Synthesis of new 2,5-dimethyl pyrrole derivatives from acetonylacetone

Article abstract of DOI:10.1016/j.cclet.2010.03.004

Acetonylacetone 1 was treated with thiourea, aniline, glycin and glutamic acid to give pyrrole derivatives 2, 3, 5, and 9 by Paal-Knorr reaction, respectively. Then 3 was successfully transformed into the related pyrrole derivative 4 by Mannich reaction. Compounds 6, 7 and 8 were obtained by reacting 5 with phenethyl alcohol, phenylallylic alcohol and leaf alcohol by esterification reactions, respectively. The structures of all new products were elucidated by IR, NMR and HRMS spectra.

Full text of DOI:10.1016/j.cclet.2010.03.004

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Chinese Chemical Letters 21 (2010) 919–921
www.elsevier.com/locate/cclet
Synthesis of new 2,5-dimethyl pyrrole derivatives
from acetonylacetone
*
Xiao Ming Ji, Ye Lu, Ming Qin Zhao , Xiao Yun Zhang, Yun Liu, Le Liu
National Tobacco Cultivation, Physiology and Biochemistry Research Center/College of Tobacco Science,
Henan Agricultural University, Zhengzhou 450002, China
Received 19 October 2009
Abstract
Acetonylacetone 1 was treated with thiourea, aniline, glycin and glutamic acid to give pyrrole derivatives 2, 3, 5, and 9 by Paal–
Knorr reaction, respectively. Then 3 was successfully transformed into the related pyrrole derivative 4 by Mannich reaction.
Compounds 6, 7 and 8 were obtained by reacting 5 with phenethyl alcohol, phenylallylic alcohol and leaf alcohol by esterification
reactions, respectively. The structures of all new products were elucidated by IR, NMR and HRMS spectra.
# 2010 Ming Qin Zhao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Acetonylacetone; Paal–Knorr reactions; Mannich reactions; Esterification reactions; Synthesis
Pyrrole derivatives, important heterocycles containing nitrogen, can be found widely in the areas of medicine, food,
agricultural chemical, household chemical and materials science etc. [1–5]. To improve the function of compounds
with new and attractive characteristics, structural modifications can be used by substitution with alkyl, acyl and other
groups. Some N-alkyl pyrrole derivatives were also proved to act as excellent perfumes [6]. In order to develop some
new pyrrole derivatives with potent perfume [7], many pyrrole derivatives should have been synthesized firstly. Here
we report the synthesis of a series of 2,5-dimethyl pyrrole derivatives.
The reaction of compound 1 with thiourea (1.0 eq) in anhydrous C2H5OH was refluxed for 48 h, then pyrrole
derivative 2 was given in 25% yield. The low yield of compound 2 was probably due to the special structure of
thiourea, which was steady P-p conjugated system, so it was difficult to have the Paal–Knorr reaction. The NMR
1
spectra of compound 2 indicated that there was no carbonyl group, meanwhile the H NMR spectrum revealed the
presence of two methyl signals at d 2.32, 2.36. The signal at d 5.84 was assigned to the hydrogens of the pyrrole ring; d
6.61 and d 7.69 were assigned to the protons on the nitrogen. The 13C NMR spectrum showed the presence of the
carbons of the pyrrole ring signals at d 109.35 and 128.74, and the signal at d 184.93 was assigned to the carbon of the
carbon-sulfur double bond. These data indicated that compound 2 was a pyrrole derivative including one thiourea
group.
Treatment of 1 with C6H5NH2 (1.2 eq) in anhydrous C2H5OH at rt for 3 h gave pyrrole derivative 3 in 83% yield.
The melting point of 3 was in agreement with reference literature [3]. The reaction of compound 3, HCHO (1.0 eq),
* Corresponding author.
E-mail address: zhaomingqin@126.com (M.Q. Zhao).
1001-8417/$ – see front matter # 2010 Ming Qin Zhao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.03.004

