Synthesis of masked 2-amino-4,5-dihydro-4-oxopyrrole-3-carboxaldehydes

Article abstract of DOI:10.1055/s-2007-983713

2-(1-Substituted-2-amino-4,5-dihydro-4-oxopyrrol-3-yl)-1, 3-dimethylbenzimidazolium and -3-methylbenzothiazolium chlorides were prepared by reaction of 2-(2,3-dihydro-1,3-dimethylbenzimidazol-2-ylidene)- and 2-(3-methylbenzothiazol-2-ylidene)-4-chloro-3-o

Full text of DOI:10.1055/s-2007-983713

PAPER
1811
Synthesis of Masked 2-Amino-4,5-dihydro-4-oxopyrrole-3-carboxaldehydes
2
-Amino-4,5-dihyd
n
ro-4-oxopyr
t
role-3-
o
carboxaldeh
n
a
Enamine Ltd., Alexandra Matrosova str. 23, 01103 Kiev, Ukraine
Fax +380(44)5373253; E-mail: atver@univ.kiev.ua
National Taras Shevchenko University of Kiev, Volodimirska str. 62, 01033 Kiev, Ukraine
b
Received 19 February 2007; revised 3 April 2007
_
A
Abstract: 2-(1-Substituted-2-amino-4,5-dihydro-4-oxopyrrol-3-
yl)-1,3-dimethylbenzimidazolium and -3-methylbenzothiazolium
chlorides were prepared by reaction of 2-(2,3-dihydro-1,3-dimeth-
+
Me
N
N
O
X
ylbenzimidazol-2-ylidene)-
and
2-(3-methylbenzothiazol-2-
X
O
ylidene)-4-chloro-3-oxobutanenitriles with primary amines. The
salts obtained were reduced to 4-(2,3-dihydro-1,3-dimethylbenzim-
idazol-2-yl)- and 4-(2,3-dihydro-3-methylbenzothiazol-2-yl)-1-
substituted-5-aminopyrrol-3(2H)-ones. These pyrrole derivatives
were shown to serve as synthetic equivalents of the corresponding
2-aminopyrrole-3-carboxaldehydes. Thus, their treatment with phe-
nylhydrazine yielded 1-substituted 2-amino-4,5-dihydro-4-oxopyr-
role-3-carboxaldehyde phenylhydrazones, whereas condensation
with malonodinitrile afforded 1-substituted 6-amino-2,3-dihydro-3-
oxopyrrolo[2,3-b]pyridine-5-carbonitriles.
H2N
H2N
N
R
N
R
1
2
Figure 1 X = S, NH, NMe
the readily available nitriles 3,48 were selected as starting
materials since both compounds have been reported to re-
act with certain electrophiles at the exocyclic carbon at-
om.8a,9 Acylation of compounds 3,4 with chloroacetyl
chloride proceeded smoothly, providing the required 4-
chlorobutanenitriles 5,6 (Scheme 1). Amination of deriv-
atives 5,6 with substituted anilines gave the target pyr-
roles 7a–c, 8a–c in 80–90% yields. The reaction was
assumed to occur through initial alkylation of the aniline,
followed by hydrogen chloride assisted intramolecular
addition of the secondary amino group in the intermediate
A to the nitrile, which was accompanied by the charge
transfer to the benzoazole moiety. In this manner, the
equivalent amount of hydrogen chloride liberated in the
first step was then utilized in the second step. Acid hy-
drazides behaved like the anilines, thus yielding the corre-
sponding 1-acylamino derivatives 7d,e and 8d,e. Similar
reactivity of acid hydrazides towards 4-halonitriles has
been observed previously.5a The structures of pyrroles 7
and 8 were confirmed by 1H and 13C NMR investigations.
Particularly, the presence of the amino group signals ob-
served in the 1H NMR spectra (d = 7.8–9.1 ppm) and the
absence of a nitrile signal both in the IR and 13C NMR
spectra, clearly indicated that ring closure had taken place.
Key words: amino aldehydes, heterocycles, nitriles, pyrroles,
reductions
Vicinal (hetero)aromatic aminoaldehydes are powerful
synthons in heterocyclic chemistry.1 However, within the
pyrrole series, these derivatives are poorly represented.
To the best of our knowledge, only a single example of 2-
aminopyrrole-3-carboxaldehyde has been described.2
Furthermore, though a few 2-(dialkylamino)pyrrole-3-
carboxaldehydes have been prepared,3 the application of
these procedures for the synthesis of corresponding amino
derivatives is questionable.
N,N¢-Dimethylbenzimidazolium and N-methylbenzothi-
azolium moieties have been widely used in organic syn-
thesis as masked aldehyde functionality.4 Their reduction
to 2,3-dihydro derivatives and further hydrolytic cleavage
liberates the formyl group.4 In our previous works,5 a fac-
ile route to aminopyrroles 1, bearing a benzoazole substit-
uent at the suitable position, has been developed
(Figure 1). Continuing our research in this field, it would
be interesting to prepare the corresponding quaternary
salts 2 and to examine their conversion into appropriate
aminoaldehydes or related synthetic equivalents. The re-
sults obtained are reported herein.
An unforeseen result was obtained during the reaction of
the chloronitriles 5 and 6 with aliphatic primary amines.
While the benzimidazole derivative 5 gave the expected
pyrroles 7f,g, the benzothiazole analogue 6 afforded prod-
ucts to which the structures 9f–h were assigned on the ba-
Since direct alkylation of compounds 1 raised some
doubts owing to the presence of a number of other groups
capable of reaction, another approach was employed. It is
known that the reaction of 4-halobutanenitriles with pri-
mary amines is a convenient method for aminopyrrole
preparation.5–7 To apply such a reaction for our purpose,
sis of H, 13C and 2D NMR (COSY, NOESY, HSQC,
1
HMBC) experiments. Perhaps, compounds 9f–h were
formed via recyclization of the intermediates A into thiols
B through intramolecular amino group attack on position
2 of the benzothiazole and subsequent trapping of thiols B
with the starting chloride 6.
SYNTHESIS 2007, No. 12, pp 1811–1818
x
x.
x
x
.
2
0
0
7
Advanced online publication: 08.06.2007
DOI: 10.1055/s-2007-983713; Art ID: P02207SS
© Georg Thieme Verlag Stuttgart · New York

1812
A. V. Tverdokhlebov et al.
PAPER
O
O
NC
Me
O
Cl
Me
Me
Cl
Cl
N
N
N
O
N
N
R
S
S
X
CN
Me
X
CN
NC
3,4
9f–h
5,6
R-NH2
6
_
Cl
O
NC
+
Me
Me
O
HN R
N
HCl
X = S
R is f,g,h
N
O
X
N
N
HS
X
CN
Me
R
H2N
A
N
R
B
7a–g
8a–e
Scheme 1 X = NMe (3, 5, 7), X = S (4, 6, 8); R = Ph (a), 4-EtC6H4 (b), 4-(MeO)C6H4 (c), PhCONH- (d), 4-(MeO)C6H4CONH- (e), Bn (f),
PhCH2CH2 (g), n-Pr (h)
s, 3.85
It is noteworthy that derivatives 9 were the only products
isolated from the reaction using different ratios of amines
and chloronitrile 6. The best yields of 9 were achieved
with a 1.5-fold excess of amine, as required by stoichiom-
etry, considering that the extra equivalent of amine scav-
enged the evolved hydrogen chloride.
H
H
t, 2.86
s, 3.46
Et
O
H
H
N
N
CN
H3C
Me
N
S
O
For structure assignments the NOESY and HMBC exper-
iments performed for derivative 9h turned out to be the
most revealing (Figure 2 and Figure 3). Thus, the NOE
correlations of n-propyl methylene (t, 2.86 ppm) allowed
assignment of the signals of the endocyclic methylene (s,
3.85 ppm) and the nearest methyl (s, 3.46 ppm) and indi-
rectly confirmed the pyrrole ring closure. Furthermore,
the set of C-H correlations from the endocyclic methylene
protons revealed in an HMBC experiment, convincingly
proved the structure of the pyrrole moiety. Likewise, for-
mation of the S–CH2 bond was confirmed by correlations
of the corresponding methylene protons (s, 4.25 ppm)
with the hydrogen (m, 7.55 ppm) and carbon (134.6 ppm)
atoms of the ortho-phenylene fragment observed in
NOESY and HMBC experiments respectively.
