Sulfanilic acid catalysed one-Pot three-component Mannich reaction for synthesis of β-amino ketones

Cite this paper: Vietnam J. Chem., 2020, 58(5), 675-687 Article 
DOI: 10.1002/vjch.202000090 
675 Wiley Online Library © 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH 
Sulfanilic acid catalysed one-pot three-component Mannich reaction for 
synthesis of β-amino ketones 
Pramod Kulkarni 
Department of Chemistry, Hutatma Rajguru Mahavidyalaya, Rajgurunagar, Pune-410505, MS India 
Submitted June 1, 2020; Accepted August 18, 2020 
Abstract 
We have reported sulfanilic acid as an exceedingly competent catalyst for one-pot Mannich reaction to give β-
amino carbonyl compounds in good to excellent yield within a short reaction time. The various organic acids have 
screened; like gallic acid, 4-hydroxy benzoic acid, 4-amino benzoic acid, phenylacetic acid, chloroacetic acid, 
sulfosalicylic acid, sulfanilic acid, chloro benzoic acid, phthalic acid, salicylic acid, cinnamic acid, hippuric acid, 1-
naphthyl acetic acid, o-amino benzoic acid, p-TSA, succinic acid, malic acid, and among them sulfanilic acid is a 
suitable catalyst. The reaction condition was optimized with respect to the solvent, the amount of catalyst as well as the 
variation of the ketone, aldehyde, and amine substrates. The procedure is mild, effective, ecofriendly, and the use of the 
minimum amount of catalyst. 
Keywords. Aldehydes, amino ketone, organic acid, multicomponent, Mannich reaction. 
1. INTRODUCTION 
Multicomponent reaction is unique important 
reactions in organic synthesis. These reactions in the 
last two decades have acknowledged the 
consideration of organic chemists because of various 
merits over conventional traditional synthesis. 
Multicomponent reactions have significant 
applications in medicinal chemistry for the creation 
of diverse scaffolds and combinatorial libraries for 
drug development.
[1]
 In the multicomponent 
reactions, three or more components have been 
reacted to form preferably one product, which has 
been containing the crucial units of all the original 
materials. MCRs have been good for the 
environment by decreasing the number of synthetic 
steps, energy consumption, and waste creation. 
Therefore, the discovery of novel MCRs and 
elaborating on the formerly known MCRs are 
substantial attention. Individual example of, this 
type is the preparation of β-amino carbonyl 
compounds by the Mannich reaction. Several β-
amino ketones and their analogues, show the 
effective medicinal properties
[2-13]
 are shown in 
figure 1. β-amino ketones, have vital intermediates 
in the preparation of various nitrogen-containing 
natural products, and pharmaceutically important 
compounds.
[14] 
It is evidence that the reaction comprises two 
equilibrating constituents (imine formation and enol 
tautomerization) and therefore, demands harsh 
reaction conditions. Due to this, it is afflicted by 
some severe weaknesses, namely complex work-up, 
and purification procedures, and unwanted side 
products.
[15] 
From the first report of the Mannich 
reaction, numerous studies have published to 
improve the reaction conditions and present new and 
efficient catalysts for this reaction. The Mannich 
reactions of ketones, aldehydes, and amines have 
been reported through Lewis acid,
[16-19]
 Lewis 
base,
[20]
 Brønsted acids,
[21-23]
 Metal Triflates,
[24-27]
and transition metal salts.
[28-30]
 Even with the merits 
of these methodologies; use of transition metal 
compounds and heavy metal compounds as the 
catalyst, preparation of the catalyst, problems 
recycling and reusing of the catalysts, toxic reagents, 
and solvents, drastic reaction conditions, toxicity, or 
difficulty in product separation has persisted 
disquiets. Hence, the exploration of the newfangled 
green method has stagnant being keenly pursued. On 
the other hand, because of growing concerns about 
environmental effects; execution of organic 
reactions using organocatalyst has extremely needed 
in recent years. Apart from being environmentally 
friendly, organocatalyst has obeyed green chemistry 
principle like casings mild conditions, consequently 
saving energy, oxygen-stable reagents and does not 
require anhydrous conditions, reducing the cost of 
the synthesis, less toxic and safer substances, stop 
the creation of metallic waste and avoids traces of 
Vietnam Journal of Chemistry Pramod Kulkarni 
© 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 676 
metals in the products.
[31]
 Here, we have used 
Sulfanilic acid as organocatalyst in a one-pot three-
component Mannich reaction for the synthesis of β-
amino ketone. 
