Clean and efficient microwave-solvent-free conversion of homochiral amines, α-amino alcohols and α-amino acids to their chiral 2-substituted pyrrole derivatives

Article abstract of DOI:10.1016/j.tet.2005.01.120

Efficient synthesis of 1,2-disubstituted homochiral pyrroles has been achieved by a two-component coupling of chloroenones and amine compounds on the surface of silica gel without any solvent under microwave irradiation.

Full text of DOI:10.1016/j.tet.2005.01.120

Tetrahedron 61 (2005) 3019–3023
Clean and efficient microwave-solvent-free conversion of
homochiral amines, a-amino alcohols and a-amino acids to their
chiral 2-substituted pyrrole derivatives
Feray Aydogana,b and Ayhan S. Demira,
*
aDepartment of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
bDepartment of Chemistry, Yildiz Technical University, 34010 Davutpasa, Istanbul, Turkey
Received 11 September 2004; revised 10 January 2005; accepted 28 January 2005
Abstract—Efficient synthesis of 1,2-disubstituted homochiral pyrroles has been achieved by a two-component coupling of chloroenones and
amine compounds on the surface of silica gel without any solvent under microwave irradiation.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
formation of the pyrrole ring with amino acids, partial
racemization often occurs. Therefore, the development of a
flexible and selective method to obtain such compounds is
desirable. As we described in our previous paper,5 we have
designed a convenient new route to 2-alkyl substituted
pyrrole rings from amines, amino alcohols and amino acids
with chloroenones. The use of microwaves for carrying out
these reactions under solvent free conditions provides
advantages for the synthesis of numerous types of pyrroles.
As part of our continued interest in the chemistry of
substituted pyrroles, we wish to report here an efficient
microwave-assisted one-pot synthesis of pyrroles by
coupling chloroenones and amine compounds onto the
surface of silica gel.
Compounds containing a pyrrole ring can be found in many
naturally occurring compounds and have been found to be
useful for applications in medicine and agriculture.1 Chiral
pyrrole derivatives of amines and amino acids are important
starting materials for the synthesis of many different
biologically active compounds. Several useful variants of
classical methods can be found in the literature.2
A
stereoselective approach to the synthesis of indolizidine
alkaloids, based on the reaction of pyrrole derivatives of
amino acids has been reported.3 C-2 substituted pyrrole
derivatives provide access to substituted indolizidine
alkaloids (A), hydroxylactams (B) unsaturated g-lactams
(C) and bicyclic lactams (D) (Fig. 1).
2. Results and discussion
Haloenones are valuable intermediates for the construction
of nitrogen heterocycles. Chloroenones 2a–d provide a four
carbon unit with a carbonyl and halide functionality to form
pyrrole rings with primary amines. As we previously
reported, the refluxing of amine compounds with chloro-
enone in benzene-triethylamine and water for 4–6 h
furnished the 2-substituted pyrrole derivatives in 71–95%
yields (Table 1).5 The use of microwaves for carrying out
reactions in the laboratory provides advantages for the
synthesis of numerous types of compounds. When the
technique is applied successfully, the most evident
improvements are reduced time of reaction, cleaner
reactions due to fewer side-reactions, and the use of
minimal quantities of solvent. Thus, microwave assisted
Figure 1.
The most widely used approach to pyrrole synthesis is the
Paal–Knorr method in which 1,4-dicarbonyl compounds4
and their masked equivalents such as tetrahydro-2,5-
dimethoxyfuran, are converted to pyrrole derivatives with
primary amines.3 During the condensation reaction for the
Keywords: Pyrrole; Microwave; Silica gel; Chloroenone.
