An effective new synthesis of 2-aminopyrrole-4-carboxylates

Article abstract of DOI:10.1016/j.tet.2005.08.050

Efficient syntheses of 2-aminopyrroles are presented starting from β-dicarbonyl compounds, bromoacetonitrile, and amines. Alkylation of β-dicarbonyl compounds with bromoacetonitrile furnished α-cyanomethyl-β-dicarbonyl compounds. The condensation reaction of α-cyanomethyl-β-dicarbonyl compounds with amines catalyzed by p-TsOH affords the corresponding enamines in good yields. Base catalyzed cyclization via the addition of an amine moiety to the carbon-nitrogen triple bond of nitrile furnished 2-aminopyrroles in high yields.

Full text of DOI:10.1016/j.tet.2005.08.050

Tetrahedron 61 (2005) 10482–10489
An effective new synthesis of 2-aminopyrrole-4-carboxylates
*
Ayhan S. Demir and Mustafa Emrullahoglu
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Received 11 June 2005; revised 26 July 2005; accepted 11 August 2005
Available online 2 September 2005
Abstract—Efficient syntheses of 2-aminopyrroles are presented starting from b-dicarbonyl compounds, bromoacetonitrile, and amines.
Alkylation of b-dicarbonyl compounds with bromoacetonitrile furnished a-cyanomethyl-b-dicarbonyl compounds. The condensation
reaction of a-cyanomethyl-b-dicarbonyl compounds with amines catalyzed by p-TsOH affords the corresponding enamines in good yields.
Base catalyzed cyclization via the addition of an amine moiety to the carbon–nitrogen triple bond of nitrile furnished 2-aminopyrroles in high
yields.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
appropriate two-carbon unit, for example, base-promoted
condensation of an amino ketone9 or a conjugated
azoalkene10 with a nitrile containing an active methylene
group; 1,3-dipolar cycloaddition of conjugated azoalkenes
with 1-propynyldiethylamine;11 or base-induced 1,3-dipolar
cycloaddition of 4,5-diaminothiazolium salts with electro-
philic alkynes.12 Recent access to 2-(alkylamino)- and
2-(arylamino)pyrroles by the addition of isocyanides to
protonated 1-azabutadienes is described by Morel et al.13
Other miscellaneous and limited methods were also
described in the review by Trofimov et al.14
Pyrrole derivatives represent a class of compounds of great
importance in heterocyclic chemistry primarily due to the
fact that many pyrroles are subunits of natural products,
pharmaceutical agents and polymers.1 The valuable and
diverse biological properties of pyrroles make the develop-
ment of efficient methods for the preparation of these
compounds, having a defined substitution pattern, a focus of
considerable synthetic effort. b-Dicarbonyl compounds are
versatile intermediates for the synthesis of pyrrole deriva-
tives.2 Pioneering work on the synthesis of pyrroles from
b-dicarbonyl compounds was carried out by Hantzsch in
1890. Many studies have been published on the synthesis of
pyrroles using the principle of Hantzsch’s method starting
from b-dicarbonyl compounds.3 Aminopyrroles have been
found to show interesting biological properties4,5 or have
been used as precursors6 for known drugs, in which they
have found use as synthetic precursors for acyclic nucleo-
side analogues of the pyrrolo[2,3-d]pyrimidine ring
system.7
To continue our investigations that are directed towards the
synthesis of substituted pyrroles15 and related compounds,16
we were especially interested in obtaining 2-amino-4-
carboxyl- derivatives of pyrroles. These compounds are
conformationally restricted GABA structure analogous
(Fig. 1).
Aminopyrroles are not readily available through general
pyrrole ring-formation methods.8 Despite the large number
of published methods for the elaboration of various pyrroles,
relatively few examples have been reported for the
preparation of simple 2-amino derivatives.
Figure 1.
Most compounds of this type have been obtained by the
reaction of a nitrogen-two-carbon compound with an
2. Results and discussion
From a synthetic point of view, 2-aminopyrroles can be
synthesized via a reaction sequence involving a-alkylation
of b-dicarbonyl compounds with bromoacetonitrile,
Keywords: 2-Aminopyrroles; Amination; Cyclization; 1,3-Dicarbonyls.
*
Corresponding author. Tel.: C90 312 2103242; fax: C90 312 2101280;
e-mail: asdemir@metu.edu.tr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.050

A. S. Demir, M. Emrullahoglu / Tetrahedron 61 (2005) 10482–10489
10483
enamine formation, and finally a ring closure reaction. This
seems like a very attractive route because a wide variety of
substituents (R1, R2, and R3) can be used, originating from
readily accessible starting materials.
1.5 equiv 3c, Al2O3): starting material and unidentified
side products.
6. p-TsOH, silica gel or K-10 Montmorillonitrite clay
supported microwave reaction19 (1 equiv 2d, 1.5 equiv
3c): product was observed, but in low yield (5–7%).
7. Stefani et al.20 described the preparation of enaminones
from b-ketoesters or b-diketones and primary amines in
water. Application of this procedure to 2d (1 equiv 2d,
2 equiv 3c, 5 ml H2O, stirred at room temperature for
3 h) furnished the decarboxylation product 6 in 10%
yield (Scheme 3).
As shown in Scheme 1, a-cyanomethyl-b-dicarbonyl
compounds 2a–e were synthesized by alkylation of
b-dicarbonyl compounds with bromoacetonitrile (NaH/
THF and DBU/benzene) according to the literature
procedure in 71–80% yields (Scheme 1).17
8. Five equivalents 3c was neutralized with 5 equiv acetic
acid added to 1 equiv 2d solution refluxed in ethanol for
24 h:21 product formed with very low yield, but was not
reproducible.
9. Finally the highest yield (46%) was achieved from 2d
and 3c without a solvent and excess amine. This reaction
was carried out at 140 8C for 4 h. Increasing temperature
increases the amount of side products, which could not
be identified. This reaction was also carried out under
microwave conditions without heat and solvent, in
which the product was obtained in 40% yield.
