Synthesis of new malonaldehyde derivatives using 2-heteroaryl-substituted trimethinium salts

Article abstract of DOI:10.1016/j.tetlet.2012.11.046

A synthetic route for obtaining 2-heteroaryl-substituted zwitterionic malonaldehydes 1c-6c is described. The synthesis involves the two-fold formylation of heteroarylacetic acids 1a-6a using the Vilsmeier-Haack reagent, followed by hydrolysis of the inter

Full text of DOI:10.1016/j.tetlet.2012.11.046

Tetrahedron Letters 54 (2013) 321–323
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Tetrahedron Letters
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Synthesis of new malonaldehyde derivatives using 2-heteroaryl-substituted
trimethinium salts
⇑
A. M. Mehranpour , S. Hashemnia, F. Azamifar
Persian Gulf University, Bushehr 75169, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic route for obtaining 2-heteroaryl-substituted zwitterionic malonaldehydes 1c–6c is described.
The synthesis involves the two-fold formylation of heteroarylacetic acids 1a–6a using the Vilsmeier–
Haack reagent, followed by hydrolysis of the intermediate trimethinium salts 1b–6b with aqueous
sodium carbonate. Elemental analysis, IR, 1H NMR, 13C NMR, and mass spectral data confirm the struc-
tures of the newly synthesized compounds.
Received 30 September 2012
Revised 28 October 2012
Accepted 8 November 2012
Available online 21 November 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Malonaldehyde
Vilsmeier–Haack reagent
2-Heteroaryl-substituted trimethinium salts
Malonaldehyde (MA) is a highly reactive biochemically important
three-carbon dialdehyde (O@CHCH2CH@O ¡ HOCH@CHCH@O),
produced, for example, as one of the end-products of lipid peroxida-
tion.1 Due to its high reactivity, MA has the ability to form adducts
the Vilsmeier–Haack formylation of aliphatic instead of aromatic
substrates was successfully first introduced by Arnold.15,17,18b
Among the N-heteroaryl acetic acids 1a–6a synthesized and the
corresponding trimethinium salts 1b–6b, compounds 1a–3a and
1b–3b are new and their structural characterizations are provided
in the experimental section and Supplementary data. Furthermore,
all of the zwitterionic malonaldehyde derivatives 1c–6c are novel
and their structures were confirmed by elemental analysis, 1H
NMR, 13C NMR, and IR spectroscopy, and by mass spectrometry
(see experimental section and the Supplementary data).
In conclusion, six novel zwitterionic malonaldehyde derivatives
1c–6c were synthesized using 2-heteroaryl-substituted trimethini-
um salts as starting compounds. These new zwitterionic malonal-
dehydes are promising candidates for the synthesis of the
corresponding heteroaryl-substituted carbo-and heterocycles.
with a-amino acids and biomolecules such as proteins or DNA. Pro-
teins are much more reactive with MA than free amino acids, result-
ing in a variety of adducts and cross-linked products. MA can also
react with DNA bases producing a variety of mutagenic and possibly
carcinogenic compounds.2–13
There has been a significant interest in the synthesis of various
malonaldehyde derivatives.14–18 In this Letter, we report on the
synthesis and structural characterization of six new 2-heteroaryl-
substituted zwitterionic malonaldehyde derivatives lc–6c. To the
best of our knowledge, almost no attention has been paid to the
synthesis of such compounds using 2-heteroaryl-substituted tri-
methinium salts as starting compounds.18 The structural charac-
terizations were performed using UV/vis absorption, IR, 1H NMR,
and 13C NMR spectroscopy, and mass spectrometry.
Typical procedure for the synthesis of N-heteroaryl acetic acids
1a–6a
The new malonaldehyde derivatives 1c–6c were synthesized
using a three-step procedure as shown in Figure 1: (i) synthesis
of N-heteroaryl acetic acids 1a–6a via the nucleophilic substitution
reaction between the heteroarenes R1–6 and bromoacetic acid; (ii)
synthesis of the corresponding 2-heteroaryl-substituted trimethi-
nium salts 1b–6b by two-fold Vilsmeier–Haack–Arnold formyla-
tion of the N-heteroaryl-substituted acetic acids 1a–6a;18–22 (iii)
synthesis of the zwitterionic malonaldehyde derivatives 1c–6c by
hydrolysis of the 2-heteroaryl substituted trimethinium salts 1b–
6b with aqueous sodium carbonate solution. The application of
Heteroarenes R1–6 (7.0 mmol) was added to bromoacetic acid
(1.00 g, 7.0 mmol) dissolved in MeCN (40 mL). The mixture was re-
fluxed at 60 °C for 7 h. The resulting colorless crystals of 1a–6a
were collected by filtration, recrystallized from 2-propanol, and
dried over P4O10 in a desiccator.19
Typical procedure for the synthesis of 2-heteroaryl-substituted
trimethinium salts 1b–6b
The formylation reagent was prepared by mixing POCl3
(8.30 mL; 0.90 mol) with DMF (16.60 mL, 0.21 mol) at 0 °C and stir-
ring at room temperature for 30 min. The N-heteroaryl acetic acid
⇑
Corresponding author. Tel./fax: +98 771 4541494.
E-mail address: ammehranpour@hotmail.com (A.M. Mehranpour).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.046