H
H
H
m, 7.55
S
CN
s, 4.25
Figure 2 Selected NOESY correlations of derivative 9h
s, 3.85
50.4
H
H
O
191.9
74.9
N
N
171.7
CN
Me
S
Me
O
N
Furthermore, in order to be certain of the structure of 9,
additional confirmation was obtained through chemical
transformations. Thus, prolonged heating of derivative 9h
with excess of propylamine resulted in pyrrole cleavage
and formation of compound 10 (Scheme 2). Alternatively,
derivative 10 was obtained by alkylation of 2-(methylami-
no)benzenethiol (11) with the chloronitrile 6. Since both
samples were shown to be the identical, the structure of 9
is thus beyond doubt.
H
H
134.6
s, 4.25
S
CN
Figure 3 Selected HMBC correlations of derivative 9h
The quaternary salts 7 and 8 (where R is aryl) were re-
duced with sodium borohydride to give the corresponding
dihydro derivatives 12 and 13 in 70–100% yields
(Scheme 3). The products appeared to react as equivalents
of the corresponding aldehydes under conditions of acidic
catalysis. Thus, treatment of compounds 12 or 13 with
phenylhydrazine, in the presence of toluenesulfonic acid,
afforded hydrazones 14. Furthermore, pyrrolo[2,3-b]py-
ridines 15a–c were prepared by ammonium chloride cata-
lyzed condensation of derivatives 12 and 13 with
malonodinitrile. Both imidazole and thiazole derivatives
12 and 13 gave the same products 14 and 15 and there was
Me
HN
Me
Me
O
S
HN
6
n-PrNH2
N
9h
HS
S
CN
10
11
Scheme 2
Synthesis 2007, No. 12, 1811–1818 © Thieme Stuttgart · New York

PAPER
2-Amino-4,5-dihydro-4-oxopyrrole-3-carboxaldehydes
1813
the compounds by DMSO. 13C NMR spectra of the salts 7 and 8
were recorded in CF3CO2D solutions because of their low solubility
in DMSO. Again, in order to obtain clear spectra it was recorded im-
mediately after dissolving the sample, since a slow deuteriation of
derivatives 7 and 8 at the methylene group occurred. 2D NMR ex-
periments were performed on a Bruker Avance 500 spectrometer
(500 MHz for 1H and 125 MHz for 13C). Chemical shifts (d) are giv-
en in ppm downfield from internal TMS. J values are in Hz. The pu-
rity of all compounds obtained was verified by 1H NMR and LC/MS
on an Agilent 1100 instrument.
no significant difference in either reactivity or yields.
However, the thiazole compounds 13 exhibited higher sta-
bility upon storage than their imidazole analogues 12,
probably due to lower sensitivity towards air oxidation.
Hence, the thiazolines 13 are more convenient equivalents
of 2-aminopyrrole-3-carboxaldehydes. Nevertheless in
the case of 1-alkyl-substituted pyrroles, only the benzim-
idazolium precursors 7f,g could be obtained, since the thi-
azole compound 6 yielded the products of structure 9.
4-Chloro-2-(2,3-dihydro-1,3-dimethylbenzimidazol-2-ylidene)-
3-oxobutanenitrile (5)
O
7a–c
8a–c
NC
Chloroacetyl chloride (2.8 mL, 0.035 mol) was added in one portion
to a cold solution of the nitrile 3 (6.48 g, 0.035 mol) and Et3N (4.83
mL, 0.035 mol) in dioxane (15 mL). After the initial exothermal re-
action had ceased, the mixture was heated on a boiling water bath
for 1 h. Upon cooling, the precipitated solid was filtered and thor-
oughly washed with H2O to give pure 5. If necessary, additional pu-
rification could be achieved by recrystallization from dioxane.
N
H2N
N
NaBH4
R
15a–c
CH2(CN)2
NH4Cl
Ph
HN
N
Me
N
Yield: 7.88 g (86%); mp 218 °C (dioxane).
1H NMR: d = 3.82 (s, 6 H, 2 × CH3), 4.29 (s, 2 H, CH2), 7.49 (m,
2 H, HAr), 7.74 (m, 2 H, HAr).
X
O
O
Ph-NHNH2
TsOH
H2N
H2N
13C NMR: d = 33.3 (2 × CH3), 46.5 (CH2), 58.4 (C-2), 112.3 (Cimid
4,7), 121.4 (CN), 125.4 (Cimid-5,6), 132.3 (Cimid-3a,7a), 151.8 (Cimid
2), 181.7 (CO).
-
-
N
N
R
R
12a–c
13a–c
14b,c
Anal. Calcd for C13H12ClN3O: C, 59.66; H, 4.62; N, 16.06; Cl,
13.55. Found: C, 59.60; H, 4.68; N, 15.95; Cl, 13.45.
Scheme 3 X = NMe (12), X = S (13); R = Ph (a), 4-EtC6H4 (b), 4-
(MeO)C6H4 (c)
4-Chloro-2-(3-methyl-2-benzothiazolylidene)-3-oxobutane-
nitrile (6)
Chloroacetyl chloride (2.8 mL, 0.035 mol) was added to a solution
of the nitrile 4 (6.59 g, 0.035 mol) in dioxane (15 mL) and the re-
sulting mixture was refluxed for 1.5 h. After cooling, the precipitate
formed was filtered, washed with H2O and recrystallized from di-
oxane to give compound 6.
In summary, a facile route to the quaternary salts 7 and 8
has been developed. Such compounds have been easily re-
duced to the corresponding derivatives 12 and 13, which
are useful equivalents of 2-aminopyrrole-3-carboxalde-
hydes. This has been demonstrated by their reactions with
phenylhydrazine and malonodinitrile. In particular, the
condensation with malonodinitrile led to the pyrrolopyri-
Yield: 7.87 g (85%); mp 195 °C (dioxane).
1H NMR: d = 4.17 (s, 3 H, CH3), 4.62 (s, 2 H, CH2), 7.45 (t, J = 7.6
dine derivatives 15. It should be noted that most syntheses Hz, 1 H, HAr), 7.61 (t, J = 7.6 Hz, 1 H, HAr), 7.79 (d, J = 7.6 Hz, 1 H,
HAr), 8.03 (d, J = 7.6 Hz, 1 H, HAr).
of pyrrolo[2,3-b]pyridines involve pyrrole ring annula-
tions to the pyridine10 and are generally based on analogy
with other known approaches to indoles. A few methods
utilizing pyridine annulations to pyrrole either required
relatively unstable and synthetically demanding 3-unsub-
stituted 2-aminopyrroles11 or are comprised of multi-step
sequences starting from 2-aminopyrrole-3-carboxylates.12
Hence, the present approach to pyrrolopyridines seems to
deserve attention. Of course, the potential of derivatives
12 and 13 for the synthesis of fused pyrroles has yet to be
fully explored and further research in this field is currently
underway and will be reported in due course.
13C NMR: d = 36.3 (CH3), 46.6 (CH2), 75.2 (C-2), 113.6 (Cthiaz-4),
119.4 (CN), 123.1 (Cthiaz-6), 125.4 (Cthiaz-7), 126.7 (Cthiaz-7a), 128.1
(Cthiaz-5), 140.3 (Cthiaz-3a), 165.9 (Cthiaz-2), 184.9 (CO).
Anal. Calcd for C12H9ClN2OS: C, 54.44; H, 3.43; N, 10.58; Cl,
13.39; S, 12.11. Found: C, 54.45; H, 3.30; N, 10.50; Cl, 13.30; S,
12.16.
Synthesis of the Quaternary Salts 7a–g and 8a–e; General Pro-
cedure
A solution of the chloronitrile 5,6 (2.5 mmol) and appropriate amine
or acid hydrazide (2.5 mmol) in DMF (5 mL) was heated at 130–
140 °C for 3–5 h. After cooling, the solid formed was filtered,
washed with DMF (1 × 2 mL) and dried in vacuo to give pure de-
rivatives 7a–g, 8a–e. If necessary, additional purification by recrys-
tallization from DMF was performed.
The starting nitriles 3 and 4 were prepared as reported.8 Other re-
agents were commercially available. Dioxane and MeOH were
dried with Na and Mg respectively and then distilled. DMF was
kept over P2O5 overnight and then distilled under reduced pressure.
All melting points were determined in open capillary tubes in a
Thiele apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded on a Varian Unity plus 400 spectrometer (400 MHz for 1H
and 100 MHz for 13C) in DMSO-d6. For derivatives 12 and 13, in
order to obtain acceptable spectra, they were recorded as quickly as
possible after dissolving the sample because of slow oxidation of
2-(2-Amino-4,5-dihydro-4-oxo-1-phenylpyrrol-3-yl)-1,3-di-
methylbenzimidazolium Chloride (7a)
Yield: 0.82 g (92%); mp >300 °C (DMF).
1H NMR: d = 3.92 (s, 6 H, 2 × CH3), 4.44 (s, 2 H, CH2), 7.40 (m,
1 H, HR-4), 7.54 (m, 4 H, HR-2,3,5,6), 7.64 (m, 2 H, Himid), 7.84 (br
s, 2 H, NH2), 7.98 (m, 2 H, Himid).