Scheme 1.
After many trials, we found that the latter procedure was the
best choice for the conversion of 2d–e to enamine 4j–l.
As shown in Scheme 2, the enamine derivatives 4a–i were
easily prepared from amines 3a–c and a-cyanomethyl-b-
dicarbonyl compounds 2a–e in benzene at reflux with the
addition of a catalytical amount of p-TsOH in 68–75%
yields after purification of the crude products by column
chromatography (Table 1). The formation of enamines by
using ethyl 2-(cyanomethyl)-3-oxo-3-phenylpropanoate
(2d) was not successful under the above described
conditions. There are many general methods for the
synthesis of b-amino-a,b-unsaturated carbonyl compounds,
but as far as we know no convenient procedure is described
in the literature for the formation of enamines starting from
2-alkyl-3-aryl-1,3-dicarbonyl compounds. Various reaction
conditions were applied in order to find a convenient
procedure for the formation of enamine 4j (ethyl-3-
(benzylamino)-2-cyanomethyl-3-phenylacrylate) with
benzylamine as described below:
The cyanomethyl substituted enamines 4a–l were also
assumed to be obtained starting from b-dicarbonyl
compounds 1a–e and amines, by the formation of enamine
followed by alkylation with bromoacetonitrile. In a
representative reaction, 1b was reacted with aniline in
benzene at reflux with the addition of a catalytical amount of
p-TsOH to give enamine 7 in 79% yield. Deprotonation of
the enamine with NaH in THF followed by alkylation with
bromoacetonitrile furnished trace amount of the desired
product. This method was not suitable for the synthesis of
enamines 4a–l.
Simple and efficient conditions were found for the
cyclization of enamines to pyrroles. This condition involved
the treatment of enamines 4a–l with potassium ethoxide in
ethanol at room temperature, in which the pyrrole
derivatives 5a–l were obtained in excellent yields in a
short reaction time (5–10 min; for aryl substituted enamines
20–30 min) (Scheme 2).
1. p-TsOH–Benzene (or Toluene), azeotropic removal of
water. (1 equiv 2d, 2 equiv 3c, 10 ml solvent, 48 h):
product was obtained in very low yield.
2. TFA–Benzene (1 equiv 2d, 2 equiv diketone, 10 ml
solvent, 48 h): trace amount of product formation
(GC–MS).
3. BF3–Et2O, Toluene (1 equiv 2d, 2 equiv 3c 10 ml
solvent): no product formation.
4. Al2O3 supported reaction18 (1 equiv 2d, 1.5 equiv 3c,
Al2O3, at 70 8C): no product formation.
5. Al2O3 supported microwave reaction (1 equiv 2d,
In addition to the above described experiments, many
attempts were made for the direct- one pot synthesis of
pyrroles starting with; (a) b-dicarbonyl compound, bromo-
acetonitrile and amine, (b) starting from enamine, bromo-
acetonitrile, heating in benzene in the presence of catalytical
amount of p-TsOH or TFA, but none of the reactions were
successful.
Scheme 2.

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A. S. Demir, M. Emrullahoglu / Tetrahedron 61 (2005) 10482–10489
Table 1. Synthesis of substituted 2-aminopyrroles
Entry
Dicarbonyl
compound 2
Amine 3
Enamine 4, Yield (%)a
Pyrrole 5, Yield (%)a
a
1
a
a
a
b
b
b
c
a, 70
a, 93
b, 94
c, 88
d, 91
e, 94
f, 89
g, 92
2
3
4
5
6
7
b
b, 71
c
c, 73
a
b
c
d, 68
e, 75
f, 71
a
g, 73

A. S. Demir, M. Emrullahoglu / Tetrahedron 61 (2005) 10482–10489
10485
Table 1 (continued)
Entry Dicarbonyl
compound 2
Amine 3
Enamine 4, Yield (%)a
Pyrrole 5, Yield (%)a
8
c
b
h, 74
h, 90
i, 92
j, 74
k, 78
l, 82
9
c
c
c
b
c
i, 71
10
d
d
e
j, 46b
11
k, 49b
12
l, 47b
a Isolated yield.
b Synthesized by solvent-free heating of a-cyanomethyl-b-dicarbonyl compounds with amines.
Scheme 3.
Scheme 4.

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A. S. Demir, M. Emrullahoglu / Tetrahedron 61 (2005) 10482–10489
All of the pyrrole derivatives were identified by spectro-
scopic methods and all spectroscopic data are in agreement
with the given structures.
CDCl3): dZ15.7, 23.5, 30.0, 62.9, 117.7, 191.5, 200.1.
Anal. Calcd for C7H9NO2 (139.15): C, 60.42; H, 6.52; N,
10.07. Found: C, 60.23; H, 6.35; N, 9.83.
The mechanism is assumed to involve the deprotonation of
the enamine, then the addition of the amine moiety to the
carbon–nitrogen triple bond to afford the cyclic intermediate
(Scheme 4). This is followed by a rearrangement to afford
pyrrole 5. The attack of nitrogen to the carbon–nitrogen
triple bond is activated by the potassium ion. This
mechanism is consistent with the generally accepted
mechanism of the nucleophilic addition to metal-activated
carbon–carbon multiple bonds.22
4.2.2. Ethyl 2-(cyanomethyl)-3-oxobutanoate (2b). Yield:
(181 mg, 71%); yellow oil. IR (neat): 2331, 2978,
1
1725 cmK1. H NMR (400 MHz, CDCl3): dZ1.27 (t, 3H,
JZ7.1 Hz), 2.32 (s, 3H), 2.73–2.79 (m, 2H), 3.75 (t, 1H, JZ
7.2 Hz), 4.23–4.26 (m, 2H). 13C NMR (100 MHz, CDCl3):
dZ14.4, 15.8, 29.6, 55.5, 62.6, 117.4, 166.6, 198.6. Anal.
Calcd for C8H11NO3 (169.7): C, 56.80; H, 6.55; N, 8.28.
Found: C, 56.66; H, 6.73; N, 7.92.
