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Green Trends in Mannich Reaction Send Orders for Reprints to [email protected] Mini-Reviews in Organic Chemistry, 2014, 11, 97-115 97 Green Trends in Mannich Reaction W. Sreevalli1, G. Ramachandran1, W. Madhuri2 and Kulathu Iyer Sathiyanarayanan1* 1Chemistry Division, School of Advanced Sciences, VIT University, Vellore – 632 014, India; 2Physics Division, School of Advanced Sciences, VIT University, Vellore – 632 014, India Abstract: The reflection of green chemistry for the synthesis of a wide range of compounds via multi-component reaction systems is discussed in this paper. It also describes the most interesting, atom-economic Mannich and Mannich type reac- tions, their processes via green methods, solvents, green solvents, solvent effects, catalysts, catalyst effects, selectivity, ki- netics, etc. They are indeed environmentally and ecologically benign. Keywords: Mannich reaction, Green Chemistry, Water. INTRODUCTION DISCUSSION Chemistry, for centuries, has been a developing, an Due to the rapidly increasing growth in all fields of the investigating and an interesting field of science. However, present day society, especially in chemistry, where the the toxicity occurring as a result of chemical processes scientists are basically responsible for avoiding usage of remains a severe problem for maintaining ecological hazardous chemicals and for ensuring the production of equilibrium and more importantly for environmental entropy potential eco-friendly products that possess variety of for the present as well as the future generations. This applications, it is considered important. All these facts requires the help of green chemistry [1]. Green chemistry emerged into “The concept of Green Chemistry”. Since its mainly involves the usage of eco-friendly solvents, catalysts, origin for more than a decade ago, green chemistry has been resulting in no wastages of starting materials, and conversion striving to meet various challenges by following the 12 basic of the maximum or all the starting materials into the desired principles laid down by Paul Anastas and John Warner. A product. few of the most important principles are atom economy, tandem reaction, less usage or no wastage of solvents and To evaluate the green methods mentioned above, usage of green solvents. Organic reactions in aqueous media Mannich or Mannich type reactions are the most relevant have attracted a great deal of attention because they induce ones. The reaction is a good example of carbon-carbon bond unique selectivity and reactivity which are not observed in forming [2] and a multi-component reaction (MCR). The reaction is named after Carl Mannich who first reported the the reactions of organic media. Due to the use of water as a solvent, it reduces the use of harmful organic solvents and reaction [3]. Classical Mannich reaction is understood as an could lead to the development of eco-friendly chemical amine-exchange reaction which precedes both by processes. substitution as well as by an elimination-addition mechanism [4]. In recent developments, Mannich reaction is understood as MCR of a non-enolisable aldehyde, a primary or ATOM ECONOMY secondary amine and an enolisable carbonyl compound to A chemical synthesis either conventional or green is afford β-amino carbonyl compounds (Scheme 1), which in fundamentally a reaction, which includes starting materials, many cases is catalyzed by organic or inorganic acids, L- solvent(s), catalyst(s), and additive(s). In green methodology proline, adinine, etc. The particular interest in Mannich a reaction has to generate substance(s) that possess little or reaction is due to the fact that β-amino carbonyl compounds no toxicity to human health or environment. Here, to are nitrogen containing intermediates which, in most cases, calculate the percentage of yield of product production, atom are biologically active compounds for the synthesis of economy [7] is best followed as denoted in (Fig. 1). natural products, plant growth regulators [5], pharmaceutical compounds [6] etc. This implies that the product must have maximum incorporation of the starting materials, less consumption or wastage of solvents. In correlation with atom economy, H R N R HN + O + another important concept of green chemistry is the H O development of tandem/cascade reaction processes. A simple O example of tandem process is palladium catalyzed multi- Scheme 1. Synthetic route for the three components Mannich rings formation in one step as shown in (Scheme 2) [8]. Reaction. SOLVENTS *Address correspondence to this author at the Chemistry Division, School Solvents are auxiliary materials for a conventional of Advanced Sciences, VIT University, Vellore - 632 014, India; Tel: +91 416 2249816; Fax: +91 416 2243092; method of reaction. Usually, the solvents used are organic E-mail: [email protected] which cause health and environmental pollution, as most of 1875-6298/14 $58.00+.00 © 2014 Bentham Science Publishers 98 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 Sreevalli