920
X.M. Ji et al. / Chinese Chemical Letters 21 (2010) 919–921
Scheme 1. Synthesis of new 2,5-dimethyl pyrrole derivatives. Reagent and conditions: (a) NH2CSNH2, CH3C6H4SO3H, C2H5OH, reflux; (b)
C6H5NH2, HCOOH, C2H5OH, rt; (c) HCHO, HOAc, C2H5NHC2H5, rt; (d) NH2CH2COOH, HCOOH, C2H5OH, rt; (e) C6H5CH2CH2OH, DCC,
DMAP, rt; (f) C6H5CH = CHCH2OH, DCC, DMAP, rt; (g) CH3CH2CH = CHCH2CH2OH, DCC, DMAP, rt; (h) NH2CH(COOH)CH2CH2COOH,
HOAc, C2H5OH, reflux.
diethylamine (1.0 eq) was carried out in HOAc at rt for 24 h, then the reaction mixture was treated with ice-water to
produce compound 4 in 18% yield. The key step of Mannich reaction was the nucleophilic addition of amine and
formaldehyde [8], which obtained imine ions. The prominent steric hindrance of diethylamine depressed the formation
of imine ions, thus it seriously affected the formation of objective product. The 13C NMR spectrum showed four
methyl singles at d 10.89, 11.66, 11.66, 12.82, and two methylene singles at d 46.18, 48.33. The signals at d 7.18–7.46
were assigned to benzene ring. So compound 4 was the target product (Scheme 1).
Compound 5 was obtained by the reaction of compound 1 with Gly (1.0 eq) in anhydrous C2H5OH at rt for 5 h in
1
87% yield. The H NMR spectrum of compound 5 was accorded with the literature [9]. In the presence of DCC
(1.1 eq), compound 5 was treated with CH2Cl2 solution of phenethyl alcohol (1.2 eq), phenylallylic alcohol (1.2 eq)
and leaf alcohol (1.2 eq) at rt for 24 h to afford ester derivative 6 in 49% yield, 7 in 25% yield and 8 in 37% yield,
respectively. The IR spectra of compounds 6, 7 and 8 showed ester group (1752 cmÀ1, 1750 cmÀ1, and 1760 cmÀ1).
Glutamic acid and compound 1 were dissolved in anhydrous C2H5OH and HOAc, and then were refluxing for 24 h
to give 9 in 65% yield. The IR spectrum of compound 9 indicated ester group (1725 cmÀ1), meanwhile the 13C NMR
spectrum showed the two carboxyl signals at d 176.00, 178.70. The preliminary tobacco flavoring showed that
compounds 3, 9 and 6, 7, 8 could improve tobacco’s taste and flavor, respectively. The structures of all the new pyrrole
derivatives were elucidated by IR, NMR and HRMS spectra [10].
Acknowledgments
We are grateful to the State Tobacco Monopoly Bureau (No. 110200401014), Henan Province Office of Education
of China (No. 2008A208013) and Technology Bureau of Zhengzhou (No. 0910SGYN12302) support of this work.

