Green Trends in Mannich Reaction

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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 reactions, their processes via green methods, solvents, green solvents, solvent effects, catalysts, catalyst effects, selectivity, kinetics, 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

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]. trifluoromethane sulfonic acid yields considerably well rather than in organic solvents as shown (Scheme 9). The The positive effect of water, as an additive in FeCl 2 common Brønsted acid H2SO4 and CH3SO3H were hardly and C-3,3’-I2-BINOL(1,1’-binaphthalen-2,2’-diol) catalyzed active for the Mannich reaction in water under the same Mannich reaction is remarkable, and the desired product was condition (entries 2, 3 in Table 1). obtained in good yield with good to high enantioselectivity. Though the highest yield has been reported with methanol, The Mannich reaction catalyzed by trifluoromethane water also showed better yields as shown (Scheme 7) [20]. sulfonic acid was also carried out in organic solvents, such On the other hand, Cordova and co-workers found water (2-5 as alcohol and dichloromethane, but its catalysis activity in equiv.) accelerated three-component Mannich reaction organic solvent was less than that in water (entries 4, 5 in catalyzed by proline or serine [21, 22]. The approach for Table 1). The recycling performance of trifluoromethane excellent diastereo and enantioselectivities via Mannich type sulfonic acid catalyzed Mannich reaction was also

ZnF2(50mol%) NHBz TfOH(1mol%) N H O/THF=1/9, 0 °C BzHN OSiMe3 2 NH O EtO + H Ph Ph EtO Ph Ph O O NH HN Yield: 89% ee>92% Ph 10mol% Ph

Scheme 6. ZnF2 catalyzed Mannich type reaction of a hydrazine ester with silyl enol ethers in water.

HO FeCl2(10mol%) HO (R)-3,3'-I2BINOL(11mol%) OSiMe3 i-Pr2NEt(25mol%) N additive(mol%) HN + OMe H CH3CN,0 °C, 16h COOMe

additive= none, 62% yield, 56%ee: additive= water(20mol%), 69% yield, 61%ee: additive= methanol(100mol%), 73% yield, 68%ee:

Scheme 7. FeCl2 catalyzed Mannich reaction with water as an additive.

PMP O N L-Proline(10mol%) PMP + NH O EtO H H 1/9 H O/THF, rt,24h EtO R 2 H O O R

R = CH2CH=CH(CH2)4CH3 Yield=88%;ee>99

Scheme 8. L-proline catalyzed Mannich reaction with water as an additive. 100 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 Sreevalli et al.

CHO O NH2 Ph NH O CH 10 mol % cat + + 3 3 mL solvent, rt Ph Ph Scheme 9. Liquid trifluoromethane sulfonic acid catalyzed Mannich reaction with water as solvent.

Table 1. Screening of Trifluoromethane Sulfonic Acid with Different Solvents for Mannich Reaction

Entry Catalyst Solvent Time h Yield, %

1 CF3SO3H H2O 18 93

2 H2SO4 H2O 24 0

3 CH3SO3H H2O 24 11

4 CF3SO3H EtOH 18 85

5 CF3SO3H DCM 18 72

6 CF3SO3H H2O 18 84(First recycle)

7 CF3SO3H H2O 18 57(Second recycle)

B(OH)2 R R1 O N HO HO + H B O HO R1 Ph O N R HO O R 1 O N R H Scheme 10. Example of a Petasis-borono-Mannich reaction. investigated under the same condition (entries 6, 7 in Table IONIC LIQUIDS-ILs 1). One more interesting Mannich type reaction in water is Ionic liquids are low temperature melting salts. Due to Petassis Borono Mannich Reaction [25-27], (named after their very high vapour pressure and high polarity, they Petassis who first used boronic acids for Mannich reaction) contribute to green chemistry and are replaced by (Scheme 10). conventional organic solvents. They even dissolve cellulose [31]. It is usually assumed that the first IL is ethyl SUPERCRITICAL CARBON DIOXIDE- ScCO2 ammonium nitrate described in 1914 by Walden. Later, the first generation of ILs emerged. These included dialkylimi- CO2 is an inexpensive, readily available, non-toxic, non- inflammable, and chemically inert gas and can be easily dazolium and dialkaly pyridinium derivatives as cations and liquefiable at reasonable pressures. The critical point of CO anions included chloroaluminates and other metal halides. 2 Nevertheless, these were found to be sensitive to water and is at 31°C and 73 atm. below this point liquid CO2 can be maintained under relatively modest pressure [28] (about 950 air which hampered their applicability. Then, in the second psi at 25°C). Above 31°C, no amount of pressure will serve generation of ILs, anions were modified to weakly coordinating anions alike BF4 or PF6 which proved to be to liquefy CO2-there exists only the supercritical fluid phase that behaves as a gas. Though highly compressed fluid is stable in water and air, thus, leading to a path for an improved research of green chemistry. Recently, the third denser than liquid CO2, the sub critical liquid phase of CO2 behaves like any other liquid while the ScCO can also act as generation of ILs has emerged. This comprises biodegrad- 2 able and readily available ions such as naturally occurring a solvent. But the ScCO2 has higher diffusivity, lower viscosity and lower surface tension than that of sub critical bases like amino acids (Ex: choline) and naturally occurring carboxylic acids. CO2 phase. Thus it is understood that ScCO2 has more advantages over liquid phase of CO2 as a solvent. A few important physical properties of ILs that make them a substitute for conventional organic solvents, as well ScCO in the synthesis of pharmaceutical products, has 2, as a potential alternative greener medium for organic been employed and has shown good efficiency as the synthesis are as follows: reaction media with good yields [29]. Further, ScCO2 is also employed for the separation of products from ionic liquids as i) High vapor pressure which makes them non-volatile ii) a co-solvent in extractions and as an anti-solvent in Poorly coordinating ions, resulting in high polarity iii) Good precipitation [30]. solvent for organic and inorganic materials to bring them Green Trends in Mannich Reaction Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 101