* Corresponding author. Tel.: +90 3122103242; Fax: C90 3122101280;
e-mail: asdemir@metu.edu.tr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.120

3020
F. Aydogan, A. S. Demir / Tetrahedron 61 (2005) 3019–3023
Table 1. The synthesis of 2-substituted pyrroles
Amine 1
Chloroenone 2
RZ
Pyrrole 3a
Heating method
Microwave
Reaction
time (h)
Yieldb
(%)ref
Reaction
time (min)
Yieldb
(%)
CH3 a
6
6
5
805b,c
5
4
6
79
68
82
a
a
b
c
a
C2H5 b
74
b
a
80
b
b
b
5
6
6
71
4
6
5
70
74
83
d
e
C6H11
c
73
a
755d,e
c
f
c
b
4
5
79
4
5
77
84
g
a
(CH3)2CH d
765b,c
h
a
c
5
5
725b,c
5
5
83
88
i
a
955d,e
d
jc

F. Aydogan, A. S. Demir / Tetrahedron 61 (2005) 3019–3023
3021
Table 1 (continued)
Amine 1
Chloroenone 2
RZ
Pyrrole 3a
Heating method
Microwave
Reaction
time (h)
Yieldb
(%)ref
Reaction
time (min)
Yieldb
(%)
e
a
5
4
845d,e
5
6
87
83
k
d
855b,c
f
l
f
c
4
815b,c
5
87
m
a
6
5
905b,c
5
4
88
84
g
n
g
b
72
o
a The compounds 3a,f,h,i,j,k,l,m,n are known and have been identified by comparison of spectral data with those reported in the literature.
b Isolated yields.
c [a]D20Z9.9 (c 1.2, CHCl3); lit.5d [a]D20ZK9.6 (c 1.2, CHCl3) for (R)-3j.
synthesis can be considered to be more economical and
environmentally friendly.6 We have explored the use of
microwaves in the pyrrole formation reaction. We tried
different reaction conditions to carry out this reaction under
microwave irradiation and found when the irradiation of
chloroenone with amine compounds was carried out on the
surface of silica gel without solvent the pyrroles were
quickly furnished in good yield (Scheme 1). In a typical
procedure, a mixture of chloroenone, amine compound and
triethylamine adsorbed on the surface of silica gel was
irradiated in a microwave oven for a certain period of time
as required to complete the reaction. Elution of the reaction
mixture with ether followed by the evaporation of solvent
furnished the crude product which was purified by column
chromatography. Conventional heating in dry media in
place of microwave leads to a messy product with the
formation of tarry material.
A wide range of chiral amine compounds were coupled with
various chloroenones by this procedure through a single step
operation to produce the corresponding alkyl substituted
pyrroles as summarized in Table 1.
The reaction of alanine methyl ester (1a) with 5-chloro-3-
pentene-2-one (2a) gave the 2-methylpyrrole derivative of
alanine methyl ester (3a) in 79–80% yield. Under similar
conditions 2-aminopropan-1-ol (1d) with 2a gave the
pyrrole derivative 3j in 88–95% yield. The compound
(S)-3j was also synthesized from the LAH reduction of
(S)-3a in 81% yield. The pyrrole derivative 3j, synthesized
from different ways showed the same optical rotation value.
This result showed that the formation of pyrrole derivative
from alanine ester works without racemization.
The pyrrole derivative of amino acid esters and amino
alcohols showed excellent separation properties by chiral
HPLC column.7 Control of the optical purity of the products
by comparing racemic mixtures using chiral HPLC column
Scheme 1.

3022
F. Aydogan, A. S. Demir / Tetrahedron 61 (2005) 3019–3023
Scheme 2.
gave the same result as the formation of a pyrrole ring from
amino acids esters in which no racemization occurs.
chloroenone (153 mg, 1.3 mmol) and triethylamine
(1.0 mmol) were 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 by a microwave oven at 500 W for
5 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 chromatography over silica
gel (EtOAc/hexane 1:2, 1:6 or 1:10) to afford the pure
product as a viscous oil (133 mg, 79%). [a]2D0ZK49.4 (c 2,
CH3OH), [lit.5b [a]D20ZK48.1(c 2, CH3OH)]; IR(neat): n
In general, the microwave assisted reactions are very fast
and clean. The yields are reasonably good for a two-
component coupling reaction. None of these operations
involves any strong acid, base or solvent.
The suggested mechanism for the formation of pyrroles 3 is
outlined in Scheme 2. It seems reasonable to suggest that the
amine reacts initially with the allylic chloride to form 4 and
the cyclisation onto the ketone occurs as the ring closing
step, followed by elimination of water to give the product 3.
