A simple and one-pot multi-component reaction to the synthesis of methylenebisamides

Article abstract of DOI:10.1007/s00706-017-2124-4

Abstract: This work described a simple and efficient method for the synthesis of some methylenebisamide derivatives. The reaction is carried out via a simple multi-component reaction between arylaldehydes, DMSO, and hydroxylamine hydrochloride. Short reaction times, excellent yields of products, inexpensive and readily available starting material, eco-friendly method, easy work-up, and high atom economy are the main advantages of this reaction.

Full text of DOI:10.1007/s00706-017-2124-4

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-017-2124-4
ORIGINAL PAPER
A simple and one-pot multi-component reaction to the synthesis
of methylenebisamides
Bagher Mohammadi1 Bahareh Rezaei Khorrami1
•
Received: 6 October 2017 / Accepted: 3 December 2017
Ó Springer-Verlag GmbH Austria, part of Springer Nature 2017
Abstract
This work described a simple and efficient method for the synthesis of some methylenebisamide derivatives. The reaction
is carried out via a simple multi-component reaction between arylaldehydes, DMSO, and hydroxylamine hydrochloride.
Short reaction times, excellent yields of products, inexpensive and readily available starting material, eco-friendly method,
easy work-up, and high atom economy are the main advantages of this reaction.
Graphical abstract
O
S
H3C CH3
NH2OH.HCl NH2OH.HCl
O
O
Ar
H
H
Ar
O
O
H2O/NaOH
Ar
N
H
N
H
Ar
Keywords Bisamide Á Multi-component reaction Á DMSO Á Hydroxylamine hydrochloride Á One pot
Introduction
HT-29 colon cancer cell line, and on a panel of human
cancer cell lines [7, 8]. In addition, some of them are used
as inhibitors of the steroidal neuroprotective N-methyl-D-
aspartate receptors (NMDAR) [9]. In particular, bisamides
are very important compounds. They are of remarkable
interest in the synthesis of peptidomimetic frameworks
[10–12]. Some of them showed good antimicrobial, anti-
inflammatory and antioxidant activities [13]. They are key
components for the introduction of gem-diaminoalkyl
residues retro-inverso pseudo-peptide derivatives [14] by
treating the appropriate amide with iodobenzene bistriflu-
oroacetate [15, 16]. Bisamides are commonly produced
from amides and another reactant such as aldehydes in the
presence of some catalysts or activators such as trifluo-
romethanesulfonic acid (CF3SO3H) [17], p-toluenesulfonic
acid [18], imidazole, sulfamic acid [19], SiO2-MgCl2 [20],
boric acid [21], phosphotungstic acid [22], B(HSO4)3 [23],
and ZnCl2 [24]. The other most common synthetic methods
Amides, an important class of organic compounds, are of
both natural and biological interest. They are part of a large
number of very important biomolecules and natural prod-
ucts such as amino acids, polyamides, peptides, and pro-
teins. Some amides have been reported to possess
antifungal [1] antituberculosis [2], insecticidal [3], anti-
convulsant [4], analgesic anti-inflammatory [5], and anti-
tumor [6] properties. They also have cytotoxic activities on
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00706-017-2124-4) contains supplementary
material, which is available to authorized users.
& Bagher Mohammadi
bagher.mohammadi@yahoo.com
1
Department of Chemistry, Payame Noor University,
P. O. Box, Tehran 19395-3697, Iran
123

