Design of Supported Organocatalysts from Carboxylic Acids for the Mannich-Type Synthesis of β -Amino Carbonyl Compounds

Article abstract of DOI:10.1080/00397911.2015.1105983

New supported acidic organocatalysts were prepared by the impregnation of three carboxylic acids (CF₃COOH, CCl₃COOH, and CH₃COOH) on silica support at room temperature in diethyl ether. The catalysts were characterized by scanning electron microscopy, energy dispersion X-ray analysis (EDX), Brunauer-Emmett-Teller-surface-area-analysis (BET), thermogravitational analysis, Fourier transform infrared, and powder X-ray diffractometry analysis. These solid acids were observed as highly efficient reusable catalysts at room temperature for the selective synthesis of β-amino carbonyl compounds via Mannich-type reactions of acetophenone, arylamine and arylaldehydes using two different conditions in CH₂Cl₂ solution and solvent-free grinding within a short time. The more acidic two catalysts could be recycled for up to five cycles with a small loss in catalytic activity.

Full text of DOI:10.1080/00397911.2015.1105983

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Designing of Supported Organocatalysts from
Carboxylic Acids for the Mannich-Type Synthesis of
β-Amino Carbonyl Compounds
Parishmita Sarma, Susmita Saikia & Ruli Borah
To cite this article: Parishmita Sarma, Susmita Saikia & Ruli Borah (2015): Designing of
Supported Organocatalysts from Carboxylic Acids for the Mannich-Type Synthesis of β-Amino
Carbonyl Compounds, Synthetic Communications, DOI: 10.1080/00397911.2015.1105983
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Date: 03 November 2015, At: 10:02

Designing of Supported Organocatalysts from Carboxylic Acids for the Mannich-
Type Synthesis of β-Amino Carbonyl Compounds
Parishmita Sarma1, Susmita Saikia1, Ruli Borah1
1Department of Chemical Sciences, Tezpur University, Napaam, Tezpur, Assam, India
Correspondence authot to Ruli Borah: Department of Chemical Sciences, Tezpur
University, Napaam-784028, Tezpur-Assam, India. E-mail: ruli@tezu.ernet.in
Abstract
New supported acidic organocatalysts were prepared by the impregnation of three
carboxylic acids (CF3COOH, CCl3COOH and CH3COOH) on silica support at room
temperature in diethyl ether. The catalysts were characterized by SEM, EDX, TGA, FT-
IR and powder XRD analysis. These solid acids were observed as highly efficient
reusable catalysts at room temperature for the selective synthesis of β-amino carbonyl
compounds via Mannich-type reactions of acetophenone, arylamine and arylaldehydes in
CH2Cl2 solution and solvent-free grinding method within short time. The more acidic two
catalysts could be recycled up to five cycles with a small loss in catalytic activity.
KEYWORDS: Organocatalysts, silica support, Mannich-type reaction, reusable solid
acid
1

INTRODUCTION
The use of organocatalysts in organic synthesis have received considerable attention for
production of fine chemicals because of lack of sensitivity to moisture and oxygen, ready
availability, low cost and low toxicity as compared to other traditional catalysts[1-6].
However, the capability and applicability of an organocatalyst in organic transformations
can be improved if its recovery and reuse procedure become more and more facile [7-10].
The recycling of an organocatalyst simplifies the purification steps, avoiding wastes and
gives potential for utilization in large-scale operations [11-13].The immobilization of
organocatalysts on inert supports (such as charcoal, alumina, silica, and polymers etc.)
makes them heterogeneous which improves the availability of active sites of catalyst for
the synthesis of small molecules under especially simple, mild and more environmentally
benign conditions [14-17]. Among the various supports, silica has special position
because of its abundant availability, thermal stability and polar surface which can easily
bind the polar groups of organic molecules that lead to the generation of more active
catalytic sites [18]. The application of such type of heterogeneous catalyst in
multicomponent reactions (MCRs) provides an attractive strategy for rapid and efficient
library generation of complex molecules with higher atom-economy [19-20].
The selective synthesis of β-amino carbonyl compounds from acid catalyzed Mannich-
type reactions of aldehydes, amines and ketone are widely applicable as synthetic
intermediates for various pharmaceuticals and natural product [21-22]. Several
modifications of the classical Mannich reaction have been developed using preformed
electrophiles such as imines and stable nucleophiles, such as enolates, enol ethers and
2