Figure 1: Medicinal properties of β-amino ketone 
Sulfanilic acid is valuable, low-cost, and eco-
friendly, and occurs as a grayish-white powder, 
which is stable and incompatible with strong 
oxidizing agents. The literature survey reveals that it 
has been applied as a catalyst for the synthesis of a 
variety of heterocyclic compounds.
[32-39]
 The 
sulfanilic acid that occurs in solid form is present as 
a zwitterion. Sulfonic acid groups (-SO3H) can be 
deprotonated to become negative sulfonate (-SO3
-
) 
and amino groups which can be protonated to 
become positive ammonium groups (-NH3
+
). The 
zwitterionic property of sulfanilic acid may be 
responsible for the excellent catalytic property in 
organic synthesis. Sulfanilic acid is commercially 
available, economical, non polluting and easy to 
handle, non-inflammable, and a stable catalyst 
related to other organoacid catalysts which are 
eroding, costly and afford intensely acidic 
conditions.
[40]
 Here we reported the use of sulfanilic 
as organocatalyst in one-pot three-component 
Mannich reaction for the synthesis of β-amino 
ketone. 
2. MATERIALS AND METHODS 
All the starting materials were got from 
commercially accessible sources and used without 
further purifi ... ituted aryl aldehydes have given the 
corresponding product, in moderate yield, due to its 
higher crowded steric effects. 
Scheme 4: Sulfanilic acid-catalyzed one-pot three-component Mannich reaction between cyclohexanone, 
substituted benzaldehyde and aniline 
Table 4: Sulfanilic acid catalyzed Mannich reactions of ketones, various aldehydes and aniline
a
Entry Aldehyde Product Time (min.) % Yield
b
 p.p. (
o
C) 
1 
4
a 
15 93 141-142 [41] 
2 
4b 
25 90 113-115 [42] 
3 
4c 
65 45 127-129 
4 
4
d 
81 78 145-147 [41] 
5 
4e 
84 125 157 
Vietnam Journal of Chemistry Sulfanilic acid catalysed one-pot three-component 
© 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 683 
6 
4f 
60 89 136-137 [43] 
7 
4g 
35 82 127-128 
8 
4
h 
10 88 154-155 [42] 
9 
4i 
15 76 125-177 
10 
4j 
45 80 171-172 
a
: Reaction condition: 5 mmol of Cyclohexanone, 5 mmol of aldehyde, 5 mmol of aniline and 20 mol% of sulfanilic 
acid in 10 ml ethanol under stirring condition at RT. 
b
: All yields of isolated product.
Next, we have extended the scope of the reaction 
with an aromatic ketone, various aromatic 
aldehydes, and various aromatic amine (scheme 5). 
The reaction has well proceeded with electron-
donating and electron-withdrawing groups on 
aromatic aldehydes (table 5). The ortho-substituted 
benzaldehydes have been afforded a low yield due to 
steric hindrance. The 2-nitrobenzaldehyde did not 
give product due to, –M, -I, and steric effect. The 
reaction has proceeded well with aromatic amines, 
with electron-donating as well as an electron-
withdrawing group. The ortho-substituted anilines 
with an electron-donating group have been afforded 
the low yield due to steric hindrance, while the 
electron-withdrawing group has not been afforded 
the product due to –M, -I, and steric effect.
Scheme 5: Sulfanilic acid - catalyzed one-pot three-component Mannich reaction between acetophenone, 
substituted benzaldehyde and substituted aniline
Vietnam Journal of Chemistry Pramod Kulkarni 
© 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 684 
Table 5: Sulfanilic acid catalyzed Mannich reactions of acetophenone, aldehydes and substituted anilines
a
Entry Aldehyde Amines Product (8) Time (min.) Yield
b
 m.p. (ºC) 
1 
8a 
2 76 212 
2 
8b 
600 NR
c
 - 
3 
8c 
400 82 164-166 
[44] 
4 
8d 
30 85 161-162 
[45] 
5 
8e 
240 78 113-114 
[46] 
6 
8f 
90 82 137-139 
7 
8g 
45 70 118 
8 
8h 
43 73 108 
9 
8i 
500 40 145-147 
Vietnam Journal of Chemistry Sulfanilic acid catalysed one-pot three-component 
© 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 685 
10 
8j 
500 33 140-142 
11 
8k 
45 24 109-111 
12 
8l 
3 82 126-128 
13 
8m 
125 78 134-137 
14 
8n 
2 62 181-184 
15 
8o 
200 60 164-166 
16 
8p 
230 74 169-172 
17 
8q 
400 NR
c
 -- 
18 
8r 
360 NR
c
 - 
a
: Reaction condition: 5 mmol of acetophenone, 5 mmol of substituted aldehyde, 5 mmol of substituted aniline and 20 
mol% of catalyst in 10 ml ethanol under stirring condition at RT. 
b
: All yields of isolated product. 
c
NR: no reaction. 