1
2897, 1778, 1463 cmK1; H NMR (400 MHz, CDCl3): d
1.70 (d, JZ7.2 Hz, 3H, CH3), 2.25 (s, 3H, CH3), 3.60 (s, 3H,
CH3), 4.80 (q, JZ7.0, 1H, CH), 5.95 (m, 1H, ]CH), 6.10
(m, 1H, ]CH), 6.75 (m, 1H, ]CH); 13C NMR (100 MHz,
CDCl3):d 12.4, 18.5, 53.1, 54.2, 108.2, 108.5, 118.0, 129.7,
173.3. The spectroscopic data are in accordance with the
literature.5b
3. Conclusion
In conclusion, the present microwave-assisted one-pot
procedure provides an efficient methodology for the
synthesis of alkyl-substituted pyrroles on the surface of
silica gel from easily available starting materials by a
condensation reaction. The notable advantages of this
procedure are: (a) reasonably good yields; (b) fast reac-
tion; (c) mild reaction conditions; (d) no racemization;
(e) general applicability and (f) above all, green synthesis
avoiding toxic reagents and solvents. Thus, it provides a
better and more practical alternative to the existing
methodologies.
4.1.2. (S)-Methyl 2-(2-ethyl-1H-pyrrol-1-yl)propanoate
(S)-3b. Light yellow oil (123 mg, 68%). [a]2D0ZK30.7
(c 0.3, CHCl3); IR (CHCl3): n 2954, 1742, 1434, 1203 cmK1
;
1H NMR (400 MHz, CDCl3): d 1.17 (t, JZ7.5 Hz, 3H,
CH3), 1.60 (d, JZ7.2 Hz, 3H, CH3), 2.45 (q, JZ7.5 Hz, 2H,
CH2), 3.62 (s, 3H, CH3), 4.67 (q, JZ7.2 Hz, 1H, CH), 5.78
(br s, 1H, ]CH), 5.99 (t, JZ3.2 Hz, 1H, ]CH), 6.58 (br s,
1H, ]CH); 13C NMR (100 MHz, CDCl3): d 13.0, 18.3,
19.4, 52.3, 53.1, 105.3, 107.9, 117.1, 134.5, 171.6; MS (m/z)
(rel abund): 181 [MC] (13), 165 (32), 122 (80), 106 (65), 94
(100), 80 (51). Anal. Calcd for C10H15NO2 (181.11): C,
66.27; H, 8.34; N, 7.73. Found: C, 66.15; H, 8.29; N, 7.85.
4. Experimental
All reagents were of commercial quality and reagent quality
solvents were used without further purification. IR spectra
were determined on a Perkin Elmer 1600 spectrometer.
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. Column chromatography was
conducted on silica gel 60 (40–63 mm). TLC was carried out
on aluminum sheets precoated with silica gel 60F254
(Merck), and the spots were visualized with UV light (lZ
254 nm). Enantiomeric excesses were determined by HPLC
analysis using a Thermo Finnigan Surveyor equipped with
an appropriate chiral phase column. MS: Thermo Quest
Finnigan multi Mass (EI, 70 eV). Optical rotations were
measured with Kru¨ss P3002RS automatic polarimeter. The
reactions are carried out in Milestone-Start microwave
instrument. Haloenones 2a–d are synthesized according to
the literature.8
4.1.3. (S)-Ethyl 2-(2-ethyl-1H-pyrrol-1-yl)-4-(methyl-
thio)butanoate (S)-3c. Yellow oil (209 mg, 82%).
