Synthesis of 1,2,3,5-tetrasubstituted pyrrole derivatives from 2-(2-bromoallyl)-1,3-dicarbonyl compounds

Article abstract of DOI:10.1016/S0040-4020(02)01298-X

2-(2-Bromoallyl)-1,3-dicarbonyl compounds are converted into β-enamino, β-hydrazino esters and ketones, followed by base-promoted cyclization, leading to the formation of the corresponding 1,2,3,5-tetrasubstituted pyrroles. 1,2,4- and 1,2,3,4-Substituted pyrroles are also isolated as minor products. Starting from the 2-(2-bromoallyl)-cyclohexane-1,3-dione the corresponding tetrahydro indolone is prepared in good yield.

Full text of DOI:10.1016/S0040-4020(02)01298-X

Tetrahedron 58 (2002) 9793–9799
Synthesis of 1,2,3,5-tetrasubstituted pyrrole derivatives
from 2-(2-bromoallyl)-1,3-dicarbonyl compounds
¨
Ayhan S. Demir, Idris M. Akhmedov and Ozge Sesenoglu
*
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Received 18 July 2002; revised 17 September 2002; accepted 10 October 2002
Abstract—2-(2-Bromoallyl)-1,3-dicarbonyl compounds are converted into b-enamino, b-hydrazino esters and ketones, followed by base-
promoted cyclization, leading to the formation of the corresponding 1,2,3,5-tetrasubstituted pyrroles. 1,2,4- and 1,2,3,4-Substituted pyrroles
are also isolated as minor products. Starting from the 2-(2-bromoallyl)-cyclohexane-1,3-dione the corresponding tetrahydro indolone is
prepared in good yield. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
this reaction, alkylation of 1,3-dicarbonyl compounds with
a-haloketones followed by enaminone formation and
cyclization furnishes pyrroles. Many studies have been
published on the synthesis of pyrroles using the principle of
Hantzsch’s method starting from 1,3-dicarbonyl com-
pounds.10 Ferraz et al. described the synthesis of N-sub-
stituted pyrrole and tetrahydroindole derivatives from
alkenyl 1,3-dicarbonyl compounds via the formation of
iodo-1,3-enamino esters followed by dehydroiodination.11
Lightner et al. described the regioselective synthesis of
substituted a-cyanopyrroles using oximino cyanoacetate
esters in a Knorr-type reductive condensation with 1,3-di-
ketones in the presence of water.12
Pyrroles are very important compounds as they occur in a
large number of natural products and display a variety of
physiological activities;1 in particular, 1,2,3,5-tetrasubsti-
tuted pyrrole derivatives2 are biologically active and
have been proven to display antibacterial,3 antiviral,4
antiinflammatory5 and antioxidant activities and to inhibit
cytokine-mediated diseases.6 Additionally, they have been
found to show potent inhibiting platelet aggregation7 and
antihypertensive activities.8
1,3-Dicarbonyl compounds are versatile intermediates for
the synthesis of pyrrole derivatives.9 Pioneering work on the
synthesis of pyrroles from 1,3-dicarbonyl compounds was
carried out by Hantzsch in 1890. Hantzsch’s pyrrole
synthesis is the condensation of a-haloketones with
1,3-dicarbonyl compounds in the presence of ammonia. In
Recently, Arcadi et al.13 described the synthesis of chiral
1,2,3,5-substituted pyrrole derivatives via gold catalyzed
amination/annulation reactions of 2-propynyl-1,3-dicarbo-
nyl compounds. Pyrroles with the same substitution pattern
Scheme 1.
Scheme 2.
Keywords: nitrogen heterocycles; pyrroles; enamine esters; cyclization.
*
Corresponding author; e-mail: asdemir@metu.edu.tr
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01298-X

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A. S. Demir et al. / Tetrahedron 58 (2002) 9793–9799
Table 1. Synthesized enamines and pyrroles
1,3-Dicarbonyl compounds (3)
Amines (4)
Enamines
Pyrroles
5
Yield (%)
6
Yield (%)a
13b
87
75
13a
a
a
93
94
82
85
11a
a
87
65
a
83
90
88
67
76
87
a
11a,19
11 b
b
95
80
20
95
87

A. S. Demir et al. / Tetrahedron 58 (2002) 9793–9799
9795
p
a
b
Trace amount is detected by GC–MS.
Yields refer to those of pure isolated products.