Synthesis 2007, No. 12, 1811–1818 © Thieme Stuttgart · New York

1814
A. V. Tverdokhlebov et al.
PAPER
2-[2-Amino-4,5-dihydro-4-oxo-1-benzylpyrrol-3-yl]-1,3-di-
methylbenzimidazolium Chloride (7f)
Yield: 0.75 g (81%); mp >300 °C (DMF).
13C NMR: d = 32.4 (2 × CH3), 59.1 (CH2), 86.2 (Cpy-3), 112.8 (C-
4,7), 125.8 (CR-2,6), 128.8 (C-5,6), 131.3 (CR-3,5), 132.8 (C-3a,7a),
133.1 (CR-4), 139.8 (CR-1), 164.0 (Cpy-2), 164.1 (C-2), 184.5 (CO).
Anal. Calcd for C19H19N4OCl: C, 64.31; H, 5.40; N, 15.79; Cl, 9.99.
Found: C, 64.18; H, 5.33; N, 15.70; Cl, 10.13.
1H NMR: d = 3.86 (s, 6 H, 2 × CH3), 3.88 (s, 2 H, CH2), 4.79 (s, 2 H,
CH2), 7.35 (m, 3 H, HR), 7.43 (m, 2 H, HR), 7.63 (m, 2 H, Himid),
7.94 (m, 2 H, Himid), 8.23 (s, 2 H, NH2).
2-[2-Amino-1-(4-ethylphenyl)-4,5-dihydro-4-oxopyrrol-3-yl]-
1,3-dimethylbenzimidazolium Chloride (7b)
Yield: 0.77 g (80%); mp 290 °C (DMF).
1H NMR: d = 1.22 (t, J = 7.2 Hz, 3 H, CH3), 2.66 (q, J = 7.2 Hz, 2 H,
CH2), 3.92 (s, 6 H, 2 × CH3), 4.40 (s, 2 H, CH2), 7.38 (d, J = 8.4 Hz,
2 H, HR), 7.45 (d, J = 8.4 Hz, 2 H, HR), 7.64 (m, 2 H, Himid), 7.80 (br
s, 2 H, NH2), 7.97 (m, 2 H, Himid).
13C NMR: d = 32.2 (2 × CH3), 49.8 (CH2), 56.3 (CH2), 86.6 (Cpy-3),
112.7 (C-4,7), 127.8 (CR-3,5), 128.7 (C-5,6), 129.8 (CR-2,6), 131.6
(CR-4), 132.7 (C-3a,7a), 139.4 (CR-1), 163.1 (Cpy-2), 164.8 (C-2),
183.2 (CO).
Anal. Calcd for C20H21N4OCl: C, 65.12; H, 5.74; N, 15.19; Cl, 9.61.
Found: C, 65.20; H, 5.80; N, 15.03; Cl, 9.81.
13C NMR: d = 13.6 (CH3), 28.2 (CH2), 32.2 (2 × CH3), 59.3 (CH2),
86.3 (Cpy-3), 112.6 (C-4,7), 125.4 (CR-2,6), 128.6 (C-5,6), 130.1
(CR-4), 130.5 (CR-3,5), 132.6 (C-3a,7a), 139.5 (CR-1), 148.9 (Cpy-
2), 163.7 (C-2), 183.8 (CO).
2-[2-Amino-4,5-dihydro-4-oxo-1-(2-phenylethyl)pyrrol-3-yl]-
1,3-dimethylbenzimidazolium Chloride (7g)
Yield: 0.87 g (91%); mp 300 °C (DMF).
1H NMR: d = 2.95 (t, J = 7.6 Hz, 2 H, CH2Ph), 3.76 (s, 6 H, 2 ×
CH3), 3.80 (t, J = 7.6 Hz, 2 H, NCH2), 3.94 (s, 2 H, CH2CO), 7.24
(t, J = 7.6 Hz, 1 H, HR-4), 7.33 (t, J = 7.6 Hz, 3 H, HR-3,5), 7.38 (d,
J = 7.6 Hz, 2 H, HR-2,6), 7.61 (m, 2 H, Himid), 7.92 (m, 2 H, Himid),
8.22 (br s, 2 H, NH2).
13C NMR: d = 32.1 (2 × CH3), 33.6 (CH2), 47.4 (NCH2), 56.5
(COCH2), 86.1 (Cpy-3), 112.6 (C-4,7), 127.9 (CR-4), 128.5 (CR-3,5),
128.6 (C-5,6), 129.5 (CR-2,6), 132.5 (C-3a,7a), 136.8 (CR-1), 139.3
(Cpy-2), 163.4 (C-2), 182.8 (CO).
Anal. Calcd for C21H23N4OCl: C, 65.88; H, 6.05; N, 14.63; Cl, 9.26.
Found: C, 65.87; H, 6.02; N, 14.68; Cl, 9.32.
2-[2-Amino-4,5-dihydro-1-(4-methoxyphenyl)-4-oxopyrrol-3-
yl]-1,3-dimethylbenzimidazolium Chloride (7c)
Yield: 0.86 g (89%); mp >300 °C (DMF).
1H NMR: d = 3.81 (s, 3 H, OCH3), 3.91 (s, 6 H, 2 × NCH3), 4.35 (s,
2 H, CH2), 7.09 (d, J = 9.2 Hz, 2 H, HR), 7.47 (d, J = 9.2 Hz, 2 H,
HR), 7.64 (m, 2 H, Himid), 7.86 (br s, 2 H, NH2), 7.96 (m, 2 H, Himid).
13C NMR: d = 32.2 (NCH3), 55.4 (OCH3), 59.4 (CH2), 86.0 (Cpy-3),
112.6 (C-4,7), 116.6 (CR-3,5), 126.2 (CR-1), 127.7 (CR-2,6), 128.6
(C-5,6), 132.6 (C-3a,7a), 139.7 (Cpy-2), 160.7 (CR-4), 164.2 (C-2),
184.3 (CO).
Anal. Calcd for C21H23N4OCl: C, 65.88; H, 6.05; N, 14.63; Cl, 9.26.
Found: C, 65.80; H, 6.23; N, 14.70; Cl, 9.19.
2-(2-Amino-4,5-dihydro-4-oxo-1-phenylpyrrol-3-yl)-3-methyl-
benzothiazolium Chloride (8a)
Yield: 0.72 g (81%); mp 270 °C (DMF).
Anal. Calcd for C20H21N4O2Cl: C, 62.42; H, 5.50; N, 14.56; Cl,
9.21. Found: C, 62.50; H, 5.40; N, 14.79; Cl, 9.20.
1H NMR: d = 4.11 (s, 3 H, CH3), 4.54 (s, 2 H, CH2), 7.44 (m, 1 H,
HR-4), 7.58 (m, 4 H, HR-2,3,5,6), 7.66 (t, J = 8.4 Hz, 1 H, Hthiaz),
7.78 (t, J = 8.4 Hz, 1 H, Hthiaz), 8.08 (d, J = 8.4 Hz, 1 H, Hthiaz), 8.31
(d, J = 8.4 Hz, 1 H, Hthiaz), 8.40 (s, 2 H, NH2).
13C NMR: d = 38.1 (CH3), 59.3 (CH2), 90.6 (Cpy-3), 116.7 (C-4),
123.8 (C-7), 125.8 (CR-2,6), 130.1 (C-6), 130.2 (C-7a), 131.1 (C-5),
131.2 (CR-4), 131.3 (CR-3,5), 133.3 (CR-1), 141.8 (C-3a), 162.5
(Cpy-2), 164.3 (C-2), 184.9 (CO).
2-[2-Amino-1-benzoylamino-4,5-dihydro-4-oxopyrrol-3-yl]-
1,3-dimethylbenzimidazolium Chloride (7d)
Yield: 0.82 g (82%); mp >300 °C (DMF).
1H NMR: d = 3.90 (s, 6 H, 2 × CH3), 4.14 (s, 2 H, CH2), 7.54 (m,
2 H, HR-3,5), 7.64 (m, 3 H, HR-4, 2 × Himid), 7.97 (m, 2 H, Himid),
8.03 (d, J = 7.6 Hz, 2 H, HR-2,6), 8.54 (s, 2 H, NH2), 11.32 (s, 1 H,
CONH).
13C NMR: d = 32.2 (2 × CH3), 57.5 (CH2), 83.1 (Cpy-3), 112.6 (C-
4,7), 127.9 (CR-3,5), 128.2 (CR-1), 128.5 (C-5,6), 129.5 (CR-2,6),
132.6 (C-3a,7a), 135.2 (CR-4), 140.5 (Cpy-2), 167.9 (C-2), 171.3
(CONH), 186.6 (CO).