Ph Ph CHO NH NH NH2 O O O H2 H2 5 min Solvent Ph Ph + 1 H1 + H + N N Anti Syn HSO SO3H 4 Scheme 11. Usage of Bronsted IL in Mannich reaction.

CH2O HC(NO2)3 MeCONH2 [MeCONHCH OH] 2 MeCONHCH2C(NO2)3 [bmim][X] (75-81 %) K2CO3

X = BF4, PF6 Scheme 12. Usage of [bmim][X] in Mannich reaction.

Me NH2 Me NHCH OH 2 Me NHCH C(NO ) CH2O 2 2 3 HC(NO2)3 N N O [bmim][BF4] N N O O N K CO O O N 2 3 O (37%)

Scheme 13. Synthesis of 3-methyl-4-(2,2,2-trinitroehtyl) aminofuroxan using [bmim][BF4]. O

O H O CH3 X NH H 2 N N SO3H R + + O

rt R2 R1 R2

R1 Scheme 14. Mannich reaction in morpholine derived ILs is exemplified. into the same homogeneous system iv) Immiscible with most limdazolium tetrafluro borate and hexafluorophosphate of the organic solvents, thus providing a non-aqueous {[bmim][BF4] and [bmim][PF6] (Scheme 12). Similarly 3- biphasic medium v) Hydrophobic ionic liquids can also be methyl-4-(2,2,2-trinitroehtyl) aminofuroxan was obtained in used as immiscible polar phases with water. 37% yield in [bmim][BF4] (Scheme 13) as the solvent medium. Here the presence of trinitroethanol in ILs failed to A very simple example of the usage of ionic liquids in produce the Mannich products. Hence, in situ generation of three component Mannich reactions has been studied using N-hydroxy methyl intermediates, and then its treating with Bronsted acid IL as a catalyst with different solvents. The yield and anti-selectivity of the product has been proved to nitroform gave corresponding Mannich products. be good with Ethanol [32] (Scheme 11 and Table 2). Another investigation by Caibo Yue et al. [34], on economical ILs of morpholine derivatives as catalyst and Table 2. A Study of Bronsted IL Catalysis in Different solvent on a three components Mannich reaction of tandem Solvents type produced the required Mannich products (Scheme 14). Even asymmetric induction can be done using ILs with Entry Solvent % Yield Anti : Syn chirality [35-38]. The most common chiral ILs may have a chiral anion or a chiral cation (Fig. 2). A few chiral ILs are 1 CH2Cl2 40 80 : 20 exemplified in (Fig. 3).

2 CH3CN 50 95 : 05 Loh et al. [39, 40], have discussed the usage of InCl3 in 3 CH OH 76 82 : 18 Mannich reaction and chiral Mannich reaction. They used 3 chiral ILs (CILs) for the induction of chirality in Mannich 4 H2O 72 63 : 37 products using different CILs in InCl3 mediated reaction and studied their influence on the Mannich products formation 5 C2H5OH 86 88 : 12 (Scheme 15). Mannich reaction catalyzed by L-Proline [41] Very recently, the catalytic activity in Mannich reaction using CILs was studied. The reaction of N-p-methoxyphenyl of acetalamide, paraformaldehyde and nitroform has been protected α-imino ethyl glyoxolate and cyclohexanone using studied by Margarita A et al. [33], using 1-butyl-3-methy- [C4C1im] [X] gave the desired Mannich product with 99% ee 102 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 Sreevalli et al.

