New and clean synthesis of N-substituted pyrroles under microwave irradiation

Article abstract of DOI:10.1016/j.tet.2007.07.013

N-Substituted homochiral pyrrole derivatives were synthesized by the ring-closure reaction of cis-1,4-dichloro-2-butene with various amine compounds on a silica surface under microwave irradiation.

Full text of DOI:10.1016/j.tet.2007.07.013

Tetrahedron 63 (2007) 9746–9750
New and clean synthesis of N-substituted pyrroles
under microwave irradiation
a
a
b
Feray Aydogan,a, Mehmet Basarir, Cigdem Yolacan and Ayhan S. Demir
*
aDepartment of Chemistry, Yildiz Technical University, 34010 Esenler, Istanbul, Turkey
bDepartment of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Received 13 April 2007; revised 21 June 2007; accepted 6 July 2007
Available online 13 July 2007
Abstract—N-Substituted homochiral pyrrole derivatives were synthesized by the ring-closure reaction of cis-1,4-dichloro-2-butene with
various amine compounds on a silica surface under microwave irradiation.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Pyrrole derivatives have great importance in organic chem-
istry because they are present in many natural, medicinal
and agricultural products, and semiconductor polymers.
They are also very convenient precursors for biologically
important compounds such as indolizidine alkaloids, bicy-
clic lactams, and unsaturated g-lactams.1 There are various
pyrrole syntheses in the literature.2 The most widely used
method is the Paal–Knorr synthesis, which involves the reac-
tion of 1,4-dicarbonyl compounds and their masked equiva-
lents, such as 2,5-dimethoxytetrahydrofuran, with primary
amines. Most of these methods are multistep reactions,
and their main problem is racemization. Therefore, the de-
velopment of effective and selective methods for obtaining
pyrrole derivatives is desirable.
The reaction of cis-1,4-dichloro-2-butene with several
amines has been studied by several groups.5 These reactions
were carried out in different solvents, such as toluene, DMF,
methanol, and benzene, at 50–60 ꢀC in the presence of pyr-
idine, triethylamine, and sodium hydride, to give 3-pyrroline
derivatives in 60–75% yield, as expected. But when we
carried out the reaction of cis-1,4-dichloro-2-butene with
various amines, amino alcohols, and amino acid esters under
microwave irradiation on silica gel, we obtained pyrrole
derivatives instead of the expected 3-pyrrolines (Scheme 1).
NH2
SiO2
N
Cl
Cl
+
R1
R2
MW
R1
R2
1
2a-i
3a-i
The use of microwaves for carrying out reactions is advanta-
geous for the synthesis of numerous types of compound. The
most evident improvements with this technique are reduced
reaction time, cleaner reactions due to fewer side reactions,
and the use of minimal quantities of solvent.3 Thus, micro-
wave-assisted synthesis can be considered as being more
economical and environmentally friendly.
Scheme 1.
We tried several different reaction conditions under micro-
wave irradiation, and found that the reaction took place on
a silica-gel surface without solvent quickly in good yield.
In a typical reaction procedure, a mixture of cis-1,4-di-
chloro-2-butene, amine, and triethylamine adsorbed on the
silica-gel surface was irradiated in a microwave oven for
a period of time long enough to complete the reaction. The
reaction mixture was washed with a minimum amount of
ether, and evaporation of the solvent furnished a crude prod-
uct that was purified by column chromatography. Using this
procedure, various chiral amine compounds were converted
to their pyrrole derivatives through a one-step operation in
49–69% yield, as summarized in Table 1. All the spectro-
scopic data of the pyrrole compounds are in full agreement
with their structures.
As a part of our ongoing research on the synthesis and reac-
tions of pyrrole derivatives,4 we wish to report here the syn-
thesis of homochiral pyrrole derivatives from the reaction of
cis-1,4-dichloro-2-butene, which is a commercially available
and inexpensive starting material, with various amines, amino
alcohols, and amino acid esters under microwave conditions.