Anal. Calcd for C18H16N3OSCl: C, 60.41; H, 4.51; N, 11.74; Cl,
9.91; S, 8.96. Found: C, 60.21; H, 4.29; N, 11.73; Cl, 9.76; S, 9.02.
2-[2-Amino-1-(4-ethylphenyl)-4,5-dihydro-4-oxopyrrol-3-yl]-3-
methylbenzothiazolium Chloride (8b)
Yield: 0.81 g (84%); mp 258 °C (DMF).
Anal. Calcd for C20H20N5O2Cl: C, 60.38; H, 5.07; N, 17.60; Cl,
8.91. Found: C, 60.27; H, 5.19; N, 17.60; Cl, 8.77.
1H NMR: d = 1.23 (t, J = 7.8 Hz, 3 H, CH3), 2.68 (q, J = 7.8 Hz, 2 H,
CH2), 4.08 (s, 3 H, NCH3), 4.51 (s, 2 H, CH2CO), 7.40 (d, J = 8.8
Hz, 2 H, HR), 7.49 (d, J = 8.8 Hz, 2 H, HR), 7.67 (t, J = 8.4 Hz, 1 H,
2-[2-Amino-4,5-dihydro-1-(4-methoxybenzoyl)amino-4-oxo-
pyrrol-3-yl]-1,3-dimethylbenzimidazolium Chloride (7e)
Yield: 0.89 g (83%); mp 289 °C (DMF).
H
H
thiaz), 7.78 (t, J = 8.4 Hz, 1 H, Hthiaz), 8.07 (d, J = 8.4 Hz, 1 H,
thiaz), 8.30 (m, 3 H, NH2, Hthiaz).
1H NMR: d = 3.84 (s, 3 H, OCH3), 3.89 (s, 6 H, 2 × NCH3), 4.12 (s,
2 H, CH2), 7.07 (d, J = 9.2 Hz, 2 H, HR-3,5), 7.65 (m, 2 H, Himid),
7.98 (m, 4 H, Himid, HR-2,6), 8.45 (s, 2 H, NH2), 11.06 (s, 1 H,
CONH).
13C NMR: d = 13.7 (CH3), 28.2 (CH2), 37.9 (NCH3), 59.2 (NCH2),
90.8 (Cpy-3), 116.6 (C-4), 123.7 (C-7), 125.5 (CR-2,6), 130.0 (CR-4),
130.1 (C-6), 130.4 (C-7a), 130.5 (CR-3,5), 131.1 (C-5), 141.7 (C-
3a), 148.8 (CR-1), 162.0 (Cpy-2), 164.0 (C-2), 184.1 (CO).
13C NMR: d = 32.3 (2 × CH3), 55.4 (OCH3), 57.6 (CH2), 83.4 (Cpy-
3), 112.8 (C-4,7), 115.1 (CR-3,5), 121.1 (CR-1), 128.7 (C-5,6), 130.7
(CR-2,6), 132.8 (C-3a,7a), 140.5 (Cpy-2), 164.9 (CR-4), 168.0 (C-2),
170.5 (CONH), 186.5 (CO).
Anal. Calcd for C20H20N3OSCl: C, 62.25; H, 5.22; N, 10.89; Cl,
9.19; S, 8.31. Found: C, 62.11; H, 5.19; N, 10.80; Cl, 8.99; S, 8.21.
2-[2-Amino-4,5-dihydro-1-(4-methoxyphenyl)-4-oxopyrrol-3-
yl]-3-methylbenzothiazolium Chloride (8c)
Yield: 0.88 g (91%); mp 261 °C (DMF).
1H NMR: d = 3.82 (s, 3 H, OCH3), 4.07 (s, 3 H, NCH3), 4.45 (s, 2 H,
CH2), 7.11 (d, J = 8.4 Hz, 2 H, HR), 7.50 (d, J = 8.4 Hz, 2 H, HR),
Anal. Calcd for C21H22N5O3Cl: C, 58.95; H, 5.18; N, 16.37; Cl,
8.29. Found: C, 58.74; H, 5.32; N, 16.58; Cl, 8.12.
Synthesis 2007, No. 12, 1811–1818 © Thieme Stuttgart · New York

PAPER
2-Amino-4,5-dihydro-4-oxopyrrole-3-carboxaldehydes
1815
7.65 (t, J = 8.0 Hz, 1 H, Hthiaz), 7.77 (t, J = 8.0 Hz, 1 H, Hthiaz), 8.04
(d, J = 8.0 Hz, 1 H, Hthiaz), 8.17 (s, 2 H, NH2), 8.28 (d, J = 8.0 Hz,
1 H, Hthiaz).
Anal. Calcd for C31H25N5O2S2: C, 66.05; H, 4.47; N, 12.42; S,
11.38. Found: C, 66.10; H, 4.40; N, 12.40; S, 11.49.
2-[(2-{[3-Cyano-3-(3-methyl-2-benzothiazolylidene)-2-oxopro-
pyl]thio}phenyl)methylamino]-4,5-dihydro-4-oxo-1-(2-phenyl-
ethyl)pyrrole-3-carbonitrile (9g)
13C NMR: d = 37.9 (NCH3), 55.4 (OCH3), 59.2 (CH2), 90.7 (Cpy-3),
116.5 (CR-3,5), 116.6 (C-4), 123.7 (C-7), 126.4 (CR-1), 127.8 (CR-
2,6), 130.0 (C-6), 130.1 (C-7a), 131.1 (C-5), 141.7 (C-3a), 160.6
(CR-4), 162.0 (Cpy-2), 164.4 (C-2), 184.1 (CO).
Yield: 0.55 g (76%); mp 232 °C (dioxane).
1H NMR: d = 2.41 (t, J = 8.2 Hz, 2 H, CH2Ph), 3.15 (t, J = 8.2 Hz,
2 H, NCH2), 3.45 (s, 3 H, NCH3), 3.84 (s, 2 H, CH2CO), 4.13 (s,
3 H, NCH3), 4.26 (s, 2 H, SCH2), 6.93 (d, J = 6.8 Hz, 2 H, HR-2,6),
7.10 (t, J = 7.4 Hz, 1 H, HR-4), 7.18 (m, 2 H, HR-3,5), 7.42 (m, 3 H,
Anal. Calcd for C19H18N3O2SCl: C, 58.83; H, 4.68; N, 10.83; Cl,
9.14; S, 8.27. Found: C, 58.94; H, 4.52; N, 10.72; Cl, 9.25; S, 8.25.
2-[2-Amino-1-benzoylamino-4,5-dihydro-4-oxopyrrol-3-yl]-3-
methylbenzothiazolium Chloride (8d)
Yield: 0.79 g (79%); mp 282 °C (DMF).
H
thiaz, 2 × o-phenylene), 7.57 (m, 2 H, Hthiaz, o-phenylene), 7.64 (d,
J = 7.2 Hz, 1 H, o-phenylene), 7.76 (d, J = 8.4 Hz, 1 H, Hthiaz), 7.97
(d, J = 8.4 Hz, 1 H, Hthiaz).
1H NMR: d = 4.05 (s, 3 H, CH3), 4.27 (s, 2 H, CH2), 7.55 (m, 2 H,
HR-3,5), 7.66 (m, 2 H, Hthiaz, HR-4), 7.79 (t, J = 8.4 Hz, 1 H, Hthiaz),
8.06 (m, 3 H, Hthiaz, HR-2,6), 8.31 (d, J = 8.4 Hz, 1 H, Hthiaz), 9.05 (s,
2 H, NH2), 11.53 (s, 1 H, CONH).
13C NMR: d = 37.9 (CH3), 57.4 (CH2), 88.3 (Cpy-3), 116.3 (C-4),
123.6 (C-7), 127.9 (CR-3,5), 128.2 (CR-1), 129.3 (CR-2,6), 129.6 (C-
7a), 129.7 (C-6), 130.8 (C-5), 135.0 (CR-4), 141.6 (C-3a), 162.9
(Cpy-2), 167.6 (C-2), 171.1 (CONH), 186.0 (CO).
13C NMR: d = 33.5 (CH2Ph), 36.3 (NCH3), 40.2 (SCH2), 43.0
(NCH3), 50.6 (NCH2), 59.9 (NCH2CO), 75.2 (C-3), 76.3 (3¢-CCN),
113.5 (Cthiaz-4), 116.3 (CN), 120.0 (CN), 123.0 (Cthiaz-7), 125.3
(Cthiaz-5), 126.7 (Cthiaz-7a), 126.9 (CR-4), 128.1 (Cthiaz-6), 128.3
(Cphen-6), 128.4 (Cphen-5), 128.8 (CR-3,5), 129.1 (CR-2,6), 129.5
(Cphen-4), 130.7 (Cphen-3), 134.6 (Cphen-2), 138.3 (CR-1), 140.3 (Cthi-
az-3a), 143.1 (Cphen-1), 165.8 (Cthiaz-2), 171.8 (C-2), 187.2 (2¢-CO),
191.8 (4-CO).