[a]2D0ZK46.0 (c 0.4, CHCl3); IR (CHCl3): n 2966, 1736,
1428, 1215 cmK1; 1H NMR (400 MHz, CDCl3): d 1.17 (m,
6H, CH3), 1.99 (s, 3H, CH3), 2.28 (m, 4H, CH2), 2.51 (q, JZ
7.5 Hz, 2H, CH2), 4.09 (m, 2H, CH2), 4.78 (m, 1H, CH),
5.76 (br s, 1H, ]CH), 6.00 (t, JZ3.2 Hz, 1H, ]CH), 6.56
(br s, 1H, ]CH); 13C NMR (100 MHz, CDCl3): d 13.1,
14.1, 15.3, 19.5, 30.2, 31.6, 55.9, 61.3, 105.1, 108.3, 117.2,
135.2, 170.4; MS (m/z) (rel abund): 255 [MC] (15), 180
(95), 152 (70), 134 (58), 108 (100), 93 (50). Anal. Calcd for
C13H21NO2S (255.13): C, 61.14; H, 8.29; N, 5.48; S, 12.56.
Found: C, 61.31; H, 8.22; N, 5.56; S, 12.43.
4.1.4. (S)-Ethyl 2-(2-methyl-1H-pyrrol-1-yl)-4-(methyl-
thio)butanoate (S)-3d. Yellow oil (169 mg, 70%).
[a]2D0ZK39.5 (c 0.8, CHCl3); IR (CHCl3): n 2978, 2910,
1
1738, 1420, 1295 cmK1; H NMR (400 MHz, CDCl3): d
1.18 (t, JZ7.2 Hz, 3H, CH3), 1.99 (s, 3H, CH3), 2.17 (s, 3H,
CH3), 2.31 (m, 4H, CH2), 4.11 (m, 2H, CH2), 4.78 (m, 1H,
CH), 5.74 (br s, 1H, ]CH), 5.96 (m, 1H, ]CH), 6.54 (m,
1H, ]CH); 13C NMR (100 MHz, CDCl3): d 12.2, 14.2,
15.3, 30.1, 31.2, 56.1, 61.4, 107.1, 108.3, 117.2, 128.9,
4.1. Representative example
4.1.1. (S)-Methyl 2-(2-methyl-1H-pyrrol-1-yl)propano-
ate (S)-3a.5b,c A mixture of amine (103 mg, 1.0 mmol),

F. Aydogan, A. S. Demir / Tetrahedron 61 (2005) 3019–3023
3023
170.4; MS (m/z) (rel abund): 241 [MC] (13), 196 (5), 166
References and notes
(84), 137 (57), 120 (91), 94 (100), 80 (40). Anal. Calcd for
C12H19NO2S (241.11): C, 59.72; H, 7.93; N, 5.80; S, 13.29.
Found: C, 59.64; H, 8.06; N, 5.71; S, 13.16.
1. Ragno, R.; Marshall, G. R.; Di Santo, R.; Costi, R.; Massa, S.;
Rompei, R.; Artico, M. Bioorg. Med. Chem. 2000, 8, 1423.
(b) Franc, C.; Denone, F.; Cuisinier, C.; Ghosez, L. Tetrahedron
Lett. 1999, 40, 4555. (c) Liu, J.; Yang, Q.; Mak, T. C.; Wong,
H. N. C. J. Org. Chem. 2000, 65, 3587. (d) Caldarelli, M.;
Habermann, J.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1999,
107. (e) Haubmann, C.; Hubner, H.; Gmeiner, P. Bioorg. Med.
Chem. Lett. 1999, 21, 3143. (f) Khanna, I. K.; Weier, R. M.; Yu,
Y.; Collins, P. W.; Miyashiro, J. M.; Koboldt, C. M.;
Veenhuizen, A. W.; Currie, J. L.; Seibert, K.; Isakson, P. C.
J. Med. Chem. 1997, 11, 1619. (g) Dieter, R. K.; Yu, H. Org.
Lett. 2000, 2, 2283.
