37, 56.97, 95.34, 96.01, 114.25, 115.80, 117.27, 120.16,
d
¼21.16, 21.74, 34.09, 34.12, 39.82, 94.67, 94.97, 118.74, 118.99,
122.80, 128.28, 129.52, 132.29, 135.76, 139.20, 139.44, 150.72,
152.88, 153.72, 166.54, 167.29, 172.71, 189.68; MS (EI, 70 eV): m/z
496 (100) [Mþ], 438 (27), 105 (69) [PhCO], 77 (30) [C6H5]. Anal.
Calcd for C26H19N3O6: C, 66.52; H, 4.08; N, 8.95. Found: C, 66.23; H,
4.26; N, 8.84.
125.65, 126.74, 126.76, 127.45, 127.64, 127.73, 127.95, 127.96, 127.98,
128.79, 128.82, 129.01, 129.16, 129.17, 129.19, 129.22, 129.24, 129.71,
131.78, 131.84, 134.17, 136.06, 137.34, 138.94, 138.98, 139.00, 139.02,
139.27, 139.31, 147.96, 148.51, 166.35, 166.36, 189.11, 189.20; MS-ESI:
408 (Mþþ1). Anal. Calcd for C26H21N3O2: C, 76.64; H, 5.19; N, 10.31.
Found: C, 76.38; H, 5.10; N, 10.34.
3-Benzoyl-7-methyl-1-(2,5-dimethoxyphenyl)-1,4-dihydropyrrolo
4.5. General procedure for the preparation of 2H-pyrido[2,3-
b]pyrrolo[2,3-e]pyrazin-2-one 7 and 2H-pyrido[2,3-b]pyrrolo
[3,2-e]pyrazin-2-one 8
[2,3-b]quinoxalin-2(4H)-one
(3c),
3-benzoyl-6-methyl-1-(2,5-
dimethoxyphenyl)-1,4-dihydropyrrolo[2,3-b]quinoxalin-2(4H)-one
(4c). Yellow needles, yield: (A): 892 mg (66%); mp: 212 ꢀC; 1H NMR
(300.13 MHz, DMSO-d6):
d
2.41 (s, 3H, 7-CH3, (3c)); 2.46 (s, 3H,
Method B. 2,3-Diaminopyridine (0.47 g, 4.3 mmol) was added to
a solution of 1 (3.3 mmol) in AcOH (25 mL) with the addition of
TsOH (0.34 g, 2 mmol). The solution was stirred at 70 ꢀC for 10 h,
allowed to cool and then poured into water. The crude product was
collected and purified by column chromatography: Al2O3/EtOAc/n-
heptane (2:1) for 7a, 8a and EtOAc/n-heptane (1:1) for 7b, 8b.
3-Benzoyl-1-benzyl-1,4-dihydro-2H-pyrido[2,3-b]pyrrolo[2,3-e]
pyrazin-2-one (7a). Yellow needles, yield: (B): 580 mg (46%); mp:
6-CH3 for 4c), 3.65 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 7.01e7.52
(m, 14H, HeAr, 3c and 4c), 7.57 (s, 1H, H-9, 3c), 7.63 (d, 1H, 3J¼8.2,
3
H-9, 4c), 7.87 (m, 4H, J¼6.7, H-200/600, 3c and 4c), 7.97 (s, 1H, H-5,
4c), 8.14 (d, 1H, 3J¼8.4, H-5, 3c), 13.76 (s, 2H, NH, 3c and 4c);
MS-ESI: 439 (Mþþ1). Anal. Calcd for C26H20N3O4: C, 71.22; H, 4.60;
N, 9.58. Found: C, 71.20; H, 4.69; N, 9.65.
3-Benzoyl-1-benzyl-2-oxo-2,4-dihydro-1H-pyrrolo[2,3-b]qui-
noxaline-7-carboxylic acid (5a), 3-benzoyl-1-benzyl-2-oxo-2,4-
dihydro-1H-pyrrolo[2,3-b]quinoxaline-6-carboxylic
186 ꢀC; Rf (Al2O3, 2:1 EtOAc/n-heptane) 0.54; IR (KBr):
(OH), 3190 (NH), 3064, 3031 (CH, Ar), 2956, 2920 (CH, CH2), 1700
n
¼3450
acid
(6a).