Anal. Calcd for C19H17N4O2SCl: C, 56.93; H, 4.27; N, 13.98; Cl,
8.84; S, 8.00. Found: C, 57.13; H, 4.28; N, 14.07; Cl, 8.82; S, 7.95.
Anal. Calcd for C32H27N5O2S2: C, 66.53; H, 4.71; N, 12.12; S,
11.10. Found: C, 66.49; H, 4.70; N, 12.01; S, 11.04.
2-[2-Amino-4,5-dihydro-1-(4-methoxybenzoyl)amino-4-oxo-
pyrrol-3-yl]-3-methylbenzothiazolium Chloride (8e)
Yield: 0.88 g (82%); mp 285 °C (DMF).
2-[(2-{[3-Cyano-3-(3-methyl-2-benzothiazolylidene)-2-oxopro-
pyl]thio}phenyl)methylamino]-4,5-dihydro-4-oxo-1-propylpyr-
role-3-carbonitrile (9h)
1H NMR: d = 3.85 (s, 3 H, OCH3), 4.04 (s, 3 H, NCH3), 4.25 (s, 2 H,
CH2), 7.09 (d, J = 8.4 Hz, 2 H, HR), 7.68 (t, J = 8.0 Hz, 1 H, Hthiaz),
7.79 (t, J = 8.0 Hz, 1 H, Hthiaz), 8.01 (d, J = 8.4 Hz, 2 H, HR), 8.07
(d, J = 8.0 Hz, 1 H, Hthiaz), 8.31 (d, J = 8.0 Hz, 1 H, Hthiaz), 8.97 (s,
2 H, NH2), 11.31 (s, 1 H, CONH).
13C NMR: d = 37.9 (NCH3), 55.2 (OCH3), 57.4 (CH2), 88.1 (Cpy-3),
114.9 (CR-3,5), 116.3 (C-4), 121.0 (CR-1), 123.6 (C-7), 129.6 (C-
7a), 129.7 (C-6), 130.5 (CR-2,6), 130.8 (C-5), 141.6 (C-3a), 163.1
(Cpy-2), 164.4 (CR-4), 167.7 (C-2), 170.2 (CONH), 186.2 (CO).
Yield: 0.53 g (82%); mp 175 °C (i-PrOH).
1H NMR: d = 0.49 (t, J = 6.3 Hz, 3 H, CH3), 1.16 (m, 2 H, CH2),
2.86 (t, J = 6.3 Hz, 2 H, NCH2), 3.50 (s, 3 H, NCH3), 3.85 (s, 2 H,
CH2CO), 4.14 (s, 3 H, NCH3), 4.25 (s, 2 H, SCH2), 7.33 (t, J = 7.0
Hz, 1 H, o-phenylene), 7.40 (m, 2 H, Hthiaz, o-phenylene), 7.48 (d,
J = 7.0 Hz, 1 H, o-phenylene), 7.57 (m, 2 H, Hthiaz, o-phenylene),
7.74 (d, J = 8.0 Hz, 1 H, Hthiaz), 7.95 (d, J = 8.0 Hz, 1 H, Hthiaz).
13C NMR: d = 11.1 (CH3), 20.6 (CH2), 36.3 (NCH3), 40.3 (SCH2),
43.0 (NCH3), 50.4 (NCH2), 59.6 (NCH2CO), 74.9 (C-3), 76.3 (3¢-
CCN), 113.5 (Cthiaz-4), 116.4 (CN), 120.0 (CN), 123.0 (Cthiaz-7),
125.3 (Cthiaz-5), 126.7 (Cthiaz-7a), 128.1 (Cthiaz-6), 128.2 (Cphen-6),
128.3 (Cphen-5), 129.5 (Cphen-4), 130.4 (Cphen-3), 134.6 (Cphen-2),
140.3 (Cthiaz-3a), 143.0 (Cphen-1), 165.8 (Cthiaz-2), 171.7 (C-2), 187.1
(3¢-CO), 191.9 (4-CO).
Anal. Calcd for C20H19N4O3SCl: C, 55.75; H, 4.44; N, 13.00; Cl,
8.23; S, 7.44. Found: C, 55.74; H, 4.50; N, 12.95; Cl, 8.18; S, 7.50.
Synthesis of Pyrrolecarbonitriles 9f–h; General Procedure
A solution of the chloronitrile 6 (0.66 g, 2.5 mmol) and appropriate
alkylamine (3.8 mmol) in DMF (5 mL) was heated at 130–140 °C
for 3 h. After cooling, it was poured into H2O (15 mL) and the pre-
cipitated solid was filtered. Further recrystallization from the appro-
priate solvent afforded derivatives 9f–h.
Anal. Calcd for C27H25N5O2S2: C, 62.89; H, 4.89; N, 13.58; S,
12.44. Found: C, 62.92; H, 4.97; N, 13.41; S, 12.40.
4-[2-(Methylamino)phenyl]thio-2-(3-methyl-2-benzothiazolyl-
idene)-3-oxobutanenitrile (10)
2-[(2-{[3-Cyano-3-(3-methyl-2-benzothiazolylidene)-2-oxopro-
pyl]thio}phenyl)methylamino]-4,5-dihydro-4-oxo-1-benzylpyr-
role-3-carbonitrile (9f)
Method A: A mixture of compound 9h (1.55 g, 3 mmol) and propyl-
amine (0.89 g, 15 mmol) in dioxane (10 mL) was stirred and heated
at 60 °C for 1 d with a high-efficiency reflux condenser, preventing
evaporation of the amine. After cooling, the precipitate was filtered,
washed with dioxane (1 × 3 mL) to give the derivative 10 (0.71 g,
64%).
Yield: 0.51 g (73%); mp 246 °C (dioxane).
1H NMR: d = 3.52 (s, 3 H, NCH3), 3.79 (s, 2 H, COCH2N), 4.16 (s,
3 H, NCH3), 4.27 (s, 2 H, SCH2), 4.34 (s, 2 H, NCH2Ph), 7.02 (d,
J = 7.6 Hz, 2 H, HR), 7.23 (m, 4 H, 3 × HR, o-phenylene), 7.33 (t,
J = 7.6 Hz, 1 H, o-phenylene), 7.43 (m, 2 H, Hthiaz, o-phenylene),
7.59 (m, 2 H, Hthiaz, o-phenylene), 7.75 (d, J = 8.4 Hz, 1 H, Hthiaz),
7.96 (d, J = 8.4 Hz, 1 H, Hthiaz).
13C NMR: d = 36.3 (NCH3), 40.2 (SCH2), 43.1 (NCH3), 52.6
(NCH2), 60.0 (5-CH2), 75.6 (C-3), 76.3 (3¢-CCN), 113.5 (Cthiaz-4),
115.8 (CN), 120.0 (CN), 123.0 (Cthiaz-7), 125.3 (Cthiaz-5), 126.8
(Cthiaz-7a), 127.2 (CR-3,5), 127.8 (CR-4), 128.0 (Cthiaz-6), 128.1
(Cphen-6), 128.3 (Cphen-5), 128.9 (CR-2,6), 129.5 (Cphen-4), 130.5
(Cphen-3), 134.5 (Cphen-2), 136.1 (CR-1), 140.3 (Cthiaz-3a), 142.6
(Cphen-1), 165.8 (Cthiaz-2), 172.7 (C-2), 187.2 (2¢-CO), 191.7 (4-CO).
Method B: A solution of compound 6 (0.66 g, 2.5 mmol), 2-(meth-
ylamino)benzenethiol13 (0.42 g, 3.0 mmol) and Et3N (0.41 mL, 3.0
mmol) in dioxane was refluxed for 1 h. After cooling, the separated
precipitate was filtered, washed with H2O (2 × 5 mL) and recrystal-
lized from dioxane to give derivative 10 (0.66 g, 72%).
Both samples were shown to be identical by IR and H and 13C
NMR, as well as by mixed mp.
1
Mp 189 °C (dioxane).
