Efficient synthesis of symmetrical bisamides catalyzed by reusable hydroxyapatite

Article abstract of DOI:10.1080/00397911.2017.1395888

Efficient synthesis of symmetrical bisamides is achieved by hydroxyapatite catalyst. Hydroxyapatite catalyzes the reaction between aldehydes and amides to afford bisamides at reflux conditions in 87–95% yields in acetonitrile medium. The catalyst is readily recovered and reused at least three times without loss in its catalytic activity. This method is noteworthy that, symmetrical bisamides are synthesized by fast, simple, effective, and environmentally benign heterogeneous protocol.

Full text of DOI:10.1080/00397911.2017.1395888

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Efficient synthesis of symmetrical bisamides
catalyzed by reusable hydroxyapatite
Gurusamy Ramachandran, Ramachandran Saraswathi, Mayilvasagam
Kumarraja, Palsamy Govindaraj & Thirumeni Subramanian
To cite this article: Gurusamy Ramachandran, Ramachandran Saraswathi, Mayilvasagam
Kumarraja, Palsamy Govindaraj & Thirumeni Subramanian (2018) Efficient synthesis of
symmetrical bisamides catalyzed by reusable hydroxyapatite, Synthetic Communications, 48:2,
216-222, DOI: 10.1080/00397911.2017.1395888
To link to this article: https://doi.org/10.1080/00397911.2017.1395888
View supplementary material
Published online: 26 Dec 2017.
Submit your article to this journal
Article views: 9
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [Gothenburg University Library]
Date: 08 January 2018, At: 06:55

SYNTHETIC COMMUNICATIONS®
2018, VOL. 48, NO. 2, 216–222
https://doi.org/10.1080/00397911.2017.1395888
Efficient synthesis of symmetrical bisamides catalyzed by
reusable hydroxyapatite
Gurusamy Ramachandrana, Ramachandran Saraswathia, Mayilvasagam Kumarrajab,
Palsamy Govindaraja, and Thirumeni Subramaniana
aDepartment of Chemistry, Saiva Bhanu Kshatriya College, Aruppukottai, India; bCentre for Research and
Post-Graduate Studies in Chemistry, Ayya Nadar Janaki Ammal College (autonomous), Sivakasi,
Tamilnadu, India
ABSTRACT
ARTICLE HISTORY
Received 31 May 2017
Efficient synthesis of symmetrical bisamides is achieved by
hydroxyapatite catalyst. Hydroxyapatite catalyzes the reaction between
aldehydes and amides to afford bisamides at reflux conditions in 87–95%
yields in acetonitrile medium. The catalyst is readily recovered and reused
at least three times without loss in its catalytic activity. This method is
noteworthy that, symmetrical bisamides are synthesized by fast, simple,
effective, and environmentally benign heterogeneous protocol.
KEYWORDS
Aldehydes; amides;
hydroxyapatite; reusability;
symmetrical bisamides
GRAPHICAL ABSTRACT
Introduction
The importance of diamides in chemistry and biology is well recognized and that play a
major role in the development and composition of biological and pharmacological
systems. In particular, symmetrical and unsymmetrical N,N0-alkylidene bisamides and
their derivatives are found as key structural subunits for the construction of peptidomi-
metic frameworks. One of the challenges facing chemists is to develop novel transforma-
tions that are not only efficient, selective and high yielding but are also environmentally
benign.[1,2] Organic transformations and preparation of industrial products are profound
transformation which accommodates sustainability criteria, invention of new methods with
green chemistry principles.[3] Use of hazardous and homogeneous catalysts is generally
connected with problems in separation, recovery and regeneration of the catalysts which
can be minimized using heterogeneously catalyzed reaction,[4] which includes easy
separation from reaction mixtures by simple filtration or centrifugation, safe disposal,
CONTACT Thirumeni Subramanian
chemsubbu84@gmail.com
Department of Chemistry, Saiva Bhanu Kshatriya
College, Aruppukottai-626101, Virudhunagar (Dist.), Tamil Nadu, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
© 2017 Taylor & Francis