Yellow needles, yield: (A): 1.23 g (94%), (C): 0.74 g (56%), (D):
(C]O), 1651 (C]N), 1620 (C]C) cmꢂ1 1H NMR (300.13 MHz,
;
259 mg (36%); mp: 337e357 ꢀC; IR (KBr): 3398, 3154, 3060, 3030,
DMSO-d6):
d
5.08 (s, 2H, CH2), 7.25 (dd,1H, 3J¼7.4, 4J¼1.0, H-40), 7.31
2919, 2851, 1703, 1688, 1655, 1620, 1588 cmꢂ1
;
1H NMR
(dddd, 2H, 3J¼7.7, 4J¼2.0, 4J¼1.0, J¼0.7, H-20/60), 7.34 (dddd, 2H,
3J¼7.7, 3J¼7.4, 4J¼1.5, 5J¼0.7, H-30/50), 7.48 (dddd, 2H, 3J¼7.8, 3J¼7.5,
4J¼1.4, 5J¼0.6, H-300/500), 7.55 (dd, 1H, 3J¼8.1, 4J¼4.8, H-7), 7.57 (dd,
5
(300.13 MHz, DMSO-d6): d 5.04 (s, 4H, CH2Ph, 5a, 6a), 7.21e7.32 (m,
10H, AreH, 5a, 6a), 7.39e7.51 (m, 7H, AreH, 5a, 6a), 7.83 (d,d 3J¼7.3,
4J¼1.5, 4H, H-200/600, 5a, 6a), 7.94 (dd, 3J¼8.5, 4J¼1.9, 1H, H-6, 6a),
8.23 (d, 3J¼8.5, 1H, H-5, 5a), 8.24 (d, 4J¼1.8, 1H, H-8, 5a), 8.82 (d,
4J¼1.8, 1H, H-5, 6a), 13.11 (s, 2H, COOH, 5a, 6a), 13.83 (s, 2H, NH, 5a,
1H, 3J¼7.5, J¼1.3, H-400), 7.84 (dddd, 2H, 3J¼7.8, 4J¼1.7, 4J¼1.3,
4
5J¼0.6, H-200/600), 8.31 (m, 3J¼8.1, 4J¼1.6, 1H, H-8), 8.57 (m, 3J¼4.8,
4J¼1.6, 1H, H-6), 13.24 (br, 1H, NH); 13C NMR (75.47 MHz, DMSO-
6a); 13C NMR (75.47 MHz, DMSO-d6):
d
42.16, 96.18, 119.59, 127, 92,
d6): d
41.4 (CH2), 95.6 (C-3), 121.1 (C-7), 127.2 (C-40), 127.2 (C-20/60),
128.15, 128.29, 128.37, 129.16, 129.48, 131.55, 132.30, 135.60, 137.73,
139.32, 140.12, 149.59, 166.84, 167.24, 189.65; MS (EI, 70 eV): m/z
423 (100) [Mþ], 318 (6) [MþꢂPhCO], 290 (19)[MþꢂPhCOꢂCO], 105
127.6 (C-300/500), 128.4 (C-30/50), 128.9 (C-200/600), 131.1 (C-8a), 131.7
(C-400), 136.5 (C-8), 137.0 (C-10), 138.7 (C-100), 140.6 (C-3a, C-4a),
145.4 (C-6), 148.7 (C-9a), 166.6 (C-2), 188.7 (C-10); MS-ESI: m/z 381

5226
K. Ostrowska et al. / Tetrahedron 67 (2011) 5219e5227
(Mþþ1). Anal. Calcd for C23H16N4O2: C, 72.62; H, 4.24; N, 14.73.
Found: C, 72.62; H, 4.17; N, 14.60.
(0.5 mL) and stirred at 70 ꢀC for 5 days. The precipitate was filtered
off and crystallised.
3-Benzoyl-1-benzyl-1,4-dihydro-2H-pyrido[2,3-b]pyrrolo[3,2-e]
pyrazin-2-one (8a). Light orange needles, yield: (B): 65 mg (5%);
4-Benzoyl-1-benzyl-3-amino-N-(2-amino-3-pyridyl)-pyrrolino-
2,5-dione (12a). Light grey needles, yield: (D): 0.270 g (40%); mp: tt.