Vietnam Journal of Chemistry Pramod Kulkarni 
© 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 686 
4. CONCLUSION 
Here we report, an efficient synthesis of a series of 
β-amino carbonyl compounds from various ketones, 
aldehydes, and anilines using sulfanilic acid as an 
organocatalyst. The method has been congenial with 
various functional groups present on the aryl 
aldehydes, and anilines. The better yield of the 
product was perceived in the solvent than solvent-
free conditions, and ethanol was found to be a best 
solvent for the reaction. The method has offered 
several merits, which include a small amount of 
catalyst loading, functional group tolerance, mild 
conditions, operational easiness, high yield, use of 
non-hazardous chemicals, and ecofriendly method. 
REFERENCES 
1. A. Davoodnia, A. Tavakoli-Nishaburi, N. Tayakoli-
Hoseini. Carbon-based solid acid catalyzed one-pot 
Mannich reaction: A facile synthesis of β-amino 
carbonyl compounds, Bull. Korean Chem. Soc., 2011, 
32, 635-638. 
2. G. X. Tang, J. F.Yan, L. Fan, J. Xu, X. L. Song, L. 
Jiang, L. F. Luo, D. C. Yang. Synthesis of novel β-
amino ketones containing a p-aminobenzoic acid 
moiety and evaluation of their antidiabetic activities, 
Science China Chemistry, 2013, 56, 490-504. 
3. H. I. Gul, A. A. Denizci, E. Erciyas. Antimicrobial 
evaluation of some Mannich bases of acetophenones 
and representative quaternary derivatives, 
Arzneimittelforschung, 2002, 52, 773-777. 
4. H. I. Gul, U. Calis, J. Vepsalainen. Synthesis of some 
mono-Mannich bases and corresponding azines 
derivatives and evaluation of their anticonvulsant 
activity, Arzneimittelforschung, 2004, 54, 359-364. 
5. H. I. Gul, A. Demirtas, G. Ucar, P. Taslimi, I. Gulcin. 
Synthesis of Mannich bases by two different methods 
and evaluation of their acetylcholine esterase and 
carbonic anhydrase inhibitory activities, Lett. Drug 
Design & Discovery, 2017, 14, 573-580. 
6. J. R Dimmock, K. K. Sidhu, M. Chen, R. S. Reid, T. 
M. Allen, G. A. Truitt. Evaluation of some Mannich 
bases of cycloalkanones and related compounds for 
cytotoxic activity, Eur. J. Med. Chem., 1993, 28, 
313-322. 
7. H. I. Gul, T. Ojanen, O. Hanninen. Antifungal 
evaluation of bis Mannich bases derived from 
acetophenones and their corresponding piperidinols, 
Biol. Pharm. Bull., 2002, 25, 1307-1310. 
8. K. K. Sivakumar, A. Rajasekaran, P. Senthilkumar, 
P. P. Wattamwar. Conventional and microwave 
assisted synthesis of pyrazolone Mannich bases 
possessing anti-inflammatory, analgesic, ulcerogenic 
effect and antimicrobial properties, Bioorg. Med. 
Chem. Lett., 2014, 24, 2940-2944. 
9. R. Kenchappa, Y. D. Bodke, S. K. Peethambar, S. 
Telkar, V. K. Bhovi. Synthesis of β-amino carbonyl 
derivatives of coumarin and benzofuran and 
evaluation of their biological activity, Med. Chem. 
Es., 2013, 22, 4787-4797. 
10. A. Arnold, F. Zhul, A. Kosinskil, T. J. Mangano, V. 
Setola, B. L. Roth, R. K. Guy. Improvement of 
pharmacological properties of irreversible thyroid 
receptor coactivator binding inhibitors, J. Med. 
Chem., 2009, 52, 3892-3901. 
11. M. L. Edwards, H. W. Ritter, D. M. Stemerick, K. T. 
Stewart. Mannich bases of 4-phenyl-3-buten-2-one. 
A new class of antiherpes agent, J. Med. Chem., 
1983, 26, 431-436. 
12. R. F. Maisey, G. Jones, A. R. Somerville, B. A. 
Whittle. Substituted 1,1-diphenyl-3-aminoprop-1-
enes and 1,1-diphenyl-3-aminopropanes as potential 
antidepressant agents, J. Med. Chem., 1971, 14, 161-
164. 
13. E. Mete, H. I. Gul, C. Kazaz. Synthesis of 1-aryl-3-
phenethylamino-1-propanone hydrochlorides as 
possible potent cytotoxic agents, Molecules, 2007, 
12, 2579-2588. 