R R R1 R2 2 1 R R1 3 R P R N N R4 N R2 N Y 4 2 Y R Y Y N R 1 R2 R3 3 Y R1 R1=R3=alkyl R1=alkyl R =R =R = R2=H,alkyl 1 2 3 R1=R2=alkyl R1=R2=R3= R2=H,alkyl R =alkyl 4 R4=alkyl

Y = Cl, Br, BF4, ClO4, PF6, SbF6, NO3, MeCO2, CH2(OH)CO2, CF3SO3, MeSO3, OTs, N(CF3SO2)2, EtSO4, C8H17SO4 , (CF3CF2)PF3, (MeO) PO , CB H , Al(OC(CF )2Ph) , BARF 2 2 11 12 3 4 Fig. (2). Ionic liquids commonly used in enantioselective catalytic reactions.

where X is BF4 or PF6. The L-proline containing CIL phases N R N R4 were reutilized, and the third successive utilization showed N N 3 N R N just a slight decrease in yield. The study was extended to H 2 Ph know the content of catalyst loading in CILs to that of R1 organic solvents (Schemes 16 and 17). R1=H,R2=C4H9 R3 = OH, OAc R1 = CH3, R2 = C4H9 R4 = C4H9, C8H17, Commonly used dialkylimidazolium ionic liquids R1 = H, R2 = CH2CH2OH C10H21, C18H33 (bmimX) provide negligible biodegradability in the Closed R1 = CH3, R2 = CH2CH2OH Bottle Test (OECD 301 D), and the usual ionic liquids - - consist of halogen containing anions like [PF6] , [BF4] , - - - [CF3COO] , [CF3SO3] or [(CF3SO2)2N] which in some HO NTf 2 PF6 regard limit their ‘‘greenness” . Hence, Fang. D et al. [42], in N R 5 N O 2009, developed Brønsted acidic task-specific ionic liquids NTf (TSILs) to replace traditional mineral liquid acid catalysts HO 2 which are used as a catalyst in three component Mannich N reactions under aqueous media. The authors functionalized a novel ionic liquid 3-(N,N-dimethyl dodecylammonium) R5 = Me, n-Bu propane sulfonic acid hydrogen sulfate ([DDPA][HSO4]) HO CO2 [43-46]. The authors further screened out the best solvents OH R7 and appropriate catalytic amount for this reaction starting from cyclohexanone, benzaldehyde and aniline. The R CO screening of solvents showed that the reaction proceeded 6 2 HO OH N CO 2 smoothly with polar solvents C2H5OH (87%), MeOH (81%), OH Ac ACN (82%) and H O (80%) (Scheme 18). O 2 R6 = Ph, R7 = OH; SO3 R6 = Me, R7 = OH, NHBoc SURFACTANTS Fig. (3). Chiral cations and anions present in CILs used in Surfactants are surface active agents. They are enantioselective catalytic reactions. amphiphillic and lower the surface tension of the biphasic

R H O R [bmim][BF4] * + OTMS H3CO N CO2Me H2N CO2Me H InCl3 OCH 3 50-86%, upto 93/7 dr R = 4-ClC6H4, C6H5, napthyl, PhCH CH 2 2

Scheme 15. InCl3-catalyzed asymmetric Mannich type reaction in [bmim][BF4]. OMe MeO O

L-Proline O HN N + [C C im][BF ] 4 1 4 CO2Et H CO2Et

Scheme16. L- Proline catalyzed asymmetric Mannich reaction. Green Trends in Mannich Reaction Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 103

NH2 OMe O L-Proline R1 + + O HN O H R2 [C4C1im][BF4] R1 R OMe 2 R1 = H, allyl R2 = 4-NO2-Ph, 2-napthyl, sBu, CH2OCH2Ph Scheme 17. L- Proline catalyzed asymmetric three-component Mannich reaction.

CHO NH2 O O

[DDPA][HSO4] + + N H Solvent, rt

Solvent - Yield %; H2O - 80; EtOH -87; MeOH - 81; CH3CN - 82; CH2Cl2 - 65.

Scheme 18. Mannich-type reaction catalyzed by the [DDPA] [HSO4].

Fig. (4). Exemplified Classification of surfactants. system or the interfacial system represented as hydrophilic groups is present in the surfactant, it is termed as and hydrophobic. zwitterionic surfactant. Surfactants are ionic, non-ionic and amphoteric, as exemplified in (Fig. 4). Hydrocarbon chains are present in the "tail" of most surfactants that can branch like linear or aromatic. Siloxane Surfactants are better green solvents than the ILs for the surfactants contain siloxane chains, and fluorosurfactants obvious reason of high degree of biodegradability. The contain fluorocarbon chains. More significant surfactants surfactants, in combination with water, are used. The organic comprise a polyether chain that possesses a highly polar reactions catalyzed by Lewis acids are water sensitive and anionic group. Ethoxylated - polyethylene oxide groups are are done in anhydrous conditions. Kabayashi.S et al., have the major reason for enlarging the hydrophilic character of a reported that Lanthanum-La, Scandium-Sc, and Ytribium-Yb surfactant. Surfactant molecules contain either one tail or triflates are stable in water [47, 48]. The reaction proceeded two. If the surfactant possesses two tails, it is said to be smoothly in micellar systems [49-51] of aqueous solutions double-chained. Surfactants are classified depending on the with surfactants and their presence showed a remarkable polar head group. If there are no charge groups in its head, enhancement of the reactivity (Fig. 5). the surfactant is said to be a non-ionic surfactant, whereas if The system was successfully applied to three components the head of the surfactant carries a net charge, it is said to be Mannich type reaction of aldehydes, amines and silyl an ionic surfactant. If surfactants possess specifically enolates in water [52] (Scheme 19). negative charge then they are anionic surfactants, whereas if surfactants possess specifically positive charge they are Recently, a new type of catalyst, Lewis acid-surfactant cationic surfactants. If the head with two oppositely charged combined catalyst (LASC), has been developed [53]. LASC 104 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 Sreevalli et al.