enamine [23-24]. But, the preferred route is the multicomponent strategies that give wide
range of structural variations. A variety of Brønsted, Lewis and solid acids, such as
HCl[25], HBF4[26-28], boric acids[29], InCl3 [30-31], Y(OTf)3[32], Yb(PFO)3[33-34],
Yb(OiPr)3 [35], Zn(BF4)2 [36], Bi(OTf)3[37-38], Zn(OTf)3[39],PS-SO3H [40],
dodecylbenzene sulfonic acid [41], iminodiacetic acid [42], heteropoly acid [43],
copper(I)-fesulphos Lewis acid [44] , K3PO4[45] silica supported AlCl3[46] etc. have
been employed as catalyst for the Mannich-type reactions. Unfortunately, many of them
require longer reaction time, excess amount of non-recyclable catalysts, use of expensive
heavy metal salts, harsh reaction condition and difficulty in product isolation. Also most
of the reported procedures were only applicable to aliphatic amines and failed to work
with aromatic amines [47-51]. Although, some the recent protocols, made this route
attractive, the development of fast, simple and environmentally benign approaches that
could be performed at ambient temperature for the Mannich-type reaction is highly
desirable. Herein we designed three reusable solid acid catalysts by supporting simple
carboxylic acids (CF3COOH, CCl3COOH and CH3COOH) on silica support by wet
impregnation method which were characterized by SEM, EDX, BET, TGA, FT-IR and
powder XRD analysis. After observing their thermal stability and surface properties, they
were utilized as highly efficient solid acid catalysts for the reaction of acetophenone,
arylamines and aryl aldehyde (Scheme-1) in CH2Cl2 solution and solvent-less
mechanochemical method at ambient temperature as compared to other reported
methods.
RESULTS AND DISCUSSIONS
3

Catalyst Preparation And Characterization
The supported acids were prepared by wet impregnation method from the mixture of
carboxylic acid (CF3COOH /CCl3COOH / CH3COOH) with silica (100-200 mesh,
neutral) in diethyl ether at room temperature stirring. Loading of each acid on the silica
was calculated based on the weight of supported organocatalysts obtained and the weight
of silica used. The loading of each supported catalysts was optimized by increasing or
decreasing the amount of supports and acids. We observed almost similar amounts of
loading in case of entry 1 and entry 2 (table -1). The preparation of catalysts was
optimized from the mixture of 4 mmol of carboxylic acids and 10 g of silica.
The IR spectra of the supported catalysts were shown in Fig-1. The broad band
appears at 1083 cm-1 and strong peak at 807 cm-1 were assigned to asymmetric and
symmetric stretching vibrations of Si–O–Si respectively. Band at 465cm-1 was assigned
to Si–O–Si bending vibrations. The carbonyl stretching vibrations of the supported acids
were observed in the increasing order at 1717, 1753, 1776 cm-1 for CH3COOH,
CCl3COOH and CF3COOH respectively.
The SEM images of organocatalysts (Fig-2) distinctly expressed the change in the
appearance and morphology of silica support. The roughness of silica surface increased
through physical interactions with carboxylic acids. All these surfaces had no definite
particle sizes. The particle sizes of trichloroacetic acid catalyst were found to be higher
than TFA and AcOH catalysts.
4