B. Mohammadi, B. R. Khorrami
elemental analysis. The m.p. values, elemental analyses,
and spectral data of some of these compounds, were also in
good agreement with those of authentic samples [33].
The possible reaction mechanism (Scheme 2) involves
in the first step the condensation of arylaldehyde 1 and
hydroxylamine hydrochloride in the presence of NaOH and
water to form arylaldehyde oxime 3. The addition of
dimethyl sulfoxide to arylaldehyde oxime 3 will form
intermediate 4. In the next step, elimination of
methyl(methylene)sulfonium 6 and H2O leads to the ben-
zimidic acid 7 which undergoes [1, 3] H-shift, yielding
Scheme 1
O
O
O
+
H
2O/NaOH
+
DMSO
NH
2OH.HCl
Ar
N
H
N
H
Ar
Ar
H
2
1
Table 1 Multi-component synthesis of methylenebisamides 2
Product 2
Ar
Yielda/%
M.p./°C
Lit. m.p./°C
2a
2b
2c
2d
2e
Ph
85
88
83
85
89
221–223
276–278
211–213
214–216
246–247
220–223 [33]
276–279 [33]
212–214 [33]
–
4-BrPh
4-MePh
4-FPh
4-ClPh
arylamide 8. Addition of arylamide
6
8
methyl(methylene)sulfonium [25] leads to N-
to the
[(methylthio)methyl]benzamide 9. Activating intermediate
9 by arylaldehyde oxime 3, yielding thioether 10. The
arylamide 8 substitutes the thioether 10 to form methyle-
nebisamides 2.
245–247 [33]
aIsolated yields
reported for the preparation of bisamides involve: (1) the
reaction of CC- or DCMT-activated DMSO with amides
[25], (2) the reaction of aldehydes in a deep eutectic sol-
vent (DES) consisting of choline chloride and urea [26],
and (3) ring opening of lactones by primary aliphatic
diamines [27].
Conclusion
In conclusion, we have developed a practical, simple, and
efficient reaction for the synthesis of bisamides. The
method has several advantages, including high yields of
products, easy experimental work-up, and use of simple
and available starting materials, high atom economy, eco-
friendly and mild reaction conditions without the use of
any catalyst and organic solvents.
Most of the reported synthetic methods suffer from
some disadvantages such as using of catalysers or activa-
tors, and organic solvents, relatively long reaction times,
unsatisfactory products yields, difficult work-up process
and long reaction steps. In addition, in most cases, amide
used as an essential and inevitable starting materials. On
the other hand, use of DMSO is not possible without dis-
tinct corresponding activating agents.
Experimental
As part of our current studies on the development of
efficient and straightforward methods to prepare organic
compounds from readily available building blocks [28–32],
herein we report a simple, efficient and green method for
the synthesis of methylenebisamides via a unprecedented
one-pot three-component reaction between arylaldehydes,
DMSO, and hydroxylamine hydrochloride to afford the
titled compound 2a–2e in excellent yields (Scheme 1 and
Table 1).
All chemicals used in this study were purchased from
Merck and used without further purification. Melting points
were determined with an Electrothermal melting point
apparatus. Infrared (IR) spectra were recorded with a Shi-
madzu 8400s FT-IR spectrometer using potassium bromide
1
pellets. H NMR spectra (400 MHz) were recorded on a
DRX-400 Avance Bruker spectrometer. Elemental analy-
ses for C, H, and N were performed using a CHN-O-Rapid
analyzer and the instrument model was Eager 300 for
EA1112. The chemical shifts are reported in ppm (d scale)
relative to internal TMS and coupling constants are
reported in CDCl3. Thin-layer chromatography (TLC) was
performed using 60 mesh silica gel plates visualized with
short-wavelength UV light.
Results and discussion
To the best of our knowledge, this is the first report in
which bisamides 2 were synthesized by a novel and simple
three-component reaction without using any activating
agent additive. This reaction carried out as a self-activated
reaction. It seems, DMSO was activated by the in situ-
formed intermediate 3 (arylaldehyde oxime) in the reaction
steps.
General procedure for the synthesis of N,N’-
methylenedibenzamide 2a
The reaction were carried out by first mixing benzaldehyde
1a (1 mmol), hydroxylamine hydrochloride (1 mmol),
sodium hydroxide (1 mmol), and 3 cm3 DMSO in 5 cm3
The structures of the products were confirmed by their
melting point, 1H NMR, 13C NMR, IR spectra, and
123