Fig. (5). A cross section of Surfactant aggregates as micellar system. OMe OMe Sc(OTf) (5 mol %) OSiMe3 3 PhCHO + SDS (20 mol %) + NH O NH2 Ph H2O, rt Ph Ph

87%

Scheme 19. Sc tris (dodecyl sulfate) Sc(DS)3 catalyzed Mannich reaction in water. O OSiMe OH 3 Catalyst/Additive PhCHO + Ph Ph Water/rt Ph

Catalyst/additive Yield Sc(OTf)3 3 Sc(OTf)3-surfactant (SDS ) 88 Sc(DS)3 92

O O Sc(DS) = Sc S 3 O O * 3

Scheme 20. Sc tris (dodecyl sulfate) Sc(DS)3 catalyzed reaction in water. is composed of water stable Lewis acid cations such as Sc The usage of non-ionic surfactants (like Triton X-100) is and anionic surfactants such as dodecyl sulfate and dodecane rarely reported. Triton X-100 is commonly used in biological sulfate, which are easily prepared. This shows a dual systems [56, 57] as a solubilizer, emulsifier and complexing activity-as a Lewis acid and as a catalyst. It also solubilizes agent in aqueous and non-aqueous media. The non-ionic the organic substrates as reactants in the aqueous medium. A surfactants have a tendency to absorb at interfaces and to very good example of such LASC is Sc tris (dodecyl sulfate) form micelles beyond their critical micelle concentration [58, Sc(DS)3 (Scheme 20) [54, 55]. The work up procedure is 59]. The notable advantage of non-ionic surfactants over simple. Just centrifugation of the reaction mixture leads to ionic surfactants is the absence of electrical double layer. the phase separation without addition of any organic Atul Kumar et al., have recently developed a highly efficient solvents. method of preparation using a non-ionic surfactant catalyzed Green Trends in Mannich Reaction Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 105

OH CHO OH N Triton X-100 (20 mol %) + + N H O O Water O O 89 % Scheme 21. Synthesis of benzylaminocoumarin derivative catalyzed by surfactant-Triton X-100. O O O O R + RNH2 NHR R'C(OR'')3 N N O H-Y-Zeolite NH H 2 MW N R' Scheme 22. Preparation of 2-substituted aminobenzamides by microwave irradiations.

Table 3. Microwave Irradiated Solvent-free Three Component Mannich Reaction with Different Substitutions

S.No. R R1 Yield % Anti/Syn

1 Benzaldehyde t-butyl aniline 87 100: 0

2 2-Chloro benzaldehyde 4-Cyano Aniline 95 100: 0

3 2-Fluoro benzaldehyde 3,4-Difluoro aniline 88 100: 0

4 Pyridine-4-carboxaldehyde 2-Methyl-5-aminoindole 88 100: 0 multi-component synthesis of benzylamino coumarin derivatives of 2-hydroxychalcones were synthesized in good derivatives via one pot Mannich type reaction among to excellent yields by microwave assisted Mannich reactions different aromatic aldehydes, secondary amines and 4- [64]. hydroxy coumarin (Scheme 21). The authors were successful O R1 in producing the desired 3-substituted coumarins without the O HN formation of bis product by studying the effect of various R CHO CeCl3 MW ionic and non-ionic surfactants. They observed that Triton + 3 min R X-100 was the best surfactant for the reaction [60]. R1 NH2 Solventfree

SOLVENT FREE REACTIONS Scheme 23. Microwave irradiated solvent-free three component Mannich reaction. The concept of solvent free reactions itself is a green method as it does not include any organic solvent(s). In ULTRASOUND IRRADIATION/ULTRA SONICA- recent developments, the solvent free reactions are done TIONS under microwave irradiations, ultrasound sonication [61] etc. These methods are advantageous over conventional organic As a part of green chemistry innovations, ultrasound synthesis with solvents such as mild conditions, shorter sonication has recently emerged as one of the most widely reaction time, and in many cases give high yields, provide used methods [65]. Various methodologies and mechanisms easy work up and are mostly less toxic. have been evolved to develop sonochemistry. Sono- chemistry, being an innovative and powerful technique, has MICROWAVE IRRADIATED REACTION’S attracted increasing interest in accelerating organic reaction [66]. The interesting features of ultrasound approach are M. Bakavoli et al., have developed a solvent free mild conditions, acceleration of reaction rates, considerably synthesis of 2-amino-N-substitued benzamides under shorter reaction time, and formation of pure, selective microwave irradiations and then H-Y-zeolietes induced products with good to excellent yields. Ultra sonication also hetero cyclization gave substituted quinozolin-4(3H)ones in conserves energy, minimizes use/wastage of solvents over high yields (Scheme 22) [62]. traditional methods [67] and has attracted an increasing A simple reaction of aromatic aldehydes and amines, attention in the past two decades [68, 69]. under microwave irradiation and solvent free conditions to Wei-Yi Chen et al., in 2009 reported a novel solvent free afford β amino ketone has been recently reported [63]. This protocol for direct vinylogous Mannich reaction with α,α- method requires very small amount of catalyst, CeCl3 and dicyano olefins and BOC-protected α amide sulfones in affords good to excellent yields of specifically anti isomer presence of K2CO3 under ultrasonication. The reaction in (Scheme 23 and Table 3). A series of Mannich base conventional method at room temperature with stirring gave 106 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 Sreevalli et al.

