J. Chem. Sci. Vol. 125, No. 3, May 2013, pp. 467–482. c Indian Academy of Sciences. Mannich reaction: A versatile and convenient approach to bioactive skeletons SELVA GANESAN SUBRAMANIAPILLAI School of Chemical and Biotechnology, SASTRA University, Thanjavur-613 401, India e-mail: [email protected] MS received 27 December 2011; revised 17 September 2012; accepted 6 December 2012 Abstract. This review gives an insight into the recent applications of Mannich reaction and its variants in the construction of bioactive molecules. Emphasis is given to the Mannich reaction that provides bioactive molecules and/or modifies the property of an existing bioactive molecule. The role of Mannich reaction in the construction of antimalarial, antitumour, antimicrobial, antitubercular, antiinflammatory and anticonvulsant molecules and also the significance of aminoalkyl Mannich side chain on the biological property of molecules is discussed here. Keywords. Mannich reaction; Mannich bases; bioactive molecules; antimalarial; antitumour; antitubercular. 1. Introduction O O R1 3 4 H R2 The development of new drugs and target specific 1 R R R N CH2O R2 R3 delivery agents with enhanced efficacy is essential to H N counter the multi-drug resistant (MDR) tumours 1a,b R1, R2 = alkyl or aryl R4 1 3 4 and microbial strains. The modification of an existing R , R = cyclic or acyclic amine β–Aminocarbonyl derivative drug molecules offers a cost and time effective conve- nient strategy to achieve new bioactive skeletons. Man- Scheme 1. Mannich reaction. nich reaction provides a suitable method to introduce aminoalkyl substituent into a molecule. 1c In several of β-aminocarbonyl compounds 1 by Mannich reaction instances, the Mannich derivatives exhibit better acti- (scheme 1). vity than the corresponding parent analogues vide infra. However, the classical Mannich reaction has limi- Moreover, the presence of Mannich side chain increases tations such as lack of selectivity, competitive aldol the solubility and hence the bioavailability of the drug reactions, etc. To overcome these limitations, modern molecule. This review surveys on the recent applica- variants of Mannich reaction utilize preformed imines, tions of multifaceted Mannich reaction in the synthesis enolates, appropriate use of catalyst and reaction con- of antimalarial, antitumour, antimicrobial, antitubercu- ditions, etc. 3a–j,5a–f Several chiral auxiliaries and chi- lar, antiinflammatory and anticonvulsant molecules. ral catalysts are often employed to carry out asymmet- ric Mannich-type reaction. 3b,6a–e Apart from this, basic nanocrystalline magnesium oxide, 7a recyclable copper 1.1 Mannich reaction and its modern variants nanoparticles, 7b poly(amidoamine) catalysed reac- tions 7c and microwave-assisted Mannich reactions 7d Mannich reaction 2 is one of the most fundamental and have also been reported recently. Hayashi et al. dis- important, C–C bond forming reactions in organic syn- covered high pressure asymmetric Mannich-type reac- thesis. Mannich reaction withstands a large diversity tion in frozen water medium. 7e Cimarelli et al. reported of functional groups and hence it has been witnessing three component Mannich reaction under neat condition a continuous growth in the field of organic chem- for the synthesis of diaminoalkylnaphthols. 7f istry. The surge of literature on Mannich reaction pro- vides an outstanding evidence for the diversity and applications of the reaction. 3a–j The Mannich reaction 1.1a Proline/organocatalysed asymmetric Mannich- and its variants offer a robust method for the prepa- type reaction: The proline/organocatalysed asymmet- ration of the aminocarbonyl and several other deriva- ric Mannich-type reaction plays a seminal role in enan- tives. 4a–e The following scheme depicts the synthesis tioselective and diastereoselective C–C bond forming 467 468 Selva Ganesan Subramaniapillai NH2 OMe et al. O (S)-proline O Through quantum mechanical calculations, Fu (10 mol%) explained the origin of stereoselectivity in amino acid N CH2O H R1 R2 RT, DMSO R1 R2 catalysed direct syn and anti selective Mannich reac- 16-17 h 11 OMe Yield = up to 94% tions. Excellent reviews are available which provides ee = >99% significant insight into the proline/organocatalysed asymmetric Mannich-type reaction. 12a–e Scheme 2. Proline catalysed enantioselective Mannich reaction. 2. Applications of Mannich reaction in bioactive reactions. Herein, we present a representative example molecule synthesis of proline catalysed highly enantioselective Mannich reaction of ketones (scheme 2). 8 The Mannich reaction and its variants are often Similarly, proline and its derivatives catalyses; mul- employed to access diverse molecules, whose ticomponent synthesis of 3-amino alkylated indoles by applications are ranging from bioactive skeletons Mannich-type reaction, 9a Mannich reaction of acetalde- to material science. A representative list of the hyde, 9b preparation of azole Mannich adducts, 9c three bioactive/therapeutic molecules obtained by Mannich component domino reactions, 9d enantioselective addi- reaction and the role of Mannich reaction in total tion of ketones to chalkogenazines, 9e synthesis of [1,4]- synthesis are presented in chart 1. The aminocarbonyl thiazines, 9f asymmetric Mannich reaction of cyclic Mannich products are useful in the construction of ketones, 9g etc. In addition to this, various organocatal- β-peptides and β-lactams, which are present in several ysed Mannich reactions have also been reported. 