A simple and one-pot multi-component reaction to the…
Scheme 2
H
H
H
O
S
S
6
S
O
O
HO
Ar
NaOH
OH
OH
S
OH
+ NH
2OH.HCl
N
H
N
3
Ar
H
Ar
N
Ar
-H
2O
H
2O
H
1
4
5
-HCl
OH
HO
Ar
N
O
O
Ar
-H
2O
NH
Ar
NH2
Ar
N
S
H
7
8
9
O
Ar
S
O
O
S
HN
HO
H2N
Ar
Ar
OH
+ Ar
N
H
N
Ar
N
HN
H
Ar
H
O
10
11
2
- MeSH
3
6. Warnecke A, Fichtner I, Saß G, Kratz F (2007) Arch Pharm
340:389
´
7. Gao LM, Matta J, Rheingold AL, Melendez E (2009) J Orga-
nomet Chem 694:4134
8. Sastry B, Babu KS, Babu TH, Chandrasekhar S, Srinivas P,
Saxena A, Rao JM (2006) Bioorg Med Chem Lett 16:4391
9. Adla SK, Slavikova B, Smidkova M, Tloustova E, Svoboda M,
Vyklicky V, Krausova B, Hubalkova P, Nekardova M, Holubova
K (2017) Steroids 117:52
water as a one-pot reaction. Then, the reaction mixture was
stirred at 80 °C for 1 h. The TLC monitoring of the reac-
tion mixture clearly indicated the formation of N,N’-
methylenedibenzamide 2a in excellent yield. Afterward,
the residue was filtered and recrystallized in ethanol and
then the product 2a was obtained as light yellow crystals;
yield: 93%.
10. Yamazaki T, Nunami KI, Goodman M (1991) Biopolymers
31:1513
11. Aleman C, Puiggali J (1995) J Org Chem 60:910
12. Goodman M, Shao H (1996) Pure Appl Chem 68:1303
13. Rayavarapu S, Kadiri S, Gajula M, Nakka M, Tadikonda R
(2014) Med Chem 4:367
N,N’-Methylenebis(4-fluorobenzamide) (2d, C15H12F2N2O2)
White powder; yield: 0.129 g (89%); m.p.: 214–216 °C; 1H
NMR (400.22 MHz, CDCl3): d = 5.06 (t, 2H, J = 6.4 Hz,
CH2), 7.4 (t, 4H, J = 8.8 Hz, 4CH), 7.52 (bs, 2H, 2NH),
3
4
7.85 (dd, 4H, JHH = 8.8, JFH = 5.2 Hz, 4CH) ppm; 13C
14. Pallai P, Struthers R, Goodman M, Moroder L, Wunsch E (1985)
Biochemistry 24:1933
NMR (100.63 MHz, CDCl3): d = 45.76 (CH2), 115.81 (d,
4
3JFC = 22.1 Hz, 2CH), 129.59 (d, JFC = 9.1 Hz, 2CH),
15. Pernak J, Błazej M, Jozef W (1994) Synthesis 12:1415
´
1
165.11 (d, JFC = 253.6 Hz, CF), 167.4 (C=O) ppm.
16. Rodriguez M, Dubreuil P, Bali JP, Martinez J (1987) J Med
Chem 30:758
17. Fernandez AH, Alvarez RM, Abajo TM (1996) Synthesis 1299
18. Anary-Abbasinejad M, Mosslemin MH, Hassanabadi A, Safa ST
(2010) Synth Commun 40:2209
19. Selvam NP, Saranya S, Perumal PT (2008) Can J Chem 86:32
20. Shafiee MRM (2011) Lett Org Chem 8:562
21. Harichandran G, Amalraj SD, Shanmugam P (2011) J Iran Chem
Soc 8:298
22. Harichandran G, Amalraj SD, Shanmugam P (2011) Indian J
Chem 50B:77
23. Karimi-Jaberi Z, Pooladian B (2013) Monatsh Chem 144:659
24. Shen XX, Shen YL, Han YF, Liu Q (2012) Adv Mater Res
441:421
Acknowledgements I gratefully acknowledge the financial support
from the Research Council of Payame Noor University (PNU),
Tehran, Iran.
References
1. Moise M, Sunel V, Profire L, Popa M, Lionte C (2008) Farmacia
(Bucharest, Rom) 56:283
2. Hegab MI, Abdel-Fattah ASM, Yousef NM, Nour HF, Mostafa
A, Ellithey M (2007) Arch Pharm 340:396
25. Wang Q, Sun L, Jiang Y, Li C (2008) Beilstein J Org Chem 4:51
26. Azizi N, Alipour M (2015) J Mol Liq 206:268
27. Stapert HR, Dijkstra PJ, Feijen J (1998) Macromol Symp 130:91
3. Graybill TL, Ross MJ, Gauvin BR, Gregory JS, Harris AL, Ator
MA, Rinker JM, Dolle RE (1992) Bioorg Med Chem Lett 2:1375
4. Siddiqui N, Alam M, Ahsan W (2008) Acta Pharm 58:445
5. Galewicz-Walesa K, Pachuta-Stec A (2003) Synthesis 58:118
123

B. Mohammadi, B. R. Khorrami
28. Mohammadi B, Shafieey M, Kazemi H, Ramazani A (2013) Chin
Chem Lett 24:497
31. Mohammadi B, Najafi EO, Azizkhani V (2017) Monatsh Chem
148:1095
29. Mohammadi B, Kazemi H, Shafieey M (2014) Monatsh Chem
145:1649
30. Mohammadi B, Shafieey M, Kazemi H (2015) Iran Chem
Commun 3:302
32. Mohammadi B, Rahmani M (2016) Iran Chem Commun 4:226
33. Moghaddam FM, Tavakoli G, Saeednia B (2017) Chem Select
2:1316
123