322
A. M. Mehranpour et al. / Tetrahedron Letters 54 (2013) 321–323
Br
R
R
R
+Na2CO3 / H2O
6 h, reflux
+ BrCH2COOH
O
+2 DMF/POCl3
NMe
O
O
2 2ClO4
R
Me2N
+HClO4
HO
-CO2
2-heteroaryl-substituted
trimethinium salt
1b-6b
malonaldehyde
zwitterionic form
1c-6c
N-heteroaryl
acetic acid
1a-6a
R
Br
+
2ClO4
N
N
N
O
NMe2
NMe2
Me2N
N
R1
O
O
HO
1b
1c
1a
+
Br
Br
2ClO4
N
N
N
N
O
HO
O
O
Me2N
Me2N
R2
2c
2a
2b
+
2ClO4
2ClO4
N
N
N
R3
N
O
O
O
NMe2
NMe2
HO
3c
3a
3b
+
Br
N
N
N
N
O
O
O
Me2N
Me2N
R4
HO
4c
4b
4a
+
Br
2ClO4
N
N
N
N
O
NMe2
O
O
R5
HO
5c
5a
5b
Br
2ClO4
+
N
N
R6
N
N
O
O
O
Me2N
NMe2
HO
6c
6b
6a
Figure 1. Synthesis of the zwitterionic malonaldehyde derivatives 1c–6c.
(1a–6a) (0.90 mol) was added to this reagent. The mixture was re-
fluxed at 80 °C for 5 h, and then set aside in a refrigerator for 12 h.
The solution was diluted with pre-cooled EtOH (100 mL). A solu-
tion of HClO4 (70%, 14.60 mL, 0.1 mol) in EtOH (30 mL) was added
and the mixture was set aside in a refrigerator for 12 h. The crystals
of the trimethinium salt (1b–6b) were collected by filtration,
washed with Et2O, and dried over P4O10 in a desiccator.20–22
40 mL of H2O was refluxed for 7 h. After cooling to room tempera-
ture, the resulting solution was extracted with CH2Cl2 (4 Â 15 mL)
and the combined organic extracts washed with H2O (2 Â 10 mL),
dried over MgSO4 and the solvent removed by distillation. The
resulting residue (1c–6c) was recrystallized from EtOH.
N-(Carboxymethyl)-4-tert-butylpyridinium bromide (1a)
Typical procedure for the synthesis of the zwitterionic
malonaldehyde derivatives 1c–6c
Colorless powder; Yield 75%; mp = 221 °C; IR: m
/cmÀ1 = 3437,
1725; 1H NMR (500 MHz, DMSO-d6): d/ppm = 1.35 (s, 9H, CH3),
5.64 (s, 2H, CH2), 8.27 (d, J = 7.2 Hz, 2H, H-pyridine), 9.05 (d,
J = 7.2 Hz, 2H, H-pyridine); 13C NMR (DMSO-d6): d/ppm = 30.3,
37.2, 60.5, 125.6, 146.3, 168.6, 171.6; MS: m/z = 194 [M+ÀBrÀ];
A mixture of 2-heteroaryl-substituted trimethinium salt (1b–
6b) (28.0 mmol) and Na2CO3 (5.7 mmol, 0.60 g) dissolved in