mp: 225 ꢀC; Rf (Al2O3, 2:1 EtOAc/n-heptane) 0.18; IR (KBr):
n
¼3454
153 ꢀC; IR (KBr):
n
¼3385, 3272, 3197.11 (NH), 3063 (CeH, Ar), 2952
(OH), 3110 (NH), 3053 (CH, Ar), 2927 (CH2), 1702 (C]O), 1652 (C]
(CeH, CH2), 1701 (O]C), 1640 (O]CeN), 1605 (C]C, Ar) cmꢂ1; 1H
N), 1615, 1590 (C]C) cmꢂ1; 1H NMR (300.13 MHz, DMSO-d6):
d
5.10
NMR (300.13 MHz, DMSO-d6): d 4.49 (s, 2H, H-CH2Ph), 6.68 (dd, 1H,
(s, 2H, CH2), 7.25 (dd, 1H, 3J¼7.5, J¼1.2, H-40), 7.32 (dddd, 2H,
3J¼7.7, 3J¼7.5, 4J¼1.3, 5J¼0.6, H-30/50), 7.36 (dddd, 2H, 3J¼7.7, 4J¼1.7,
4J¼1.2, 5J¼0.6, H-20/60), 7.49 (dddd, 2H, 3J¼7.7, 3J¼7.5, 4J¼1.4, 5J¼0.7,
H-300/500), 7.57 (dd, 1H, 3J¼8.2, 3J¼4.6, H-6), 7.57 (dd, 1H, 3J¼7.5,
4J¼1.2, H-400), 7.85 (dddd, 2H, 3J¼7.7, 4J¼1.2, 4J¼1.0, 5J¼0.7, H-200/600),
8.61 (dd, 1H, 3J¼8.2, 4J¼1.6, H-5), 8.65 (m, 3J¼4.6, 4J¼1.6, 1H, H-7),
3J¼6.8, J¼7.7, H-5000), 7.00 (dd, 1H, 4J¼1.4, J¼7.7, H-4000), 7.14e7.32
4
3
3
(m, 8H, HeAr), 7.37 (s, 2H, NH2), 7.43 (m, 2H, HeAr, H-20/60), 13.01
(s,1H, NH); 13C NMR (75.47 MHz, DMSO-d6):
d 40.74 (CeCH2), 99.25
(C-4), 114.69, 120.86, 123.36, 127.98, 128.10, 128.34, 128.35, 129.43,
129.49, 130.72, 134.50, 139.17, 142.67 (CeAr), 166.55 (C-3), 172.10
(C-2), 176.15 (C-5), 187.50 (O]CePh); MS-ESI: 352 (MþꢂH2OꢂCO).
Anal. Calcd for C23H18N4O3þH2O: C, 66.34; H, 4.84; N, 13.45. Found:
C, 66.75; H, 4.45; N, 13.16.
13.88 (br, 1H, NH); 13C NMR (75.47 MHz, DMSO-d6):
d 41.5 (CH2),
94.9 (C-3), 122.3 (C-6), 123.9 (C-4a), 127.2 (C-40), 127.3 (C-20/60),
127.6 (C-300/500), 127.7 (C-5), 128.4 (C-30/50), 128.7 (C-200/600), 131.5 (C-
400), 137.0 (C-10), 138.7 (C-100), 139.4 (C-3a), 146.1 (C-8a), 147.0 (C-7),
151.0 (C-9a), 166.2 (C-2), 188.8 (C-10); MS-ESI: m/z 381 (Mþþ1).
Anal. Calcd for C23H16N4O2: C, 72.62; H, 4.24; N, 14.73. Found: C,
72.34; H, 4.17; N, 14.60.
3-Benzoyl-1-(2-phenylethyl)-1,4-dihydro-2H-pyrido[2,3-b]pyr-
rolo[2,3-e]pyrazin-2-one (7b). Yellow needles, yield: (B): 643 mg
(49%); mp: 179 ꢀC; Rf (Al2O3, 1:1, EtOAc/n-heptane) 0.38; IR (KBr):
3-Benzoyl-1-benzyl-1,4-dihydro-2H-pyrido[2,3-b]pyrrolo[2,3-e]
pyrazin-2-one (7a), 3-benzoyl-1-benzyl-1,4-dihydro-2H-pyrido[2,3-
b]pyrrolo[3,2-e]pyrazin-2-one (8a). Yield: (D): 205 mg (32%).