10a–g bioactive molecules such as taxol (antitumour agent), OMe O Et HO OH OH N OH Me N N N O NMe2 H N H 4 OH 2 3 5 Tramadol Osnervan Moban Mulundocandin Mannich analogue (Analgesic) (Antiparkinsonic) (Neuroleptic) (Antifungal activity with increased (Ref 5a) (Ref 5a) (Ref 5a) aqueous solubility) (Ref 15) AcOH N N N 1 aq. (CH3)2NH R1 R R1 N 6 N H C N formalin, RT H3C 3 H3C CH3 Zolpidem N O (hypnotic drug) 1 CH3 (Ref 16) R = 4-MeC6H4 N CH H C 3 H C 3 3 O N CH3 CH3 O OH Amine N Fe NH N R2 H C N S O 3 8 9 N 7 Isothiazolopyridine Mannich bases Ferrocenic aminohydroxy- Quinoline Mannich base (2-10 times potent than acetylsalicylic acid) naphthoquinones (vasorelaxing property) (Ref 20) (antimicrobial activity) (Ref 18) (Ref 21) O O Me OH Me O Me N Me N H Me N O Me CO Me Me 2 CO2Me 11 12 10 Aza-cyclo-octane Epoxy-hexahydrofuroazocine Bicyclic lactam (alkaloid-like derivative) (alkaloid-like derivative) (precursor of pumiliotoxin 251D) (Ref 22) (Ref 22) (Ref 23) TBSO OTBS MeO 10 mol% L-proline O O O CHO propanal, pyridine NH O CHO NMP, -20 oC Me NHBz Me 13 NH2 N-Terminal aminoacid equivalent of nikkomycin (Ref 24) Chart 1. Bioactive Mannich derivatives. Bioactive skeletons via Mannich reaction 469 R CH O HO O Ph 2 HO O Ph 1o or 2o amine MeO 2-propanol, reflux MeO OH O 14 1-2 h OH O Oroxylin-A 15 R = pyrrolidinyl, piperidinyl, n-butylamino, methyl benzylamino, diphenylamino N-methyl furfuryl amino, morpholinyl, N-methylpiperzinyl, benzylamino, 1-Boc piperzinyl Scheme 3. Mannich reaction of oroxylin-A. bestatine (immunological response modifier) and activity against Toxoplasma gondii and atovaquone SCH48461 (anti-cholesterol agent). 13a–d Tramadol 2, resistant strain of T. gondii. osnervan 3 and moban 4 are bioactive β-aminocarbonyl Mannich reaction also plays a significant role in derivatives with analgesic, antiparkinson and neurolep- bioactive skeleton target synthesis. Chernov et al. tic properties (chart 1). 5a It is believed that the solubil- reported the synthesis of alkaloid-like molecules 10 ity of the Mannich derivatives increases in water due and 11 from lambertianic acid via Mannich-type intra- to protonation of basic amine nitrogen atom. 14 Mulun- molecular ring closure reaction (chart 1). 22 Martin et al. docandin, a class of lipopeptides, showed excellent in employed vinylogous Mannich reaction to synthesize vitro activity against Candida species. However, poor bicyclic lactam 12,akeyintermediateusedinthetotal solubility restricts its widespread application. Lal et al. synthesis of alkaloid pumiliotoxin 251D (chart 1). 23 carried out a semi-synthetic modification of mulundo- Proline catalysed asymmetric Mannich reaction played candin by Mannich reaction. 15 The Mannich derivatives a vital role in the synthesis of N-terminal amino acid of mulundocandin 5 exhibited significant improvement equivalent moiety 13 of peptide antibiotic, nikkomycin in solubility, while retaining the activity (chart 1). (chart 1). 24 Babu et al. synthesized biologically signifi- Mannich reaction was useful for the preparation of cant 8-aminoalkylated derivatives of oroxylin-A 15,by zolpidem 6, a hypnotic drug used for the treatment of Mannich reaction. 25 The α-glucosidase inhibitory insomnia (chart 1). 16 The Mannich bases are obtained activity of the aminoalkyl derivatives was found to be by the condensation reaction of C–H acidic substrates superior to that of their parent molecule oroxylin-A 14 (ketones, phenols, etc.,), amine (cyclic or acyclic) and (scheme 3). aldehyde. The Mannich bases are an important class of molecules with significant biological activity. The cationic surfactant molecules obtained from Mannich 2.1 Synthesis of antimalarial molecules bases possess excellent fungicidal property along with good biocidal property against Gram-positive Malaria is one of the most widespread infectious dis- and Gram-negative bacteria. 17 The quinoline derived eases in the world. Though effective antimalarial drug Mannich base 7 possess vasorelaxing properties like chloroquine exists, drug resistance has become (chart 1). 18 Such molecules are useful in the treatment a great challenge. The development of new inexpen- of hypertension. 1,2,4-Triazole derived Mannich bases sive antimalarial drugs is vital in developing coun- exhibited anticancer activity. 19 The isothiazolopyridine tries to counter multi-drug resistant Plasmodium fal- derived Mannich bases 8 were found to be 2 to 10 times ciparum. 26 The discovery of new molecular skeletons more potent than the reference drug acetylsalicylic is always in need to circumvent the drug resistance acid (chart 1). 20 The Mannich reaction is useful for the and to provide good antimalarial activity.