1H NMR: d = 2.74 (d, J = 5.0 Hz, 3 H, NHCH3), 3.85 (s, 2 H, CH2),
4.10 (s, 3 H, NCH3), 5.60 (q, J = 5.0 Hz, 1 H, NH), 6.48 (t, J = 8.0
Synthesis 2007, No. 12, 1811–1818 © Thieme Stuttgart · New York

1816
A. V. Tverdokhlebov et al.
PAPER
Hz, 1 H, o-phenylene), 6.52 (d, J = 8.0 Hz, 1 H, o-phenylene), 7.16
(t, J = 8.0 Hz, 1 H, o-phenylene), 7.28 (d, J = 8.0 Hz, 1 H, o-phe-
nylene), 7.39 (t, J = 8.5 Hz, 1 H, Hthiaz), 7.55 (t, J = 8.5 Hz, 1 H,
Hthiaz), 7.72 (d, J = 8.5 Hz, 1 H, Hthiaz), 7.97 (d, J = 8.5 Hz, 1 H, Hthiaz).
13C NMR: d = 30.5 (CH3), 36.2 (CH3), 41.8 (CH2), 76.4 (C-2), 109.9
(Cphen-3), 113.4 (Cthiaz-4), 115.9 (Cphen-3), 116.2 (Cphen-5), 120.1
(CN), 123.0 (Cthiaz-6), 125.1 (Cthiaz-7), 126.8 (Cthiaz-7a), 128.0
(Cthiaz-5), 130.9 (Cphen-6), 136.3 (Cphen-4), 140.3 (Cthiaz-3a), 150.6
(Cphen-2), 165.6 (Cthiaz-2), 188.2 (CO).
5-Amino-4-(2,3-dihydro-3-methyl-2-benzothiazolyl)-2,3-dihy-
dro-1-phenylpyrrol-3-one (13a)
Yield: 0.68 g (84%); mp 235 °C (EtOH).
1H NMR: d = 2.60 (s, 3 H, CH3), 4.07 (d, J = 16.8 Hz, 1 H, H-2),
4.10 (d, J = 16.8 Hz, 1 H, H-2), 5.95 (s, 1 H, CH), 6.56 (d, J = 7.6
Hz, 1 H, Hthiaz), 6.69 (t, J = 7.6 Hz, 1 H, Hthiaz), 6.97 (m, 3 H, Hthiaz
NH2), 7.05 (d, J = 7.6 Hz, 1 H, Hthiaz), 7.27 (t, J = 7.2 Hz, 1 H, HR-
4), 7.38 (d, J = 7.6 Hz, 2 H, HR-2,6), 7.46 (dd, J = 7.2, 7.6 Hz, 2 H,
HR-3,5).
,
Anal. Calcd for C19H17N3OS2: C, 62.10; H, 4.66; N, 11.43; S, 17.45.
Found: C, 62.27; H, 4.79; N, 11.26; S, 17.50.
13C NMR: d = 33.7 (CH3), 59.3 (CH2), 68.8 (Cthiaz-2), 88.1 (C-4),
109.7 (Cthiaz-4), 120.0 (Cthiaz-7), 122.2 (Cthiaz-5), 124.7 (CR-2,6),
126.0 (Cthiaz-6), 126.3 (CR-4), 126.8 (Cthiaz-7a), 130.2 (CR-3,5),
139.0 (CR-1), 149.2 (Cthiaz-3a), 166.4 (C-2), 188.1 (3-CO).
5-Aminopyrrol-3-ones 12a–c and 13a–c; General Procedure
NaBH4 (0.19 g, 5.0 mmol) was added portionwise to a stirred solu-
tion of the salt 7a–c or 8a–c (2.5 mmol) in MeOH (10 mL) at 10–
15 °C. After addition was complete, the mixture was stirred for 20
min and then diluted with H2O (20 mL). The solid formed was fil-
tered and recrystallized from the appropriate solvent to give com-
pounds 12a–c, 13a–c.
Anal. Calcd for C18H17N3OS: C, 66.85; H, 5.30; N, 12.99; S, 9.91.
Found: C, 66.69; H, 5.18; N, 13.17; S, 9.91.
5-Amino-4-(2,3-dihydro-3-methyl-2-benzothiazolyl)-1-(4-eth-
ylphenyl)-2,3-dihydropyrrol-3-one (13b)
Yield: 0.85 g (97%); mp 215 °C (EtOH).
1H NMR: d = 1.19 (t, J = 7.6 Hz, 3 H, CH3), 2.61 (m, 5 H, CH2,
NCH3), 4.02 (d, J = 17.2 Hz, 1 H, H-2), 4.07 (d, J = 17.2 Hz, 1 H,
H-2), 5.94 (s, 1 H, CH), 6.55 (d, J = 7.6 Hz, 1 H, Hthiaz), 6.68 (t,
J = 7.6 Hz, 1 H, Hthiaz), 6.86 (br s, 2 H, NH2), 6.96 (t, J = 7.6 Hz,
1 H, Hthiaz), 7.04 (d, J = 7.6 Hz, 1 H, Hthiaz), 7.29 (s, 4 H, HR).
13C NMR: d = 16.0 (CH3), 28.2 (CH2), 33.7 (NCH3), 59.4 (2-CH2),
68.9 (Cthiaz-2), 87.9 (C-4), 109.7 (Cthiaz-4), 120.0 (Cthiaz-7), 122.2
(Cthiaz-5), 124.9 (CR-2,6), 126.0 (Cthiaz-6), 126.8 (Cthiaz-7a), 129.4
(CR-3,5), 136.5 (CR-4), 142.1 (CR-1), 149.2 (Cthiaz-3a), 166.5 (C-2),
188.1 (3-CO).
5-Amino-4-(2,3-dihydro-1,3-dimethylbenzimidazol-2-yl)-2,3-
dihydro-1-phenylpyrrol-3-one (12a)
Yield: 0.58 g (72%); mp 181 °C (i-PrOH).
1H NMR: d = 2.55 (s, 6 H, 2 × CH3), 4.09 (s, 2 H, CH2), 4.78 (s, 1 H,
CH), 6.46 (m, 2 H, Himid), 6.60 (m, 2 H, Himid), 6.85 (br s, 2 H, NH2),
7.22 (t, J = 7.5 Hz, 1 H, HR-4), 7.41 (m, 4 H, HR).
13C NMR: d = 33.9 (2 × CH3), 58.9 (CH2), 85.0 (Cimid-2), 88.3 (C-
4), 107.2 (Cimid-4,7), 119.6 (Cimid-5,6), 123.7 (CR-2,6), 125.4 (CR-4),
130.0 (CR-3,5), 139.5 (CR-1), 143.1 (Cimid-3a,7a), 167.4 (C-5),
188.8 (3-CO).
Anal. Calcd for C20H21N3OS: C, 68.35; H, 6.02; N, 11.96; S, 9.12.
Found: C, 68.42; H, 6.08; N, 11.90; S, 9.20.
Anal. Calcd for C19H20N4O: C, 71.23; H, 6.29; N, 17.49. Found: C,
71.26; H, 6.12; N, 17.40.
5-Amino-4-(2,3-dihydro-3-methyl-2-benzothiazolyl)-2,3-dihy-
dro-1-(4-methoxyphenyl)pyrrol-3-one (13c)
Yield: 0.65 g (74%); mp 232 °C (EtOH).
1H NMR: d = 2.59 (s, 3 H, NCH3), 3.76 (s, 3 H, OCH3), 3.96 (d,
J = 16.5 Hz, 1 H, H-2), 4.01 (d, J = 16.5 Hz, 1 H, H-2), 5.94 (s, 1 H,
CH), 6.54 (d, J = 8.0 Hz, 1 H, Hthiaz), 6.67 (t, J = 8.0 Hz, 1 H, Hthiaz),
6.76 (br s, 2 H, NH2), 6.96 (t, J = 8.0 Hz, 1 H, Hthiaz), 7.01 (m, 3 H,
5-Amino-4-(2,3-dihydro-1,3-dimethylbenzimidazol-2-yl)-1-(4-
ethylphenyl)-2,3-dihydropyrrol-3-one (12b)
Yield: 0.75 g (86%); mp 194 °C (i-PrOH).
1H NMR: d = 1.19 (t, J = 7.4 Hz, 3 H, CH3), 2.55 (s, 6 H, 2 × CH3),
2.61 (q, J = 7.4 Hz, 2 H, CH2), 4.07 (s, 2 H, CH2), 4.78 (s, 1 H, CH),
6.47 (m, 2 H, Himid), 6.62 (m, 2 H, Himid), 6.80 (br s, 2 H, NH2), 7.28
(s, 4 H, 4 × HR).
13C NMR: d = 16.0 (CH3), 28.1 (CH2), 33.9 (NCH3), 59.2 (CH2),
85.0 (Cimid-2), 88.2 (C-4), 107.3 (Cimid-4,7), 119.7 (Cimid-5,6), 124.4
(CR-2,6), 129.4 (CR-3,5), 136.7 (CR-4), 141.6 (CR-1), 143.0 (Cimid
3a,7a), 167.2 (C-5), 189.2 (3-CO).
Hthiaz, 2 × HR), 7.30 (d, J = 9.0 Hz, 2 H, HR).