4.1.5. (S)-Ethyl 2-(2-cyclohexyl-1H-pyrrol-1-yl)-4-
(methylthio)butanoate (S)-3e. Dark yellow oil (229 mg,
74%). [a]2D0ZK34.8 (c 0.6, CHCl3); IR (CHCl3): n 2927,
1
1735, 1444, 1211 cmK1; H NMR (400 MHz, CDCl3): d
1.17 (t, JZ7.5 Hz, 3H, CH3), 1.30 (m, 4H, CH2), 1.75 (m,
6H, CH2), 1.99 (s, 3H, CH3), 2.17 (m, 2H, CH2), 2.31 (m,
2H, CH2), 2.45 (m, 1H, CH), 4.10 (m, 2H, CH2), 4.81 (m,
1H, CH), 5.75 (m, 1H, ]CH), 5.99 (m, 1H, ]CH), 6.51 (m,
1H, ]CH); 13C NMR (100 MHz, CDCl3): d 14.1, 15.3,
26.2, 26.7, 26.8, 30.3, 31.9, 33.8, 34.3, 35.4, 55.8, 61.3,
103.8, 108.4, 116.8, 139.5, 170.5; MS (m/z) (rel abund): 309
[MC] (8), 292 (13), 260 (14), 234 (67), 205 (21), 191 (34),
179 (80), 166 (82), 152 (59), 147 (34), 118 (55), 106 (100),
81 (27). Anal. Calcd for C17H27NO2S (309.18): C, 65.98; H,
8.79; N, 4.53; S, 10.36. Found: C, 66.12; H, 8.67; N, 4.45; S,
10.44.
2. Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1999, 20, 2849.
3. (a) Jefford, C. W.; Tang, Q.; Zaslona, A. J. Am. Chem. Soc.
1991, 113, 3513. (b) Wasserman, H. H.; Vu, C. B.; Cook, J. D.
Tetrahedron 1992, 48, 2101. (c) Rassu, G.; Carta, P.; Pinna, L.;
Battistini, L.; Zanardi, F.; Acquotti, D.; Casiraghi, G. Eur.
J. Org. Chem. 1999, 1395. (d) Nemr, A. E. Tetrahedron 2000,
56, 8579. (e) Jefford, C. W. Curr. Org. Chem. 2000, 4, 205.
4. (a) Jefford, C. W.; Naide, F.; Sienkiewicz, de V.K. Tetrahedron:
Asymmetry 1996, 7, 1069. (b) Grigg, R.; Yoganathan, G.
Tetrahedron: Asymmetry 1996, 7, 273. (c) Bird, C. W.;
Cheeseman, G. W. H. In Comprehensive Heterocyclic Chem-
istry, Vol. 4; Pergamon: Oxford, 1994. (d) Baltazzi, B.; Kirmen,
L. I. Chem. Rev. 1963, 63, 511. (e) Earle, M. J.; Heaney, H.
Synlett 1992, 745.
4.1.6. (S)-Ethyl 2-(2-ethyl-1H-pyrrol-1-yl)-3-hydroxy-
propanoate (S)-3g. Light yellow oil (162 mg, 77%).
[a]2D0ZK27.1 (c 0.6, CHCl3); IR (CHCl3): n 3451, 2973,
2927, 1735, 1479, 1287 cmK1 1H NMR (400 MHz,
;
CDCl3): d 1.15 (m, 6H, CH3), 2.48 (q, JZ7.5 Hz, 2H,
CH2), 2.53 (br s, 1H, OH), 3.80 (m, 1H, CHA), 3.98 (m, 1H,
CHB), 4.10 (m, 2H, CH2), 4.63 (t, JZ6.7 Hz, 1H, CH), 5.78
(m, 1H, ]CH), 5.98 (t, JZ3.2 Hz, 1H, ]CH), 6.56 (m, 1H,
]CH); 13C NMR (100 MHz, CDCl3): d 13.1, 14.1, 19.4,
59.3, 61.6, 63.0, 105.3, 108.3, 117.7, 135.3, 169.5; MS (m/z)
(rel abund): 211 [MC] (15), 195 (38), 137 (38), 106 (55), 94
(100), 80 (82). Anal. Calcd for C11H17NO3 (211.12): C,
62.54; H, 8.11; N, 6.63. Found: C, 62.49; H, 8.24; N, 6.54.
5. (a) Demir, A. S.; Akhmedov, I. M.; Sesenoglu, O. Tetrahedron
2002, 58, 9793. (b) Demir, A. S.; Akhmedov, I. M.; Sesenoglu,
O.; Alpturk, O.; Apaydin, S.; Gercek, Z.; Ibrahimzade, N.