4.2.3. Ethyl 2-(cyanomethyl)-3-oxopentanoate (2c).
Yield: (146 mg, 80%); yellow oil. IR (neat): 2326, 2975,
1
1720 cmK1. H NMR (400 MHz, CDCl3): dZ1.05 (t, 3H,
3. Conclusions
JZ7.2 Hz), 1.23 (t, 3H, JZ7.1 Hz), 2.43–2.67 (m, 2H),
2.74 (d, 2H, JZ7.2 Hz), 3.77 (t, 1H, JZ7.2 Hz), 4.18 (q,
2H, JZ7.1 Hz). 13C NMR (100 MHz, CDCl3): dZ12.7,
14.7, 22.4, 30.1, 52.5, 62.2, 116.7, 192.4, 198.1. Anal. Calcd
for C9H13NO3 (183.2): C, 59.00; H, 7.15; N, 7.65. Found: C,
58.82; H, 7.33; N, 7.39.
This investigation has resulted in the elaboration of a
convenient procedure for the preparation of 2-aminopyrrole
derivatives. The condensation reaction of a-cyanomethyl-b-
dicarbonyl compounds with amines catalyzed by p-TsOH
affords the corresponding enamines in good yields. Base
catalyzed cyclization via the addition of an amine moiety to
the carbon–nitrogen triple bond furnished 2-aminopyrroles
in high yields.
4.2.4. Ethyl 2-(cyanomethyl)-3-oxo-3-phenylpropanoate
(2d). Yield: (198 mg, 78%); colorless oil. IR (neat): 2978,
2249, 1736, 1689 cmK1. 1H NMR (400 MHz, CDCl3): dZ
1.20 (t, 3H, JZ7.1 Hz), 3.07 (dd, 1H, JZ5.4, 17.0 Hz), 3.12
(dd, 1H, JZ6.9, 17.0 Hz), 4.20 (q, 2H, JZ7.1 Hz), 4.66 (t,
1H, JZ7.2 Hz), 7.53–8.05 (m, 5H). 13C NMR (100 MHz,
CDCl3): dZ13.3, 16.1, 49.7, 62.0, 116.4, 128.3, 128.5,
133.7, 134.5, 166.0, 190.4. Anal. Calcd for C13H13NO3
(231.25): C, 67.52; H, 5.67; N, 6.06. Found: C, 67.38; H,
5.33; N, 5.71.
4. Experimental
4.1. Materials and methods
NMR spectra were recorded on a Bruker DPX 400.
Chemical shifts d are reported in ppm relative to CHCl3
(1H: dZ7.27), CDCl3 (13C: dZ77.0) and CCl4 (13C: dZ
96.4) as internal standards. IR spectra were recorded on a
Perkin Elmer 1600 FTIR series instrument.
4.2.5. Ethyl 2-(cyanomethyl)-3-(2-fluorophenyl)-3-oxo-
propanoate (2e). Yield: (199 mg, 80%); yellow oil. IR
(neat): 2954, 2212, 1732, 1679 cmK1. 1H NMR (400 MHz,
CDCl3): dZ1.17 (t, 3H, JZ7.0 Hz), 2.93 (dd, 1H, JZ7.2,
16.8 Hz,), 3.05 (dd, 1H, JZ6.7, 16.8 Hz), 4.17 (q, 2H, JZ
7.0 Hz), 4.62 (t, 1H, JZ7.0 Hz), 7.14–7.94 (m, 4H). 13C
NMR (100 MHz, CDCl3): dZ13.3, 15.8, 53.2, 61.7, 95.7,
116.1 (d, JZ23 Hz), 123.6 (d, JZ11 Hz), 124.3 (d, JZ
3 Hz), 130.8, 135.1 (d, JZ9 Hz), 161.3 (d, JZ253 Hz),
166.2, 189.0. Anal. Calcd for C13H12FNO3 (249.24): C,
62.65; H, 4.85; N, 5.62. Found: C, 62.41; H, 4.76; N, 5.31.
Column chromatography was conducted on silica gel 60
(40–63 mm). TLC was carried out on aluminum sheets pre-
coated with silica gel 60F254 (Merck), and the spots were
visualized with UV light (lZ254 nm). Optical rotations
were measured with a Kru¨ss P3002RS automatic
polarimeter.
4.2. General procedure for alkylation of b-dicarbonyl
compounds
4.3. General procedure for enamine formation
NaH (1.5 mmol) was added slowly to a stirred solution of
b-dicarbonyl compound (1 mmol) in THF at room
temperature under argon. The reaction mixture was stirred
for 1 h and then a solution of bromoacetonitrile (1.2 mmol)
in THF (15 ml) was added slowly and stirred for 4 h. The
reaction was monitored by TLC. Water was added, the
mixture extracted with ethyl acetate and the combined
organic layers were dried over MgSO4. After the evapo-
ration of the solvent under reduced pressure, the crude
product was purified on silica gel to afford 2a–e (hexane–
ethyl acetate (4–1)).
Alkylated b-dicarbonyl compound (1 mmol) was dissolved
in benzene (10 ml). Corresponding amine (1.2 mmol)
together with catalytic amount of PTSA was added to the
stirring mixture and heated at 80 8C for 6–10 h using a
Dean-Stark trap. Reaction was monitored by TLC. The
reaction mixture was extracted with ethyl acetate. The
extract was dried over MgSO4 and the solvent evaporated
under reduced pressure and the crude product purified by
column chromotography.(hexane–ethyl acetate (4–1)).