NC CN NC CN NHBoc NHBoc K2CO3, US + R R SO2Ph Solventfree X X Scheme 24. Ultrasound assisted vinylogous Mannich reaction. 75% yield, on refluxing percentage yield increased to 88. SOLVENT FREE: (APART FROM MICROWAVE/ But under ultrasonications, the yield increased to 92% with ULTRASOUND SONICATIONS) the only anti selectivity of the product [70] (Scheme 24 and Apart from the processes of reactions under Table 4). Under similar conditions, the effect of various microwave/ultrasound irradiations, a few solvent free catalysts has also been verified among Na2CO3, K3PO4, methodologies have also been reported, and are discussed NaOAc, NaOH and K2CO3. Among which K2CO3 proved to here. An efficient solvent free condition for Mannich be the best. reaction catalyzed by Guanidine hydrochloride (GuHCl) has Table 4. Ultrasound Assisted Vinylogous Mannich Reaction been reported by M.H. Heravi et al. [72], where the study of with Different Substitutions solvent effect on a model reaction of acetophenone, benzaldehyde and aniline proved to be the best in solvent free condition. The use of GuHCl avoids the use of any base, S.No. R X Time h Yield % metal or Lewis acid catalyst (Scheme 26). Ph 1 C6H5 S 1.5 92 Ph Ph COMe GuHCl, 10 mol % O HN 2 C H O 1.5 90 NH Ph 6 5 2 + CHO Solvent Ph Ph 3 C H CH 2 89 6 5 2 Scheme 26. The preparation of β-aminoketones with 10 mol %

4 4-F C6H4 CH2 2 91 GuHCl, as catalyst. Another interesting solvent free condition to form Not only solvent free conditions, but also ultrasound Mannich product is the usage of Molecular I [73] as irradiation reactions have been done in water, [71] using 2 reported by Gang et al. Molecular I2 acts as a Lewis acid to Bi(OTF)3.4H2O (bismuth (III) trifluoromethane sulphate) as catalyze the reaction. To know the exact amount of I to be catalyst, as recently reported by S.A. Oztorkcan et al. The 2 used, the amount of I2 versus time has been studied using rapid method of synthesis of various β amino ketones from benzaldehyde, acetophenone and aniline as a model reaction. cyclohexamine, substituted aromatic amines and aromatic This showed 5 mol% and 5h to be the appropriate reaction and hetero aromatic aldehydes via ultrasound assisted direct condition. But when acetophenone was replaced with type catalytic Mannich reaction afforded good yields with cyclohexanone the appropriate reaction conditions were anti selectivity (Scheme 25 and Table 5). changed drastically to 1 mol% and 1h (Scheme 27).

Table 5. A Comparison of Conventional Method Verses Ultrasound Assisted Mannich Reaction with Different Substitutions

Conventional Method Ultrasound Assisted Entry R R1 Time h Yield % Time h Yield % Anti:Syn

1 4-BrPh CH3 24 76 1 89 97:3

2 4-BrPh CH2CN 24 69 1.5 77 69:31

3 4-ClPh CH3 24 73 1 84 99:1

4 3-thienyl CH3 48 38 2 67 99:1

R1 R1 O NH2

R CHO NH O NH O + R R +

(Anti) (Syn) Scheme 25. A comparison of conventional method verses ultrasound assisted Mannich reaction. Green Trends in Mannich Reaction Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 107

Ph Ph I2, 5 mol % O HN COMe 92 % Solvent free Ph Ph Ph Ph CHO + + NH2 O Ph O HN

I2, 1 mol % 97 % Ph Solvent free

Scheme 27. Synthesis of β- aminoketones in solvent free conditions catalysed by molecular I2.

Table 6. A Study of Catalysts and Solvents over Time and Yield to Synthesize β-amino Esters Using Imines and Malonic Esters

Entry Catalyst Solvent Time h Yield %

1 CuBr2 CH2Cl2 24 33

2 CuBr2 ------24 NR

3 ZnCl2 CH2Cl2 24 70

4 ZnCl2 ------6 min 90

5 ZnBr2 ------6 min 71

6 Zn(OTf)2 ------6 min 87

O O O O O O O O Catalyst + H CO N 3 H3CO NH O O rt O O

Scheme 28. ZnCl2 catalyzed Mannich type reaction.

