Synthesis of New N-alkyl-5-formyl-2-methylpyrrole Derivatives from Glucosamine

Article abstract of DOI:10.1002/jhet.3122

Glucosamine hydrochloride 1 was treated with 1,3-dicarbonyl compounds to obtain 2-methyl-5-(1,2,3,4-tetrahydroxy-butyl) pyrrole 2a and 2b, respectively. Under the role of NaIO₄, 2a and 2b were successfully transformed into the related 5-formal pyrrole derivative 3a and 3b, respectively. Compounds 4a–4d and 5a–5e were obtained by reacting 3a and 3b with chlorinated hydrocarbons by alkylation reactions, respectively. The structures of all new products were confirmed by IR, NMR, and HRMS spectra.

Full text of DOI:10.1002/jhet.3122

Month 2018
Synthesis of New N-alkyl-5-formyl-2-methylpyrrole Derivatives from
Glucosamine
b
a
a
a
Tao Tao,a
*
Hua Xin Zhao, Xiao Ming Ji, Miao Lai, and Ming Qin Zhao
aCollege of Tobacco Science, Henan Agricultural University, Zhengzhou 450002, China
bCollege of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China
*
E-mail: jxm0371@163.com
Received December 29, 2016
DOI 10.1002/jhet.3122
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
Glucosamine hydrochloride 1 was treated with 1,3-dicarbonyl compounds to obtain 2-methyl-5-(1,2,3,4-
tetrahydroxy-butyl) pyrrole 2a and 2b, respectively. Under the role of NaIO4, 2a and 2b were successfully
transformed into the related 5-formal pyrrole derivative 3a and 3b, respectively. Compounds 4a–4d and
5a–5e were obtained by reacting 3a and 3b with chlorinated hydrocarbons by alkylation reactions, respec-
tively. The structures of all new products were confirmed by IR, NMR, and HRMS spectra.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
carbonyl group, meanwhile the 13C NMR spectrum
showed the presence of four double bond C signals at δ
108.0, 119.8, 130.5, and 137.9 ppm, which indicated
compound 2a to form a pyrrole ring. The 13C NMR
signals at δ 73.8, 71.2, 66.3, and 62.4 ppm were
assigned to four C─O bonds, and the HRMS of 2a
exhibited molecular ions [M + H]+ at m/z 244.1188,
these data indicated that 2a was a pyrrole derivative
including one tetrahydroxy group [8]. 13C NMR signal
of 2b at δ 168.3 ppm indicated that there was an ester
carbonyl group, and the HRMS of 2b exhibited
The special structure and the biological activity made
the pyrrole derivatives widely applicated in the food,
material, medicine, and perfume industry [1–5]. Recently,
the synthesis of new pyrrole derivatives has especially
gained popularity because these flavor precursors, having
pyrrole derivatives with potent perfume properties, in the
course of processing and storage, could avoid the
volatility of flavoring substances under the condition of
heat cracking, those formed aldehyde, ester compounds,
ketone are the pyrolysis products of the tobacco
composition [6].
molecular ions [M
compound 2b is the target product.
+
Na]+ at m/z 296.1118. So
In our previous work, three N-(2, 5-dimethylpyrrole)
glycine esters were synthesized [7], among them N-(2,5-
dimethylpyrrole) glycine benzyl ester, produced to
enhance the aroma quality and volume of aroma, reduce
irritancy, and improve the aftertaste. In order to develop
some new pyrrole derivatives with potent perfume
properties, here, we report the synthesis of a series of N-
Alkyl-5-formyl-2-methylpyrrole derivatives.
The 13C NMR spectrum of 3a showed two methyl
signals at δ 14.3 and 28.2 ppm and two carbonyl signals
at δ 179.1 and 194.4 ppm. The 13C NMR revealed
pyrrole ring at δ 123.5, 123.8, 130.1, and 143.6 ppm. The
13C NMR spectrum of 3b showed two methyl signals at
δ 13.6 and 14.5 ppm, two carbonyl signals at δ 164.3 and
179.0 ppm, and one methylene signal at δ 60.0 ppm. The
13C NMR revealed pyrrole ring at δ 115.4, 123.7, 130.5,
and 143.2 ppm. So compounds 3a and 3b are objective
products [9].
RESULTS AND DISCUSSION
The 13C NMR of compounds 4a, 4b, 4c, and 4d showed
N─C signals at δ 45.1, 47.7, 51.7, and 43.8 ppm,
respectively. The 13C NMR spectra of 5a–5e showed the
N─C signals at δ 45.4, 48.9, 52.0, 44.0, and 46.8 ppm,
respectively. Compounds 4a–4d and 5a–5e are target
products [10].