4.3.1. (Z)-3-acetyl-4-(phenylamino)pent-3-enenitrile
(4a). Yield: (149 mg, 70%); brown oil. IR (neat): 2987,
2242, 1592, 1570 cmK1. 1H NMR (400 MHz, CDCl3): dZ
2.03 (s, 3H), 2.22 (s, 3H), 3.29 (s, 2H), 7.09–7.19 (m, 5H),
13.51 (s, 1H, NH). 13C NMR (100 MHz, CDCl3): dZ19.0,
4.2.1. 3-Acetyl-4-oxopentanenitrile (2a). Yield: (105 mg,
1
76%); yellow oil. IR (neat): 2333, 2976, 1723 cmK1. H
NMR (400 MHz, CDCl3): dZ2.25 (s, 6H), 2.73 (d, 2H, JZ
7.1 Hz), 4.02 (t, 1H, JZ7.1 Hz). 13C NMR (100 MHz,

A. S. Demir, M. Emrullahoglu / Tetrahedron 61 (2005) 10482–10489
10487
1
20.5, 30.4, 98.3, 120.6, 128.0, 128.8, 131.6, 140.6, 163.0,
196.7. Anal. Calcd for C13H14N2O (214.26): C, 72.87; H,
6.59; N, 13.07. Found: C, 72.62; H, 6.45; N, 12.75.
3489, 2967, 2360, 2253, 1646 cmK1. H NMR (400 MHz,
CDCl3): dZ1.06 (t, 3H, JZ7.6 Hz), 1.29 (t, 3H, JZ7.2 Hz),
2.37 (q, 2H, JZ7.6 Hz), 3.27 (s, 2H), 4.18 (q, 2H, JZ
7.2 Hz), 7.01–7.11 (m, 5H), 10.99 (s, 1H, NH). 13C NMR
(100 MHz, CDCl3): dZ12.7, 14.5, 16.0, 22.0, 59.8, 84.7,
119.0, 126.2, 126.3, 129.2, 138.9, 164.2, 169.1. Anal. Calcd
for C15H18N2O2 (258.32): C, 69.74; H, 7.02; N, 10.84.
Found: C, 69.61; H, 7.17; N, 10.61.
4.3.2. (R)-(Z)-4-(1-phenylethylamino)-3-acetylpent-3-
enenitrile (4b). Yield: (171 mg, 71%); white solid, mpZ
105–106 8C, [a]2D2 K586 (1.2, CHCl3). IR (in CHCl3): 3441,
1
2962, 2921, 2357, 2240, 1598 cmK1. H NMR (400 MHz,
CDCl3): dZ1.48 (d, 3H, JZ6.7 Hz), 1.84 (s, 3H), 2.14 (s,
3H), 3.11 (d, 1H, JZ18.6 Hz), 3.19 (d, 1H, JZ18.6 Hz),
4.60–4.65 (m, 1H), 7.17–7.44 (m, 5H), 12.56 (d, 1H, JZ
7.1 Hz, NH). 13C NMR (100 MHz, CDCl3): dZ16.0, 18.4,
25.2, 28.3, 54.1, 94.7, 118.8, 125.8, 127.8, 129.3, 144.2,
163.0, 193.8. Anal. Calcd for C15H18N2O (242.32): C,
74.35; H, 7.49; N, 11.56. Found: C, 74.11; H, 7.22; N, 11.33.
4.3.8. (R)-(Z)-ethyl 3-(1-phenylethylamino)-2-(cyano-
methyl)pent-2-enoate (4h). Yield: (211.5 mg, 74%);
yellow oil, [a]2D2 365 (1.7, CHCl3). IR (neat): 3321, 3127,
2978, 2142, 1423 cmK1. 1H NMR (400 MHz, CDCl3): dZ
0.97 (t, 3H, JZ7.6 Hz), 1.28 (t, 3H, JZ7.1 Hz), 1.47 (d, 3H,
JZ6.8 Hz), 2.13–2.26 (m, 2H), 3.11 (d, 1H, JZ17.8 Hz),
3.21 (d, 1H, JZ17.8 Hz), 4.09–4.21 (m, 2H), 4.48–4.62 (m,
1H), 7.21–7.25 (m, 5H), 9.87 (s, 1H, NH). 13C NMR
(100 MHz, CDCl3): dZ12.1, 14.6, 15.8, 22.2, 25.3, 53.0,
59.5, 82.5, 119.3, 125.3, 127.3, 128.9, 144.9, 165.5, 169.3.
Anal. Calcd for C17H22N2O2 (286.37): C, 71.30; H, 7.74; N,
9.78. Found: C, 71.12; H, 7.71; N, 9.57.
4.3.3. (Z)-3-acetyl-4-(benzylamino)pent-3-enenitrile (4c).
Yield: (166 mg, 73%); brown oil. IR (neat): 3436, 3028,
2917, 2346, 2240, 1599 cmK1 1H NMR (400 MHz,
.
CDCl3): dZ1.92 (s, 3H), 2.10 (s, 3H), 3.17 (s, 2H), 4.37
(d, 2H, JZ5.9 Hz), 7.11–7.21 (m, 5H), 12.32 (s, 1H, NH).
13C NMR (100 MHz, CDCl3): dZ15.6, 18.5, 28.3, 47.5,
119.0, 127.0, 127.9, 129.2, 137.7, 163.7, 193.8. Anal. Calcd
for C14H16N2O (228.90): C, 73.66; H, 7.06; N, 12.27.
Found: C, 73.46; H, 7.24; N, 11.88.
4.3.9. (Z)-ethyl 3-(benzylamino)-2-(cyanomethyl)pent-2-
enoate (4i). Yield: (193 mg, 71%); yellow oil. IR (neat):
1
3456, 3123, 2903, 2344, 1599 cmK1. H NMR (400 MHz,
CDCl3): dZ1.16 (t, 3H, JZ7.7 Hz), 1.25 (t, 3H, JZ7.1 Hz),
2.34 (q, 2H, JZ7.7 Hz), 3.22 (s, 2H), 4.08 (q, 2H, JZ
7.1 Hz). 7.19–7.22 (m, 5H), 9.80 (s, NH). 13C NMR
(100 MHz, CDCl3): dZ12.1, 14.6, 15.9, 21.9, 46.8, 59.5,
82.6, 119.3, 126.2, 127.6, 128.9, 138.2, 165.8 169.2. Anal.