A. M. Mehranpour et al. / Tetrahedron Letters 54 (2013) 321–323
323
Anal. Calcd for C11H16O2NBr: C, 48.19; H, 5.88; N, 5.11%; Found: C,
48.02; H, 6.01; N, 4.99%.
with this article can be found in the supplementary data) associ-
ated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.11.046.
1,1,5,5-Tetramethyl-3-(4-tert-butylpyridinium)-1,5-
diazapentadienium bis(perchlorate) (1b)
References and notes
1. Shamberger, R. J.; Shamberger, B. A.; Wills, C. E. J. Nutr. 1997, 107, 1404.
2. Mukai, F. H.; Goldstein, B. D. Science 1976, 191, 868.
3. Brooks, B. R.; Klamerth, O. L. Eur. J. Biochem. 1968, 5, 178.
4. Singh, R.; Leuratii, C.; Joysuta, S.; Sipowicz, M. A.; Diwan, B. A.; Kasprazak, K. S.;
Schut, H. A.; Marnett, L. J.; Anderson, L. M.; Shuker, D. E. G. Carcinogenesis 2001,
22, 1281.
5. Marnett, L. J.; Tuttle, M. A. Cancer Res. 1980, 40, 276.
6. Aldini, G.; le-Donne, I.; Facino, R. M.; Milzani, A.; Carini, M. Med. Res. Rev. 2007,
27, 817.
7. Jacobs, A. T.; Marnett, L. J. Acc. Chem. Res. 2010, 43, 673.
8. Foettinger, A.; Leitner, A.; Lindner, W. J. Mass Spectrom. 2006, 41, 623.
9. Slatter, D. A.; Murray, M.; Bailey, A. J. FEBS Lett. 1998, 421, 180.
10. Nair, V.; Vietti, D. E.; Cooper, C. S. J. Am. Chem. Soc. 1981, 103, 3030.
11. Burg, A.; Silberstein, T.; Yardeni, G.; Tavor, D.; Blumenfeld, J.; Zilbermann, I.;
Saphier, O. J. Agric. Food Chem. 2010, 58, 2347.
12. Bergamo, P.; Fedele, E.; Balestrieri, M.; Abrescia, P.; Ferrara, L. J. Agric. Food
Chem. 1998, 46, 2171.
13. Del Rio, D.; Stewart, A. J.; Pellegrini, N. Nutr. Metab. Cardiovasc. Dis. 2005, 15,
316.
14. Arendaruk, A. P.; Godzhello, T. M.; Mel’yantseva, V. N.; Protopopova, T. V.;
Skoldinov, A. P. Pharm. Chem. J. 1973, 7, 545.
15. Arnold, Z.; Šorm, F. Collect. Czech. Chem. Commun. 1958, 23, 452.
16. Meguellati, K.; Spichty, M.; Ladame, S. Mol. Biosyst. 2010, 6, 1694.
17. Král, V.; Semenov, V. V.; Kanishchev, M. I.; Arnold, Z.; Shevelev, S. A.;
Fainzilberg, A. A. Collect. Czech. Chem. Commun. 1988, 53, 1519.
18. (a) Reichardt, C.; Mormann, W. Chem. Ber. 1815, 1972, 105; (b) Reichardt, C. J.
Prakt. Chem. 1999, 341, 609.
Yellow powder; Yield 62%; mp = 250 °C; IR:
m
/cmÀ1 = 3121,
2965, 1634, 1091; 1H NMR (500 MHz, DMSO-d6): d/ppm = 1.40 (s,
9H, CH3), 2.36 (s, 6H, NMe2), 3.36 (s, 6H, NMe2), 8.01–9.05 (m,
6H, H-vinyl and H-pyridine); 13C NMR (DMSO-d6): d/ppm = 30.2,
37.8, 38.7, 50.6, 108.1, 139.7, 146.9, 151.1, 158.2, 168.65; MS: m/
z = 261 [M+À2ClO4À]; Anal. Calcd for C16H27N3(ClO4)2: C, 41.75;
H, 5.91; N, 9.13%. Found: C, 42.01; H, 6.21; N, 8.72%.
2-(4-tert-Butylpyridinium-1-yl)propane-1,3-dialate (1c)
Yellow powder; Yield 50%; decomposition at 156 °C; IR:
m/
cmÀ1 = 3435, 2962, 1587; 1H NMR (500 MHz, DMSO-d6): d/
ppm = 1.37 (s, 9H, CH3), 8.07 (d, 3J = 7.2 Hz, 2H, H-pyridine), 8.69
(d, 3J = 7.2 Hz, 2H, H-pyridine), 8.78 (s, 2H, H-vinyl); 13C NMR
(DMSO-d6): d/ppm = 30.0, 36.4, 123.7, 124.1, 144,7, 167.6, 177.5;
UV: kmax (DMSO)/nm
[14072.1] and 254 [28855]; MS: m/z = 205 [M+]; Anal. Calcd for
12H15N3O2N: C, 70.22; H, 7.37; N, 6.82%. Found: C, 70.30; H,
[
emax
/
MÀ1cmÀ1] = 375 [4726], 270
C
7.31; N, 6.75%.
19. Lloyd, D.; Tucker, K. S.; Marshall, D. R. J. Chem. Soc., Perkin Trans. 1 1981, 726.
20. Knorr, R.; Loew, P.; Hassel, P.; Bronberger, H. J. Org. Chem. 1984, 49, 1288.
21. Mehranpour, A. M.; Hashemnia, S.; Maghamifar, R. Synth. Commun. 2010, 40,
3594.
Acknowledgement
Financial support of this work by the Research Council of the
Persian Gulf University is gratefully acknowledged.
22. Mehranpour, A. M.; Hashemnia, S.; Shayan, Z. Synth. Commun. 2011, 41, 3501.
Supplementary data
Supplementary data (materials and measurements and the
structural characterization of 2a, 3a, 2b, 3b, and 2c–6c associated