Small amount of free carboxylic acid is detected by GC–MS.
were synthesized by Mu¨ller et al. in good yields in a one-
pot, three-step, four-component process by a coupling-
isomerization-Stetter reaction Paal–Knorr sequence of an
electron-poor aryl halide, a terminal propargyl alcohol, an
aldehyde, and a primary amine.14
procedure the reaction of enamine 5a with K2CO3/DMSO
yielded no products. After many trials, we found that
potassium t-butoxide in a mixture of DMSO and t-BuOH is
the best choice for the conversion of enamine 5a to pyrrole
6a. This solvent mixture with potassium t-butoxide is used
by Jiang et al.17 for the preparation of (Z)-b-trifluoromethyl
enamines by the reaction of 2-bromo-3,3,3-trifluropropene
with N-alkyl toluenesulfonamides via Michael addition and
elimination processes.
In our work on pyrrole chemistry15 we found a convenient
method for the synthesis of 1,2,3,5-tetrasubstituted pyrroles
through enamines from 2-(2-bromoallyl)-1,3-dicarbonyl
compounds.
The reaction of 2-(2-bromoallyl) enaminones and enhydra-
zinones 5a–h with t-BuOK/t-BuOH/DMSO at 808C
furnished the pyrrole derivatives 6a–h in 65–87% yields
as major products. In addition to these products, the
enamine derivatives 5a–f furnished 2,4-dimethyl-3-acetyl
derivative of pyrroles 7a–f (5–7%) and the corresponding
2,4-dimethyl pyrrole derivatives 8a–f22 (2–3%) as minor
products. The enamine derivatives 5g,h from b-ketoester
gave 2,4-dimethyl-3-carbethoxy derivatives 7g,h23 as minor
products (4–5%) (Table 1).
2. Results and discussion
From a synthetic point of view, 1,2,5-trisubstituted-3-acyl
pyrroles can be synthesized via a reaction sequence
involving a-alkylation of carbonyl compounds with
2,3-dibromoprop-1-ene, enamine formation, and finally a
ring closure reaction (Scheme 1). This seems a very
attractive route because of the wide variety of substituents
(R1, R2 and R3) that can be used, originating from readily
accessible starting materials.
All of the pyrrole derivatives were identified by spectro-
scopic methods. Under conditions similar to those described
above, starting from cyclohexane-1,3-dione derivative 3i
and aniline (4b) 2-methyl-1-phenyl-1,5,6,7-tetrahydro-4H-
indol-4-one (6i) was synthesized in 87% yield as a colorless
solid (Scheme 3).
As shown in Scheme 2, 2-(2-bromoallyl)-1,3-dicarbonyl
compounds 3a–c were synthesized by regiospecific alkyl-
ation of 1,3-dicarbonyl compounds with 2,3-dibromoprop-
1-ene according to the literature procedure in 85–92%
yields.16 The enamine derivatives 5a–h were easily
prepared from amines 4a–d, hydrazines 4e,f and 2-(2-
bromoallyl)-1,3-dicarbonyl compounds in refluxing ben-
zene with the addition of a catalytical amount of p-TsOH in
83–95% yields after purification of the crude products
by column chromatography (Table 1). 2-(2-Bromoallyl)-
1,3-diketones are versatile intermediates for the formation
of furan rings. Zefirov et al. showed that the reaction of 2-(2-
bromoallyl)-1,3-diketones can be converted into substituted
furans by the use of K2CO3/DMSO.16 According to this
For the formation of the pyrrole ring from enamines we
Scheme 3.

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A. S. Demir et al. / Tetrahedron 58 (2002) 9793–9799
Scheme 4.
Scheme 5.
suggest two possible mechanisms. The enamine could form
either the allene or alkyne intermediate after HBr elimi-
nation. The formation of allene is more likely than the
formation of alkyne because of the higher acidity of the
allylic proton. Then the reaction of N-deprotonated enamine
with allene can give the carbanion intermediate, which
furnishes the desired product after protonation (Scheme 4).
By the other possible mechanism the deprotonated enamine
can react with the vinylic carbon to form a 5-methylene
pyrrole derivative via a nucleophilic vinylic substitution
reaction. This compound then isomerizes to the pyrrole
derivatives (Scheme 5). As shown in Scheme 6, for the
formation of 2,4-dimethyl-3-acetyl-substituted pyrroles 7,
first isomerization of enamine into imine, and then
formation of a-carbanion and intramolecular cyclization
furnishes the cyclopropane derivative, which then forms the
methylene derivative via ring opening and a cyclization
reaction. Isomerization of the methylene compound forms a
pyrrole ring. A similar mechanism is suggested by Zefirov
et al. for the formation of a furan derivative starting with
2-bromoallyl-1,3-diketone derivatives.16b Careful moni-
toring of this reaction with GC–MS showed that during
the formation of 2,4-dimethylpyrrole derivative 8 first
3-acetyl derivative 7 is formed and then a deacetylation
reaction occurred.18 This deacetylation process works only
with 2,4-dimethyl-3-acetyl pyrrole derivatives, not with
1,2,5-trisubstituted 3-acetyl pyrroles. This different course
of the reactions is currently being investigated.
the formation of 1,2,3,5-tetrasubstituted pyrroles in good
yields starting from simple easily accessible 2-(2-bromo-
allyl)-1,3-dicarbonyl compounds. In addition to these
products, 1,2,3,4-tetra- and 1,2,4-tri-substituted pyrroles
are formed as minor products.