Another interesting method for the synthesis of β amino OH O ether via ZnCl2 catalyzed Mannich type reaction of imines + N and malonate ester under solvent free conditions is reported N by Chen et al. [74]. The primary study included the OH screening of different Lewis acid catalysts for the reaction to occur in dichloromethane or in solvent free conditions. But + N O N the best results have come with ZnCl2 catalyzed imine and malonate ester under solvent free conditions within a short period of 6 min (Scheme 28 and Table 6). Scheme 29 and Scheme 30. Schematic representation of vinylogous Mannich reaction. MANNICH TYPE REACTION Z.L. Yuan et al., [76] have reported asymmetric vinylo- Apart from the usual type of Mannich reaction of a non- gous Mannich reactions (VMR) using a chiral ligand, phenyl enolisable aldehyde, a primary or secondary amine and an methanol as additive and AgOAc as catalyst. The generality enolisable carbonyl compound to afford β-amino carbonyl of the VMR is screened with different chiral ligands, compounds, there are few interesting mannich type reactions different additives and for different aldimines. An optimized which are discussed below. VMR reaction with different aldimines is tabulated in (Scheme 31 and Table 7). VINYLOGOUS MANNICH REACTION MANNICH TYPE-BETTI BASED CONDENSATION This is the Mannich reaction that is typified as the REACTION addition of enols to iminium salts (Scheme 29) to afford β amino carbonyl compounds. The vinylog of the Mannich Mannich Type-Betti Based Condensation for the reaction, in which the addition of a dienol (or equivalent) to synthesis of 2,4-disubstituted 1,3-oxazines and Schiff bases an iminium ion to produce δ amino carbonyl group is that contain either identical or two different aryl substitutions represented (Scheme 30) [75]. in an environmentally benign, cost effective and selective 108 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 Sreevalli et al.

Table 7. An Optimized VMR Reaction with Different Aldimines

Entry R R1 Yield % Anti : Syn

1 4-NO2C6H4 C6H5 51 99 : 1

2 4-MeOC6H4 C6H5 56 99 : 1

3 3-CF3C6H4 C6H5 90 99 : 1

4 4-BrC6H4 4-BrC6H4 78 99 : 1

Cl Cl N

PPh2

11 mol % R1 R HN 1 AgOAc (10 mol %) N BuOH (1.8 Equiv) S + R -78 °C for 6 h, then R R OTMS O warm to rt naturally O for overnight O Scheme 31. Scope of VMR reaction of aldimine and siloxyfuran.

OH R 2 R4 R 1 H R3 N N AcONH4, + O OH O EtOH, rt OR

R R1=2Cl;R2=4Cl; 73% R3 = R4 = 4-OEt; 86 % R1=2F;R2=4Cl; 78% R3 = 2Me; R4 = 4-OEt; 58 % R =2F;R =4F; 88% R = 2Me; R = 4Me; 66 % 1 2 3 4 Scheme 32. Mannich Type-Betti Based Condensation for the synthesis of 2, 4-substituted 1, 3-oxazines and Schiff bases. method using ammonium acetate as a catalyst as well as a TANDEM MANNICH REACTION reagent has been recently developed by K. Satiyanaranan et al., [77] . The synthesis of Morita-Baylis-Hillman adducts using an inter-molecular tandem Michael/ Mannich type reaction of The authors chose 2-napthol, and two differently acetylenic ketones or esters with imines in presence of substituted benzaldehydes in the presence of ammonium nucleophilic halides has been reported by Li et al. [78]. The acetate. 2-napthol which reacted with the highly reactive intra molecular Michael / Mannich type reaction of α-β- benzaldehyde to form o-quinone methide intermediate in the unsaturated carbonyl compounds [79, 80] possessing an presence of ammonium acetate (acts as catalyst). Evans oxazolidinone as the chiral auxiliary and N- Consequently, the less reactive substituted benzaldehyde acyliminium ion intermediate mediated by TiCl4/n-Bu4NI reacted with ammonium acetate (acts as reagent) to form [81] has been reported by Y.Koseki et al. (Scheme 33). aldimine intermediate. The in situ reaction between the two Another interesting tandem Mannich reaction is reported intermediates resulted in the formation of 2,4-disubstituted by R. Ramachandran et al. [82]. The reaction is of benzal- 1,3-oxazines and Schiff bases. The substitution on the benzaldehyde was a major factor that influenced the final dehyde, aniline and methyl acetoacetate using silica boron trifluoride (BF .SiO ) as solid super acid catalyst affording product to be an oxazine or a Schiff base. The benzaldehyde 3 2 highly functionalized tetrahydropyridines (Fig. 6). The with electron withdrawing substitution increased the reaction is screened to optimize the catalyst using 4-iso- electrophilicity of the imine carbon resulting the cyclization propyl benzaldehyde, α-bromo aniline and methyl aceto- to give a cyclic skeleton of 2,4-disubstituted 1,3-oxazines. acetate under different amounts of catalysts, and under polar On the contrary, the electron donating substitution on benzaldehyde resulted in the formation of Schiff base solvent as methanol and ethanol has been done and 15 mol% of catalyst is found to give very good yields (Scheme 34). skeleton (Scheme 32). Green Trends in Mannich Reaction Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 109

O O O O O H TiCl4 (3 equiv) O N N O n-Bu4NI (1.5 equiv) N N O I AcOEt/CH2Cl2 H OEt R -20 °C to 40 °C. R

Scheme 33. Cyclization of compound to indolizidine via an N-acyliminium ion intermediate by TiCl4/n-Bu4NI.