1
The H NMR spectrum of 2a revealed the presence of
two methyl signals at δ 2.32 and 2.36 ppm, and the signal
at δ 6.45 ppm was assigned to the double bond C. Its 13C
NMR signal at δ 199.9 ppm indicated that there was a
© 2018 Wiley Periodicals, Inc.

T. Tao, H. X. Zhao, X. M. Ji, M. Lai, and M. Q. Zhao
Vol 000
Scheme 1. Synthesis of N-alkyl-5-formyl-2-methylpyrrole derivatives.
[2] Zeng, X. C.; Xu, S. H.; Li, Y. Q.; Shi, W. B.; Deng, Q. Y.
Chinese Journal of Organic Chemistry 2004, 24, 802 (in Chinese).
[3] Reddy, V. P.; Kumar, A. V.; Rao, K. R. Tetrahedron Lett 2011,
52, 777.
[4] Yavari, I.; Ghazvini, M.; Azad, L.; Sanaeishoar, T. Chinese
Chem Lett 2011, 22, 1219.
[5] Soret, A.; Müller, C.; Guillot, R.; Blanco, L.; Deloisy, S. Tetra-
hedron 2011, 67, 698.
[6] Wu, D. F.; Chen, H. L.; Ji, X. M.; Zhao, M. Q. Fine Chemicals
2014, 31, 54 (in Chinese).
CONCLUSION
The structures of all the new pyrrole derivatives (4a, 4b,
4c, 4d, 5a, 5b, 5c, 5d, and 5e) were in agreement with
infrared, NMR, and HRMS spectra. These compounds
could be useful in the chemical and perfume–chemical
fields. Further studies on these pyrrole derivatives are
now in progress.
[7] Ji, X. M.; Lu, Y.; Zhao, M. Q.; Zhang, X. Y.; Liu, Y.; Liu, L.
Chinese Chem. Lett. 2010, 21, 919.
[8] Yan, L.; Kong, J.; Hou, L. L. Journal of Henan University
(Natural Science) 2011, 41, 257 (in Chinese).
EXPERIMENTAL
[9] Jin, Y. Z.; Fu, D. X.; Ma, N.; Li, Z. C.; Liu, Q. H.; Xiao, L.;
Zhang, R. H. Molecules 2011, 16, 9368.
In the presence of NaHCO3, the reaction of glucosamine
hydrochloride 1 with acetyl acetone (1.2 eq) in H2O at 90°C
for 8 h afforded 2-methyl-5-(1,2,3,4-tetrahydroxy-butyl)
pyrrole 2a in 86% yield. Similarly, treatment of 1 with
ethyl acetoacetate (1.2 eq) gave a 2-acetyl-5-(1,2,3,4-
tetrahydroxy-butyl) pyrrole 2b in 81%. Oxidation of 2a
and 2b with NaIO4 in methanol at 45°C for 3 h gave 5-
formyl-2-methyl pyrrole derivative 3a in 80% yield and
3b in 90% yield, respectively. In the presence of
tetrabutylammonium bromide, compound 3a was treated
with R"-Cl (1.0 eq) in CH2Cl2 at 65°C for 10 h, then the
mixture was evaporated in vacuum to dryness, treated
with water to remove the K2CO3, followed by extraction
with EtOAC, affording 4a in 81% yield, 4b in 81% yield,
4c in 84% yield, and 4d in 81% yield. The reaction of
compound 3b with R"'-Cl (1.0 eq) in CH2Cl2 at 65°C for
10 h gave 5a in 78% yield, 5b in 75% yield, 5c in 82%
yield, 5d in 78% yield, and 5e in 80% yield (Scheme 1).