13C NMR: d = 33.7 (NCH3), 55.9 (OCH3), 59.9 (2-CH2), 68.9
(Cthiaz-2), 87.5 (C-4), 109.6 (Cthiaz-4), 115.4 (CR-3,5), 119.9 (Cthiaz-7),
122.2 (Cthiaz-5), 126.0 (Cthiaz-6), 126.9 (Cthiaz-7a), 127.3 (CR-2,6),
131.4 (CR-1), 149.2 (Cthiaz-3a), 158.2 (CR-4), 166.9 (C-2), 188.2 (3-
CO).
-
Anal. Calcd for C21H24N4O: C, 72.39; H, 6.94; N, 16.08. Found: C,
72.40; H, 7.11; N, 16.10.
Anal. Calcd for C19H19N3O2S: C, 64.57; H, 5.42; N, 11.89; S, 9.07.
Found: C, 64.51; H, 5.40; N, 11.66; S, 9.10.
5-Amino-4-(2,3-dihydro-1,3-dimethylbenzimidazol-2-yl)-2,3-
dihydro-1-(4-methoxyphenyl)pyrrol-3-one (12c)
Yield: 0.75 g (86%); mp 174 °C (i-PrOH).
1H NMR: d = 2.55 (s, 6 H, 2 × CH3), 3.78 (s, 3 H, OCH3), 4.02 (s,
2 H, CH2), 4.78 (s, 1 H, CH), 6.47 (m, 2 H, Himid), 6.61 (m, 4 H,
NH2, Himid), 7.01 (d, J = 8.8 Hz, 2 H, HR), 7.31 (d, J = 8.8 Hz, 2 H,
HR).
Phenylhydrazones 14b and 14c; General Procedure
A solution of compound 12b,c or 13b,c (3.0 mmol), phenylhydra-
zine (0.49 g, 4.5 mmol) and PTSA (0.052 g, 0.3 mmol) in EtOH (15
mL) was refluxed for 3–4 h. The solvent was removed under vacuo
and the residual solid was recrystallized from i-PrOH to give deriv-
atives 14b,c.
13C NMR: d = 33.9 (NCH3), 55.9 (OCH3), 59.7 (CH2), 85.0 (Cimid
2), 87.8 (C-4), 107.2 (Cimid-4,7), 115.3 (CR-3,5), 119.6 (Cimid-5,6),
126.8 (CR-2,6), 131.7 (CR-1), 143.1 (Cimid-3a,7a), 157.9 (CR-4),
167.7 (C-2), 189.3 (3-CO).
-
2-Amino-1-(4-ethylphenyl)-4,5-dihydro-4-oxopyrrole-3-car-
boxaldehyde Phenylhydrazone (14b)
Yield: 0.61 g (64%); mp 238 °C (i-PrOH).
1H NMR: d = 1.19 (t, J = 7.8 Hz, 3 H, CH3), 2.61 (q, J = 7.8 Hz, 2 H,
CH2), 4.10 (s, 2 H, CH2), 6.62 (t, J = 7.2 Hz, 1 H, HPh-4), 6.77 (d,
J = 7.5 Hz, 2 H, HPh-2,6), 7.14 (dd, J = 7.2, 7.5 Hz, 2 H, HPh-3,5),
7.31 (m, 4 H, HR), 7.84 (m, 3 H, CH=N, NH2), 9.55 (s, 1 H, NH).
Anal. Calcd for C20H22N4O2: C, 68.55; H, 6.33; N, 15.99. Found: C,
68.28; H, 6.50; N, 15.90.
Synthesis 2007, No. 12, 1811–1818 © Thieme Stuttgart · New York

PAPER
2-Amino-4,5-dihydro-4-oxopyrrole-3-carboxaldehydes
1817
13C NMR: d = 16.0 (CH3), 28.2 (CH2), 59.3 (5-CH2), 93.3 (C-3),
111.5 (CPh-2,6), 117.8 (CPh-4), 124.1 (CR-3,5), 129.4 (CPh-3,5),
129.5 (CR-2,6), 135.3 (C=N), 136.1 (CR-4), 142.1 (CR-1), 146.5
(CPh-1), 164.9 (C-2), 187.1 (4-CO).
Anal. Calcd for C15H12N4O2: C, 64.28; H, 4.32; N, 19.99. Found: C,
64.30; H, 4.29; N, 19.90.
Acknowledgment
Anal. Calcd for C19H20N4O: C, 71.23; H, 6.29; N, 17.49. Found: C,
71.30; H, 6.26; N, 17.69.
The authors wish to thank Dr Vitaliy V. Polovinko (Enamine Ltd.)
for 2D NMR studies.
2-Amino-4,5-dihydro-1-(4-methoxyphenyl)-4-oxopyrrole-3-
carboxaldehyde Phenylhydrazone (14c)
Yield: 0.62 g (64%); mp 234 °C (i-PrOH).
References
1H NMR: d = 3.77 (s, 3 H, CH3), 4.05 (s, 2 H, CH2), 6.61 (t, J = 7.0
Hz, 1 H, HPh-4), 6.77 (d, J = 7.0 Hz, 2 H, HPh-2,6), 7.02 (d, J = 8.0
Hz, 2 H, HR), 7.13 (t, J = 7.0 Hz, 2 H, HPh-3,5), 7.34 (d, J = 8.0 Hz,
2 H, HR), 7.71 (s, 2 H, NH2), 7.84 (s, 1 H, CH=N), 9.51 (s, 1 H,
NH).
13C NMR: d = 55.9 (OCH3), 59.7 (CH2), 93.0 (C-3), 111.5 (CPh-2,6),
115.4 (CR-3,5), 117.7 (CPh-4), 126.6 (CR-2,6), 129.5 (CPh-3,5),
131.0 (CR-1), 135.4 (C=N), 146.6 (CPh-1), 158.2 (CR-4), 165.3 (C-
2), 187.1 (4-CO).
(1) For a review, see: Caluwe, P. Tetrahedron 1980, 36, 2359.
(2) Eger, K.; Pfahl, J. G.; Folkers, G.; Roth, H. J. J. Heterocycl.
Chem. 1987, 24, 425.
(3) (a) Abd El-Nabi, H. A. Tetrahedron 2000, 56, 3013.
(b) Zaytsev, A. V.; Anderson, R. J.; Meth-Cohn, O.;
Groundwater, P. W. Tetrahedron 2005, 61, 5831. (c) Abd
El-Nabi, H. A. J. Chem. Res., Synop. 2004, 5, 325.
(4) (a) Craig, J. C.; Ekwuribe, N. N.; Fu, C. C.; Walker, K. A.
M. Synthesis 1981, 303. (b) Chikashita, H.; Ikegami, S.;
Okumura, T.; Itoh, K. Synthesis 1986, 375. (c) Chikashita,
H.; Ishibaba, M.; Ori, K.; Itoh, K. Bull. Chem. Soc. Jpn.
1988, 61, 3637. (d) Corey, E. J.; Boger, D. L. Tetrahedron
Lett. 1978, 5. (e) Corey, E. J.; Boger, D. L. Tetrahedron
Lett. 1978, 9. (f) Corey, E. J.; Boger, D. L. Tetrahedron Lett.
1978, 13. (g) Chikashita, H.; Itoh, K. Heterocycles 1985, 23,
295.
(5) (a) Volovenko, Yu. M.; Tverdokhlebov, A. V.; Gorulya, A.
P.; Shishkina, S. V.; Zubatyuk, R. I.; Shishkin, O. V. Eur. J.
Org. Chem. 2002, 663. (b) Tverdokhlebov, A. V.;
Volovenko, Yu. M.; Shokol, T. V. Chem. Heterocycl.
Compd. (Engl. Transl.) 1998, 34, 44; Khim. Geterotsikl.
Soedin. 1998, 50. (c) Resnyanskaya, E. V.; Shokol, T. V.;
Volovenko, Yu. M.; Tverdokhlebov, A. V. Chem.
Heterocycl. Compd. (Engl. Transl.) 1999, 35, 1230; Khim.
Geterotsikl. Soedin. 1999, 1412. (d) Resnyanskaya, E. V.;
Tverdokhlebov, A. V.; Volovenko, Yu. M.; Shokol, T. V.
Russ. J. Org. Chem. (Engl. Transl.) 2004, 40, 368; Zh. Org.
Khim. 2004, 40, 398. (e) Tverdokhlebov, A. V.; Lyashenko,
A. B.; Volovenko, Yu. M.; Tolmachev, A. A. Chem.
Heterocycl. Compd. (Engl. Transl.) 2004, 40, 1536; Khim.
Geterotsikl. Soedin. 2004, 1783.
(6) (a) Eldin, A. M. S. Heteroat. Chem. 2003, 14, 612.