Keywords: Pyrrole; Microwave; cis-1,4-Dichloro-2-butene; Silica gel.
* Corresponding author. Tel.: +90 2124491746; fax: +90 2124491514;
e-mail: feray_aydogan@yahoo.com
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.013

F. Aydogan et al. / Tetrahedron 63 (2007) 9746–9750
9747
Table 1. The synthesis of pyrrole derivatives
Amine 2
Pyrrole 3
Reaction time (min)
Yielda (%)
63
NH2
(R)-2a
Ph
(R)-3a6
2
2
3
N
Ph
NH2
(S)-2a
Ph
N
(S)-3a
65
49
51
Ph
NH2
(R)-2b
CO2Me
(R)-3b7–11
N
CO2Me
NH2
N
(S)-2c
(S)-3c7–9
2
4
CO2Me
CO2Me
NH2
(S)-3d1e,2b
CO2Et
52
N
(S)-2d
EtO2C
HO
CO2Et
EtO2C
NH2
CO2Et
N
(S)-2e
(S)-3e
CO2Et
2
2
55
58
HO
NH2
(S)-2f
(S)-3f
N
HO
HO
HO
NH2
N
(1R, 2S)-2g
(1R, 2S)-3g10
2
66
HO
HO
Ph
Ph
Ph
NH2
N
(1S, 2R)-2g
(1S, 2R)-3g10
2
2
62
61
HO
HO
Ph
NH2
(R)-2h
(R)-3h
N
HO
NH2
N
HO
OH
(1S, 2S)-2i
(1S, 2S)-3i
2
69
HO
OH
Ph
Ph
a
Isolated yield.
It is obvious that the reaction takes place via simple substi-
tution of chlorine by nitrogen, followed by dehydrogenation
(Scheme 2). The reaction of cis-1,4-dichloro-2-butene with
(R)-phenylethylamine has also been carried out in toluene
or DMF at 55–60 ꢀC in the presence of pyridine or triethyl-
amine without microwave irradiation. The GC–MS analysis
of the crude products obtained from these reactions showed
that trace amounts of the pyrrole derivatives were formed,

9748
F. Aydogan et al. / Tetrahedron 63 (2007) 9746–9750
but that the 3-pyrroline was the main product. This result
showed that the oxidation of pyrroline to pyrrole can take
place in atmospheric oxygen and supported our mechanism.
4.2.1. (R)-1-(1-Phenylethyl)-1H-pyrrole (R)-3a. Colorless
liquid (107 mg, 63%). [a]2D0 ꢁ6.6 (c 2.7, CHCl3); lit.6
[a]2D0 ꢁ14.4 (c 1.2, CHCl3); IR (neat): n 3029, 2963, 1603,
1377 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.75 (d,
;
J¼7.02 Hz, 3H, CH3), 5.20 (q, J¼7.02 Hz, 1H, N–CH),
6.11 (br s, 2H, ]CH), 6.68 (br s, 2H, ]CH), 7.01 (d,
J¼7.80 Hz, 2H, ArH), 7.14 (m, 3H, ArH); 13C NMR
(100 MHz, CDCl3): d 21.0, 57.0, 106.9, 118.4, 124.7,
126.3, 127.5, 142.5; MS (m/z) (rel abund): 171 [M+] (57),
105 (100), 77 (26), 67 (27). Anal. Calcd for C12H13N
(171.24): C, 84.17; H, 7.65; N, 8.18. Found: C, 84.25; H,
7.57; N, 8.21.