The impregnation of trichloroacetic acid on the surface of silica support was confirmed
by the presence of Cl atom in EDX spectra (Fig.3). The EDX analysis of silica-TFA
catalyst didn’t identify any F atom on its surface due to fluorine mobility during EDX
analysis[52].The lower bond dissociation energy of C-F bond (453kJ/mol) may facilitate
the formation of anions or free radicals of fluorine from impregnated CF3COOH under
strong electron beam irradiation. After that the negatively charged F- anions are slowly
migrating away from the irradiated area by the possible repulsive interactions with the
accumulated negative charge of electron beam. This ionic mobility of F atom prevents
their detection with EDX spectra. The presence of fluoride in the catalyst was further
confirmed by the fluoride ion selective electrode (Orion multiparameter kit) using
Lassaigne filtrate of SiO2-TFA catalyst.
The TGA curves furnished information about the thermal stability of loaded carboxylic
acids on silica support (Fig.4). The weight loss around 80-90 oC may include loss of
surface physisorbed water and some amount of organic acids from SiO2-AA (b), SiO2-
TCA (c) and SiO2-TFA(d) catalysts.
The XRD patterns of supported acids showed slight sharpening in the appearance of basic
broad amorphous peak of silica at 2ѳ = 25o (Fig. 5).
The BET surface area analysis depicted a slight decreasing trend of surface areas due to
immobilization of carboxylic acids in this sequence SiO2-AA>SiO2-TFA>SiO2 (table-2).
5

Applications Of The Catalysts For The Mannich-Type Reaction
After knowing the thermal stability and optimized amount of loading of each
carboxylic acids on the surface of silica, we were tested the catalytic performance of
these organocatalysts for the Mannich-type reactions of acetophenone, arylamines and
arylaldehydes in dichloromethane (Scheme-1, table-3). The lone carboxylic acids resulted
in 20-57 % yield of β-amino carbonyl compound without silica support during 4-48 h
time in solution at room temperature stirring (table-3, entries 2-4) [53]. We did not
observe any product using 40 mg of silica for the same reaction in CH2Cl2 (table-3, entry
1).
The amount of acidic catalyst was optimized for the reaction of benzaldehyde (1mmol),
aniline (1mmol) and acetophenone(1 mmol) in different solvents at room temperature
(table-3, entries 5-11). The best result utilized 40 mg of catalysts to give 80-90 % yields
of products in CH2Cl2 (table 3, entry-6).The higher catalytic activity shown by SiO2-TCA
and SiO2-TFA in solution. The reaction also generated excellent yields of products in
solvent-free mechanochemical method with 40 mg of catalysts (table 3, entry-12). The
optimization conditions for the synthesis of β-amino carbonyl compounds extended for
various aromatic aldehydes and arylamines in presence of both SiO2-TCA(c) and SiO2-
TFA (d) catalysts. We also conducted a comparative study of the synthesis of few β-
amino carbonyl compounds under solvent-free grinding method using 40 mg of SiO2-
TCA(c) and SiO2-TFA (d) catalysts. The results are summarized in table-4 and table-5.
The nature of aryl substituents had no effects on the yields of products irrespective of
6

electron withdrawing or donating groups (table-4). The solvent-less method completed
the reactions within 15-25 min reaction time (table-5).
Recycling Of The Catalysts Sio2-TCA And Sio2-TFA
The used catalysts were again recycled for each run after washing with dichloromethane
and dried at 70°C for 2 h. The recyclability of the above catalysts was investigated by
performing the already mentioned model reaction with the reactivated catalysts in CH2Cl2
for five cycles. The results obtained were included in table-6. From these results it was
clear that the percentage yields of products were similar after subsequent runs and
therefore the catalyst can be used up to 5th cycle with small loss of its activity.
Characterization Of Spent Catalysts
The reused FT-IR spectra of SiO2- TCA and SiO2- TFA (Fig.-1) clearly supported the
experimental results of recyclability. Similarly, the EDX analyses of spent SiO2-TCA and
SiO2-TFA catalysts after 5th run showed the stability of loaded CCl3COOH and
CF3COOH on the silica support under the reaction conditions (Fig- 6).
Leaching Test Of The Catalysts
The stability of both SiO2-TCA and SiO2-TFA silica-supported catalysts in solution
was examined to evaluate if the carboxylic acid from silica support could be leached out
by solvent. In a control experiment, the optimized amount of catalyst (40 mg of SiO2-
TCA or SiO2-TFA) was stirred at room temperature in 3 mL of dichloromethane for 1 h
7

