The Mukaiyama Reagent: an Efficient Condensation Agent

SPOTLIGHT ██135

SYNLETT Thespotlight Mukaiyama Reagent: Spotlight 417 An Efficient Condensation Agent Compiled by Irina Novosjolova This feature focuses on a re- Irina Novosjolova was born in Jēkabpils, Latvia, in 1986. She reagent chosen by a postgradu- ceived her BSc and MSc in Chemical Engineering from Riga Tech- ate, highlighting the uses and nical University (RTU), Latvia. She is currently pursuing her preparation of the reagent in doctoral degree under the supervision of Professor Maris Turks and current research Professor Erika Bizdena at RTU. Her research is focused on struc- ture and reactivity studies of bis(triazolyl)purine nucleosides. Faculty of Material Science and Applied Chemistry, Riga Technical University, Azenes Str. 14/24, LV-1007 Riga, Latvia E-mail: [email protected] Introduction It is widely used for the synthesis of esters,3 lactones,4 The Mukaiyama reagent (2-chloro-1-methylpyridinium amides,5 lactams,6 and ketenes7 from the corresponding iodide, CMPI) is one of the most valuable reagents for carboxylic acids, as well for obtaining carbodiimides from activation of hydroxyl groups of carboxylic acids and thioureas8 and thiocyanates from alcohols.9 CMPI was in- alcohols.1 It is a pale yellow crystalline solid which is sta- troduced as an useful reagent for the synthesis of carbox- ble at room temperature in closed containers under normal ylic esters by Teruaki Mukaiyama in 1975,10 after that the storage and handling conditions. CMPI is commercially miscellaneous N-alkyl-2-halopyridinium salts had been available, but can be easily synthesized from 2-chloro- developed as activating agents.1 Nowadays, several poly- pyridine and methyliodide.2a–d mer-supported CMPI analogues have been used for the synthesis of esters and amides due to user-friendly purifi- cation procedures.11 The reagent analogues are also valu- + MeI 12 N Cl N Cl + able for peptide synthesis. Me I–

Scheme 1 Abstracts

(A) The Mukaiyama reagent is widely used for activation of carbox- O ylic acids in the synthesis of carboxylic esters. A recent example + HO2C(CH2)nNHBoc + deals with the synthesis of N-Boc-glycine and N-Boc-β-alanine es- N Cl N O (CH2)nNHBoc base ters in the presence of various fatty-acid-derived alcohols.3 Nucleo- Me I– Me I– base⋅HCl philic attack of the carboxylate anion on CMPI (1) produces 12 pyridinium salt 2. Further reaction between 2 and an alcohol produc- ROH RO2C(CH2)nNHBoc + + base⋅HI es esters 3, 4 and 1-methyl-2-pyridone 5. The reagent is also useful base N O 3 n = 1 (74–86% yield) for the kinetic resolution of racemic carboxylic acids and alcohols 4 n = 2 (72–80% yield) Me with enantiomerically pure alcohols or carboxylic acids, respective- 5 6 ly.13

(B) Macrolactonization is very important for the total synthesis of CO2Me CO2Me macrolide antibiotics. Macrolactonization is possible in the presence MOMO MOMO of CMPI.14 Synthesis of lactones from ω-hydroxy carboxylic acids N Cl (n = 5, 6, 7, 10, 11, 14) has been developed under mild conditions in + Me I– 1,4 O O good yields using the Mukaiyama reagent. Both small and large OH Et3N, MeCN CO2H macrocycles can be obtained. H Δ H 96% yield This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

H H OH OH

(C) The Mukaiyama reagent can also be used for C–N bond formation, for example for synthesis of 3-alkylquinazolin-4-ones. The lat- O + O ter are valuable molecular scaffolds in medicinal chemistry. Thus, a N Cl – R formal transamidation occurs under very mild reaction conditions.15 NH Me I N + RNH2 CH2Cl2, DIPEA, r.t. N 44–87% yield N

SYNLETT 2013, 24, 0135–0136 Advanced online publication: 04.12.20120936-52141437-2096 DOI: 10.1055/s-0032-1317530; Art ID: ST-2012-V0424-V © Georg Thieme Verlag Stuttgart · New York 136 I. Novosjolova SPOTLIGHT

(D) CMPI is applicable for the construction of β-lactams from β- amino acids. When compared with the dicyclohexyl carbodiimid + 2 N Cl 3 method and the Ph3P(PyS)2 method of β-lactam synthesis, the Mu- R O R O – kaiyama method is often more effective. The reaction proceeds un- R1 Me I N OH N der mild reaction conditions which are compatible with the acid- and H Et3N 3 R2 R1 base-sensitive β-lactam ring.6 For example, the use of Mukaiyama R 60–95% yield salt in the macrobislactamization step shortened the synthesis of tetraaromatic tetraamide macrocycles.16

(E) Substituted benzyl alcohols can be converted into alkyl thiocyanates both under solvent and solvent-free conditions using CMPI. + + NH4SCN The proposed mechanism involves the formation of 1-methyl-2- N Cl thiocyanatopyridinium iodide (MTPI) from the reaction of CMPI OH Me I– SCN with NH SCN as the first step. Next, the reaction of the alcohol with MeCN, 60 °C, 0.5–7 h 4 R MTPI produces the desired alkyl thiocyanates.9 or grinding, 90 °C, 5 min R 60–96% yield

(F) When triethylammonium dithiocarbamate, easily prepared from OBn 1. CS OBn amine, carbon disulfide, and triethylamine, is treated with 2-chloro- O 2 2. Mukaiyama reagent O BnO NH 1-methylpyridinium iodide at room temperature, isothiocyanate is 2 Et N, CH Cl , r.t. 17 3 2 2 BnO NCS produced in a high yield. 50–88% yield

(G) 2-Chloro-1-methylpyridinium iodide is used in the synthesis of N i S ii R1 C S C N carbodiimides 3 from N,N’-disubstituted thioureas 2. The former can R1 N be transformed into derivatives 4 which upon treatment with CMPI NH NH and acetic acid provides 1,3,5-triazines 5.8 1 2 3 R1 R1 NH N N N iii S N N S N N H H 5 4 i) R1NH, MeCN, r.t., 3 h

ii) Mukaiyama reagent, Et3N, DMF, r.t., 1 h, 77–98 yield iii) Mukaiyama reagent, Et3N, AcOH, DMAP, DMF, 4 h, 68–74% yield.

(H) After the discovery of the Mukaiyama reagent, various N-alkyl-

2-halopyridinium salts were developed, with the purpose to achieve 1a Rf = C10F21 (87% yield) N Cl Tf O N Cl 1b Rf = C8F17 (84% yield) better yields in the condensation reactions. Recently, a number of OH 2 1c Rf = C6F13 (60% yield) 18a–c Rf – fluorous tagged reagents have been developed. They are useful CH2Cl2, 45 °C, 24–48 h TfO 1d Rf = C4F9 (41% yield) recrystallization in ester- and amide-forming reactions. 1e Rf = C10F21 (33% yield) from EtOAc Rf

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