NH2
Cl
Cl
+
N
R1
R2
-2 HCl
R1
R2
O
1
2
4
4.2.2. (S)-1-(1-Phenylethyl)-1H-pyrrole (S)-3a. Colorless
liquid (111 mg, 65%). [a]2D0 +6.8 (c 2.7, CHCl3); IR (neat):
N
R1
R2
n 3027, 2965, 1603, 1377 cmꢁ1 1H NMR (400 MHz,
;
3
CDCl3): d 1.75 (d, J¼7.02 Hz, 3H, CH3), 5.20 (q,
J¼7.02 Hz, 1H, N–CH), 6.11 (br s, 2H, ]CH), 6.68 (br s,
2H, ]CH), 7.01 (d, J¼7.80 Hz, 2H, ArH), 7.14 (m, 3H,
ArH); 13C NMR (100 MHz, CDCl3): d 21.0, 57.0, 106.9,
118.4, 124.7, 126.3, 127.5, 142.5; MS (m/z) (rel abund):
171 [M+] (57), 105 (100), 77 (26), 67 (27). Anal. Calcd for
C12H13N (171.24): C, 84.17; H, 7.65; N, 8.18. Found: C,
84.24; H, 7.59; N, 8.21.
Scheme 2.
3. Conclusion
A new microwave-assisted one-pot synthesis of N-
substituted pyrrole derivatives has been achieved on a silica-
gel surface under solvent-free conditions from commercially
available materials. This environmentally friendly method
provides various advantages, such as reasonably good yield,
fast reaction under mild and solvent-free reaction condi-
tions, and no racemization.
4.2.3. (R)-Methyl 2-(1H-pyrrol-1-yl)propanoate (R)-3b.
Colorless oil (75 mg, 49%). [a]2D0 +12.83 (c 1.1, CHCl3);
1
IR (neat): n 3102, 2992, 2954, 1747, 1378, 1282 cmꢁ1; H
NMR (500 MHz, CDCl3): d 1.65 (d, J¼7.33 Hz, 3H,
CH3), 3.64 (s, 3H, OCH3), 4.69 (q, J¼7.33 Hz, 1H, N–
CH), 6.11 (apparent t, J¼2.44, 1.96 Hz, 2H, ]CH), 6.67
(apparent t, J¼2.44, 1.95 Hz, 2H, ]CH); 13C NMR
(125 MHz, CDCl3): d 18.6, 53.0, 57.4, 109.4, 120.6, 171.9;
MS (m/z) (rel abund): 153 [M+] (71), 94 (100), 79 (26), 67
(56), 52 (49), 40 (92). Anal. Calcd for C8H11NO2
(153.18): C, 62.73; H, 7.24; N, 9.14. Found: C, 62.59; H,
7.26; N, 9.17.
4. Experimental
4.1. General
All reagents were of commercial quality and reagent quality
solvents were used without further purification. IR spectra
were determined on a Perkin–Elmer, Spectrum One FTIR
spectrometer. NMR spectra were recorded on Mercury
VX-400 MHz and Varian Unity-Inova 500 MHz spectrome-
ters. Chemical shifts d are reported in parts per million rela-
tive to CHCl3 (1H: d¼7.27), CDCl3 (13C: d¼77.0) and TMS
as internal standard. Column chromatography was carried
out on silica gel 60 (40–63 mM). TLC was carried out on
aluminum sheets precoated with silica gel 60F254 (Merck).
MS were determined on Thermo Finnigan multi Mass (EI,
70 eV). Elemental analyses were carried out on Thermo
Flash EA 1112 series apparatus. Optical rotations were mea-
sured with AA-55 Polarimeter. The reactions were carried
out in Milestone-Start microwave instrument.