14. R. Müller, H. Goesmann, H. Waldmann. N, N-
Phthaloylamino acids as chiral auxiliaries in 
asymmetric Mannich-type reactions, Angew. Chem. 
Int. Ed., 1999, 38, 184-187. 
15. C-T. Chang, B-S. Liao, S-T. Liu. Mannich-type 
reactions in a colloidal solution formed by sodium 
tetrakis(3,5-trifluoromethylphenyl)borate as a 
catalyst in water, Tetrahedron Lett., 2006, 47, 9257-
9259. 
16. S. S. Mansoor, K. Aswin, K. Logaiya, S. P. N. 
Sudhan. An efficient synthesis of β-amino ketone 
compounds through one-pot three-component 
Mannich-type reactions using bismuth nitrate as 
catalyst, J. Saudi Chem. Soc., 2015, 19, 379-386. 
17. Y. Wu, X. Wang, Y. Luo, J. Wang, Y. Jian, H. Sun, 
G. Zhang, W. Zhang, Z. Gao. Solvent strategy for 
unleashing the Lewis acidity of titanocene dichloride 
for rapid Mannich reaction, RSC Adv., 2016, 6, 
15298-15303. 
18. Y. Zhang, J. Han, Z-J. Liu. Diaryliodonium salts as 
efficient Lewis acid catalysts for direct three 
component Mannich reactions, RSC Adv., 2015, 5, 
28485-25488. 
19. R. Qiu, X. Xu, L. Peng, N. Li, S. Yin. Strong Lewis 
acids of air-stable metallocene 
bis(perfluorooctanesulfonate)s as high-efficiency 
catalysts for carbonyl-group transformation reactions, 
Chem. Eur. J., 2012, 18, 6172-6182. 
20. Q. Guo, J. C-G. hao, H. Arman. Base-catalyzed 
three-component direct Mannich reaction of 
enolizable ketones with high syn-selectivities, 
Tetrahedron Lett., 2012, 53, 4866-4869. 
21. Akiyama, J. Takaya, H. Kagoshima. Brønsted acid- 
catalyzed Mannich-type reactions in aqueous media, 
Adv. Synth. Cataly., 2002, 344, 338-347. 
22. T. Akiyama, K. Matsuda, K. Fuchibe. HCl-catalyzed 
stereoselective Mannich reaction in H2O-SDS 
system, Synlett, 2005, 322-324. 
23. M. Barbero, S. Cadamuro, S. Dughera. Brønsted acid 
Vietnam Journal of Chemistry Sulfanilic acid catalysed one-pot three-component 
© 2020 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 687 
catalyzed enantio- and diastereoselective one-pot 
three component Mannich reaction, Tetrahedron: 
Asymmetry, 2015, 26, 1180-1188. 
24. S-B. Han, J-Y. Wei, X-C. Peng, R. Liu, S-S. Gong, 
Q. Sun. Hf(OTf)4 as a highly potent catalyst for the 
synthesis of Mannich bases under solvent-free 
conditions, Molecules, 2020, 25, 388. DOI: 
https://doi.org/10.3390/molecules25020388. 
25. T. Ollevier, E. Nadeau. Bismuth Triflate-catalyzed 
three-component Mannich-type reaction, J. Org. 
Chem., 2004, 69, 9292-9295. 
26. S. Yamasaki, T. Iida, M. Shibasaki. Direct catalytic 
asymmetric Mannich reaction of unmodified ketones: 
cooperative catalysis of an AlLi bis(binaphthoxide) 
complex and La(OTf)3.nH2O, Tetrahedron, 1999, 55, 
8857-8867. 
27. Y-Y. Yang, W-G. Shou, Y-G. Wang. Synthesis of β-
amino carbonyl compounds via a Zn(OTf)2-catalyzed 
cascade reaction of anilines with aromatic aldehydes 
and carbonyl compounds, Tetrahedron, 2006, 62, 
10079-10086. 
28. S. Pal, L. H. Choudhury, T. Arvin. VCl3 catalyzed 
imine-based multicomponent reactions for the facile 
access of functionalized tetrahydropyridines and β-
amino carbonyls, Mol. Diver., 2012, 16, 129-143. 
29. R. Wang, B. Li, T. Huang, L. Shi, X. Lu. NbCl5 - 
catalyzed one-pot Mannich-type reaction: three 
component synthesis of β-amino carbonyl 
compounds, Tetrahedron Lett., 2007, 48, 2071-2073. 