Fig. (6). Plausible transition structures involving the reaction mechanism for the formation of product. Br O NH2

NH O 2 2 15 mol % BF3-SiO2 O + O O Br Solvent, time Temperature N O

Scheme 34. BF3-SiO2 catalyzed synthesis of highly functionalized tetrahydropyridines. Another interesting tandem Mannich reaction of β hydrodibenzo [a, i] phenanthridine is reported with para tetralone, benzaldehyde, ammonium acetate in ethanol at substitution on benzaldehyde. (Scheme 35). room temperature to afford 5-aryl-7,8,13,14-tetrahydrodi- The mechanism for the formation of 2, 4-diaryl-6, 7- benzo [a,i] phenanthridine [83] has been reported by Natesan benzo-3-azabicyclo [3.3.1] nonan-9-one proceeds in three Sundaramurthy Karthikeyan et al. In contrast to the usual steps. The first step is the reaction between two molecules of formation of 2,4 diaryl-6,7-benzo-3-azabiclyclo[3.3.1] nonan-9-ones, the formation of 5-aryl-7,8,13,14-tetra 2-tetralone to form binaphthalenone while the second step is 110 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 Sreevalli et al.

R = 4-F; 64 % O R = 4-Me;93 % N

R OR AcONH4, + 5-aryl-7,8,13,14-tetrahydro dibenzo-[a,i]phenanthridine O EtOH, rt

R O R = 2-F; 96 % R = 2-Me;72 % N H R R 2,4-diaryl-6,7-benzo-3- azabicyclo[3.3.1]nonan-9-ones Scheme 35. The Reaction of 2-tetralone with aromatic aldehydes in presence of ammonium acetate.

Step -3 F ormat i on of P henanth ridi ne NH2 O HO C H H O H H H H

H N H2 OH N N O -H2O

-H2

(4)

Fig. (7). Proposed mechanism for the formation of phenanthridine. Green Trends in Mannich Reaction Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 111

R NH R Nu R Nu R + CH2O 1 N N R1 R 1 4 1 2 3

R Nu N

R R R1 Nu / 5 7 (Major) N + CH2O N R R + 1 1 R R N N 5 2 R R1 1 6 (aza quinone methide)

9 (Minor) Scheme 36. Schematic representation of unusual Mannich type reaction.

N O OEt A O O H3BO3 O N + CH2O + OEt 90 °C, 0.5 h. +

N N

Scheme 37. Unusual Mannich type reaction of ethyl acetoacetate, formaldehyde and N,Ndimethylaniline. the formation of aldimine ion starting from benzaldehyde [84] cannot form the iminium salt 3 (Scheme 36) with the and ammonium acetate, and the final step is the reaction aldehyde. However, an intermediate N-alkyl-N-(4- between these two intermediates to form the product. The methylenecyclohexa-2,5-dienylidene) alkylaminium 6, as proposed mechanism for the formation of phenanthridine is equivalent iminium salt of 3, is suggested to form on represented in (Fig. 7). reaction of tertiary aromatic amines with a non-enolizable aldehyde. This intermediate 6 reacts with different nuclides AN UNUSUAL MANNICH TYPE REACTION WITH to generate Mannich type products. TERTIARY AMINES Thus, a reaction of N, N-dimethylaniline, with In general, Mannich reaction proceeds with initial formaldehyde and methyl acetoacetate was screened with formation of iminium salt (intermediate 3). Then this reacts different catalysts, and boric acid was found to yield well in with different nucleophiles to give product known as aqueous micelles of sodium dodecyl sulfate (SDS) with high Mannich bases. Under typical conditions, tertiary amines regioselectivity to form Mannich product (Scheme 37).

A FEW OTHER GENERALIZED PROCESSES OF MANNICH REACTION OF INTEREST

Reaction S.No. Reaction Remarks Conditions

O CHO + NH2 + The reaction is first optimized by varying Ph Ph adinine mol% with respect to time. Then Adinine [85] as by varying volume of 30% H2O2 with major catalyst respect to time to evaluate the yield along 1 Ph Ph O HN O HN with 30% H2O2 with syn - anti %. Finally the reaction is as additive optimized with 20 mol% adenine and 40 µl Ph Ph + 30% H2O2 for 6h, which gave better Syn diastereo selectivity with excellent yield. Anti 112 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 Sreevalli et al.

