Please inquire for pricing and availability of listed products to our local sales representatives. Multicomponent Reactions (MCR) Multicomponent reaction (MCR) is a synthetic methodology in In 1891, an Italian chemist, P. Biginelli has reported the three- which three or more reactants come together in a single reaction component MCR using b-keto esters such as ethyl acetoacetate vessel to form a new product. The characteristic aspect of MCRs [A0649], aromatic aldehydes such as benzaldehyde [B2379], is that the final products contain almost all portions of substrates, and ureas (or thioureas) in the presence of acid catalyst (Brönsted generating almost no by-products. That makes MCRs an or Lewis acids), affording dihydropyrimidinone derivaties.4) extremely ideal and eco-friendly reaction system. Target Dihydropyrimidinones have been paid much attention because of compounds can be obtained in one pot with much fewer steps. their various bioactivities such as anti-inflammatory or anti- Therefore, MCRs have been paid much attention in various bacterial activities. For an example of pharmaceuticals developed research fields, such as discovery of lead compounds in by using the reaction, several anti-tubercular agents have been medicinal chemistry, or combinatorial chemistry. reported as below.5) There have been a number of reports on MCRs so far, and Examples of Anti-tubercular Agents using Biginelli Reaction typical examples are described as below. NO2 1. Strecker reaction N N O (Three-component reaction: 3CR) F EtO C N NH 2 NH H Strecker Reaction (Amino Acid Synthesis) N O N O H H O NH2 + NH2 NaCN, NH3 H3O R H R CN R COOH 4. Passerini reaction (3CR) This reaction was reported by A. Strecker in 1850, and is Passerini Reaction extremely famous as the synthesis of a-amino acids. This O R2 H reaction is an MCR which comprises three components, N R1 COOH + R2 CHO + R3 NC R1 O R3 aldehydes, hydrogen cyanide, and ammonia as substrates, and O is recognized as the world’s first MCR.1) In 1921, an Italian chemist, M. Passerini et al. have reported the 2. Hantzsch dihydropyridine synthesis (3CR) three-component reaction using carboxylic acids, aldehydes, and isonitriles, affording a-acyloxy amides.6) The Passerini Hantzsch Dihydropyridine Synthesis 3 O O R O reaction also has been applied into pharmaceutical research, for O 2 2 R2O R O OR example, Hulme et al. have reported the library synthesis of novel 2 + 3 + NH3 R H 7) 1 R1 N R1 norstatine derivatives bearing benzimidazole moieties. R O H This reaction was reported by A. R. Hantzsch in 1881, and is the NHBoc BocHN R2 2 CN BocHN R O NHBoc best-known three-component MCR, which affords 1,4-dihydro- 1 H R COOH ++ N 2) CHO R1 O b CH2Cl2, rt, 18 h pyridine derivatives using -keto esters, aldehydes, and ammonia. O For an example, a calcium channel blocker, “Nifedipine”, is also Passerini Products 3) 2 synthesized by this reaction. H2N R O NH2 H Acyl Migration N R1 O 10% TFA / CH2Cl2, Et3N / MeOH (1 : 3), rt, 24 h O rt, 2 h 1 CHO NO2 R O MeO C NH MeO C CO Me 2 2 2 + + 3 2 2 HN R O R N NH2 O NO2 H 1 N 10% TFA / DCE, R N N HO H H N MW, 100°C, 20 min OH H O Nifedipine 3.Biginelli reaction (3CR) N O N O O CH3 N N N N N N N Biginelli reaction H H H H OH H H OH MeO OH O R3 O R3 X H+ 2 4 CH3 4 5 R O NR R2O + + R R Ph Ph H O N N O CH3 N O N O N H H R1 N X N HN R1 O 5 N N N N N N (X = O or S) R H H H H H H OH OH OH 2 Please inquire for pricing and availability of listed products to our local sales representatives. Multicomponent reaction (MCR) 8) OMOM OMe 5. Gröbcke-Blackburn-Bienaymé reaction Me BnO Me CH3 CHO + NH2 ++MeO NC O I (3CR) MeOH, reflux O BocHN OTBDPS CO H Gröbcke-Blackburn-Bienaymé Reaction 2 R3 NH OMe OMe + H Me OBn HO Me N N MeO 1 2 3 1 2 OAc R + R CHO + R NC R R H I Me NH2 N OMOM NH N Me NHBoc S Me CH3 N O O N O H OH O O This reaction is a three-component MCR using aldehydes, O O O TBDPSO MeO isonitriles, and a-aminoazines such as 2-aminoimidazole or NH Ugi Products (Y. 90%) HO 2-aminopyridine in the presence of acid catalyst. The reaction is Ecteinascidin 743 applicable for the synthesis of fused nitrogen-containing aromatic compounds as below. Other examples of MCR N N ●MCR using p-toluenesulfonylmethyl isocyanide N S N N N N (TosMIC) (3CR) N NHBn NHBn NHBn p-Toluenesulfonylmethyl isocyanide (TosMIC) [T1046] is