4.2.4. (S)-Methyl 3-methyl-2-(1H-pyrrol-1-yl)butanoate
(S)-3c. Colorless oil (92 mg, 51%). [a]2D0 ꢁ2.8 (c 4.2,
CHCl3); IR (neat): n 3055, 2986, 1727, 1372, 1285 cmꢁ1
;
1H NMR (400 MHz, CDCl3): d 0.67 (d, J¼6.65 Hz, 3H,
CH3), 0.91 (d, J¼6.65 Hz, 3H, CH3), 2.32 (m, 1H, CH),
3.63 (s, 3H, CH3), 4.00 (d, J¼10.23 Hz, 1H, N–CH),
6.02 (br s, 2H, ]CH), 6.63 (br s, 2H, ]CH); 13C
NMR (100 MHz, CDCl3): d 18.7, 19.4, 32.0, 51.9,
68.8, 108.5, 120.1, 171.0. Anal. Calcd for C10H15NO2
(181.23): C, 66.27; H, 8.34; N, 7.73. Found: C, 66.25; H,
8.36; N, 7.75.
4.2. General procedure
4.2.5. (S)-Diethyl 2-(1H-pyrrol-1-yl)pentandioate (S)-3d.
Colorless oil (117 mg, 52%). [a]2D0 ꢁ12.3 (c 1.3, CHCl3);
lit.1e [a]D20 ꢁ12.2 (c 1.3, CHCl3); IR (neat): n 3062,
A mixture of amine (1.0 mmol), cis-1,4-dichloro-2-butene
(1.0 mmol), and triethylamine (2.0 mmol) was uniformly
adsorbed on the surface of silica gel (5 g) in a Pyrex round
bottomed flask at rt. The flask was then placed on a bed of
silica gel in a porcelain basin and irradiated in a microwave
oven at 500 W for 2–4 min (TLC). The reaction mass was
eluted with ether and the ether extract was evaporated to
leave the crude product, which was purified by column chro-
matography over silica gel (EtOAc/hexane 1:2, 1:6 or 1:10)
to afford pure product.
2985, 1732, 1284 cmꢁ1 1H NMR (400 MHz, CDCl3):
;
d 1.19–1.25 (m, 6H, CH3), 2.09–2.36 (m, 3H, CH2 and
CHA), 2.38–2.42 (m, 1H, CHB), 4.12 (q, J¼7.32 Hz, 2H,
CH2), 4.19 (q, J¼7.25 Hz, 2H, CH2), 4.75 (m, 1H, N–
CH), 6.19 (apparent t, J¼2.24 Hz, 2H, ]CH), 6.72 (appar-
ent t, J¼2.24 Hz, 2H, ]CH); 13C NMR (100 MHz,
CDCl3): d 14.0, 14.1, 28.0, 29.9, 60.5, 60.7, 61.6, 108.9,
120.1, 170.1, 173.2. Anal. Calcd for C13H19NO4

F. Aydogan et al. / Tetrahedron 63 (2007) 9746–9750
9749
(253.29): C, 61.64; H, 7.56; N, 5.53. Found: C, 61.67; H,
7.49; N, 5.51.
2H, ]CH), 6.70 (apparent t, J¼2.34, 1.95 Hz, 2H, ]CH);
13C NMR (100 MHz, CDCl3): d 10.8, 25.1, 64.1, 66.3,
108.4, 119.3. Anal. Calcd for C8H13NO (139.19): C, 69.03;
H, 9.41; N, 10.06. Found: C, 68.97; H, 9.45; N, 10.08.
4.2.6. (S)-Ethyl 3-hydroxy-2-(1H-pyrrol-1-yl)propanoate
(S)-3e. Yellow oil (101 mg, 55%). [a]2D0 +4.63 (c 1.7,
CHCl3); IR (neat): n 3532, 3099, 2982, 2934, 1738, 1371,
4.2.11. (1S,2S)-1-Phenyl-2-(1H-pyrrol-1-yl)propane-1,3-
diol (1S,2S)-3i. Yellow oil (149 mg, 69%). [a]2D0 +93.5
(c 0.5, CHCl3); IR (neat): n 3525, 3050, 1605, 1375,
1281 cmꢁ1
;
1H NMR (500 MHz, CDCl3): d 1.95 (t,
J¼7.32 Hz, 3H, CH3), 1.95 (br s, 1H, OH), 3.97 (apparent
q, J¼6.83 Hz, 1H, HA), 4.06 (apparent q, J¼5.85 Hz, 1H,
HB), 4.15 (q, J¼7.32 Hz, 2H, CH2), 4.66 (apparent t,
J¼6.83, 5.86 Hz, 1H, N–CH), 6.13 (apparent t, J¼2.44,
1.95 Hz, 2H, ]CH), 6.69 (apparent t, J¼2.44, 1.96 Hz,
2H, ]CH); 13C NMR (125 MHz, CDCl3): d 13.0, 60.8,
62.3, 62.4, 107.9, 119.4, 168.2; MS (m/z) (rel abund): 183
[M+] (39), 110 (55), 81 (100), 66 (41), 52 (42), 40 (22).