[10] Compound 2a; yield 86%; 1H NMR (400.1MHz, D2O): δ 6.45
(s, 1H, H-4), 4.70 (s, 1H, H-30), 3.65 (m, 2H, H-10, H-40), 3.58 (d,
J=2.9Hz, 1H, H-30), 3.47–3.57 (dd, J=6.5Hz, 1H, H-20), 2.36 (s, 3H,
═─CH3), 2.32 (s, 3H, COCH3); 13C NMR (100.6MHz, D2O): δ 199.9
(C═O), 137.9 (C-2), 130.5 (C-5), 119.8 (C-3), 108.0 (CH═C), 73.8 (C-
10), 71.2 (C-20), 66.3 (C-30), 62.4 (C-40), 27.5 (═─CH3), 13.1 (COCH3);
HRMS: Calcd. For C11H17NO5 [M + H]+ 244.1185, found [M + H]+
244.1188; Compound 2b: yield 81%, mp 153–154°C; 1H NMR (400
MHz, D2O): δ 1.21 (t, 3H, J=7.1Hz, OCH2CH3), 2.34 (S, 3H, ═─CH3),
3.47 (dd, 1H, J=7.70Hz, J=4.9Hz, OH), 3.58 (m, 1H, H-20), 3.64 (m,
2H, H-l', H-40), 4.15 (q, 2H, J=7.1 Hz, OCH2CH3), 4.72 (m, 2H, H-30,
OH), 6.36 (s, 1H, H-4); 13C NMR (100MHz, D2O): δ 12.1 (OCH2CH3),
13.6(═─CH3), 60.7 (OCH2CH3), 62.4 (C-40), 66.4 (C-30), 71.3 (C-20),
74.0 (C-10), 107.1 (C-4), 110.0 (C-3), 130.3 (C-5), 137.5 (C-2),
168.3(C═O); IR (KBr), v: 2932, 1702, 1224, 1090cmꢀ1; HRMS: Calcd
for C12H19NO6 [M + Na]+ 296.1110, found [M + Na]+ 296.1l18; Com-
pound 3a, 80%, mp 144–145°C; 1H NMR (400 MHz, CDCl3): δ 2.49
(s, 3H, CH3), 2.68 (s, 3H, ═─CH3), 7.32–7.33 (d, J=2.44MHz, 1H,
═CH), 9.46 (s, 1H, O═CH), 10.80 (s, 1H, NH); 13C NMR (100 MHz,
CDCl3): δ 14.3 (═─CH3), 28.2 (COCH3), 123.5 (C-3), 123.8 (C-4),
130.1 (C-2); 143.6 (C-5), 179.1 (HC═O), 194.4(COCH3); HRMS: Calcd
for C8H9NO2 [M + H]+ 152.0670, found [M + H]+ 152.0668; Compound
3b; yield 90%, mp 133–134°C; 1H NMR (400 MHz, CDCl3): δ 1.35 (t,
J=7.1Hz, 3H, OCH2CH3), 2.62 (s, 3H,═─CH3), 4.30 (q, J=7.1Hz, 2H,
OCH2CH3), 7.36 (s, ═CH), 9.43 (s, 1H, O═CH), 10.16 (s, 1H, NH);
13C NMR (100 MHz, CDCl3), δ: 13.6 (═─CH3), 14.5 (OCH2CH3), 60.0
(OCH2CH3), 115.4 (C-4), 123.7 (C-3), 130.5 (C-2), 143.2 (C-5), 164.3
(OC═O), 179.0 (HC═O); IR (KBr), v: 3400, 2970, 1709, 1670, 1544,
1128cmꢀ1; HRMS: Calcd for C9H11NO3 [M + H]+ 182.0817, found
[M + H]+ 182.0817; Compound 4a: yield 81%; 1H NMR (400 MHz,
Acknowledgments. We are grateful to the Science and
Technology Office of Henan Province (no. 152102210058) for
financial support of this work.
CDCl3):
δ 0.90 (t, J=7.4Hz, 3H, CH2CH2CH3), 1.34 (m, 4H,
REFERENCES AND NOTES
CH2CH2CH2CH2CH3), 1.66 (m, 2H, CH2CH2CH2CH2CH3), 2.45 (s,
3H, COCH3), 2.61 (s, 3H, ═─CH3), 4.31 (m, 2H, N─CH2), 7.28 (s, 1H,
C═CH), 9.49 (s, 1H, O═CH); 13C NMR (100 MHz, CDCl3): δ 11.4
(═─CH3), 13.9 (CH2CH2CH2CH2CH3), 22.9 (CH2CH2CH2CH2CH3),
[1] Cai, J. C.; Hu, B. C.; Lv, C. X. Chin J Appl Chem 2006, 23,
798 (in Chinese).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Pyrrole derivatives