4-Benzoyl-1-(2-phenylethyl)-3-amino-N-(2-amino-3-pyridyl)-
pyrrolino-2,5-dione (12b). Light grey needles, yield: 0.552 g (79%);
mp: 158 ꢀC; IR (KBr):
(CeH, Ar), 2946.82 (CeH, CH2), 1698.22 (C]O), 1637.98 (O]CeN),
n
¼3381.95, 3279.64, 3195.79 (NH), 3061.07
1605.59 (C]C, Ar) cmꢂ1 1H NMR (300.13 MHz, DMSO-d6):
; d 2.74
n
¼3405 (OH), 3185 (NH), 3055, 3023 (CH, Ar), 2936 (CH, CH2), 1707
(t, 2H, HeCH2Ph), 3.55 (t, 2H, 1CHeCH2N), 6.67 (dd, 1H, 3J¼6.3,
(C]O), 1651 (C]N), 1624 (C]C) cmꢂ1 1H NMR (300.13 MHz,
;
3J¼7.7, H-5000), 7.01 (dd, 1H, 4J¼1.4, J¼7.7, H-4000), 7.10e7.35 (m, 9H,
3
DMSO-d6):
d
3.03 (m, 2H, CH2Ph), 4.10 (m, 2H, CH2N), 7.19 (dd, 1H,
HeAr), 7.39e7.44 (m, 4H, HeAr, H-20, H-60, NH2), 13.1 (s, 1H, NH);
3J¼7.4, 4J¼1.0, H-40), 7.22 (dddd, 2H, 3J¼7.7, 4J¼2.0, 4J¼1.0, 5J¼0.7, H-
13C NMR (75.47 MHz, DMSO-d6):
d 35.04 (2CeCH2), 38.5 (1CeCH2),
20/60), 7.27 (dddd, 2H, 3J¼7.7, 3J¼7.4, 4J¼1.5, J¼0.7, H-30/50), 7.46
99.33 (C-4), 114.64, 120.84, 123.41, 127.28, 128.12, 129.42, 129.52,
129.71, 130.82, 134.52, 139.90, 142.51, 145.79 (CeAr), 166.44 (C-3),
172.35 (C-2), 176.51 (C-5), 187.68 (O]CPh); MS-ESI: 366
(MþꢂH2OꢂCO). Anal. Calcd for C24H20N4O3þH2O: C, 66.97; H, 5.15;
N, 13.02. Found: C, 66.45; H, 5.05; N, 12.71.
5
(dddd, 2H, 3J¼7.8, 3J¼7.5, 4J¼1.4, J¼0.6, H-300/500), 7.57 (dd, 1H,
5
3J¼4.8, 3J¼1.6, H-7), 7.57 (dd, 1H, 3J¼7.5, J¼1.3, H-400), 7.74 (dddd,
4
2H, 3J¼7.8, 4J¼1.7, 4J¼1.3, J¼0.6, H-200/600), 8.32 (m, 3J¼8.1, 4J¼1.6,
5
1H, H-8), 8.56 (m, 3J¼4.8, 4J¼1.6, 1H, H-6), 13.44 (br, 1H, NH); 13C
NMR (75.47 MHz, DMSO-d6):
d
33.6 (CH2Ph), 39.6 (CH2N), 95.5 (C-
3-Benzoyl-1-(2-phenylethyl)-1,4-dihydro-2H-pyrido[2,3-b]pyr-
rolo[3,2-e]pyrazin-2-one (8b). Yield: (D): 226 mg (34%); mp: 242 ꢀC.
3), 121.1 (C-7), 126.3 (C-40), 127.6 (C-300/500), 128.3 (C-30/50), 128.7 (C-
20/60), 128.9 (C-200/600), 131.0 (C-8a), 131.7 (C-400), 136.4 (C-8), 138.4
(C-10), 138.4 (C-100), 140.7 (C-4a), 142.2 (C-3a), 145.4 (C-6), 148.6 (C-
9a), 166.5 (C-2), 188.7 (C-10); MS-ESI: m/z 395 (Mþþ1). Anal. Calcd
for C24H18N4O2: C, 73.08; H, 4.60; N, 14.20. Found: C, 72.72; H, 4.40;
N, 14.20.