without addition of reactant and then filtered. A mixture of benzaldehyde (1 mmol),
aniline (1 mmol) and acetophenone (1 mmol) was added to the filtrate and then it was
continued to stirring for 75 min. We didn’t observe any product on thin layer
chromatographic plate which clearly confirmed the absence of free acidic species in the
reaction medium through leaching. Furthermore, the recovered catalyst amounts after
work up process were also identical with the initial amounts of catalysts. The isolated
catalysts again utilized to complete one cycle of reaction with the optimized amount of
substrates for the preparation of (4a) derivative. This evidence showed that the reaction
procedure is heterogeneous and no leaching occurs within the reaction time.
CONCLUSION
In summary, we have prepared three efficient heterogeneous organocatalysts from three
non-recyclable carboxylic acids. The solid catalysts were characterized in terms of
optimization of loading, presence of carboxylic acid, thermal stability, and morphology.
The efficiency of the solid catalysts was evaluated for the Mannich-type reactions of
acetophenone, aryl amines and aryl aldehydes to β-amino carbonyl compounds in CH2Cl2
and solvent-less grinding method at ambient temperature within less time which was
observed to be several hours in case of many reported methods. The notable advantages
of these catalysts are high catalytic activity at mild condition, simple operation coupled
with easy work up procedure, recyclability, and low cost.
EXPERIMENTAL
8

The thermal stability of the three supported organocatalysts was performed on
Shimadzu TGA 50. The scanning electron microscopy (SEM) analyses were carried out
using a JEOL JSM-6390LV SEM, equipped with an Energy-Dispersive X-ray analyzer.
The powder X-ray diffraction patterns were recorded on a Rigaku Multiflex instrument
using a nickel-filtered CuKα (0.15418 nm) radiation source and scintillation counter
detector. All known β-amino carbonyl compounds 4 were identified by comparison of
their melting points, FT-IR, 1H NMR and 13C NMR spectroscopic data with those of
authentic compounds (prepared by known method) and literature reported data [54-
58].The 1H NMR and 13C NMR spectra of selected β-amino carbonyl compounds 4 were
included in supplementary file.
Experimental Procedure For The Preparation Of Silica-Supported Organocatalysts
Based On Carboxylic Acids (Sio2-TFA, Sio2-TCA, Sio2-AA)
Silica(10g, 100-200mesh, neutral) was charged in a 100 mL two necked round bottom
flask in anhydrous diethyl ether (50 mL). After that, 4 mmol of the organic acid
(CF3COOH /CCl3COOH / CH3COOH) was added to the above mixture over a period of 5
min at room temperature. The mixture was stirred for 2 h. Finally, the reaction mixture
was filtered and the solid residue was washed with diethylether ( 2 x10 mL), dried at
70°C for 20 h and silica-supported acid was obtained as a white powder. The loading of
acids were observed as 0.365 mmol/g of SiO2-TFA, 0.357 mmol/g of SiO2-TCA and
0.343 mmol/g of SiO2-AA.
Typical Procedure For The Synthesis Of Β-Amino Carbonyl Compound 4a
9