4. Experimental
4.1. General
NMR spectra were recorded on a Bruker DPX 400
spectrometer. Column chromatography was conducted on
silica gel 60 (mesh size 40–63 mm). GC–MS spectra were
determined on a Phenomenex Zebron ZB-5 capillary
column (5% phenylmethylsiloxane) on a Thermo Quest
Trace 2000 Series and Thermo Quest Finnigan Automass.
Optical rotations were measured with an Autopol IV
automatic polarimeter.
4.2. General procedure for the synthesis of enamines,
5a–i
To a mixture of 1,3-diketone (0.010 mol) 3a–c, and amine
(0.015 mol) 4a–f, in 60 mL benzene was added a catalytic
amount of p-TsOH and the resulting mixture was refluxed
for 10 h, cooled to room temperature and stirred overnight.
After evaporation of the solvent in vacuo, flash column
chromatography was performed to afford enamines in
83–95% yields.
3. Conclusion
4.2.1. 5-Bromo-3-{(E)-1-[(R)-(1-phenylethyl)amino]-
ethylidene}hex-5-en-2-one (5a). Viscous oil; 2.81 g
In this work, we describe a simple and selective method for
Scheme 6.

A. S. Demir et al. / Tetrahedron 58 (2002) 9793–9799
9797
(87%); [a]2D0¼þ9.7 (c 5, CHCl3); nmax: 3053, 2916, 1617,
115.5, 134.5, 165.7, 194.8. Anal. calcd for C14H23BrN2O2
(331.25 g/mol): C 50.76, H 7.00, N 8.46. Found: C 50.53, H
7.21, N 8.15.
1552, 1432, 1285, 1111 cm21
;
1H NMR (400 MHz,
CDCl3): 1.69 (d, J¼7.1 Hz, 3H), 1.92 (s, 3H), 2.28 (s,
3H), 3.51 (s, 2H), 4.83 (q, J¼7.1 Hz, 1H), 5.57 (s, 1H), 5.70
(s, 1H), 7.28–7.47 (m, 5H), 12.72 (s, 1H); 13C NMR
(100 MHz, CDCl3): 15.7, 25.3, 27.9, 42.2, 53.9, 101.5,
115.9, 125.8, 127.6, 129.2, 134.4, 144.8, 163.4, 195.6. Anal.
calcd for C16H20BrNO (322.24 g/mol): C 59.64, H 6.26, N
4.35. Found: C 59.61, H 6.21, N 4.55.
4.2.7. Ethyl 2-[(E)-1-anilinoethylidene]-4-bromopent-4-
enoate (5g). Viscous oil; 2.78 g (88%); nmax: 3035, 2917,
2369, 1649, 1591, 1562, 1435, 1257, 1198 cm21; 1H NMR
(400 MHz, CDCl3): 1.27 (t, J¼7.1 Hz, 3H), 2.01 (s, 3H),
3.43 (s, 2H), 4.16 (q, J¼7.1 Hz, 2H), 5.40 (s, 1H), 5.58
(s, 1H), 7.02–7.31 (m, 5H), 11.23 (s, 1H); 13C NMR
(100 MHz, CDCl3): 14.9, 16.9, 39.9, 59.6, 93.4, 115.2,
124.7, 125.3, 129.4, 134.4, 139.9, 158.5, 170.3. Anal. calcd
for C15H18BrNO2 (324.21 g/mol): C 55.57, H 5.60, N 4.32.
Found: C 55.32, H 5.31, N 4.11.
4.2.2. 3-[(E)-1-Anilinoethylidene]-5-bromohex-5-en-2-
one (5b). Viscous oil; 2.69 g (93%); nmax: 3061, 2927,
1
1622, 1548, 1412, 1273, 1211 cm21; H NMR (400 MHz,
CDCl3): 1.89 (s, 3H), 2.08 (s, 3H), 3.34 (s, 2H), 5.40 (s, 1H),
5.58 (s, 1H), 6.49–6.51 (m, 1H), 6.94–7.22 (m, 4H), 13.61
(s, 1H); 13C NMR (100 MHz, CDCl3): 16.7, 27.9, 42.2,
103.1, 116.1, 125.8, 126.1, 129.5, 133.9, 139.2, 160.9,
196.7. Anal. calcd for C14H16BrNO (294.19 g/mol): C
57.16, H 5.48, N 4.76. Found: C 57.31, H 5.26, N 4.65.