Anal. Calcd for C9H13NO3 (183.20): C, 59.00; H, 7.15; N,
7.65. Found: C, 59.19; H, 7.06; N, 7.62.
1
1284 cmꢁ1; H NMR (400 MHz, CDCl3): d 2.00 (br s, 1H,
OH), 2.45 (br s, 1H, OH), 3.72 (m, 2H, CH2), 4.06 (m, 1H,
N–CH), 4.92 (d, J¼6.6 Hz, 1H, O–CH), 6.15 (apparent t,
J¼1.95 Hz, 2H, ]CH), 6.70 (apparent t, J¼2.34, 1.95 Hz,
2H, ]CH), 7.19 (m, 2H, ArH), 7.31 (m, 3H, ArH);
13C NMR (100 MHz, CDCl3): d 63.1, 67.7, 74.7, 108.8,
120.7, 126.6, 128.6, 128.8, 140.4; MS (m/z) (rel abund):
217 [M+] (7), 168 (7), 111 (14), 106 (42), 93 (100), 77 (33),
67 (32), 51 (39). Anal. Calcd for C13H15NO2 (217.26):
C, 71.87; H, 6.96; N, 6.45. Found: C, 71.83; H, 7.02; N, 6.42.
4.2.7. (S)-2-(1H-Pyrrol-1-yl)propan-1-ol (S)-3f. Colorless
oil (73 mg, 58%). [a]2D0 +8.25 (c 2.2, CHCl3); IR (neat): n
3524, 3098, 2982, 1558, 1378, 1280 cmꢁ1 1H NMR
;
References and notes
(400 MHz, CDCl3): d 1.37 (d, J¼7.02 Hz, 3H, CH3), 1.63
(br s, 1H, OH), 3.59 (m, 2H, CH2), 4.09 (m, 1H, N–CH),
6.10 (br s, 2H, ]CH), 6.67 (br s, 2H, ]CH); 13C NMR
(100 MHz, CDCl3): d 17.6, 57.7, 67.7, 108.4, 119.1; MS
(m/z) (rel abund): 125 [M+] (84), 94 (95), 79 (23), 67 (59),
52 (56), 40 (100). Anal. Calcd for C7H11NO (125.17): C,
67.17; H, 8.86; N, 11.19. Found: C, 67.22; H, 8.83; N, 11.23.
1. (a) Ragno, R.; Marshall, G. R.; Di Santo, R.; Costi, R.; Massa,
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2002, 58, 9793; (b) Demir, A. S.; Akhmedov, I. M.; Sesenoglu,
O.; Alpturk, O.; Apaydin, S.; Gercek, Z.; Ibrahimzade, N.
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Asymmetry 2002, 13, 601; (f) Aydogan, F.; Demir, A. S.
Tetrahedron 2005, 61, 3019; (g) Demir, A. S.; Igdir, A. C.;
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K.; Suzuki, K. Tetrahedron: Asymmetry 2001, 12, 2989; (c)
Ohno, T.; Sato, H. Jpn. Patent 20,011,270,862, 2001; (d)
Taylor, E. C.; Ahmed, Z.; Robke, D. J.; Kempton, R. J.