O CHO H P OEt Ph + OEt Y Ph NH2

H2N NH2 A one pot synthesis of α-amino phosphonates and bis (α-amino phosphonates) FeCl3 in THF O via Mannich type reaction catalyzed by 2 [86] solution 5 (2.2 mmol) FeCl .THF (5 mol %) at 60°C EtO P OEt mol% 3 affording excellent yields with a time Ph N Ph period of 0.75h. H

O O EtO P OEt EtO P OEt

Ph N N Ph H H

(a) 10 mol% (a) A simple one pot three components Mannich reaction catalyzed by SnCl2 SnCl2 [87] room temperature, (10mol %) is first reported by H.Wang et al. EtOH, 10 h. (b) Primarily the mol% of catalyst is CHO verified with time to optimize the reaction. NH2 COMe (b) CeCl3. 7H2O Further the catalyst effect of different Ph + Ph + Ph [88] in Methanol catalysts is verified. The scrutinized Lewis 3 mol% 2 h acid catalysts are CuSO , CeCl .7H O, 3 4 3 2 Ph (c) 10 mol% of CuCl2, ZnCl2 and AlCl3 where ZnCl2 and O HN SiO2-AlCl3 [89] AlCl3 gave poor yields. (silica supported (c) Mannich reaction mediated by Silica Ph Ph aluminum supported AlCl3 proves to be an environ- chloride) mentally healthy reaction with excellent reaction at room yields. Apart from AlCl3 and SiO2 with no temperature in product formation, the physical mixture of EtOH SiO2 and AlCl3 gave optimal yields.

O A catalytic study of hetero poly acid CHO NH (a) 0.04 (g) Cs + 2 + 2.5 (HPA) over Mannich reaction is done Ph Ph H0.5PW12O40. where K5CoW12O40 is a best example for H2O [90] at ro- HPA but its effect on Mannich reaction is om temperature not effective. But the catalysis of 4 Ph for 80 min O HN Cs2.5H0.5PW12O40 was first reported by E. (b) 0.15 mol% Rafiee et al., and later the effect of Ph AlPW12O40 [91] AlPW12O40 was reported by Li Gang et al. 1 h The effect of different HPA on Mannich Anti reaction is done and reported as in table.

CHO COMe CN Cat + Ph + Ph A one pot three component Mannich N Cu(II)ptholo reaction in the presence of different cyanine [92] 5 Cat N N metalloptholocyanines is reported. Among (Cu(II)Pc) (3 N Cu N which Cu(II)Pc proved to be more mol %) 70 °C O HN O N N productive.

N Ph Ph Green Trends in Mannich Reaction Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 113

NH Ph CHO 3 + L-Proline catalyzed three components Ph Mannich reaction (domino reaction) of S CO2Et ethyl-2-[(2-oxo-2-aryl ether) sulfanyl] O L-Proline [93] acetates, aromatic aldehydes and ammonia 6 O (50 mol %), to give trans-6-aryl-5-aryl-3-thiomarpholi- S EtOH, rt, 12 h. Ph nones,yields being average to good. A scrutiny of different bases is done to Ph N O identify the catalyst as L-Proline. H

CONCLUSION Amines and Silyl Enol Ethers for the Synthesis of [3-Amino Ketones and Esters. Tetrahedron Lett., 1998, 39, 323-326. The paper is so reviewed that the Mannich reaction under [16] Loh, T.P.; Sarah, B.K.W.L.; Kee-Leng, T.; Lin-Li, W. Three green condition is exemplified via solvents, catalyst, Component Synthesis of β-Amino Carbonyl Compounds Using selectivity of solvents and catalyst, kinetics, etc. The Indium Trichloride-Catalyzed One-pot Mannich-type Reaction in Water. Tetrahedron, 2000, 56, 3227-3237. screening for the selectivity of the solvent and the catalyst [17] Brinbaban, C.R.; Samanta, S.; Sankar, K.G. Zinc tetraflouroborate was also reviewed with respect to the type of Mannich catalyzed Mannich reaction of aldimines and silyl enol ethers in reaction under variable conditions towards green synthesis. aqueous medium. Tetrahedron, 2002, 58, 983-988. In view of the recent developments reviewed here, it is [18] Chongfeng, P.; Zhiyong, W. Catalytic asymmetric formation of carbon-carbon bond in the presence of water. Coord. Chem. Rev., necessary to initiate and develop greener methods of 2008, 252, 736-750. synthesizing Mannich products. [19] Kobayashi, S.; Hamada, T.; Manabe, K. Catalytic Asymmetric Mannich-type Reactions in Aqueous Media. J. Am. Chem. Soc., CONFLICT OF INTEREST 2002, 124, 5640-5641. [20] Yamashita, Y.; Ueno, M.; Kuriyama, Y.; Kobayashi, S. Catalytic The authors confirm that this article content has no Asymmetric Mannich-type Reactions using a novel chiral Iron conflicts of interest. Complex. Adv. Synth. Catal., 2002, 344, 929-931. [21] Ibrahem.; Cordova, A. Amino acid catalyzed direct enantioselective formation of carbohydrates: one-step de novo ACKNOWLEDGEMENTS synthesis of ketoses. Tetrahedron Lett., 2005, 46, 3363-3367. [22] Ibrahem, I.; Zou, W.; Xu, Y.; Cordova, A. 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Received: May 16, 2013 Revised: July 02, 2013 Accepted: July 03, 2013