Calcd for C16H20N2O2 (272.34): C, 70.56; H, 7.40; N,
10.29. Found: C, 70.34; H, 7.32; N, 9.88.
4.3.4. (Z)-ethyl 2-(cyanomethyl)-3-(phenylamino)but-2-
enoate (4d). Yield: (166 mg, 68%); colorless oil. IR (neat):
3214, 3135, 2981, 2933, 2245, 1606 cmK1 1H NMR
.
(400 MHz, CDCl3): dZ1.26 (t, 3H, JZ7.1 Hz), 2.02 (s,
3H), 3.29 (s, 2H), 4.17 (q, 2H, JZ7.1 Hz), 6.96–7.11 (m,
5H), 11.16 (s, 1H, NH). 13C NMR (100 MHz, CDCl3): dZ
14.9, 16.6, 17.9, 31.5, 60.2, 86.1, 118.0, 118.7, 119.0, 125.8,
126.1, 129.5, 130.1, 139.1, 159.0, 168.9. Anal. Calcd for
C14H16N2O2 (244.29): C, 68.83; H, 6.60; N, 11.47. Found:
C, 68.78; H, 6.57; N, 11.15.
4.3.10. (Z)-ethyl 3-(benzylamino)-2-(cyanomethyl)-3-
phenylacrylate (4j). Yield: (146 mg, 46%) brown oil. IR
(neat): 3496, 3321, 2765, 2346, 1587 cmK1 1H NMR
.
(400 MHz, CDCl3): dZ1.27 (t, 3H, JZ7.1 Hz), 2.78 (s,
2H), 3.99 (d, 2H, JZ6.3 Hz), 4.12 (q, 2H, JZ7.1 Hz), 7.18–
7.22 (m, 10H), 9.63 (br s, 1H, NH). 13C NMR (100 MHz,
CDCl3): dZ14.5, 17.8, 30.7, 48.5, 59.7, 84.9, 119.3, 126.7,
127.3, 127.6, 129.1, 129.4, 133.5, 138.5, 163.9, 169.0. Anal.
Calcd for C20H20N2O2 (320.38): C, 75.42; H, 6.63; N, 8.38.
Found: C, 75.35; H, 6.58; N, 7.92.
4.3.5. (R)-(Z)-ethyl 3-(1-phenylethylamino)-2-(cyano-
methyl)but-2-enoate (4e). Yield: (203 mg, 75%); yellow
oil, [a]2D2 K278 (2.1, CHCl3). IR (neat): 3492, 2981, 2363,
2243, 1653 cmK1. 1H NMR (400 MHz, CDCl3): dZ1.28 (t,
3H, JZ7.1 Hz), 1.46 (d, 3H, JZ6.7 Hz), 1.81 (s, 3H), 3.07
(d, 1H, JZ17.9 Hz), 3.28 (d, 1H, JZ17.9 Hz), 4.01–4.11
(m, 2H), 4.49–4.57 (m, 1H), 7.13–7.22 (m, 5H), 9.88 (d, 1H,
JZ5.6 Hz, NH). 13C NMR (100 MHz, CDCl3): dZ15.0,
16.0, 16.5, 25.4, 53.8, 59.8, 83.4, 119.4, 125.7, 127.6, 129.3,
144.9, 161.3, 169.2. Anal. Calcd for C16H20N2O2 (272.34):
C, 70.56; H, 7.40; N, 10.29. Found: C, 70.41; H, 7.32; N,
10.02.
4.3.11. (R)-(Z)-ethyl 3-(1-phenylethylamino)-2-(cyano-
methyl)-3-phenylacrylate (4k). Yield: (168 mg, 49%);
brown oil, [a]2D2 K420 (2.0, CHCl3). IR (neat): 3436,
3028, 2917, 2240, 1587 cmK1 1H NMR (400 MHz,
.
CDCl3): dZ1.30 (t, 3H, JZ7.6 Hz), 1.37 (d, 3H, JZ
6.8 Hz), 2.69 (d, 1H, JZ17.4 Hz), 2.80 (d, 1H, JZ17.4 Hz),
4.00–4.06 (m, 1H), 4.18–4.23 (m, 2H), 6.65–7.51 (m, 10H),
9.69 (d, 1H, JZ8.8 Hz, NH). 13C NMR (100 MHz, CDCl3):
dZ14.5, 17.6, 24.6, 29.7, 54.3, 59.8, 84.8, 119.6, 125.5,
127.0, 127.2, 127.8, 128.5, 128.7, 129.0, 129.3, 133.7,
144.5, 163.4, 169.2. Anal. Calcd for C21H22N2O2 (334.4):
C, 75.42; H, 6.63; N, 8.38. Found: C, 75.38; H, 6.40; N,
8.12.
4.3.6. (Z)-ethyl 3-(benzylamino)-2-(cyanomethyl)but-2-
enoate (4f). Yield: (183 mg, 71%); yellow oil. IR (neat):
3254, 2980, 2357, 2242, 1646, 1597 cmK1 1H NMR
.
(400 MHz, CDCl3): dZ1.20 (t, 3H, JZ7.0 Hz), 1.90 (s,
3H), 3.20 (s, 2H), 4.07 (q, 2H, JZ7.0 Hz), 4.31 (d, 2H, JZ
6.0 Hz), 7.11–7.21 (m, 5H), 9.82 (s, 1H, NH). 13C NMR
(100 MHz, CDCl3): dZ14.9, 15.6, 16.6, 47.5, 59.8, 83.6,
119.5, 125.7, 127.3, 127.9, 128.5, 129.3, 138.5, 161.7,
169.1. Anal. Calcd for C15H18N2O2 (258.32): C, 69.74; H,
7.02; N, 10.84. Found: C, 69.61; H, 6.91; N, 10.62.