X.M. Ji et al. / Chinese Chemical Letters 21 (2010) 919–921
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[10] Compound 2: yield 25%, mp 219.9–221.4 8C; IR (cmÀ1): 3098 (NH), 3053 (C CH), 2973 (CH3), 1595 (C C), 1492(C C), 1400 (C C),
1218 (C S); 1H NMR (400 MHz, DMSO-d6): d 2.00 (s, 3H, CH3), 5.69 (s, 1H, CH C), 6.58 (s, 1H, NH), 8.22 (s, 1H, NH), 10.22 (s, 1H, NH);
13C NMR (100 MHz, DMSO-d6): d 11.09 (CH3), 104.19 (CH C), 127.16 (C C), 182.68 (C S); HRMS calcd. for C7H10N2S [M+H]+
155.0643, found 155.0646. Compound 3: yield 83%, mp 49.5–51.0 8; IR (cmÀ1): 3157 (C CH), 2960 (CH3), 1616 (C C), 1503 (C C). 1H
NMR (400 MHz, CDCl3): d 2.03 (s, 3H, CH3), 5.91 (s, 1H, CH), 7.2–7.47 (m, 5H, Ph-H); 13C NMR (100 MHz, CDCl3): d 12.99 (CH3), 105.51
(CH C), 127.59 (C C), 128.19 (Ph-C), 128.78 (Ph-C), 129.01 (Ph-C), 138.90 (Ph-C). HRMS calcd. for C12H13N [M+H]+ 172.1126, found
172.1128. Compound 4: yield 18%, IR (cmÀ1): 3061 (C CH), 2968 (CH2), 2926 (CH2), 1598 (C C), 1499 (C C), 1451 (C C), 1383 (CH3);
1H NMR (400 MHz, CDCl3): d 1.09 (m, 3H, CH2CH3), 1.98 (s, 3H, CH3), 2.01 (s, 3H, CH3), 2.57 (dd, 2H, CH2), 3.46 (s, 2H, CH2), 5.91 (s, 1H,
CH C), 7.18–7.46 (m, 5H, Ph-H); 13C NMR (100 MHz, CDCl3): d 10.89 (CH3), 11.66 (CH2CH3), 12.82 (CH3), 46.18 (CH2), 48.33 (NCH2),
107.97 (CH C), 126.48 (Ph-C), 127.43 (Ph-C), 127.62 (Ph-C), 128.34 (Ph-C), 128.92 (Ph-C), 139.09 (Ph-C). HRMS calcd. for C17H24N2
[M+H]+ 257.2018, found 257.2019. Compound 5: yield 87%, IR (cmÀ1): 3104 (C CH), 2928 (CH2), 1728 (C O). 1H NMR (400 MHz,
CDCl3): d 2.18 (s, 3H, CH3), 4.55 (s, 2H, CH2), 5.83 (s, H, CH C), 7.25 (s, 1H, COOH); 13C NMR (100 MHz, CDCl3): d 12.26 (CH3), 44.64
(CH2), 105.99 (C CH), 127.95 (C C), 174.98 (C O). HRMS calcd. for C8H11NO2 [M+H]+ 154.0868, found 154.0866. Compound 6: yield
49%, IR (cmÀ1): 2930 (CH2), 1752 C O), 1656 (C C). 1H NMR (400 MHz, CDCl3): d 2.10 (s, 3H, CH3), 2.93 (t, 2H, CH2), 4.37 (t, 2H, CH2),
4.44 (s, 2H, CH2), 5.80 (s, 1H, CH C), 7.14–7.31 (m, 5H, Ph-H); 13C NMR (100 MHz, CDCl3): d 12.2 (CH3), 34.9 (CH2), 45.1 (CH2), 65.7
(CH2), 105.6 (CH C), 126.5 (Ph-C), 127.8 (C C), 128.4 (Ph-C), 128.8 (Ph-C), 137.2 (Ph-C), 168.7 (C O). HRMS calcd. for C16H19NO2
[M+H]+ 258.1494, found 258.1493. Compound 7: yield 25%, IR (cmÀ1): 3387 (–COO–), 2931 (CH2), 1750 (C O), 1654 (C C). 1H NMR
(400 MHz, CDCl3): d 2.18 (s, 3H, CH3), 4.53 (s, 2H, CH), 4.81 (d, 2H, CH2), 5.82 (s, 1H, CH C), 6.25 (m, 1H, CH C), 6.62 (d, 1H, C CH),
7.25–7.38 (m, 5H, Ph-H); 13C NMR (100 MHz, CDCl3): (12.3 (CH3), 45.2 (CH2), 65.8 (CH2), 105.8 (C CH), 122.2 (CH C), 126.6 (Ph-C),
127.9 (Ph-C), 128.2 (C CH), 128.6 (Ph-C), 134.7 (CH-Ph), 136.0 (Ph-C), 168.7 (C O). HRMS calcd. for C17H19NO2 [M+H]+ 270.1494,
found 270.1495. Compound 8: yield 37%, IR (cmÀ1): 2927 (CH2), 1760 (C O), 1612 (C C). 1H NMR (400 MHz, CDCl3): d 0.95 (t, 3H,
CH3), 2.03 (m, 2H, CH2), 2.12 (m, 3H, CH3), 2.39 (t, 2H, CH2), 4.14 (dd, 2H, CH2), 4.45 (t, 2H, CH2), 5.27 (m, 1H, CH C), 5.50 (m, 1H,
C
CH), 5.80 (s, 1H, CH C); 13C NMR (100 MHz, CDCl3): d 12.3 (CH3), 14.2 (CH3), 20.6 (CH2), 26.6 (CH2), 45.1 (CH2), 64.9 (CH2), 105.7
(CH C), 123.2 (CH CH), 127.9 (CH CH), 134.9 (CH CH), 168.9 (C O). HRMS calcd. for C14H21NO2 [M+Na]+ 258.1470, found
258.1471. Compound 9: yield 65%, IR (cmÀ1): 2958 (CH2), 1725 (C O), 1591 (C C), 1388 (CH3); 1H NMR (400 MHz, CDCl3): d 2.16 (s,
3H, CH3), 2.31 (s, 2H, CH2), 2.55 (d, 2H, CH2), 4.88 (m, 1H, CH), 5.78 (s, 1H, CH C), 8.87 (s, 1H, COOH); 13C NMR (100 MHz, CDCl3): d
13.1 (CH3), 25.6 (CH2), 29.7 (CH2), 55.4 (CH), 107.1 (C C), 128.1 (C CH), 176.0 (COOH), 178.7 (COOH). HRMS calcd. for C11H15NO4
[M+Na]+ 248.0899, found 248.0897.