a synthetic reagent, developed by Leusen et al., and has both an 6. Kabachnik-Fields reaction (3CR) isonitrile group and a tosyl group (leaving group) in one molecule.13) Different from other isonitrile compounds with odor Kabachnik-Fields Reaction R2 character, TosMIC is an odorless and solid compound. Because O O HN OR3 2 O 3 + R NH2 + H P OR of its easy-handling property, TosMIC has been widely used for R1 H OR3 R1 P OR3 the synthesis of nitrogen-containing aromatic heterocyclic compounds, such as oxazoles.14) TosMIC also has been used In 1952, M. I. Kabachinik et al. have reported the three-component for MCRs, for example, Tsoleridis et al. have reported the MCR using aldehydes, amines, and dialkyl phosphites in the synthesis of quinoxaline derivatives via the three-component presence of acid catalyst (Brønsted or Lewis acids), affording condensation of o-phenylenediamines, aromatic aldehydes and a-aminophosphonates.9) In recent years, much attention has been TosMIC.15) paid to a-aminophoshonates since they can be considered as structural analogues of the corresponding a-amino acids and 1 R NH2 O transition state mimics of peptide hydrolysis. Thus, a-amino- + ArCHO + CH3 S CH2NC R2 NH phoshonates have been applied into several research areas, such 2 O TosMIC [T1046] as development of renin inhibitors or HIV protease inhibitors.10) 1 Base R N Ar 7. Ugi reaction (4CR) Toluene,reflux,4h R2 N Ugi Reaction 2 O R Entry 1 2 O R R Ar Base Quinoxaline(Y.%) 3 4 2 3 4 R N R + R NH2 + R NC + R COOH N 1 H H phenyl DABCO 91 R1 H H R1 O 2 HH2,4-dimethylphenyl DABCO 81 3 HH 4-chlorophenyl DABCO 84 This reaction is the four-component MCR reported by I. K. Ugi et 4 Me Me phenyl DBU 86 al. in 1962 for the first time.11) It enables one-pot condensation of 5 Me Me 2-methylphenyl DBU 85 four components (aldehydes, amines, isonitriles, and carboxylic acids), thus, it can be said that the Ugi reaction is the most versatile among MCRs. For an example of applications using this reaction, ●MCR using benzynes (3CR) Fukuyama et al. have reported the synthesis of a marine tunicate, Recently, there also have been several reports on MCRs using Ecteinascidin 743, which has extremely potent antitumor acitivity, benzynes. For example, Yoshida et al. have reported the three- using the Ugi reaction as a key step below.12) component MCR using in situ generated benzynes, imines, and carbon dioxide, affording benzoxadinones.16) Recently, much attention has been paid on organic synthesis using carbon dioxide as a carbon source from the ecological point of view, thus, the reaction above is an extremely useful and eco-friendly MCR. Please inquire for pricing and availability of listed products to our local sales representatives. 3 Multicomponent reaction (MCR) KF Me TCI offers a variety of aldehyde, amine, carboxylic acid, b-keto TMS NMe 18-Crown-6 N Ar R + + CO R 2 O ester, urea & thiourea, and dialkyl phosphite compounds readily OTf Ar H THF, 0 °C available in MCRs. For aldehyde, amine, and carboxylic acid Benzyne Precursor O Ar = 2,4,6-trimethyphenyl compounds, typical products selected are listed judging from reports on MCRs so far. In addition, benzyne precursors, Lewis Benzyne Precursor Reaction time (h) Product acids, and ionic liquids used in MCRs are also listed in this Me TMS N Ar brochure. 15 O OTf O (Y. 82%) Me Me F TMS N Ar F N Ar 63 O O OTf F and O (Y. 63%, 4 : 1) O References OMe Me TMS N Ar 1) A. Strecker, Ann. 1850, 75, 27. 46 O OTf 2) A. Hantzsch, Ber. 1881, 14, 1637. OMe O (Y. 73%) 3) R. Alajarin, J. J. Vaquero, J. L. G. Navio, J. A-Builla, Synlett 1992, 297; R. Alajarin, Me TMS N Ar P. Jordan, J. J. Vaquero , J. A-Builla, Synthesis, 1995, 389; B. M. Khadilkar, A. A. 60 O OTf Chitnavis, Ind. J. Chem. 1995, 34B, 652; B. M. Khadilkar, V. G. Gaikar, A. A. O (Y. 44%) Chitnavis, Tetrahedron Lett. 1995, 36, 8083. Thus, MCR is a strong synthetic methodology to enable 4) P. Biginelli, Ber. 1891, 24, 1317; P. Biginelli, Ber. 1891, 24, 2962. condensation of various substrates in one pot, however, in 5) A. R. Trivedi, V. R. Bhuva, B. H. Dholariya, D. K. Dodiya, V. B. Kataria, V. H. some cases, reactions require long times for completion or Shah, Bioorg. Med. Chem. Lett. 2010, 20, 6100; V. Virsodia, R. R. S. Pissurlenkar, result in undesired side reactions even after optimization of D.