ISSN 1349-4848 number157 CONTENTS 2 Contribution - Study of Ion-supported Reagents for Organic Synthesis: IS-Ph3P, IS-MSO, IS-MS, and IS-DIB Hideo Togo Professor of Graduate School of Science, Chiba University 10 Chemistry Chat –Focusing on the Elements- - Elements for the Fight against Cancer Kentaro Sato 14 Science “Spring” Seminar - Carbonyl Olenation (2) Takeshi Takeda Professor of Department of Applied Chemistry, Tokyo University of Agriculture and Technology 20 Short Topic: More ways to use reagents - Hydrolysis of Thioacetals Using Oxidizing Reagents Haruhiko Taguchi Tokyo Chemical Industry Co., Ltd. 24 New Products Information : - Ru-Re Supramolecular Complex Photocatalyst Capable of Eciently Reducing CO2 to CO - High Regioregular p-type Organic Semiconducting Polymer - Novel Aromatic Triuoromethylating Reagent - Homologation Reaction by Ketene Dithioacetalization - HDAC Inhibitor No.157 No.157 Study of Ion-supported Reagents for Organic Synthesis: IS-Ph3P, IS-MSO, IS-MS, and IS-DIB Hideo Togo Graduate School of Science, Chiba University 1. Introduction mixture and reuse of those ion-supported reagents for the same reactions, as shown in Fig. 1. The great advantages of these In organic synthesis, most reactions require organic ion-supported reagents are the simple isolation of the desired reagents and therefore, after each reaction, the desired product products by diethyl ether extraction of the reaction mixture must be purified by column chromatography to remove organic and subsequent removal of the solvent, and their recyclable co-products derived from organic reagents. In view of use for the same reactions through high recovery and efficient environmentally benign organic synthesis, novel ion-supported regeneration, and therefore those ion-supported reagents are reagents, such as ion-supported Ph3P (IS-Ph3P A and B), ion- user-friendly and environmentally benign. Experimental supported methyl sulfoxide (IS-MSO C and D), ion-supported procedure for the reaction with ion-supported reagents, isolation methyl sulfide (IS-MS E and F), ion-supported (diacetoxyiodo)- of the products, and regeneration and reuse of the ion-supported benzene (IS-DIB G and H), and super-DIB (I) were developed reagents is shown in Fig. 2 for easy isolation of desired products from the reaction O Br CH3 P CH3 S (CH2)n N N (CH3)3N TsO IS-Ph3P A Appel reaction The Mitsunobu reaction IS-MSO C: n = 6 CH3 Wittig reaction IS-MSO D: n = 10 Heck reaction Oxidation of Alcohols to N Sonogashira reaction Aldehydes or Ketones P CH S (CH ) CH3 High yields with high purity 3 2 n N N Br by simple extraction of High yields with high purity by reaction mixture with diethyl TsO simple extraction of reaction IS-Ph3P B ether mixture with diethyl ether IS-MS E: n = 6 IS-MS F: n = 10 O N(CH3)3 AcO I O O N O Oxidation of Alcohols (AcO) I OTs CH3 OTs to Aldehydes or Ketones 2 (AcO) I 2 High yields with high IS-DIB G IS-DIB H purity by simple extraction NO2 of reaction mixture with Alcohols IS-DIB Aldehydes or Ketones Super-DIB I diethyl ether N,N-Diisopropylbenzylamines G or H Aromatic Aldehydes Primaryl Amides Methyl Carbamates Propiophenones Methyl 2-Arylpropanoates Acetophenones 4-Aryl-2-methyloxazoles High yields with high purity by simple extraction of reaction mixture with diethyl ether Figure 1. Ion-supported reagents. Target Product high yield high purity Extraction 1) Et2O extraction 2) concentration reactions with ion-supported reagent concentration residue regeneration recovery of ion-supported reagent Figure 2. Reaction, recovery, regeneration, and reuse of ion-supported reagents. 2 No.157 2. Ion-supported Ph3P (IS-Ph3P) 2-2. Mitsunobu reaction Ph3P is one of the most important reagents for organic IS-Ph3P A and B could be also used for esterification of synthesis, because it can be used for the halogenation of 3-(4'-methoxyphenyl)propanoic acid with 2-phenylethanol and 1) alcohols with CBr4 or I2 / imidazole (Appel reaction), diisopropyl azodicarboxylate (DIAD) in dichloromethane to esterification of carboxylic acids with alcohols and diethyl provide the corresponding 2"-phenylethyl 3-(4'-methoxyphenyl)- azodicarboxylate (DEAD) (Mitsunobu reaction),2) olefination propanoate in good yields, as shown in Table 2. After the of aldehydes with phosphonium ylide (Wittig reaction),3) Pd- reaction, diethyl ether was added to the reaction mixture to catalyzed reaction as a ligand (Sonogashira reaction, Mizoroki- separate the IS-Ph3PO and the oil. After filtration and removal 4) Heck reaction), etc. However, Ph3PO as a co-product is of ether solvent from the filtrate, the corresponding ester was formed in the Appel reaction, the Mitsunobu reaction, and the obtained in high yields with high purity (>90%) in both IS- Wittig reaction, and therefore, it must be removed by column Ph3P A and B, respectively, without chromatography. Each chromatography carefully. Even for the Pd-catalyzed reaction IS-Ph3PO was recovered in over 90% yield. Again, after the with Ph3P as a ligand, the reaction mixture must be purified by O-methylation of the recovered ion-supported Ph3PO with column chromatography. dimethyl sulfate and the subsequent reduction with LiAlH4, IS-Ph3P A and B could be regenerated and reused for the same esterification reaction, maintaining good yield with high 5) 2-1. Halogenation of alcohols purity. On the other hand, when Ph3P was used for the same esterification of 3-(4'-methoxyphenyl)propanoic acid under IS-Ph3P A and B are solid, respectively, and IS-Ph3P A the same conditions, Ph3PO was recovered only in 30% yield, and B are efficient reagents for the bromination and iodination together with the ester in 87% yield after purification from of alcohols with CBr4 and I2 / imidazole, respectively. After ether extracts, as shown in Table 2. This result indicates again the reaction, diethyl ether was added to the reaction mixture to IS-Ph3P A and B are efficiently recyclable reagents for the separate the IS-Ph3PO and the oil. After filtration and removal esterification of carboxylic acids and the purity of ether extracts of ether solvent from the filtrate, the corresponding alkyl halides from the reaction mixture is enough high. were obtained in high yields with high purity (>90%) in both IS-Ph3P A and B, without chromatography, by simple diethyl ether extraction of the reaction mixture and subsequent removal 2-3. Wittig reaction of the solvent, as shown in Table 1. Moreover, ion-supported Ph3PO, 4-(diphenylphosphino)benzyltrimethylammonium IS-Ph3P A and B were used for the Wittig reaction. Thus, bromide and N-methyl-N-[4-(diphenylphosphino)benzyl]- ion-supported phosphonium salts A1 and B1, which were pyrrolidinium bromide, were recovered in over 90% yield. prepared from the reactions of IS-Ph3P A and B with ethyl After the O-methylation of the recovered ion-supported Ph3PO bromoacetate, respectively, reacted with aromatic and aliphatic with dimethyl sulfate and the subsequent reduction with LiAlH4, aldehydes in the presence of K2CO3 to give the corresponding IS-Ph3P A and B could be regenerated in high yield, and could α,β−unsaturated ethyl esters in good yields with high purity be reused for the same halogenation reaction, keeping high yield by simple filtration of the reaction mixture and subsequent and high purity of alkyl halides under the same conditions and removal of the solvent from the filtrate, as shown in Table procedure.5) 3. Similarly, ion-supported phosphonium salts A2 and B2, Table 1. Halogenation of alcohols. Table 2. Esterification of carboxylic acid. A (1.2 eq.), B (1.5 eq.), or Ph3P (1.2 eq.) ROH (1.1 eq.) n OH n X A , B, or Ph3P (1.5 eq.) ClCH2CH2Cl CO H 2 DIAD (1.5 eq.) 60 °C, 2 h Product CH2Cl2 40 °C, 2 h Bromination: CBr4 (1.1 eq.) and A, B, or Ph3P CH3O , Iodination: I2 (1.5 eq.), imidazole (1.5 eq.), KI (5 eq.) CO2R A Product / % CH O n = 0n = 1 n = 2 R = CH2CH2Ph 3 X = Br a b 86 95, 88 , 76 91 Yield of Ester / % X = I 80 80 85 Reuse 012 A a b B Product / % 84 79 70 a b n = 0n = 1 n = 2 B 87 80 77 a b Ph P c X = Br 89 95, 93 , 87 97 3 87 -- X = I 85 83 83 a Yield of ester with the first regenerated A or B. b Yield of ester with the second regenerated A or B. Ph P c 3 Product / % Ph3PO was recovered in 30% yield. n = 0n = 1 n = 2 X = Br 72c 68c 53c a Yield of product with the first regenerated A or B. b Yield of product with the second regenerated A or B. c Purity of the product after removal of ether from the extracts was 14%~43%. Ph3PO was recovered in 42~44% yield. 3 No.157 No.157 which were prepared from the reactions of IS-Ph3P A and converted into the corresponding IS-Ph3P A and B again in B with p-methylbenzyl bromide, respectively, reacted with high yields using dimethyl sulfate, followed by the reduction aromatic and aliphatic aldehydes in the presence of NaH to with LiAlH4. Recovered and regenerated IS-Ph3P A and B provide the corresponding p-methylstyrene derivatives in good could be reused for the same Wittig reaction while maintaining yields with high purity by simple filtration of the reaction good yields of ethyl (E)-3-(4'-chlorophenyl)-2-propenoate and mixture and the subsequent removal of the solvent from the 1-(4'-chlorophenyl)-2-(4"-methylphenyl)ethene with high purity filtrate. In both reactions, the co-product, ion-supported Ph3PO, by simple filtration and removal of the solvent from the filtrate, could be obtained quantitatively by simple filtration, and was as shown in Tables 3 and 4, respectively.6) Table 3.