SYNTHETIC COMMUNICATIONS®
217
low cost, tolerance to a wide range of temperatures and pressures, long lifetime,
eco-friendly nature and regenerability.[5] The catalysts must be pure, mixed with other
catalysts or dispersed on an inert support, e.g., hydroxyapatite, layered double hydroxide
(LDHs), zeolites, and clays.[6,7]
Hydroxyapatite, Ca5(PO4)3(OH) (HAP), is the integral part of bone and numerous
reports available as bioceramics and catalysts.[8,9,10] Hydroxyapatite catalyst easily available
in nature like accessory minerals in igneous rocks, small quantities in most metamorphic
rocks and the mineral of teeth also in bone is an impure form of hydroxyapatite.[11,12]
Hydroxyapatite possess a number of interesting properties such as adsorption and thermal
stability, ion-exchange character, acid-base properties, and interesting important properties
of synthetic hydroxyapatite is its ability to undergo substitution of both cations (Ca2þ) and
anions (PO34À and/or OH−) by the ion exchange. This ion exchange of Ca2þ by either
bivalent or trivalent ions can be expected to influence the biological, chemical and physical
properties of hydroxyapatite. Hydroxyapatite has also been used as novel support for many
organic transformations such as Suzuki–Miyaura and Heck type cross-coupling,[13]
oxidation of primary amines,[14] chalcone derivatives,[15] aldol condensation,[16]
5‐Substituted 1H‐Tetrazoles,[17] Sonogashira reaction,[18] epoxidation of styrene,[19] Coup-
ling of diiodoalkenes,[20] selective hydrogenation of nitroarenes[21] which must be
attributed to hydroxyapatite cation-exchanged ability.
The amides are highly useful and valuable compounds that have numerous biological
applications.[22,23] Among the amides, the N,N0-alkylidene bisamides are helps to
construction of peptide frameworks,[24,25] HIV inhibitors, calcium channel blockers,
α-adrenergic and neuropeptide Y antagonists, antihypertensive, antitumor, antibacterial
and anti-inflammatory agent.[26] Bulky bisamides are served as lubricants in polymer
applications, powder coatings, defoamers and flow modifiers in asphalt applications.
Symmetrical alkylidene bisamides are synthesized by the direct reaction of aldehydes
and amides with various catalysts such as p-TSA,[27] boric acid,[28] phosphotungtic acid,[29]
triflic acid[30] and silica supported polyphosphoric acid (SiO2-PPA)[31] although the results
were not satisfying, long reaction time, harsh reaction conditions, unsatisfactory yields and
use of large quantity of catalyst. Therefore, improvements with respect to the above have
been continuously sought. In recent years, many reports focus on the catalytic properties of
hydroxyapatite. Our careful literature survey at this stage revealed that there is no report on
the use of hydroxyapatite catalyst for the synthesis of symmetrical bisamides. As part of our
continuing interest in developing efficient and environmental benign synthetic
methodologies,[32–35] herein we report a convenient and efficient method for the synthesis
of symmetrical bisamides by condensing aryl aldehydes and amides using hydroxyapatite
as a reusable and heterogeneous catalyst.
Results and discussion
Typical reaction parameters including several catalysts, solvents, time and temperature are
screened in preliminary studies. Acetamide and benzaldehyde are chosen as the model
substrate to optimize the reaction conditions. Without any catalyst, this reaction did not
take place in ethanol solvent at room temperature and even at 80°C (Table 1, entries 1
and 2). Next, the above test reaction is investigated in the presence of various catalysts such
as FeCl3, ZnCl2, and CuNO3 separately in refluxing acetonitrile (Table 1, entries 3–5), all