4.2.8. Ethyl 2-[(E)-1-(benzylamino)ethylidene]-4-bromo-
pent-4-enoate (5h). Viscous oil; 3.18 g (95%); nmax: 2927,
1
1587, 1512, 1397, 1265, 1157 cm21; H NMR (400 MHz,
CDCl3): 1.24 (t, J¼7.1 Hz, 3H), 1.89 (s, 3H), 3.37 (s, 2H),
4.08 (q, J¼7.1 Hz, 2H), 4.42 (d, J¼6.1 Hz, 2H), 5.35 (s,
1H), 5.51 (s, 1H), 7.22–7.31 (m, 5H), 9.94 (br.s, 1H); 13C
NMR (100 MHz, CDCl3): 14.6, 14.9, 39.5, 46.9, 58.7, 89.9,
114.5, 126.4, 127.2, 128.6, 134.7, 138.7, 161.3, 170.0. Anal.
calcd for C16H20BrNO2 (338.24 g/mol): C 56.82, H 5.96, N
4.14. Found: C 56.58, H 5.91, N 4.33.
4.2.3. 3-[(E)-1-(Benzylamino)ethylidene]-5-bromohex-5-
en-2-one (5c). Viscous oil; 2.87 g (94%); nmax: 3061, 2927,
1
1622, 1548, 1412, 1273, 1211 cm21; H NMR (400 MHz,
CDCl3): 1.82 (s, 3H), 2.04 (s, 3H), 3.25 (s, 2H), 4.39 (d,
J¼6.1 Hz, 2H), 5.38 (d, J¼1.4 Hz, 1H), 5.52 (d, J¼1.4 Hz,
1H), 7.13–7.26 (m, 5H), 12.42 (br.s, 1H); 13C NMR
(100 MHz, CDCl3): 15.3, 27.9, 42.3, 47.5, 115.9, 126.9,
127.4, 128.6, 129.2, 134.4, 138.3, 164.0, 195.7. Anal. calcd
for C15H18BrNO (308.21 g/mol): C 58.45, H 5.89, N 4.54.
Found: C 58.26, H 5.73, N 4.22.
4.2.9. 3-Anilino-2-(2-bromoallyl)cyclohex-2-en-1-one
(5i). Colorless solid; 2.88 g (95%); nmax: 3102, 2945,
1
1612, 1557, 1487, 1312, 1161 cm21; mp 118–1208C; H
NMR (400 MHz, CDCl3): 1.90–1.96 (m, 2H), 2.36–2.40
(m, 2H), 2.47–2.50 (m, 2H), 3.61 (s, 2H), 5.46 (s, 1H), 5.69
(s, 1H), 6.79 (br.s, 1H), 7.05–7.07 (m, 2H), 7.18–7.22 (m,
1H), 7.32–7.36 (m, 2H); 13C NMR (100 MHz, CDCl3):
21.8, 27.2, 35.0, 36.5, 108.6, 116.4, 125.0, 125.7, 129.2,
131.6, 138.4, 159.7, 194.2. Anal. calcd for C15H16BrNO
(306.20 g/mol): C 58.84, H 5.27, N 4.57. Found: C 58.66, H
5.37, N 4.33.
4.2.4. 5-Bromo-3-{(E)-1-[(pyridin-2-ylmethyl)amino]-
ethylidene}hex-5-en-2-one (5d). Viscous oil; 2.72 g
(87%); nmax: 3057, 2895, 1587, 1535, 1397, 1281,
;
1016 cm21 1H NMR (400 MHz, CDCl3): 1.86 (s, 3H),
2.05 (s, 3H), 3.30 (s, 2H), 4.51 (d, J¼9.9 Hz, 2H), 5.39 (s,
1H), 5.54 (s, 1H), 7.08–7.17 (m, 2H), 7.56–7.64 (m, 1H),
8.46 (d, J¼4.3 Hz, 1H), 12.52 (s, 1H); 13C NMR (100 MHz,
CDCl3): 15.4, 27.9, 42.3, 49.2, 101.7, 115.9, 120.9, 122.5,
128.6, 134.4, 137.1, 149.8, 158.0, 163.8, 195.8. Anal. calcd
for C14H17BrN2O (309.20 g/mol): C 54.38, H 5.54, N 9.06.