J. Chem. Soc. Perkin Trans. 1 2001, 1162. (c) Demir, A. S.;
Akhmedov, I. M.; Tanyeli, C.; Gercek, Z.; Gadzhili, R. A.
Tetrahedron: Asymmetry 1997, 8, 753. (d) Aydogan, F.; Demir,
A. S. Tetrahedron: Asymmetry 2004, 15, 259. (e) Demir, A. S.;
Aydogan, F.; Akhmedov, I. M. Tetrahedron: Asymmetry 2002,
13, 601.
4.1.7. (R)-2-Ethyl-1-(1-phenylethyl)-1H-pyrrole (R)-3o.
Light yellow oil (167 mg, 84%). [a]2D0ZK20.7 (c 0.4,
6. (a) Deshayes, S.; Liagre, M.; Loupy, A.; Luche, J.-L.; Petit, A.
Tetrahedron 1999, 55, 10851. (b) Perreux, L.; Loupy, A.
Tetrahedron 2001, 57, 9199 and references therein.
(c) Alexandre, F.-R.; Berecibar, A.; Wrigglesworth, R.; Besson,
T. Tetrahedron Lett. 2003, 44, 4455. (d) Jiao, G.-S.; Castro,
J. C.; Thorensen, L. H.; Burgess, K. Org. Lett. 2003, 5, 3675.
(e) Paul, S.; Gupta, M.; Gupta, R.; Loupy, A. Synthesis 2002,
75. (f) De La Hoz, A.; Diaz-Ortiz, A.; Langa, F. In Microwaves
in Organic Synthesis; Loupy, A., Ed.; Wiley-VCH: Germany,
2003. (g) Cheng, Q.; Zhang, W.; Tagami, Y.; Oritani, T. J.
Chem. Soc. Perkin Trans. 1 2001, 452. (h) Rao, H. S. P.;
Jothilingam, S. Tetrahedron Lett. 2001, 42, 6595.
CHCl3); IR (CHCl3): n 3055, 2985, 2927, 1450, 1211 cmK1
;
1H NMR (400 MHz, CDCl3): d 1.07 (t, JZ7.5 Hz, 3H,
CH3), 1.70 (d, JZ7.1 Hz, 3H, CH3), 2.23 (m, 1H, CHA),
2.40 (m, 1H, CHB), 5.17 (q, JZ7.1 Hz, 1H, CH), 5.82 (br s,
1H, ]CH), 6.02 (t, JZ3.2 Hz, 1H, ]CH), 6.66 (m, 1H,
]CH), 7.00 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3): d
13.0, 19.6, 22.7, 54.5, 105.3, 107.1, 116.9, 125.3, 125.6,
127.1, 128.6, 135.0, 144.1; MS (m/z) (rel abund): 199 [MC]
(15), 105 (100), 95 (67), 80 (93). Anal. Calcd for C14H17N
(199.14): C, 84.37; H, 8.60; N, 7.03. Found: C, 84.23; H,
8.56; N, 7.15.
7. Optical purity is determined by chiral HPLC analysis (Chiral
pack AD column, UV detection at 220 nm, 90/10 i-hexane/
isopropanol, flow rate 0.75 ml/min).
Acknowledgements
8. Barbry, D.; Faven, C.; Ajana, A. Synth. Commun. 1993, 23(19),
2647. (b) Ibragimov, I. I.; Mamedov, E. I.; Ismailov, A. T.;
Aliev, A. G.; Mekhtieva, Sh. Z.; Dzhafarov, V. G.; Belyaeva,
V. I. Zhurnal Organicheskoi Khimii 1990, 26(8), 1648.
(c) Ibragimov, E. I.; Ismailov, A. T.; Mekhtieva, Sh. Z.;
Mamedov, N. N.; Belyaeva, V. I. Zhurnal Organicheskoi
Khimii 1990, 26(11), 2294.
Financial support from the Middle East Technical Univer-
sity (BAP-2004), the Scientific and Technical Research
Council of Turkey (TUBITAK), the Turkish Academy of
Sciences (TUBA), the Turkish State Planning Organization
(DPT) and the Yildiz Technical University is gratefully
acknowledged.
¨