218
G. RAMACHANDRAN ET AL.
Table 1. Effect of catalyst on model reaction for synthesis of symmetrical bisamides.a
Entry
Catalyst
Solvents
Time (h)
Temp (°C)
Yield (%)b
1
2
None
None
24
24
3
Rt
80
None
None
55
None
Ethanol
3
FeCl3.3H2O
ZnCl2
CuNO3
Acetonitrile
Acetonitrile
Acetonitrile
Ethanol
reflux
reflux
reflux
80
4
3
58
5
3
62
6
Calcium nitrate
10
10
10
10
3
42
7
Diammonium hydrogen phosphate
Ammonium hydroxide
Hydroxyapatite
Ethanol
Rt
38
8
Ethanol
Rt
40
9
None
Rt
22
10
Hydroxyapatite
Acetonitrile
80
95
aReaction conditions: Benzaldehyde (1 mmol), acetamide (2 mmol), solvent (2 ml), catalyst (50 mg).
bIsolated yields.
the catalysts did catalyze the reaction, albeit in low efficiency. We then turned our attention
toward sources of hydroxyapatite such as diammonium hydrogen phosphate, ammonium
hydroxide, calcium nitrate and only moderate yields are observed (Table 1, entries 6,7 and
8; yields 42, 38, 40 correspondingly), which might indicates that these should be interaction
form with active sites PO34À of hydroxyapatite to form product. Lowering the temperature
(Rt) became detrimental to the reaction (Table 1, entry 9), while increasing the temperature
(80 °C) has significant effect on the reaction (Table 1, entry 10). The result demonstrated
that 80 °C is found to be the optimum temperature. Better catalytic performance is
observed in hydroxyapatite with 95% yield in acetonitrile medium at 80 °C. Higher catalytic
activity may be attributed to the higher surface property of hydroxyapatite catalyst.
Our next attempts are focused on the evaluation of the efficiency of various solvents.
The reaction did not take place in the absence of solvent (Table 2, entry 1). Significant
amount of symmetrical bisamide is detected when the reaction performed in chloroform
(Table 2, entry 2). Moderate yields are observed when the reaction proceeded in
acetone, methanol, etc (Table 2, entries 3–10). Optimizations revealed that the acetonitrile
solvent can accelerate the reaction, enabling the completion at 80 °C within 3 h to produce
a 95% yield (Table 2, entry 11).
These interesting preliminary results promoted us to expand the scope of hydroxyapatite
catalyst with a wide range of substrate combinations and the results are summarized in
Table 3. It is found that there is no remarkable electron and position effects from the
aromatic aldehydes for this reaction, as evidenced by benzaldehydes with either an p-nitro,
p-Cl, and o-hydroxy substituent, also achieved greater yields with aldehydes bearing electron-
withdrawing groups. In addition, our catalytic system efficiently reacts with benzamides too
and affords the corresponding bisamide derivatives in excellent yields (Table 3, entries 2, 4, 6,
8, 10, and 12). Notably, sterically demanding ortho-substituents did not dampen the reaction

SYNTHETIC COMMUNICATIONS®
219
Table 2. Screening impact of solvents on the reaction between benzaldehyde and acetamide catalyzed
by hydroxyapatite.a
Entry
Solvents
Time (h)
Temp (°C)
Yield (%)
1
2
None
10
8
8
8
3
3
5
8
5
5
3
80
50
None
68
Chloroform
3
Dichloromethane
Toluene
Methanol
Ethanol
Ethylacetate
1,4-dioxane
Dimethyl sulfoxide
Dimethyl formamide
Acetonitrile
50
55
4
80
35
5
80
70
6
80
72
7
50
45
8
60
60
9
100
100
reflux
74
10
11
70
95
aReaction conditions: Benzaldehyde (1 mmol), acetamide (2 mmol), solvent (2 mL), catalyst 50 mg.
bIsolated yields.
Table 3. Hydroxyapatite catalyzed synthesis of various substitutes bisamides.a
MP (°C)
Entry
R
R0
Yield (%)
Product
Found
Report (lit)
1
2
C6H5–
C6H5–
CH3–
C6H5–
CH3–
C6H5–
CH3–
C6H5–
CH3–
C6H5–
CH3–
C6H5–
CH3–
C6H5–
CH3–
C6H5–
CH3–
CH3–
95
92
88
90
87
91
95
94
93
94
92
90
90
91
88
89
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
239–240
243–245
225–228
188–190
195–197
244–246
271–273
265–267
244–246
160–162
260–262
243–245
222–224
228–230
225–226
226–228
239–240[30]
241–243[35]
226–228[35]
191–193[35]
196–198[35]
246–248[35]
270–272[35]
265–267[30]
246–248[35]
162–164[30]
258–260[35]
241–243[35]
221–222[27]
230–232[27]
224–226[27]
225–228[27]
3
o-OHC6H5–
o-OHC6H5–
C6H5CH CH–
C6H5CH CH–
4
=
=
5
6
7
p-NO2C6H5–
p-NO2C6H5–
p-BrC6H5–
8
9
10
11
12
13
14
15
16
p-BrC6H5–
p-ClC6H5–
p-ClC6H5–
p-OCH3C6H5–
m-NO2C6H5–
p-CH3C6H5–
o-OCH3C6H5–
aReaction conditions: Aldehyde (1 mmol), amide (2 mmol), acetonitirile (2 mL), time (3 h), hydroxyapatite catalyst (50 mg),
refluxed conditions.
bIsolated yields.