3-Benzoyl-1-(2-phenylethyl)-1,4-dihydro-2H-pyrido[2,3-b]pyr-
rolo[3,2-e]pyrazin-2-one (8b). Light orange needles, yield: (B):
160 mg (12%); mp: 242 ꢀC; Rf (Al2O3, 1:1, EtOAc/n-heptane) 0.08; IR
4.6. General procedure for the reaction with 3,4-diamino-
pyridine
Method B. 3,4-Diaminopyridine (0.47 g, 4.3 mmol) was added to
a solution of 1 (3.3 mmol) in AcOH (25 mL) with the addition of TsOH
(0.34 g, 2 mmol). The solution was stirred at 70 ꢀC for 50 h. The
crude products (salt 9a$1a, 9b, salt 9d$1d) precipitated from the
reaction mixture were collected and crystallised from acetic acid.
Salt of 3-benzoyl-1-benzyl-1,4-dihydro-2H-pyrido[3,4-b]pyrrolo
[3,2-e]pyrazin-2-one 9a and 4-[hydroxy(phenyl)methylene]-1-
benzylpyrrolidine-2,3,5-trione 1a. Yellow needles, yield: (B):
(KBr):
n
¼3471 (OH), 3225 (NH), 3079, 3053, 3023 (CH, Ar), 2945
1H NMR
3.04 (m, 2H, CH2Ph), 4.11 (m, 2H, CH2N),
(CH, CH2), 1716 (C]O), 1653 (C]N), 1618 (C]C) cmꢂ1
;
(300.13 MHz, DMSO-d6):
d
7.20 (dd, 1H, 3J¼7.4, J¼1.0, H-40), 7.24 (dddd, 2H, 3J¼7.7, 4J¼2.0,
4J¼1.0, 5J¼0.7, H-20/60), 7.28 (dddd, 2H, 3J¼7.7, 3J¼7.4, 4J¼1.5, 5J¼0.7,
H-30/50), 7.47 (dddd, 2H, 3J¼7.8, 3J¼7.5, 4J¼1.4, 5J¼0.6, H-300/500), 7.57
(dd, 1H, 3J¼7.5, 4J¼1.3, H-400), 7.62 (dd, 1H, 3J¼8.1, 3J¼4.8, H-6), 7.76
4
487 mg (43%); mp: 275 ꢀC; IR (KBr):
3032 (CH, Ar), 2968, 2931 (CH, CH2), 1740, 1720, 1707 (C]O), 1644
(C]N), 1625, 1600 (C]C) cmꢂ1 1H NMR (300.13 MHz, DMSO-d6):
n
¼3436 (OH), 3153 (NH), 3059,
;
(dddd, 2H, 3J¼7.8, 4J¼1.7, 4J¼1.3, J¼0.6, H-200/600), 8.65 (m, 3J¼8.1,
d 4.49 (s, 2H, CH2), 5.03 (s, 2H, CH2), 7.15e33 (m, 13H, HeAr), 7.45
5
4J¼1.6, 1H, H-5), 8.69 (m, 3J¼4.8, 4J¼1.6, 1H, H-7), 13.76 (br, 1H, NH);
(m, 4H, HeAr), 7.56 (m,1H, HeAr), 7.80 (d, 3J¼7.0, 2H, H-200/600), 8.24
(d, 3J¼6.5, 1H, H-5), 8.60 (d, 3J¼6.5, 1H, H-6), 9.25 (s, 1H, H-8); MS:
m/z 381 (Mþþ1 for 7a). Anal. Calcd for C41H29N5O6: C, 71.61; H,
4.25; N, 10.18. Found: C, 71.28; H, 4.20; N, 10.30.
13C NMR (75.47 MHz, DMSO-d6):
d 33.5 (CH2Ph), 39.5 (CH2N), 94.9
(C-3), 122.2 (C-6), 124.0 (C-4a), 126.3 (C-40), 127.6 (C-300/500), 128.2
(C-5), 128.4 (C-30/50), 128.7 (C-20/60), 128.7 (C-200/600), 131.6 (C-400),
138.4 (C-10), 138.5 (C-100), 139.3 (C-3a), 145.5 (C-7), 145.8 (C-8a),
151.3 (C-9a), 166.0 (C-2), 188.7 (C-10); MS-ESI: m/z 395 (Mþþ1).
Anal. Calcd for C24H18N4O2þEtOAc: C, 69.70; H, 5.43; N, 11.61.
Found: C, 71.10; H, 5.88; N, 11.14.