(b) Gewald, K.; Hentschel, M. J. Prakt. Chem. 1976, 318,
663. (c) Teuber, H.-J.; Schütz, G.; Erkenbrecher, E. Arch.
Pharm. 1980, 313, 851. (d) Dave, C. G.; Shah, P. R.;
Upadhyaya, S. P. J. Indian Chem. Soc. 1987, 64, 713.
(e) Dave, C. G.; Desai, N. D. J. Heterocycl. Chem. 1999, 36,
729.
(7) (a) Volovenko, Yu. M.; Volovnenko, T. A.; Tverdokhlebov,
A. V.; Ryabokon, I. G. Russ. J. Org. Chem. (Engl. Transl.)
2001, 37, 1323; Zh. Org. Khim. 2001, 37, 1389.
(b) Tverdokhlebov, A. V.; Tolmachev, A. A.; Volovenko,
Yu. M. Collect. Czech. Chem. Commun. 2004, 69, 414.
(c) Volovenko, Yu. M.; Resnyanska, E. V.; Tverdokhlebov,
A. V. Collect. Czech. Chem. Commun. 2002, 67, 356.
(d) Volovenko, Yu. M.; Resnyanskaya, E. V.;
Anal. Calcd for C18H18N4O2: C, 67.07; H, 5.63; N, 17.38. Found: C,
67.10; H, 5.55; N, 17.40.
Pyrrolo[2,3-b]pyridines 15a–c; General Procedure
A mixture of compound 12a–c or 13a–c (3.0 mmol), malonodini-
trile (0.40 g, 6.0 mmol) and NH4Cl (0.02 g, 0.3 mmol) in dioxane
(10 mL) was refluxed for 4–5 h. After cooling, the precipitate
formed was filtered, washed with H2O (1 × 5 mL) and recrystallized
from DMF to give derivatives 15a–c.
6-Amino-2,3-dihydro-3-oxo-1-phenylpyrrolo[2,3-b]pyridine-5-
carbonitrile (15a)
Yield: 0.51 g (68%); mp 296 °C (DMF).
1H NMR: d = 4.40 (s, 2 H, CH2), 7.11 (m, 1 H, HR-4), 7.37 (m, 2 H,
HR-2,6), 7.67 (s, 2 H, NH2), 7.88 (m, 2 H, HR-3,5), 8.03 (s, 1 H, H-
4).
13C NMR: d = 62.2 (CH2), 83.7 (C-5), 108.3 (CN), 125.0 (CR-2,6),
131.3 (CR-3,5), 131.6 (CR-4), 132.7 (C-3a), 145.2 (C-4), 157.5 (CR-
1), 158.8 (C-7a), 158.9 (C-6), 192.1 (CO).
Anal. Calcd for C14H10N4O: C, 67.19; H, 4.03; N, 22.39. Found: C,
66.95; H, 4.10; N, 22.30.
6-Amino-1-(4-ethylphenyl)-2,3-dihydro-3-oxopyrrolo[2,3-b]py-
ridine-5-carbonitrile (15b)
Yield: 0.55 g (66%); mp 289 °C (DMF).
1H NMR: d = 1.17 (t, J = 7.6 Hz, 3 H, CH3), 2.59 (q, J = 7.6 Hz, 2 H,
CH2), 4.41 (s, 2 H, CH2), 7.21 (d, J = 8.8 Hz, 2 H, HR), 7.78 (m, 4 H,
NH2, HR), 8.08 (s, 1 H, H-4).
13C NMR: d = 13.4 (CH3), 28.2 (CH2), 62.5 (2-CH2), 83.4 (C-5),
108.4 (CN), 124.8 (CR-2,6), 130.1 (C-3a), 130.7 (CR-3,5), 145.1 (C-
4), 149.5 (CR-4), 157.5 (CR-1), 158.8 (C-6), 158.9 (C-7a), 192.5
(CO).
Anal. Calcd for C16H14N4O: C, 69.05; H, 5.07; N, 20.13. Found: C,
69.10; H, 4.97; N, 20.03.
Tverdokhlebov, A. V. Chem. Heterocycl. Compd. (Engl.
Transl.) 2002, 38, 324; Khim. Geterotsikl. Soedin. 2002,
360.
6-Amino-2,3-dihydro-1-(4-methoxyphenyl)-3-oxopyrrolo[2,3-
b]pyridine-5-carbonitrile (15c)
(8) (a) Rudnev, M. I.; Kurbatov, V. P.; Chub, N. K.; Osipov, O.
A. J. Gen. Chem. USSR (Engl. Transl.) 1988, 58, 2077; Zh.
Obshch. Khim. 1988, 58, 2334. (b) Van Dormael, A.; Nys,
J. Bull. Soc. Chim. Belg. 1950, 59, 588. (c) Doyle, F. P.;
Kendall, J. D. US Patent 2542401, 1951; Chem. Abstr. 1951,
45, 10109.
Yield: 0.56 g (67%); mp 300 °C (DMF).
1H NMR: d = 3.75 (s, 3 H, OCH3), 4.38 (s, 2 H, CH2), 6.94 (d,
J = 9.2 Hz, 2 H, HR), 7.76 (m, 4 H, NH2, HR), 8.06 (s, 1 H, H-4).
13C NMR: d = 55.4 (OCH3), 62.7 (CH2), 83.5 (C-5), 108.2 (CN),
116.6 (CR-3,5), 125.8 (C-3a), 127.2 (CR-2,6), 145.2 (C-4), 157.6
(CR-1), 159.2 (C-6), 159.3 (C-7a), 161.2 (CR-4), 192.2 (CO).
Synthesis 2007, No. 12, 1811–1818 © Thieme Stuttgart · New York

1818
A. V. Tverdokhlebov et al.
PAPER
(9) (a) Zakhs, E. R.; Ponyaev, A. I.; Subbotina, M. A.; El’tsov,
A. V. Russ. J. Gen. Chem. (Engl. Transl.) 2001, 71, 1076;
Zh. Obshch. Khim. 2001, 71, 1142. (b) Yagupolsky, L. M.;
Kulchitsky, M. M.; Ilchenko, A. Ya. J. Org. Chem. USSR
(Engl. Transl.) 1974, 10, 1326; Zh. Org. Khim. 1974, 10,
1321. (c) Zakhs, E. R.; Subbotina, M. A.; El’tsov, A. V. J.
Org. Chem. USSR (Engl. Transl.) 1979, 15, 178; Zh. Org.
Khim. 1979, 15, 200.
(10) For reviews, see: (a) Merour, J. Y.; Joseph, B. Curr. Org.
Chem. 2001, 5, 471. (b) Willette, R. E. Adv. Heterocycl.
Chem. 1968, 9, 27. (c) Yakhontov, L. N.; Prokopov, A. A.
Usp. Khim. 1980, 49, 814; Chem. Abstr. 1980, 93, 71588.
(d) Yakhontov, L. N. Usp. Khim. 1968, 37, 1258; Chem.
Abstr. 1969, 70, 11585.
(11) (a) Benoit, R.; Dupas, G.; Bourguignon, J.; Queguiner, G.
Synthesis 1987, 1124. (b) Levacher, V.; Leroy, C.; Dupas,
G.; Bourguignon, J.; Queguiner, G. Synth. Commun. 1994,
24, 2697. (c) Brodrick, A.; Wibberley, D. G. J. Chem. Soc.,
Perkin Trans. 1 1975, 1910. (d) Monnet, M. O.; Fauret, T.;
Levacher, V.; Dupas, G.; Bourguignon, J.; Queguiner, G. J.
Heterocycl. Chem. 1989, 26, 1029. (e) Hodge, C. N.;
Aldrich, P. E.; Wasserman, Z. R.; Fernandez, C. H.; Nemeth,
G. A.; Arvanitis, A.; Cheeseman, R. S.; Chorvat, R. J.;
Ciganek, E.; Christos, T. E.; Gilligan, P. J.; Krenitsky, P.;
Scholfield, E.; Strucely, P. J. Med. Chem. 1999, 42, 819.
(12) (a) Vishwakarma, L. C.; Sowell, J. W. J. Heterocycl. Chem.
1985, 22, 1429. (b) Toja, E.; Tarzia, G.; Ferrari, P.; Tuan, G.
J. Heterocycl. Chem. 1986, 23, 1555. (c) Abdelhamid, A.
O.; Abdel-Galil, F. M.; Saleh, S. S. Heterocycles 1988, 27,
1861.
(13) Kiprianov, A. I.; Pazenko, Z. N. Zh. Obshch. Khim. 1949,
19, 1521; Chem. Abstr. 1950, 44, 1097.
Synthesis 2007, No. 12, 1811–1818 © Thieme Stuttgart · New York