Found: C 54.19, H 5.33, N 9.35.
4.3. General procedure for the synthesis of pyrroles
2.2 g (6.8 mmol) enamine 5a–i was dissolved in a mixture
of 7 mL t-BuOH and 14 mL DMSO. Then 1.15 g t-BuOK
(10.2 mmol) was added, followed by heating at 808C for
4–5 h. After cooling to room temperature, the mixture was
poured into 50 mL water and extracted with ether. Com-
bined organic layers were dried over MgSO4, concentrated
and purified by flash column chromatography to afford
pyrroles.
4.2.5. 5-Bromo-3-[(E)-1-morpholin-4-ylethylidene]hex-
5-en-2-one (5e). Viscous oil; 2.47 g (83%); nmax: 3145,
;
2876, 1612, 1497, 1345, 1218, 1112 cm21 1H NMR
(400 MHz, CDCl3): 2.01 (s, 3H), 2.11 (s, 3H), 2.87–2.92
(m, 4H), 3.45 (s, 2H), 3.75–3.81 (m, 4H), 5.47 (s, 1H), 5.55
(s, 1H), 13.57 (br.s, 1H); 13C NMR (100 MHz, CDCl3):
11.9, 26.7, 42.4, 56.2, 66.4, 102.1, 114.5, 134.3, 162.5,
196.4. Anal. calcd for C12H19BrN2O2 (303.20 g/mol): C
47.54, H 6.32, N 9.24. Found: C 47.77, H 6.51, N 8.94.
4.3.1. 1-[2,5-Dimethyl-1-((R)-1-phenylethyl)-1H-pyrrol-
3-yl]ethan-1-one, 6a.13b Viscous oil; 1.23 g (75%);
[a]2D0¼þ11.98 (c 0.7, CHCl3); nmax: 3051, 3011, 1671,
;
1H NMR (400 MHz,
1501, 1411, 1312, 1287 cm21
4.2.6. 5-Bromo-3-((Z)-1-{[(2S)-2-(methoxymethyl)pyrro-
lidin-1-yl]amino}ethylidene)hex-5-en-2-one (5f). Viscous
oil; 2.85 g (90%); [a]2D0¼þ35 (c 12, CHCl3); nmax: 3050,
3016, 2875, 2833, 2400, 2300, 1708, 1626, 1591, 1558,
CDCl3): 1.72 (d, J¼7.1 Hz, 3H), 1.86 (s, 3H), 2.19 (s,
3H), 2.30 (s, 3H), 5.39 (q, J¼7.1 Hz, 1H), 6.03 (s, 1H),
6.69–6.85 (m, 2H), 7.07–7.17 (m, 3H); 13C NMR
(100 MHz, CDCl3): 12.9, 14.1, 19.2, 28.9, 52.7, 110.0,
120.6, 126.2, 127.6, 127.8, 129.1, 135.4, 141.2, 194.7. Anal.
calcd for C16H19NO (241.33 g/mol): C 79.63, H 7.94, N
5.80. Found: C 79.60, H 7.91, N 5.75.
1425, 1266, 1216, 1100 cm21
;
1H NMR (400 MHz,
CDCl3): 1.64–2.02 (m, 4H), 2.06 (s, 3H), 2.09 (s, 3H),
2.71–2.73 (m, 1H), 2.87–2.94 (m, 1H), 3.16–3.21 (m, 1H),
3.27 (s, 3H), 3.33 (s, 2H), 3.28–3.35 (m, 2H), 5.46 (s, 1H),
5.59 (s, 1H), 12.59 (s, 1H); 13C NMR (100 MHz, CDCl3):
14.4, 21.3, 26.0, 27.5, 42.2, 57.5, 59.1, 66.1, 73.9, 98.9,
4.3.2. 2,4-Dimethyl-1-(1-phenylethyl)-1H-pyrrole, 8a.
Viscous oil; 27 mg (2%); nmax: 3106, 1505, 1419, 1342,

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A. S. Demir et al. / Tetrahedron 58 (2002) 9793–9799
1
1297, 1118 cm21; H NMR (400 MHz, CDCl3): 1.67 (d,
J¼7.1 Hz, 3H9, 1.96 (s, 3H), 2.00 (8s, 3H), 5.10 (q, J¼
7.1 Hz, 2H), 5.63 (s, 1H), 6.42 (s, 1H), 6.87–6.89 (m, 2H),
7.12–7.21 (m, 3H); 13C NMR (100 MHz, CDCl3):
12.6, 14.3, 22.8, 54.9, 106.8, 109.2, 115.0, 117.6, 126.0,
126.4, 127.3, 128.9, 144.4. Anal. calcd for C14H17N
(199.29 g/mol): C 84.37, H 8.60, N 7.03. Found: C 84.15,
H 8.51, N 6.83.