4.3.12. (Z)-ethyl 3-(benzylamino)-2-(cyanomethyl)-3-(2-
fluorophenyl)acrylate (4l). Yield: (158 mg, 47%); yellow
oil. IR (neat): 3412, 3123, 2923, 2221, 1598 cmK1. 1H NMR
(400 MHz, CDCl3): dZ1.24 (t, 3H, JZ7.1 Hz), 2.65 (d, 1H,
JZ18.2 Hz), 3.03 (d, 1H, JZ18.2 Hz), 3.92–4.09 (m, 2H),
4.3.7. (Z)-ethyl 2-(cyanomethyl)-3-(phenylamino)pent-2-
enoate (4g). Yield: (188 mg, 73%); colorless oil. IR (neat):

10488
A. S. Demir, M. Emrullahoglu / Tetrahedron 61 (2005) 10482–10489
4.12–4.21 (m, 2H), 7.01–7.31 (m, 9H), 9.61 (br s, 1H, NH).
13C NMR (100 MHz, CDCl3): dZ14.5, 17.6, 48.6, 59.9,
85.5, 116.3 (d, JZ20 Hz), 118.8, 120.1, 124.9, 126.9, 127.4,
128.6, 130.0, 131.7, 137.9, 157.8, 161.2 (d, JZ252 Hz),
168.7. Anal. Calcd for C20H19FN2O2 (338.38): C, 70.99; H,
5.66; N, 8.28. Found: C, 70.83; H, 5.61; N, 7.92.
2342, 1688 cmK1. 1H NMR (400 MHz, CDCl3): dZ1.24 (t,
3H, JZ7.1 Hz), 1.81 (d, 3H, JZ6.7 Hz), 2.40 (s, 3H), 2.67
(s, 2H, NH2), 4.18 (q, 2H, JZ7.1 Hz), 5.51–5.59 (m, 1H),
5.76 (s, 1H), 7.13–7.28 (m, 5H). 13C NMR (100 MHz,
CDCl3): dZ12.2, 14.9, 18.3, 51.8, 59.5, 110.5, 126.3, 127.7,
129.1, 131.6, 134.8, 141.3, 166.2. Anal. Calcd for
C16H20N2O2 (272.34): C, 70.56; H, 7.40; N, 10.29. Found:
C, 70.52; H, 7.34; N, 9.92.
4.4. General procedure for base catalyzed cyclization
Enamine (1 mmol) was added to potassium ethoxide in
ethanol solution (5 ml, 24 wt%) and stirred for 5–30 min at
room temperature. The reaction was monitored by TLC.
Then water was added and the mixture extracted with ethyl
acetate. The extract was dried over MgSO4 and the solvent
evaporated under reduced pressure. The crude pruduct was
purified by column chromotography. (hexane–ethyl acetate
(4–1)).
4.4.6. Ethyl 5-amino-1-benzyl-2-methyl-1H-pyrrole-3-
carboxylate (5f). Yield: (229 mg, 89%); yellow oil. IR
(neat); 3305, 2980, 2933, 2343, 1683 cmK1 1H NMR
.
(400 MHz, CDCl3): dZ1.24 (t, 3H, JZ7.1 Hz), 2.34 (s,
3H), 2.82 (s, 2H, NH2), 4.13 (q, 2H, JZ7.1 Hz), 4.95 (s,
2H), 5.78 (s, 1H), 7.09–7.21 (m, 5H). 13C NMR (100 MHz,
CDCl3): dZ11.6, 15.0, 45.6, 59.3, 96.1, 110.3, 126.2, 127.7,
129.2, 131.4, 134.0, 137.7, 165.8. Anal. Calcd for
C15H18N2O2 (258.32): C, 69.74; H, 7.02; N, 10.84. Found:
C, 69.61; H, 7.05; N, 10.58.
4.4.1. 1-(5-Amino-2-methyl-1-phenyl-1H-pyrrol-3-yl)
ethanone (5a). Yield: (199 mg, 93%); brown oil. IR
(neat); 3370, 2989, 1644 cmK1
.
1H NMR (400 MHz,
4.4.7. Ethyl 5-amino-2-ethyl-1-phenyl-1H-pyrrole-3-
carboxylate (5g). Yield: (263 mg, 92%); colorless oil. IR
CDCl3): dZ2.20 (s, 3H), 2.28 (s, 3H), 2.95 (s, 2H, NH2),
5.65 (s, 1H), 7.17–7.30 (m, 5H). 13C NMR (100 MHz,
CDCl3): dZ13.1, 28.9, 92.3, 128.7, 129.1, 130.0, 130.9,
135.2, 136.2, 194.7. Anal. Calcd for C13H14N2O (214.26):
C, 72.87; H, 6.59; N, 13.07. Found: C, 72.76; H, 6.40; N,
12.78.
(neat): 3375, 2970, 2913, 2340, 1681 cmK1 1H NMR
.
(400 MHz, CDCl3): dZ0.91 (t, 3H, JZ7.3 Hz), 1.27 (t, 3H,
JZ7.2 Hz), 2.59 (q, 2H, JZ7.3 Hz), 2.86 (br s, 2H, NH2),
4.20 (q, 2H, JZ7.2 Hz), 5.70 (s, 1H), 7.28–7.38 (m, 5H).
13C NMR (100 MHz, CDCl3): dZ14.5, 19.0, 29.7, 58.9,
92.0, 109.9, 114.9, 128.7, 129.4, 134.6, 136.3, 137.3, 165.0.
Anal. Calcd for C15H18N2O2 (286.37): C, 69.74; H, 7.02; N,
10.84; O. Found: C, 69.68; H, 7.01; N, 10.61.
4.4.2. (R)-1-(5-amino-2-methyl-1-(1-phenylethyl)-1H-
pyrrol-3-yl)ethanone (5b). Yield: (201 mg, 94%); oil,
[a]2D2 33 (0.7, CHCl3). IR (neat): 3418, 2901, 2924, 2355,
1
1645 cmK1. H NMR (400 MHz, CDCl3): dZ1.80 (d, 3H,
4.4.8. (R)-ethyl 5-amino-2-ethyl-1-(1-phenylethyl)-1H-
pyrrole-3-carboxylate (5h). Yield: (257 mg, 90%); color-
less oil, [a]2D2 197 (1.4, CHCl3). IR (neat): 3298, 2934, 2984,
JZ7.0 Hz), 2.21 (s, 3H), 2.40 (s, 3H), 2.60 (s, 2H, NH2),
5.53 (q, 1H, JZ7.0 Hz), 5.61 (s, 1H), 7.14–7.23 (m, 5H).
