Multicomponent Reaction (MCR)

1 Multicomponent Reactions (MCR). Multicomponent Reaction (MCR) is a synthetic methodology In 1891, an Italian chemist, P. Biginelli has reported the three- in which three or more reactants come together in a single component MCR using b-keto esters such as ethyl acetoacetate Reaction vessel to form a new product. The characteristic aspect (A0649), aromatic aldehydes such as benzaldehyde (B2379), of MCRs is that the nal products contain almost all portions of and ureas (or thioureas) in the presence of acid catalyst substrates, generating almost no by-products. That makes (Br nsted or Lewis acids), affording dihydropyrimidinone MCRs an extremely ideal and eco-friendly Reaction system.

2 Dihydropyrimidinones have been paid much Target compounds can be obtained in one pot with much fewer attention because of their various bioactivities such as anti- steps. Therefore, MCRs have been paid much attention in in ammatory or anti-bacterial activities. For an example of various research elds, such as discovery of lead compounds in pharmaceuticals developed by using the Reaction , several anti- medicinal chemistry, or combinatorial chemistry. tubercular agents have been reported as ). 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.

3 (Three-component Reaction : 3CR) O. F N NH. EtO2C H. NH. N O. Strecker Reaction (Amino Acid Synthesis) N O H. H. O NaCN, NH3 NH2 H3O+ NH2. 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 rst ). 2. Hantzsch dihydropyridine synthesis (3CR) In 1921, an Italian chemist, M. Passerini et al. have reported the three-component Reaction using carboxylic acids, aldehydes, and isonitriles, affording a-acyloxy ) The Passerini Hantzsch Dihydropyridine Synthesis O O R3 O Reaction also has been applied into pharmaceutical research, for O.

4 2 R O. 2. + + NH3. R2O OR2 example, Hulme et al. have reported the library synthesis of R3 H. R1 O R1 N. H. R1 novel norstatine derivatives bearing benzimidazole ). NHBoc This Reaction was reported by A. R. Hantzsch in 1881, and is BocHN R2 CN. BocHN. O. R2. NHBoc H. R1 COOH + + N. the best-known three-component MCR, which affords CHO CH2Cl2, rt, 18 h R1 O. O. 1,4-dihydropyridine derivatives using b-keto esters, aldehydes, Passerini Products and ) For an example, a calcium channel blocker, H2N R2. 3) O NH2 Acyl Migration Nifedipine , is also synthesized by this Reaction . H. N. R1 O. 10% TFA / CH2Cl2, Et3N / MeOH (1 : 3), rt, 24 h O rt, 2 h R1 O. CHO NO2 HN R2 R2 N. O. MeO2C + + NH3 MeO2C CO2Me H.

5 NH2. R1 N N. N 10% TFA / DCE, O NO2 HO H H. MW, 100 C, 20 min OH. N O. H. Nifedipine 3. Biginelli Reaction (3CR) N O N CH3 N. O O. N N N N N N. H H H H H H. OH OH OH. MeO. Biginelli Reaction CH3. O R3 Ph Ph O O CH3 N O N O N. R3 X H+ N HN. R2O NR4 N N N N N N. 2. R O + + R 4. N N. R5 H. OH. H H. OH. H H. OH. H. H O. 1. H H R1 N5 X. R O (X = O or S) R. 2 Please inquire for pricing and availability of listed products to our local sales representatives. Multicomponent Reaction (MCR). OMOM OMe BnO Me 8) Me 5. Gr bcke-Blackburn-Bienaym Reaction CH3 CHO + NH2 + MeO NC + I. (3CR). O. BocHN MeOH, reflux O. OTBDPS. CO2H. OMe OMe Gr bcke-Blackburn-Bienaym Reaction HO Me Me OBn R3 MeO.

6 OAc NH H. I Me H+ OMOM NH. NHBoc N Me N N S N. R1 + R2 CHO + R3 NC R1 R2 Me CH3. O O. NH2 N N O H OH. O O. O O O. TBDPSO MeO. NH. This Reaction is a three-component MCR using aldehydes, Ugi Products (Y. 90%) HO. isonitriles, and a-aminoazines such as 2-aminoimidazole or Ecteinascidin 743. 2-aminopyridine in the presence of acid catalyst. The Reaction is applicable for the synthesis of fused nitrogen-containing aromatic compounds as below. Other examples of MCR. N N MCR using p-toluenesulfonylmethyl isocyanide N. N S 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.

7 Kabachnik-Fields Reaction (3CR) isonitrile group and a tosyl group (leaving group) in one ) Different from other isonitrile compounds with odor Kabachnik-Fields Reaction character, TosMIC is an odorless and solid compound. Because O O HN. R2 of its easy-handling property, TosMIC has been widely used for OR3 O. + R2 NH2 + H P OR3 the synthesis of nitrogen-containing aromatic heterocyclic R1 H OR3 R1 P. OR3. compounds, such as ) TosMIC also has been used for MCRs, for example, Tsoleridis et al. have reported the In 1952, M. I. Kabachinik et al. have reported the three- synthesis of quinoxaline derivatives via the three-component component MCR using aldehydes, amines, and dialkyl condensation of o-phenylenediamines, aromatic aldehydes and phosphites in the presence of acid catalyst (Br nsted or Lewis ).

8 9). acids), affording a-aminophosphonates. In recent years, much attention has been paid to a-aminophoshonates since they can R1 NH2 O. be considered as structural analogues of the corresponding + ArCHO + CH3 S CH2NC. a-amino acids and transition state mimics of peptide hydrolysis. R2 NH2 O. T1046 (TosMIC). Thus, a-aminophoshonates have been applied into several research areas, such as development of renin inhibitors or HIV. Base R1 N Ar protease ). Toluene, reflux, 4 h R2 N. 7. Ugi Reaction (4CR) Entry R1 R2 Ar Base Quinoxaline (Y. %). 1 H H phenyl DABCO 91. 2 H H 2,4-dimethylphenyl DABCO 81. Ugi Reaction O R2 3 4-chlorophenyl DABCO 84. O H H. R3 N R4. R1 H. + R2 NH2 + R3 NC + R4 COOH N.

9 4 Me Me phenyl DBU 86. H. R1 O. 5 Me Me 2-methylphenyl DBU 85. This Reaction is the four-component MCR reported by I. K. Ugi et al. in 1962 for the rst ) It enables one-pot condensation of four components (aldehydes, amines, isonitriles, and MCR using benzynes (3CR). carboxylic acids), thus, it can be said that the Ugi Reaction is the most versatile among MCRs. For an example of applications Recently, there also have been several reports on MCRs using this Reaction , Fukuyama et al. have reported the synthesis using benzynes. For example, Yoshida et al. have reported the of a marine tunicate, Ecteinascidin 743, which has extremely three-component MCR using in situ generated benzynes, potent antitumor acitivity, using the Ugi Reaction as a key step imines, and carbon dioxide, affording ).

10 12). below. Recently, much attention has been paid on organic synthesis using carbon dioxide as a carbon source from the ecological Please inquire for pricing and availability of listed products to our local sales representatives. 3. Multicomponent Reaction (MCR). point of view , thus, the Reaction above is an extremely useful and Ionic liquids can be generally recovered and recycled, which eco-friendly MCR. can help to reduce the waste of traditional solvents which are rarely reused. In addition, ionic liquids have attracted much KF Me attention as excellent solvents due to their low volatility. Judging TMS 18-Crown-6 N Ar NMe R + + CO2 R from these points , this Reaction can be regarded as a more eco- Ar H O.