2.93–3.01 (m, 4H), 3.75–3.81 (m, 4H), 6.18 (s, 1H); 13C
NMR (100 MHz, CDCl3): 12.3, 13.4, 28.5, 57.5, 69.7,
108.5, 119.4, 127.6, 129.9, 197.5. Anal. calcd for
C12H18N2O2 (222.28 g/mol): C 64.84, H 8.16, N 12.60.
Found: C 64.65, H 8.33, N 12.38.
4.3.9. 4-(2,4-Dimethyl-1H-pyrrol-1-yl)morpholine, 8e.
Viscous oil; 37 mg (3%); nmax: 3048, 2987, 1462, 1312,
1
1227, 1147 cm21; H NMR (400 MHz, CDCl3): 2.02 (s,
4.3.3. 1-(2,5-Dimethyl-1-phenyl-1H-pyrrol-3-yl)ethan-1-
one, 6b.13a Viscous oil; 1.18 g (82%); nmax: 3052, 3018,
3H), 2.14 (s, 3H), 2.96–2.98 (m, 4H), 3.79–3.82 (m, 4H),
5.49 (s, 1H), 6.55 (s, 1H); 13C NMR (100 MHz, CDCl3):
10.9, 12.2, 55.9, 66.9, 104.5, 109.3, 116.5, 127.9. Anal.
calcd for C10H16N2O (180.25 g/mol): C 66.63, H 8.95, N
15.54. Found: C 66.44, H 8.78, N 15.35.
2985, 1649, 1503, 1419, 1261, 1216 cm21 1H NMR
;
(400 MHz, CDCl3): 1.97 (s, 3H), 2.29 (s, 3H), 2.38 (s,
3H), 6.27 (s, 1H), 7.15–7.17 (m, 2H), 7.34–7.48 (m, 3H);
13C NMR (100 MHz, CDCl3): 13.1, 13.3, 28.8, 108.7,
121.0, 122.9, 126.8, 128.5, 128.9, 129.7, 136.2, 195.4. Anal.
calcd for C14H15NO (213.28 g/mol): C 78.84, H 7.09, N
6.57. Found: C 78.79, H 7.01, N 6.49.
4.3.10. 1-{1-[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]-
2,5-dimethyl-1H-pyrrol-3-yl}ethan-1-one, 6f. Viscous
oil; 1.29 g (76%); [a]2D0¼þ13 (c 9, CHCl3); nmax: 3041,
3016, 2976, 2401, 2309, 1633, 1416, 1267, 1212 cm21; 1H
NMR (400 MHz, CDCl3): 1.78–1.84 (m, 2H), 1.91–1.94
(m, 2H), 2.05–2.11 (m, 2H), 2.24 (s, 3H), 2.38 (s, 3H), 2.45
(s, 3H), 3.00–3.07 (m, 1H), 3.12–3.19 (m, 1H), 3.25 (s,
3H), 3.26–3.29 (m, 1H), 6.51 (s, 1H); 13C NMR (100 MHz,
CDCl3): 11.6, 13.9, 21.6, 26.6, 30.9, 55.9, 58.8, 65.9, 73.6,
115.2, 118.2, 119.2, 137.9, 194.2. Anal. calcd for
C14H22N2O2 (250.34 g/mol): C 67.17, H 8.86, N 11.19.
Found: C 67.23, H 8.76, N 10.91.
4.3.4. 1-(2,4-Dimethyl-1-phenyl-1H-pyrrol-3-yl)ethan-1-
one, 7b. Viscous oil; 58 mg (4%); nmax: 3052, 2987, 1420,
1
1261, 1117 cm21; H NMR (400 MHz, CDCl3): 2.29 (s,
3H), 2.38 (s, 3H), 2.44 (s, 3H), 6.44 (s, 1H), 7.21–7.23 (m,
2H), 7.35–7.50 (m, 3H); 13C NMR (100 MHz, CDCl3):
13.9, 14.0, 31.5, 108.5, 121.0, 126.7, 128.6, 128.9, 129.6,
135.9, 137.9, 195.3. Anal. calcd for C14H15NO
(213.28 g/mol): C 78.84, H 7.09, N 6.57. Found: C 78.73,
H 7.18, N 6.32.