220
G. RAMACHANDRAN ET AL.
Table 4. Reusablity of hydroxyapatite in the synthesis of N,N-alkylidene bisamides.a
Reuse
Yield(%)b
1st
95
2nd
3rd
90
94%
aReaction conditions: Benzaldehyde (1 mmol), acetamide (2 mmol) acetonitrile (2 mL) refluxed for 3 h.
bIsolated yield.
Table 5. Comparison with reported catalytic systems for synthesis of bisamides.
Entry
Catalyst
Temp (°C)
Time (h)
Yield (%)
Reusability of catalysts
1
2
3
4
5
p-TSA[27]
100
1
87–99
32–85
65–94
66–83
88–95
–
–
–
–
3
Boric acid[28]
Reflux (Toluene solvent)
20–72
20–72
1–3
3
Phosphotungstic acid[29]
SiO2-PPA[30]
Reflux (Toluene solvent)
100
80
Our systema
aReaction conditions. Aldehyde (1 mmol), amide (2 mmol) acetonitrile (3 mL) refluxed for 3 h.
(Table 3, entries 3 and 4). The substrate of p-bromobenzaldehyde proceeds smoothly to give
the corresponding bisamides in 91% yield (Table 3, entries 9 and 10).
One of the main advantages of heterogeneous catalyst is the recovery and reuse of the
catalyst after the reaction. In this connection the reusability of hydroxyapatite for the
synthesis of symmetrical bisamides is investigated under same reaction condition. After
completion of reaction, catalyst is recovered by simple filtration, washed, dried and reused
for next cycle. Even after the third recycle, it exhibits good catalytic activity with 90% yield
as shown in Table 4.
The present catalytic system is compared with other reported works based on the reac-
tion conditions used, activity and efficiency for the synthesis of symmetrical bisamide is
given in Table 5. The results indicate our catalytic system (entry 5) exhibits better catalytic
performance compared to conventional catalysts such as same reaction conditions (entries
2 and 3), higher temperature (entries 1–4), lower yield (entries 2–4) and poor reusability
(entries 1–4).
Conclusion
In the present study we describe a practical and inexpensive method for the preparation of
symmetrical bisamides through a condensation reaction between aldehydes and amides.
Hydroxyapatite has been successfully used as effective catalyst for the synthesis of
symmetrical N,N0-alkylidene bisamides for the first time. This procedure has advantages
in competition with the previously reported methods, in terms of yield, green catalyst, mild
reaction condition, simple procedure, lack of toxicity, and low cost. The salient feature of
this heterogeneous method offers several advantages such as atom efficiently, greener, atom
economically, reusability ecofriendly, protocols as the reactions requires neither high tem-
perature nor harsh acids or bases and produces high yields. It suitability with consist of

SYNTHETIC COMMUNICATIONS®
221
activity for least three cycles is also established, indicating hydroxyapatite is a green catalyst
and has potential values for industrial application
Experimental
Preparation of hydroxyapatite Ca10(PO4)6(OH)2
The synthesis of hydroxyapatite (HAp) in powder state is performed by coprecipitation
method. 250 ml solution containing 7.93 g of diammonium hydrogen phosphate,
maintained at a pH greater than 12, by addition of ammonium hydroxide (60–70) ml,
are dropped under constant stirring into 150 ml of a solution containing 23.6 g of calcium
nitrate [Ca(NO3)24H2O]. The suspension is refluxed for 4 h. The hydroxyapatite crystallites
are filtered, washed with DDW, dried over night at 80°C and calcined in air at 900 °C for
30 min prior to use. Synthesized hydroxyapatite catalysts are characterized by FT-IR and
SEM (see the Supporting Information).
Typical procedure for hydroxyapatite catalyzed synthesis of bisamides
Aldehyde (1 mmol) and amide (2 mmol) are successively added to hydroxyapatite catalyst
(50 mg) in 2 mL of acetonitrile solvent then mixture is refluxed for 2–3 h, after completion
of the reaction, the mixture is extracted with polar solvent. After removing the catalyst by
simple filtration, followed by solvent evaporation the resulting crude product is obtained
and purified by column chromatography (silica gel). The purified products are confirmed
1
by their H-NMR as well as by melting point data which are all found to be comparable
with the reported ones. Full experimental details and 1H NMR, 13C NMR for all
compounds can be found in the Supplementary Content section which can be accessed
through the articles web page.
Acknowledgements
The authors gratefully acknowledge the financial support from Management of Saiva Bhanu
Kshatriya College, Aruppukottai, Tamil Nadu.
References
[1] Santoro, S.; Kozhushkov, S. I.; Ackermann, L.; Vaccaro, L. Green Chem. 2016, 18, 3471.
[2] Schlogl, R. Angew. Chem. 2015, 54, 3465.
[3] Anastas, P. T.; Williamson, T. C. Oxford University Press, Oxford, Green Chemistry: Frontiers in
Chemical Synthesis and Processes (Eds.), 2008.
[4] Anastas, P. T.; Kirchhoff, M. M. Acc. Chem. Res. 2002, 35, 686.
[5] Sheldon, R.; Arends, I.; Hanefeld, U. Green Chemistry and Solid Catalysis (Eds.), Wiley-VCH:
Weinheim, Germany, 2009.
[6] Munnik, P.; de Jongh, P. E.; de Jong, K. P. Chem. Rev. 2015, 115, 6687.
[7] Zhou, C. H. Appl. Clay. Sci. 2011, 53, 85.
[8] Wei, G.; Ma, P. X. Biomaterials 2004, 25, 47, 49.
[9] Cawthray, J. F.; Creagh, A. L.; Haynes, C. A.; Orvig, C. Inorg. Chem. 2015, 54, 1440.
[10] Palmer, L.; Newcom, C.; Kaltz, S.; Spoerke, E.; Stupp, S. Chem. Rev. 2008, 108, 4754.
[11] Li, L.; Pan, H.; Tao, J.; Xu, X.; Mao, C.; Gu, X. J. Mat. Chem. 2008, 18, 4079.
[12] Aoki, H. Science and Medical Applications of Hydroxyapatite, JAAS: Tokyo. 1991.
[13] Masuyama, Y.; Sugiokaa, Y.; Chonana, S.; Suzukia, N.; Fujita, M.; Harac, K.; Fukuokac, A.
J. Mol. Catal. A: Chem. 2012, 352, 81.