28.3
(COCH3),
28.7
(CH2CH2CH2CH2CH3),
30.3
3404.9, 2959, 1713, 1668, 1548, 1480, 1216cmꢀ1; HRMS: Calcd for
(CH2CH2CH2CH2CH3), 45.1 (NCH2), 122.4 (C-4), 126.6 (C-5), 130.1
C14H21NO3 [M + H]+ 252.1600, found [M + H]+ 252.1597; Compound
5b: yield 75%; 1H NMR (400 MHz, CDCl3): δ 1.35 (t, J=7.1Hz, 3H,
OCH2CH3), 1.54 (d, J=7.0Hz, 6H, CH(CH3)2), 2.68 (s, 3H, ═─CH3),
4.29 (q, 2H, J=7.1Hz, OCH2CH3), 5.14 (s, 1H, N─CH), 7.38 (s, 1H,
C═CH), 9.41 (s, 1H, HC═O); 13C NMR (100 MHz, CDCl3): δ 14.4
(OCH2CH3), 14.4 (═─CH3) 21.0 (CH(CH3)2), 48.9 (NCH), 59.9
(OCH2CH3), 114.4 (C-4), 128.8 (C-3), 130.8 (C-2), 144.5 (C-5), 164.2
(O═C─O), 178.3(HC═O); IR (KBr), v: 3408, 2977, 1709, 1674, 1546,
1130 cmꢀ1; HRMS: Calcd for C12H17NO3 [M + H]+ 224.1287, found
[M + H]+ 224.1287; Compound 5c: yield 82%;1H NMR (400 MHz,
CDCl3): δ 0.89 (d, J=6.8Hz, 6H, CH(CH3)2), 1.36 (t, J=7.1Hz, 3H,
OCH2CH3), 2.05 (m, 1H, CH(CH3)2), 2.58 (s, 3H, ═─CH3), 4.14 (d,
J=7.2Hz, 2H, N─CH2), 4.30 (q, J=7.1Hz 2H,O─CH2CH3), 7.35 (s, 1H,
C═CH), 9.45 (s, 1H, HC═O);13C NMR (100 MHz, CDCl3): δ 11.6
(═─CH3), 14.4 (OCH2CH3), 19.6 (CH(CH3)2), 29.9 (CH(CH3)2), 52.0
(NCH2), 59.9 (O─CH2CH3), 114.3 (C-4), 126.9 (C-3), 130.8 (C-2),
144.6 (C-5), 164.3 (O═C─O), 179.0 (HC═O); IR (KBr), v: 3317, 2963,
1710, 1667, 1548, 1065cmꢀ1; HRMS: Calcd for C13H19NO3 [M + H]+
238.1443, found [M + H]+ 238.1441; Compound 5d: yield 78%; 1H
NMR (400MHz, CDCl3): δ 0.98 (d, J=6.6Hz, 6H, CH(CH3)2), 1.35 (t,
J=7.1Hz, 3H, OCH2CH3), 1.55 (m, 2H, NCH2CH2), 1.70 (m, 1H,
CH(CH3)2), 2.59 (s, 3H, ═─CH3), 4.31 (m, 4H, O─CH2CH3, N─CH2),
7.32 (s, 1H, C═CH), 9.46 (s, 1H, O═CH); 13C NMR (100 MHz, CDCl3):
δ 10.8 (═─CH3), 14.4 (OCH2CH3), 22.4 (CH(CH3)2), 26.2 (NCH2CH2),
39.4 (NCH2CH2), 44.0 (NCH2), 59.9 (O─CH2CH3), 114.3 (C-4), 126.6
(C-3), 130.3 (C-2), 143.9 (C-5), 164.2 (O═C─O), 179.0 (HC═O); IR
(KBr), v: 2959, 1709, 1667, 1547, 1191cmꢀ1; HRMS: Calcd for
C14H21NO3 [M + H]+ 252.1600, found [M + H]+ 252.1597; Compound
5e: yield 80%, 1H NMR (400 MHz, CDCl3): δ 0.93 (t, J=7.4Hz, 3H,
CH2CH2CH3), 1.36 (t, J=7.1Hz, 3H, OCH2CH3), 1.70 (m, 2H,
CH2CH2CH3), 2.59 (s, 3H, ═─CH3), 4.29 (m, 4H, N─CH2; O─CH2CH3),
7.33(s, 1H, C═CH), 9.46(s, 1H, O═CH); 13C NMR (100 MHz, CDCl3): δ
10.9 (═─CH3), 13.7 (CH2CH2CH3), 14.4 (OCH2CH3), 23.9
(CH2CH2CH3), 46.8 (NCH2), 59.9 (O─CH2CH3), 114.3 (C-4), 126.7
(C-3), 130.5 (C-2), 144.2 (C-5), 164.3 (O═C─O), 179.0 (HC═O); IR
(KBr), v: 2971, 1709, 1667, 1546, 1480, 1386, 1247, 1192cmꢀ1; HRMS:
Calcd for C12H17NO3 [M + H]+ 224.1287, found [M + H]+ 223.1281.