4.3.11. Ethyl 2,5-dimethyl-1-phenyl-1H-pyrrole-3-car-
boxylate, 6g.11a,19 Colorless solid; 1.44 g (87%); mp
42–448C (lit. 45–468 (MeOH)); nmax: 3035, 2986, 2311,
1685, 1536, 1420, 1269, 1219, 1163, 1071 cm21; 1H NMR
(400 MHz, CDCl3): 1.27 (t, J¼7.1 Hz, 3H), 1.96 (s,
3H), 2.27 (s, 3H), 4.27 (q, J¼7.1 Hz, 2H), 6.32 (s, 1H),
7.23–7.42 (m, 5H); 13C NMR (100 MHz, CDCl3):
12.2, 12.6, 14.6, 58.9, 107.7, 115.7, 119.9, 126.2, 128.1,
129.0, 137.8, 165.2. Anal. calcd for C15H17NO2
(243.30 g/mol): C 74.05, H 7.04, N 5.76. Found: C 74.01,
H 6.98, N 5.68.
4.3.5. 2,4-Dimethyl-1-phenyl-1H-pyrrole, 8b.21 Viscous
oil; 23 mg (2%); nmax: 3035, 2897, 1417, 1272, 1116,
1041 cm21; 1H NMR (400 MHz, CDCl3): 2.09 (s, 3H), 2.17
(s, 3H), 5.83 (s, 1H), 6.49 (s, 1H), 7.19–7.44 (m, 5H); 13C
NMR (100 MHz, CDCl3): 12.4, 13.3, 110.7, 118.9, 119.4,
125.9, 126.7, 128.9, 129.3. Anal. calcd for C12H13N
(171.24 g/mol): C 84.17, H 7.65, N 8.18. Found: C 84.06,
H 7.58, N 8.09.
4.3.6. 1-(1-Benzyl-2,5-dimethyl-1H-pyrrol-3-yl)ethan-1-
one, 6c.11a Viscous oil; 1.31 g (85%); nmax: 3053, 2985,
1649, 1520, 1420, 1273 cm21
;
1H NMR (400 MHz,
4.3.12. Ethyl 2,4-dimethyl-1-phenyl-1H-pyrrole-3-car-
boxylate, 7g. Viscous oil; 83 mg (5%); nmax: 3037, 2979,
2319, 1687, 1542, 1402, 1305, 1212, 1115 cm21; 1H NMR
(400 MHz, CDCl3): 1.37 (t, J¼7.1 Hz, 3H), 2.25 (s, 3H),
2.40 (s, 3H), 4.28 (q, J¼7.1 Hz, 2H), 6.44 (s, 1H), 7.24–
7.46 (m, 5H); 13C NMR (100 MHz, CDCl3): 12.4, 12.5,
14.4, 58.7, 112.3, 119.8, 120.9, 126.0, 127.4, 128.0, 128.7,
139.1, 165.4. Anal. calcd for C15H17NO2 (243.30 g/mol): C
74.05, H 7.04, N 5.76. Found: C 74.11, H 7.21, N 5.48.
CDCl3): 2.11 (s, 3H), 2.36 (s, 3H), 2.46 (s, 3H), 5.01 (s,
2H), 6.24 (s, 1H), 6.84–6.86 (m, 2H), 7.19–7.29 (m, 3H);
13C NMR (100 MHz, CDCl3): 12.1, 12.6, 28.8, 46.9, 108.9,
120.7, 125.8, 127.8, 127.9, 129.3, 135.3, 137.2, 194.7. Anal.
calcd for C15H17NO (227.30 g/mol): C 79.26, H 7.54, N
6.16. Found: C 79.18, H 7.48, N 6.07.
4.3.7. 1-[2,5-Dimethyl-1-(pyridin-2-ylmethyl)-1H-pyr-
rol-3-yl]ethan-1-one, 6d. Viscous oil; 1.01 g (65%); nmax
:
3057, 2847, 1649, 1591, 1521, 1418, 1271 cm21; 1H NMR
(400 MHz, CDCl3): 2.16 (s, 3H), 2.36 (s, 3H), 2.47 (s, 3H),
5.12 (s, 2H), 6.26 (s, 1H), 6.52 (d, J¼7.8 Hz, 1H), 7.15–
7.19 (m, 1H), 7.57–7.61 (m, 1H), 8.54 (br.s, 1H); 13C NMR
(100 MHz, CDCl3): 11.6, 12.1, 28.3, 48.4, 108.5, 119.5,
120.3, 120.4, 127.4, 134.7, 137.0, 149.3, 156.8, 194.1. Anal.