13C NMR (100 MHz, CDCl3): dZ12.1, 18.2, 50.8, 59.5,
110.4, 126.3, 127.4, 129.3, 131.3, 134.7, 141.2, 166.2. Anal.
Calcd for C15H18N2O (242.32): C, 74.35; H, 7.49; N, 11.56.
Found: C, 74.21; H, 7.23; N, 11.35.
1
2323, 1645 cmK1. H NMR (400 MHz, CDCl3): dZ1.08
(t, 3H, JZ7.4 Hz), 1.26 (t, 3H, JZ6.9 Hz), 1.86 (d, 3H, JZ
7.0 Hz), 2.52 (br s, 2H, NH2), 2.95 (q, 2H, JZ7.4 Hz), 4.17
(q, 2H, JZ7.0 Hz), 5.45 (q, 1H, JZ7.0 Hz), 5.67 (s, 1H),
7.10–7.19 (m, 5H). 13C NMR (100 MHz, CDCl3): dZ14.6,
15.0, 18.1, 18.7, 51.3, 58.8, 95.4, 109.4, 125.9, 127.3, 128.8,
134.1, 137.0, 141.2. Anal. Calcd for C17H22N2O2 (286.37):
C, 71.30; H, 7.74; N, 9.78. Found: C, 71.33; H, 7.68; N,
9.59.
4.4.3. 1-(5-Amino-1-benzyl-2-methyl-1H-pyrrol-3-yl)
ethanone (5c). Yield: (200 mg, 88%); brown oil. IR
(neat): 3388, 3007, 2917, 2849, 1656 cmK1 1H NMR
.
(400 MHz, CDCl3): dZ2.27 (s, 3H), 2.41 (s, 3H), 2.82 (s,
2H, NH2), 4.99 (s, 2H), 5.76 (s, 1H), 7.15–7.29 (m, 5H). 13
C
NMR (100 MHz, CDCl3): dZ12.1, 28.9, 30.1, 45.5, 119.4,
126.1, 127.9, 129.3, 131.1, 133.8, 137.4, 194.6. Anal. Calcd
for C14H16N2O (228.18): C, 73.66; H, 7.06; N, 12.27.
Found: C, 73.55; H, 7.25; N, 11.88.
4.4.9. Ethyl 5-amino-1-benzyl-2-ethyl-1H-pyrrole-3-
carboxylate (5i). Yield: (244 mg, 92%); yellow oil. IR
(neat): 3323, 2979, 2934, 2334, 1675 cmK1 1H NMR
.
(400 MHz, CDCl3): dZ1.02 (t, 3H, JZ7.4 Hz), 1.27 (t, 3H,
JZ7.1 Hz), 2.81 (br s, 2H, NH2), 2.86 (q, 2H, JZ7.1 Hz),
4.21 (q, 2H, JZ7.4 Hz), 5.12 (s, 2H), 5.72 (s, 1H), 6.81–
7.38 (m, 5H). 13C NMR (100 MHz, CDCl3): dZ14.6, 18.7,
29.6, 45.1, 58.8, 96.01, 109.3, 125.6, 127.3, 127.3, 133.3,
137.6, 137.6, 165.0. Anal. Calcd for C16H20N2O2 (286.37):
C, 70.56; H, 7.40; N, 10.29. Found: C, 70.53; H, 7.29;
N, 9.95.
4.4.4. Ethyl 5-amino-2-methyl-1-phenyl-1H-pyrrole-3-
carboxylate (5d). Yield: (222 mg, 91%); yellow oil. IR
(neat); 3315, 2982, 2926, 2336, 1687 cmK1 1H NMR
.
(400 MHz, CDCl3): dZ1.24 (t, 3H, JZ7.1 Hz), 2.18 (s,
3H), 2.93 (s, 2H, NH2), 4.18 (q, 2H, JZ7.1 Hz), 5.68 (s,
1H), 7.13–7.30 (m, 5H). 13C NMR (100 MHz, CDCl3): dZ
12.59, 15.0, 59.4, 92.2, 96.5, 128.8, 128.9, 129.9, 131.3,
135.2, 136.6, 165.7. Anal. Calcd for C14H16N2O2 (244.12):
C, 68.83; H, 6.60; N, 11.47. Found: C, 68.76; H, 6.64; N,
11.24.
4.4.10. Ethyl 5-amino-1-benzyl-2-phenyl-1H-pyrrole-3-
carboxylate (5j). Yield: (236 mg, 74%); yellow oil. IR
(neat): 3312, 2978, 2923, 2332, 1679 cmK1 1H NMR
.
(400 MHz, CDCl3): dZ1.03 (t, 3H, JZ7.1 Hz), 2.87 (br s,
2H, NH2), 4.01 (q, 2H, JZ7.1 Hz), 4.84 (s, 2H), 5.93 (s,
1H), 6.84–7.28 (m, 10H). 13C NMR (100 MHz, CDCl3): dZ
14.2, 46.4, 58.9, 95.7, 111.7, 125.7, 127.3, 127.9, 127.9,
4.4.5. (R)-ethyl 5-amino-2-methyl-1-(1-phenylethyl)-1H-
pyrrole-3-carboxylate (5e). Yield (255 mg, 94%); yellow
oil, [a]2D2 332 (1.0, CHCl3). IR (neat); 3243, 2923, 2854,

A. S. Demir, M. Emrullahoglu / Tetrahedron 61 (2005) 10482–10489
10489
Pereira, F. L. C.; Leite, F. S.; Nunes, M. R. S.; Payret-Arrua,
M. E. Tetrahedron 1999, 55, 10915–10924.
128.8, 130.8, 132.2, 132.9, 133.9, 135.0, 137.8, 164.5. Anal.