A mixture of benzaldehyde (1mmol), aniline (1mmol) and acetophenone(1mmol) in
dichloromethane (3 mL) was stirred at room temperature (or grinded in mortar with a
pestle in absence of solvent) in presence of silica supported organocatalyst (40 mg) for
appropriate time. After completion of the reaction, as monitored by TLC, the
dichloromethane solution was filtered (or diluted the mixture with 3mL of CH2Cl2 for
solvent-less reaction) to separate the solid catalyst from the crude product. The used
catalyst was again regenerated after washing with CH2Cl2 (3mL) and dried at 70°C for 2
h. The filtrate was evaporated under reduced pressure to yield the crude solid product.
The product was precipitated in pure state from the solution of hexane (2mL).
1,3-Diphenyl-3-(Phenylamino)Propan-1-One ( Entry 1, Table-4, 4a )
White solid; Mp.168.5-169°C (169-170 °C)[26] ;
FTIR(KBr):3382,3020,2921,2873,2372, 1668,1597,1506, 1446, 1368,1291, 1218, 1175,
1072,993,858,746,689 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.92(d, J = 7.3 Hz, 2H),
7.56(t, J = 7.4Hz, 1H), 7.40-7.45(m, 3H), 7.32(t, J = 7.3Hz, 2H), 7.19-7.25(m, 2H),
7.07(t, J = 7.8Hz, 2H), 6.66(t, J = 7.4Hz, 1H), 6.57(d, J = 7.8Hz, 2H), 5 (t, J=5Hz, 1H),
3.49(dd, J =5.5 Hz, J= 16 Hz, 1H), 3.42(dd, J =7.4 Hz, J=16Hz, 1H); 13C NMR (100
MHz, CDCl3): δ198.3, 147.0, 143.0, 136.8, 133.4, 129.1, 128.8,128.7, 128.2, 127.4,
126.4, 117.8, 113.9, 54.9, 46.3 ;Elemental analysis for C21H19NO Calcd. C, 83.69; H,
6.35; N, 4.65; Found C, 83.64; H, 6.40; N, 4.63.
ACKNOWLEDGEMENT
10

The authors are thankful to Sophisticated Analytical Instrumentation Centre, T.U. for
analyses of various samples for this work and also to CSIR, New Delhi, India for
granting a research project no. 02(0067)/12/EMR-II to R. B.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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14

Table 1. Optimization of the catalyst loading
Entry
Silica support (gm) Carboxylic Acids Loading (mmol/ g)a /(b) /(c)
(mmol)
1
2
3
10
4
0.441/0.355/0.346
0.343/0.358/0.365
10
aSiO2-AA(a), SiO2-TCA(b), SiO2-TFA(c)
15

Table 2. Surface area obtained from nitrogen adsorption isotherms
Catalyst
SiO2
Surface area (m2g-1)
525
470
355
365
SiO2-AA
SiO2-TCA
SiO2- TFA
16

Table 3. Optimization of the Mannich-type reaction catalyzed by silica supported acids at
room temperature
Entry Catalyst
Catalyst
Time (min) Solvents
(b)/(c)/(d)
Yield(%)b 4a
(b)/(c)/(d)
No reaction
57 [53]
(mg)a
1
SiO2
40
10 h
4 h
CH2Cl2
EtOH
2
TFA
0.5 mmol
3
TCA
0.5 mmol
4 h
EtOH/CH2Cl2 50/55
4
AA
0.5 mmol
48 h
90
EtOH
CH2Cl2
CH2Cl2
CH2Cl2
EtOH
THF
20
5
(b)/(c)/(d)
(b)/(c)/(d)
(b)/(c)/(d)
(b)/(c)/(d)
(b)/(c)/(d)
(b)/(c)/(d)
(b)/(c)/(d)
(b)/(c)/(d)
20
40
62
40
40
40
40
40
45/65/70
80/87/90
82/88/93
25/52/54
-/35/40
6
70/50/45
45
7
8
60
9
45
10
11
12
45
CH3CN
H2O
-/60/70
120
60/25/20
No reaction
-
82/90/93c
b
a Amount of catalyst against 1 mmol of benzaldehyde, aniline and acetophenone;
Methods: Using SiO2-AA (b), SiO2-TCA (c) and SiO2-TFA (d); c Under solvent-free
grinding at room temperature.
17