222
G. RAMACHANDRAN ET AL.
[14] Mori, K.; Yamaguchi, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Chem. Commun. 2001, 461.
[15] Solhya, A.; Tahir, R.; Sebti, S.; Skouta, R.; Bousmina, M.; Zahouily M.; Larzek, M. Appl. Catal.
A: Gen. 2010, 374, 189.
[16] Subramanian, M.; Vanangamudi, G.; Thirunarayanan, G. Spectrochimica Acta Part A:
Molecular and Biomolecular Spectroscopy 2013, 116.
[17] Kantam, M. L.; Balasubrahmanyam, V.; Shiva Kumar, K. B. Synth. Commun. 2006, 36, 1809.
[18] Saha, D.; Chatterjee, T.; Mukherjee, M.; Ranu, B. C. J. Org. Chem. 2012, 77, 9379.
[19] Liu, Y.; Tsunoyama, H.; Akitabc, T.; Tsukuda, T. Chem. Commun. 2010, 46, 550.
[20] Ranu, B. C.; Adak, L.; Chattopadhyay, K. J. Org. Chem. 2008, 73, 5609.
[21] Huang, L.; Luo, P.; Pei, W.; Liu, X.; Wang, Y.; Wang, J.; Xing, W.; Huanga, J. Adv. Synth. Catal.
2012, 354, 2689.
[22] Allen, C. L.; Williams, J. M. J. Chem. Soc. Rev. 2011, 40, 3405.
[23] Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606.
[24] Yamazaki, T.; Nunami, K. I.; Goodman, M. Biopolymers 1991, 3, 1513.
[25] Yoon, G.; Kang, B. Y.; Cheon, S. H. Arch. Pharm. Res. 2007, 30, 313.
[26] Abbasinejad, M. A.; Mosslemin M. H.; Hassanabadi, A.; Safa, S. T. Synth. Commun. 2010, 1,
2209.
[27] Harichandran, G.; David Amalraja, S.; Shanmugam, P. J. Iran. Chem. Soc. 2011, 1, 298.
[28] Harichandran, G.; David Amalraja, S.; Shanmugam, P. Indian J. Chem. 2011, 50B, 77.
[29] Fernandez, A. H.; Alvarez, R. M.; Abajo, T. M. Synthesis 1996, 1299.
[30] Reza, M.; Shafiee, M. Journal of Saudi Chemical Society 2014, 18, 115.
[31] Subramanian, T.; Pitchumani, K. Chem Cat Chem 2012, 4, 1917.
[32] Subramanian T.; Pitchumani, K. Catal. Sci, Tech. 2012, 2, 296.
[33] Subramanian, T.; Kumar Raja, M.; Pitchumani, K. J. Mol. Cat. A: Chem. 2012, 363–364, 115.
[34] Subramanian, T.; Pitchumani, K. Catal. Commun. 2012, 26, 39–43.
[35] Abbasinejad, M. A.; Mosslemin, M. H.; Hassanabadi, A. J. Chem. Res. 2009, 218.