calcd for C14H16N2O (228.29 g/mol): C 73.66, H 7.06, N
12.27. Found: C 73.61, H 7.21, N 11.97.
4.3.13. Ethyl 1-benzyl-2,5-dimethyl-1H-pyrrole-3-car-
boxylate, 6h.11 Viscous oil; 1.39 g (80%); nmax: 3029,
2987, 2317, 1647, 1567, 1418, 1326, 1221 cm21; 1H NMR
(400 MHz, CDCl3): 1.33 (t, J¼7.1 Hz, 3H), 2.09 (s, 3H),
2.43 (s, 3H), 4.23 (q, J¼7.13 Hz, 2H), 5.00 (s, 2H), 6.31 (s,
1H), 6.83–6.85 (m, 2H), 7.18–7.27 (m, 3H); 13C NMR
(100 MHz, CDCl3): 11.6, 12.5, 15.0, 47.1, 59.3, 108.4,
111.7, 125.9, 127.7, 127.9, 129.2, 135.7, 137.4, 165.8. Anal.
calcd for C16H19NO2 (257.33 g/mol): C 74.68, H 7.44, N
5.44. Found: C 74.55, H 7.37, N 5.38.
4.3.8. 1-(2,5-Dimethyl-1-morpholin-4-yl-1H-pyrrol-3-
yl)ethan-1-one, 6e. Viscous oil; 1.03 g (67%); nmax: 3052,
2985, 2305, 1650, 1542, 1420, 1264, 1111 cm21; 1H NMR
(400 MHz, CDCl3): 1.99 (s, 3H), 2.12 (s, 3H), 2.27 (s, 3H),
4.3.14. 2-Methyl-1-phenyl-1,5,6,7-tetrahydro-4H-indol-
4-one, 6i.20 Colorless solid; 1.33 g (87%); mp 150–1528C

A. S. Demir et al. / Tetrahedron 58 (2002) 9793–9799
10. Hantzsch, A. Berichte 1890, 23, 1474.
9799
(lit. 150–1518 (hexane)); nmax: 3048, 2979, 2310, 1650,
1547, 1419, 1268 cm21; 1H NMR (400 MHz, CDCl3): 2.04
(s, 3H), 2.06–2.11 (m, 2H), 2.43–2.45 (m, 2H), 2.51–2.54
(m, 2H), 6.34 (s, 1H), 7.22–7.27 (m, 2H), 7.43–7.51 (m,
3H); 13C NMR (100 MHz, CDCl3): 12.6, 22.7, 23.8, 37.8,
103.8, 120.8, 127.5, 128.5, 129.4, 130.9, 137.2, 143.8,
193.5. Anal. calcd for C15H15NO (225.29 g/mol): C 79.97,
H 6.71, N 6.22. Found: C 79.89, H 6.65, N 6.14.
11. (a) Ferraz, H. M. C.; Pereira, F. L. C.; Leite, F. S.; Nunes, M. R.
S.; Payret-Arrua, M. E. Tetrahedron 1999, 55, 10915.
(b) Ferraz, H. M. C.; Oliveria, E.; Payret-Arrua, M. E.; Brandt,
C. A. J. Org. Chem. 1995, 60, 7357.
12. Cheng, L.; Lightner, D. A. Synthesis 1999, 1, 46.
13. (a) Arcadi, A.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. Adv.
Synth. Catal. 2001, 343, 443. (b) Arcadi, A.; Di Giuseppe, S.;
Marinelli, F.; Rossi, E. Tetrahedron: Asymmetry 2001, 12,
2715.
Acknowledgements
14. Braun, R. U.; Zeitler, K.; Mu¨ller, T. J. J. Org. Lett. 2001, 3,
3297.
The financial support of the Scientific and Technical
Research Council of Turkey (TUBITAK), the Turkish
State Planning Organization (for GC–LC–MS) and Middle
East Technical University (AFP 2002) is gratefully
acknowledged.
15. (a) Demir, A. S.; Akhmedov, I. M.; Sesenoglu, O.; Alpturk, O.;
Apaydin, S.; Gercek, Z.; Ibrahimzade, N. J. Chem. Soc.,
Perkin Trans. 1 2001, 1162. (b) Demir, A. S.; Akhmedov,
I. M.; Tanyeli, C.; Gercek, Z.; Gadzhili, R. A. Tetrahedron:
Asymmetry 1997, 8, 753.
16. (a) Akhmedov, S. T.; Sadygov, N. S.; Ismailov, V. M.;
Achundova, M. A.; Sadovaya, H. K.; Karimov, F. N.; Zefirov,
N. S. Khim. Geterotsikl. Soedin. 1986, 12, 1602.
(b) Akhmedov, S. T.; Sadygov, N. S.; Ismailov, V. M.;
Sadovaya, H. K.; Karimov, F. N.; Zefirov, N. S. Khim.
Geterotsikl. Soedin. 1984, 10, 1428.
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