Method D. SOCl2 (212 mg, 0.13 mL, 1.78 mmol) was added to an
ice-cooled stirred solution of 1 (1.7 mmol) in CH2Cl2 (30 mL) at
0 ꢀC. After 1 h, the mixture was warmed to rt and stirred for 24 h;
then H2O (100 mL) was added to the stirred mixture. The CH2Cl2
phase was separated and dried (MgSO4). Aromatic o-diamine
(1.7 mmol) was added to the CH2Cl2 phase. The mixture was
stirred for 5 days at rt. The precipitate 12ab was filtered and,
without purification, was dissolved in EtOH (50 mL) with AcOH
3-Benzoyl-1-(2-phenylethyl)-1,4-dihydro-2H-pyrido[3,4-b]pyr-
rolo[3,2-e]pyrazin-2-one 9b. Yellow needles, yield: (B): 493 mg
(38%); mp: 298 ꢀC; IR (KBr):
n
¼3455 (OH), 3057, 3015 (CH, Ar), 2903
(CH2), 1671 (C]O), 1643 (C]N), 1618, 1592 (C]C) cmꢂ1 1H NMR
;
(300.13 MHz, DMSO-d6): d
Table 2; 13C NMR (75.47 MHz, DMSO-
d6):
d
Table 2; MS-ESI: m/z 395 (Mþþ1). Anal. Calcd for C24H18N4O2:
C, 73.08; H, 4.60; N, 14.20. Found: C, 72.54; H, 4.44; N, 14.20.
Salt of 3-benzoyl-(4-methylphenyl)-1,4-dihydro-2H-pyrido[3,4-b]
pyrrolo[3,2-e]pyrazin-2-one 9d and 4-[hydroxy(phenyl)methylene]-
1-(4-methylphenyl)pyrrolidine-2,3,5-trione 1d. Yellow needles,
yield: (B): 486 mg (43%); mp: 278e9 ꢀC; IR (KBr):
n
¼3574 (OH),
3106 (NH), 3073 (CH, Ar), 2920, 2858 (CH3), 1740, 1727, 1707 (C]O),

K. Ostrowska et al. / Tetrahedron 67 (2011) 5219e5227
7. Vinot, N.; Maitte, P. J. Heterocycl. Chem. 1989, 26, 1013e1021.
5227
1668 (C]N), 1631, 1590 (C]C) cmꢂ1; 1H NMR (300.13 MHz, DMSO-
8. Gazit, A.; App, H.; McMahon, G.; Chen, J.; Levitzki, A.; Bohmer, F. D. J. Med.
Chem. 1996, 39, 2170e2177.
d6): d 2.26 (s, 3H, CH3), 2.34 (s, 3H, CH3), 7.12e7.56 (m, 16H, HeAr),
7.83 (d, J¼7.0, 2H, H-200/600), 8.23 (d, 3J¼6.5, 1H, H-5), 8.59 (d,
3J¼6.5,1H, H-6), 9.18 (s,1H, H-8); MS-ESI: 403 (MþNa)þ. Anal. Calcd
for C41H29N5O6: C, 71.61; H, 4.25; N, 10.18. Found: C, 71.24; H, 4.06;
N, 10.09.
3
9. Hui, X.; Desrivot, J.; Bories, Ch.; Loiseau, P. M.; Franck, X.; Hocquemiller, R.;
ꢁ
Figadere, B. Bioorg. Med. Chem. Lett. 2006, 16, 815e820.
10. Kolehmainen, E.; Kucyba1a, Z.; Gawinecki, R.; Pa˛czkowski, J.; Kaca1a, A. Tetra-
hedron 1999, 55, 8475e8480.
ꢀ
€
11. Linden, A. A.; Johansson, M.; Hermanns, N.; Backvall, J.-E. J. Org. Chem. 2006, 71,
3849e3853.
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€
€
12. Linden, A. A.; Hermanns, N.; Ott, S.; Kruger, L.; Backvall, J.-E. Chem.dEur. J.
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_
13. Ostrowska, K.; Zylewski, M.; Walocha, K. Heterocycles 2002, 57, 1413e1421.
_
ꢀ
14. Jamrozy, K.; Szymoniak, K.; Ostrowska, K. Heterocycles 2008, 75, 2275e2282
We thank Dr. Andrzej Gorecki, Department of Physical Bio-
and references therein.
chemistry, for assistance in the lifetime measurements and helpful
discussions, and Dr. Edward Szneler, Department of Organic
Chemistry, for the NOESY measurements of 3a.
15. Saalfrank, R. W.; Horner, B.; Reck, S.; Nachtrab, J.; Peters, E.-M.; Peters, K.;
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