30. B. Eftekhari-Sis, A. Abdollahifar, M. M. Hashemi, 
M. Zirak. Stereoselective synthesis of β-amino 
ketones via direct Mannich-type reactions, catalyzed 
with ZrOCl2.8H2O under solvent-free conditions, 
Eur. J. Org., 2006, 5152-5157. 
31. V. G. Oliveira, M. F. C. Cardoso, L. S. M. Forezi. 
Organocatalysis: A brief overview on its evolution 
and applications, Catalysts, 2018, 8, 605. 
32. H. Kiyani, A. Mosallanezhad. Sulfanilic acid-
catalyzed synthesis of 4-arylidene-3-substituted 
isoxazole-5(4H)-ones, Current Org. Synth., 2018, 15, 
715-722. 
33. R. M. Borik. Comparison on microwave and 
ultrasound accelerated synthetic route to 
dihydropyrimidinones catalyzed by sulfanilic acid in 
water, Aus. J. Basic and Applied Sci., 2013, 7, 543-
547. 
34. U. P. Tarpada, B. B. Thummar, D. K. Raval. A green 
protocol for the synthesis of quinoxaline derivatives 
catalyzed by polymer supported sulphanilic acid, 
Arabian J. Chem., 2017, 10, S2902-S2907. 
35. J. N. Sangsheeti, N. D. Kokare, D. B. Shinde. 
Sulfanilic acid catalyzed solvent-free synthesis of 
1,5-benzodiazepine derivatives, Chinese Chem. Lett., 
2007, 18, 1305-1308. 
36. H. M. Mirzaei, B. Karimi. Sulfanilic acid as a 
recyclable bifunctional organocatalyst in the selective 
conversion of lignocellulosic biomass to 5-HMF, 
Green Chem., 2016, 18, 2282-2286. 
37. B. Kumar, N. S. Rathore, K. L. Ameta. Synthesis of 
some new substituted oxiranes from 4’-hydroxy-3’5’-
dinitrochalcones and their sulfanilic acid-catalyzed 
aminolysis, Res. Chem. Intermed., 2014, 40, 555-567. 
38. A. F. Mohammed, N. D. Kokare, J. N. Sangshetti, D. 
B. Shinde. Sulfanilic acid catalyzed facile one-pot 
synthesis of 2,4,5-triarylimidazoles from 
benzyl/benzoin and aromatic aldehydes, J. Korean 
Chem. Soc., 2007, 51, 418-422. 
39. F. Adam, K. M. Hello, T. H. Ali. Solvent free liquid-
phase alkylation of phenol over solid sulfanilic acid 
catalyst, Applied Catalysis A: General, 2011, 399, 
42-49. 
40. R. K. Singh, B. Singh, R. Duvedi, S. Kumar. 
Sulfanilic acid: a versatile and efficient catalyst 
amongst various organoacids screened for the 
synthesis of 1-amido-2-naphthols under solvent-free 
condition, Res. Chem. Intermed., 2015, 41, 4083-
4099. 
41. Q. Xu, Z. Yang, D. Yin, J. Wang. One-pot three-
component Mannich reaction catalyzed by sucrose 
char sulfonic acid, Front. Chem. Eng. China, 2009, 3, 
201-205. 
42. J. Li-li, L. Yun-tao. One-pot three-component 
Mannich reaction catalyzed by 2-hydroxylpyridine, 
Chem. Res. Chin. Univ., 2013, 29, 710-713. 
43. M. Kidwai, A. Jahan. Cerium chloride as a highly 
efficient catalyst for one-pot three-component 
Mannich reaction, J. Braz. Chem. Soc., 2010, 21, 
21125-2179. 
44. V. Yekkirala, R. K. Sudhagani, L. Panuganti. 
Yttrium(III) chloride catalyzed Mannich reaction: An 
efficient procedure for the synthesis of β-amino 
carbonyl compounds, Org. Commun., 2014, 7, 123-
129. 
45. H. Li, H. Zeng, H. Shao. Bismuth(III) chloride-
catalyzed one-pot Mannich reaction: three component 
synthesis of β-amino carbonyl compounds, 
Tetrahedron Lett., 2009, 50, 6858-6860. 
46. B. Zhao, L. Jiang, Z. Liu, D. Qigang, L. Wang, B. 
Song, Y. Gao. Microwave-assisted Michael addition 
of 2-amino pyridine to chalcones under catalyst-free 
conditions, Res. Chem. Intermed., 2015, 49, 5809-
5819.
Corresponding author: Pramod Kulkarni 
Department of Chemistry, Hutatma Rajguru Mahavidyalaya 
Rajgurunagar, Pune-410505, MS India 
E-mail: pramodskulkarni3@gmail.com.