Table 4. Synthesis of β- amino carbonyl compounds 4 catalysed by SiO2- TFA and SiO2-
TCA
Entry
2 R1
3 R2
Product Yield% (Time in References
4
min) (c) /(d)a
87(50) / 90 (45)
88 (50) / 90(50)
86(50) /92(50)
82(70) / 85(1h)
84(50)/ 87(45)
90(45)/93(40)
86(50)/90(45)
83(45)/85(40)
1
2
3
4
5
6
7
8
H 2a
H 2a
H 2a
H 2a
H 2a
H 2a
H 3a
[46]
[45]
[46]
[46]
[54]
[46]
[46]
[46]
4a
4b
4c
4d
4e
4f
4-OCH3 3b
4-CH3 3c
4-NO2 3d
4-(CH3)2CH- 3e
4-Cl 3f
H 3a
4-Cl 2b
4-OCH3
2c
4g
4h
H 3a
9
4-CH3 2d H 3a
80(45)/85(45)
89(55)/92(45)
[46]
[46]
4i
10
11
12
4-CH3 2d 4-CH3 3c
4-NO2 2e 4-CH3 3c
4j
4k
4l
80(70)/86(1 h) [55]
4-OCH3
2c
4-CH3 3c
86(45) / 91(40)
[56]
13
14
15
4-Cl 2b
4-Cl 2b
3-Br 2f
4-Cl 3f
84(45)/88(45)
83(55)/87(50)
86(50)/92(50)
[46]
[46]
[58]
4m
4n
4o
4-NO2 3d
4-CH3 3c
aUsing 40 mg of SiO2-TCA (c) and SiO2-TFA(d) catalysts against 1 molar equivalents
of arylaldehyde, arylamine and acetophenone in DCM at 25°C.
18

Table 5. Synthesis of β-amino carbonyl compounds 4 under solvent-less condition
Entry
2 R1
3 R2
Product Yield% (Time in
4
mins) (c) /(d)a
90(25) / 93(20)
88(25) / 92(20)
85(34) / 85(25)
86(22) / 85(18)
92(27) / 96(15)
84(33) / 88(17)
84(30) / 89(20)
1
2
3
4
5
6
7
H 2a
H 3a
4a
4c
4d
4h
4j
H 2a
4-CH3 3c
4-NO2 3d
H 3a
H 2a
4-OCH3 2c
4-CH3 2d
4-NO2 2e
4-Cl 2b
4-CH3 3c
4-CH3 3c
4-NO2 3d
4k
4n
a All the reactions were carried out using grinding method using 40 mg of SiO2-TCA (c)
and SiO2-TFA (d) catalysts against 1 mmol of aryl aldehyde, aryl amine and
acetophenone.
19

Table 6. Recycling of SiO2-TCA and SiO2-TFA catalysts in CH2Cl2
Entry
Cycle
Time (min) (c)/(d)
Product a (4a) Yield
(%) (c)/(d)
87/90
1
2
3
4
5
1st
2nd
3rd
4th
5th
50/45
50/45
65/55
65/55
70/60
85/87
83/85
80/83
78/80
20

Scheme 1. Mannich-type reactions catalysed by silica supported organic acids
21

Fig. 1. FT- IR spectra of SiO2 (a), SiO2-AA(b), SiO2-TCA(c), SiO2-TCA 3rd run(d), SiO2-
TCA 5th run(e), SiO2-TFA(f), SiO2-TFA 3rd run(g) and SiO2-TFA 5th run(h)
22

Fig. 2 SEM images of silica (a), SiO2- AA (b); SiO2-TCA (c) ; SiO2-TFA(d)
23

Fig. 3. EDX spectra of SiO2-TCA(c)and SiO2-TFA(d)
24

Fig. 4. TGA curve ofSiO2- AA (b) ; SiO2- TCA (c) ; SiO2-TFA(d)
25

Fig. 5. Powder XRD of silica (a) ; SiO2-AA (b) ; SiO2-TCA (c) and SiO2-TFA(d)
26

Fig. 6. EDX analysis of reused catalyst SiO2-TCA (c) and SiO2-TFA (d) after 5th run
27