J. Org. Chem. 1991, 56, 5443; (e) Warmus, J. S.; Dilley,
G. J.; Meyers, A. I. J. Org. Chem. 1993, 58, 270; (f)
Brandange, S.; Rodriguez, B. Synthesis 1988, 347; (g)
Hercouet, A.; Neu, A.; Peyronel, J. F.; Carboni, B. Synlett
2002, 829; (h) Nemia, M. B.; Lee, J.; Joullie, M. M. Synth.
Commun. 1983, 13, 1117; (i) Palmer, B. D.; Denny, W. A.
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4.2.8. (1R,2S)-1-Phenyl-2-(1H-pyrrol-1-yl)propan-1-ol
(1R,2S)-3g. Yellow oil (133 mg, 66%). [a]2D0 +26.8 (c 3.6,
CHCl3); IR (neat): n 3523, 3055, 2992, 1605, 1376,
1283 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.32 (d,
;
J¼7.00 Hz, 3H, CH3), 2.11 (br s, 1H, OH), 4.08 (m, 1H,
N–CH), 4.61 (d, J¼4.68 Hz, 1H, O–CH), 5.93 (br s, 2H,
]CH), 6.47 (br s, 2H, ]CH), 7.04 (d, J¼7.60 Hz, 2H,
ArH), 7.17 (m, 3H, ArH); 13C NMR (100 MHz, CDCl3):
d 14.9, 60.8, 77.8, 107.9, 119.2, 126.0, 127.7, 128.2,
140.9; MS (m/z) (rel abund): 201 [M+] (21), 115 (7), 106
(16), 94 (100), 77 (63), 66 (45), 50 (49), 40 (78). Anal. Calcd
for C13H15NO (201.26): C, 77.58; H, 7.51; N, 6.96. Found:
C, 77.59; H, 7.56; N, 6.88.
4.2.9. (1S,2R)-1-Phenyl-2-(1H-pyrrol-1-yl)propan-1-ol
(1S,2R)-3g. Yellow oil (124 mg, 62%). [a]2D0 ꢁ26.5 (c 3.6,
CHCl3); IR (neat): n 3526, 3053, 2989, 1605, 1377,
1283 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.32 (d,
;
J¼7.00 Hz, 3H, CH3), 2.11 (br s, 1H, OH), 4.08 (m, 1H,
N–CH), 4.61 (d, J¼4.68 Hz, 1H, O–CH), 5.93 (br s, 2H,
]CH), 6.47 (br s, 2H, ]CH), 7.04 (d, J¼7.60 Hz, 2H,
ArH), 7.17 (m, 3H, ArH); 13C NMR (100 MHz, CDCl3):
d 14.9, 60.8, 77.8, 107.9, 119.2, 126.0, 127.7, 128.2,
140.9; MS (m/z) (rel abund): 201 [M+] (21), 115 (7), 106
(16), 94 (100), 77 (63), 66 (45), 50 (49), 40 (78). Anal. Calcd
for C13H15NO (201.26): C, 77.58; H, 7.51; N, 6.96. Found:
C, 77.61; H, 7.54; N, 6.87.
4.2.10. (R)-2-(1H-Pyrrol-1-yl)butan-1-ol (R)-3h. Color-
less oil (85 mg, 61%). [a]2D0 +14.3 (c 0.4, CHCl3); IR
1
(neat): n 3517, 3048, 2998, 1602, 1376, 1282 cmꢁ1; H
NMR (400 MHz, CDCl3): d 0.85 (t, J¼7.41 Hz, 3H, CH3),
1.68 (br s, 1H, OH), 1.77 (m, 2H, CH2), 3.73 (m, 2H, CH2),
3.85 (m, 1H, N–CH), 6.18 (apparent t, J¼2.34, 1.95 Hz,

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F. Aydogan et al. / Tetrahedron 63 (2007) 9746–9750
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