Calcd for C20H20N2O2 (320.15): C, 74.98; H, 6.29; N, 8.74.
Found: C, 74.80; H, 6.21; N, 8.51.
4. (a) Trani, A.; Bellasio, E. Farmaco Ed. Sci. 1983, 38, 940–949.
(b) Yaroslavsky, C.; Bracha, P.; Glaser, R. J. Heterocycl.
Chem. 1989, 26, 1649–1654.
4.4.11. (R)-ethyl 5-amino-2-phenyl-1-(1-phenylethyl)-
1H-pyrrole-3-carboxylate (5k). Yield: (260 mg, 78%);
yellow oil, [a]2D2 413 (3.0, CHCl3). IR (neat): 3298, 2976,
2943, 2321, 1675 cmK1. 1H NMR (400 MHz, CDCl3): dZ
1.08 (t, 3H, JZ7.1 Hz), 1.84 (d, 3H, JZ7.0 Hz), 2.65 (br s,
2H, NH2), 4.06 (q, 2H, JZ7.1 Hz), 5.21 (q, 1H, JZ7.0 Hz),
5.85 (s, 1H), 7.21–7.38 (m, 10H). 13C NMR (100 MHz,
CDCl3): dZ14.2, 17.8, 52.5, 58.9, 95.3, 111.5, 126.0, 127.3,
127.7, 128.0, 128.8, 130.9, 132.8, 133.8, 135.6, 141.1,
164.5. Anal. Calcd for C21H22N2O2 (334.17): C, 75.42; H,
6.63; N, 8.38. Found: C, 75.24; H, 6.55; N, 8.12.
5. (a) Cocco, M. T.; Congiu, C.; Maccioni, A.; Schivo, M. L.; De
Logu, A.; Palmieri, G. Farmaco Ed. Sci. 1988, 43, 951–960.
(b) Howard, O. M. Z.; Oppenheim, J. J.; Melinda, M. G.;
Covey, J. M.; Bigelow, J. J. Med. Chem. 1998, 41, 2184–2193.
6. (a) Krawezyk, S. H.; Nassiri, M. R.; Kucera, L. S.; Kern, E. R.;
Ptak, R. G. J. Med. Chem. 1995, 38, 4106–4114. (b) Baxter,
A. J. G.; Futher, J.; Teague, S. J. Synthesis 1994, 207–211.
7. Bennett, S. M.; Ba Nghe, N.; Ogilvie, K. K. J. Med. Chem.
1990, 33, 2162–2173.
8. (a) Baltazzi, E.; Krimen, L. I. Chem. Rev. 1963, 63, 511.
(b) Gossauer, A. Die Chemie der Pyrrole; Springer: Berlin,
1974. (c) Patterson, J. M. Synthesis 1976, 281. (d) Jones, R. A.;
Bean, G. P. The Chemistry of Pyrroles; Academic: London,
1977.
4.4.12. Ethyl 5-amino-1-benzyl-2-(2-fluorophenyl)-1H-
pyrrole-3-carboxylate (5l). Yield: (277 mg, 82%); yellow
oil. IR (neat): 3294, 2985, 2934, 2234, 1656 cmK1. 1H NMR
(400 MHz, CDCl3): dZ1.02 (t, 3H, JZ7.1 Hz), 2.93 (br s,
2H, NH2), 3.98–4.05 (m, 2H), 4.71 (d, 1H, JZ16.3 Hz),
4.88 (d, 1H, JZ16.3 Hz), 5.97 (s, 1H), 6.76–7.21 (m, 9H).
13C NMR (100 MHz, CDCl3): dZ14.7, 46.6, 50.4, 59.1,
92.6, 113.3, 115.4 (d, JZ22 Hz), 120.1, 123.4, 126.0, 126.3,
127.2, 127.5, 128.4, 128.8, 130.1 (d, JZ8 Hz), 133.1, 137.0,
138.9, 139.9, 161.1 (d, JZ253 Hz), 164.3. Anal. Calcd for
C20H19FN2O2 (338.38): C, 70.99; H, 5.66; N, 8.28. Found:
C, 70.91; H, 5.54; N, 8.11.
9. (a) Wamhoff, H.; Wehling, B. Synthesis 1976, 51. (b) Laks,
J. A. S.; Ross, J. R.; Bayomi, S. M.; Sowell, J. W. Synthesis
1985, 291–293. (c) Pichler, H.; Folker, G.; Roth, H. J.; Eger, K.
Liebigs Ann. Chem. 1986, 1485–1505. (d) Ross, J. R.;
Vishwakarma, J. W.; Sowell, J. W. J. Heterocycl. Chem.
1987, 24, 661–665 and references therein.
10. (a) Attanasi, O. A.; Liao, Z.; McKillop, A.; Santeusanio, S.;
Serra-Zanetti, F. J. Chem. Soc., Perkin Trans. 1 1993,
315–320. (b) Attanasi, O. A.; Fillipone, P.; Giovagnoli, D.;
Mei, A. Synthesis 1994, 181–184 and references therein.
11. Burger, K.; Rottegger, S. Tetrahedron Lett. 1984, 25,
4091–4094.
Acknowledgements
12. Berree, F.; Morel, G. Tetrahedron 1995, 51, 7019–7034.
13. Marchand, E.; Morel, G.; Sindanhit, S. Eur. J. Org. Chem.
1999, 7, 1729–1738.
The financial support from the Scientific and Technical
Research Council of Turkey (TUBITAK), the Turkish
¨
Academy of Sciences (TUBA), the Turkish State Planning
Organization (for LC–MS and HPLC), and the Middle East
Technical University is gratefully acknowledged.
14. Sobenina, L. N.; Mikhaleva, A. I.; Trofimov, B. A. Russ.
Chem. Rev. 1989, 58, 163–180.
15. Aydogan, F.; Demir, A. S. Tetrahedron 2005, 61, 3019–3023
and references therein.
16. Aydogan, F.; Demir, A. S. Tetrahedron: Asymmetry 2004, 15,
259–265.
References and notes
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