et al. Reaction Yield = (Quantity of product isolated / Theoretical quantity of product) ×100! Atom Economy = (Molecular weight of desired product / Molecular weight of all products) ×100%.! Fig. (1). Definition of the fundamental difference in the manner in which the reaction and the atom economy yields are generated. OCH3 OCH3 PhO2S PhO S 2 PhO2S PhO2S 2.5%(dba)3Pd2ICHCl3 Ph3P, HOAc PhH, 50 oC Scheme 2. Multiple conversions in a single step- tandem reaction. H2O + + O COCH3 COCH3 Scheme 3. Diels-alder reaction in water. the solvents are water immiscible and are not easily solvents or catalysts. One of the latest trends is solvent-free biodegradable. The conventional method includes the use of reactions, which employ microwave irradiations and organic solvents for dissolving the starting materials and as a ultrasound sonications. In the present context of green medium for the reaction to occur. After the reaction is methods in Mannich reaction, the usage and the effects of complete, the product most of the times is in a dissolved the above solvents and catalysts are discussed. state and has to be separated in pure form. For all these to happen, organic solvents are being used in large quantities WATER and are the main and major source of wastages causing health and environmental hazards [9-11]. Conventional organic synthesis understands water [13, 14] as a contaminant and hence, more precautions have to be Based on the above criteria, a solvent, to be green, has to taken by the chemist to perform a complete anhydrous follow the twelve principles of green chemistry such as atom reaction. But the recent developments in green chemistry and economy, recyclability, safety etc., and can be defined as an the usage of water as a solvent have proved to have healthier, ideal solvent which allows the mass transfer but does not get economical and environmental benefits. The physical and dissolved. chemical properties of water, like large surface tension, high In addition, a green solvent is one that is naturally non- specific heat, network of hydrogen bonding etc. lead to toxic, easily available and cheap. A natural and readily special reactivity and selectivity of the reaction which cannot available solvent on earth is water. Life in water makes be attained with conventional organic solvents make it chemicals bond very easily but as far as organic synthesis is unique. Finally, the isolation of product from water becomes concerned, most organic compounds do not dissolve in easy because in many cases it is not soluble in water and water. In such cases, water acts as a medium wherein the un- thus, can be easily filtered off or separated. dissolved compounds float and get reacted. Thus, the primary usage of water in organic reactions was reported by The usage of water in Mannich/ Mannich type reactions Diels-Alder [12] (Scheme 3). is in pure form as a solvent/additive, and in most cases is differently catalyzed. One of the primary studies of Mannich In contrast to water, another natural solvent is CO2, either reaction in pure water was done by Loh T.P. and co workers liquid or Supercritical Carbon dioxide (ScCO2). Although [15, 16] using indium chloride as catalyst, which resulted in some energy is consumed in its production, ScCO2 has moderate to good yields. The reaction was of an aldehyde, an different features compared to water; as it readily evaporates, amine and ester or ketone derived silyl enol ether to obtain is an easily dissolving organic compound of low viscosity, the corresponding β amino esters or ketones as shown in non-inflammable, fast drying and has better fluidity. These (Scheme 4). A similar Mannich reaction of cyclic ketone features make ScCO2 a better green solvent for organic derived silyl enol ethers and aldimines in presence of synthesis. Zn(BF4)2 in THF/H2O media leading to β amino ketones in a Other non-natural solvents which are less toxic compared short time (Scheme 5) [17]. Kabayashi et al. also reported to conventional organic solvents are ionic liquids (ILs) and that ZnF2 catalyzed Mannich type reaction of a hydrazine surfactants. These ILs and surfactants are also used as co- ester with silyl enol ethers in water with acidic additives of Green Trends in Mannich Reaction Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 99 CHO NH 2 Ph R R1 InCl3 NH O + + H O 2 Ph OCH3 H3CO OTMS R R1 Yield :57% R=R1=Me Yield :75% R=R1=H Scheme 4. Indium chloride catalyzed Mannich reaction in water. Ph Ph reactions using water as additive is with unmodified N 6 min NH O aldehydes and N-paramethoxy phenyl (N-PMP) protected α- + 40% Aq Zn(BF ) imino ethyl glyoxylate catalyzed by L-proline and the only Ph Ph OTMS 4 4 Ph Ph THF:H2O=1:1 detectable product being β-formyl functionalized-α-amino ester (Scheme 8) [23]. Scheme 5. Zn (BF ) catalyzed Mannich reaction in water. 4 2 It has been recently proved by Li Gang [24] and co- TfOH gives good yields with high enantioselectivity workers that Mannich reaction in water catalyzed by liquid (Scheme 6) [18, 19].
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