(C-3), 143.8 (C-2), 178.8 (HC═O), 194.2 (O═CCH3), IR (KBr), v:
2958, 1659, 1536, 1482, 1430, 1351cmꢀ1
; HRMS: Calcd for
C13H19NO2 [M + H]+ 222.1494, found [M + H]+ 222.1500; Compound
4b: yield 81%; 1H NMR (400 MHz, CDCl3): δ 1.55 (d, J=7.0Hz, 6H,
CH(CH3)2), 2.45 (s, 3H, COCH3), 2.70 (s, 3H, ═─CH3), 5.17 (m, 1H,
N─CH), 7.32 (s, 1H, C═CH), 9.47 (s, 1H, O═CH); 13C NMR
(100MHz, CDCl3): δ 20.0 (═─CH3), 27.4 (COCH3), 47.7 (NCH), 121.4
(C-4), 128.3 (C-5), 129.5 (C-3), 143.3 (C-2), 177.1 (HC═O),
193.3(O═C); IR (KBr), v: 2977, 1657, 1531, 1481, 1432, 1376cmꢀ1
;
HRMS: Calcd for C11H15NO2 [M + H]+ 194.1181, found [M + H]+
194.1189; Compound 4c: yield 84%; 1H NMR (400 MHz, CDCl3): δ
0.90 (d, J=6.8Hz, 6H, CH(CH3)2), 2.06 (m, CH, CH(CH3)2), 2.46 (s,
3H, COCH3), 2.60 (s, 3H, ═─CH3), 4.15 (m, 2H, N─CH2), 7.29 (s, 1H,
C═CH), 9.48 (s, 1H, O═CH); 13C NMR (100MHz, CDCl3): δ 12.1
(═─CH3), 19.6 (CH(CH3)2), 28.3 (COCH3), 29.9 (CH(CH3)2), 51.7
(NCH2), 122.4 (C-4), 126.9 (C-5), 130.6 (C-3), 144.4 (C-2), 178.9
(HC═O), 194.3 (O═C); IR (KBr), v: 2961, 1659, 1532, 1481, 1428,
1389, 1349cmꢀ1; HRMS: Calcd for C12H17NO2 [M + H]+ 208.1338,
found [M + H]+ 208.1347; Compound 4d: yield 81%; 1H NMR (400
MHz, CDCl3): δ 0.97 (t, J=6.6Hz, 6H, CH2CH2CH(CH3)2), 1.55 (t,
J=7.1Hz, 1H, CH2CH2CH(CH3)2), 1.71 (m, 2H, CH2CH2CH(CH3)2),
2.45 (s, 3H, COCH3), 2.60 (s, 3H, ═─CH3), 4.33 (m, 2H, N─CH2),
7.26 (s, 1H, C═CH), 9.49 (s, 1H, O═CH); 13C NMR (100MHz, CDCl3):
δ 11.3 (═─CH3), 22.4 (CH2CH2CH(CH3)2), 26.2 (CH2CH2CH(CH3)2),
28.3 (COCH3), 39.3 (CH2CH2CH(CH3)2), 43.8 (NCH2), 122.4 (C-4),
126.5 (C-5), 130.1 (C-3), 143.8 (C-2), 178.8 (HC═O), 194.2(O═C), IR
(KBr), v: 2955, 1677, 1656, 1537, 1478, 1389cmꢀ1; HRMS: Calcd for
C13H19NO2 [M + H]+ 222.1494, found [M + H]+ 222.1511; Compound
5a: yield 78%; 1H NMR (400 MHz, CDCl3): δ 0.90 (d, J=7.0Hz, 3H,
NCH2CH2CH2CH2CH3), 1.35 (m, 4H, NCH2CH2CH2; 3H,
OCH2CH3),1.65 (m, 2H, NCH2CH2), 2.59 (s, 3H, ═─CH3), 4.30 (m,
4H, OCH2;NCH2), 7.32 (s, 1H, C═CH), 9.46 (s, 1H, O═CH); 13C NMR
(100 MHz, CDCl3): δ 11.0 (═─CH3), 13.9 (CH2CH2CH2CH2CH3), 14.4
(OCH2CH3), 22.3 (CH2CH2CH2CH3), 28.7 (CH2CH2CH3), 30.3
(NCH2CH2), 45.4 (NCH2), 59.9 (OCH2), 114.3 (C-4), 126.6 (C-3),
130.3 (C-2), 144.1 (C-5), 164.2 (O═C─O), 179.0(HC═O); IR (KBr), v:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet