The Mukaiyama Reagent: An Efficient Condensation Agent

Introduction

The Mukaiyama reagent (2-chloro-1-methylpyridinium iodide, CMPI) is one of the most valuable reagents for ­activation of hydroxyl groups of carboxylic acids and ­alcohols.[ ¹ ] It is a pale yellow crystalline solid which is stable at room temperature in closed containers under normal storage and handling conditions. CMPI is commercially available, but can be easily synthesized from 2-chloro­pyridine and methyliodide.[2a] [b] [c] [d]

Scheme 1

It is widely used for the synthesis of esters,[ ³ ] lactones,[ ⁴ ] ­amides,[ ⁵ ] lactams,[ ⁶ ] and ketenes[ ⁷ ] from the corresponding carboxylic acids, as well for obtaining carbodiimides from thioureas[ ⁸ ] and thiocyanates from alcohols.[ ⁹ ] CMPI was introduced as an useful reagent for the synthesis of carboxylic esters by Teruaki Mukaiyama in 1975,[ ¹⁰ ] after that the miscellaneous N-alkyl-2-halopyridinium salts had been developed as activating agents.[ ¹ ] Nowadays, several polymer-supported CMPI analogues have been used for the synthesis of esters and amides due to user-friendly purification procedures.[ ¹¹ ] The reagent analogues are also valuable for peptide synthesis.[ ¹² ]

Abstracts

(A) The Mukaiyama reagent is widely used for activation of carboxylic acids in the synthesis of carboxylic esters. A recent example deals with the synthesis of N-Boc-glycine and N-Boc-β-alanine esters in the presence of various fatty-acid-derived alcohols.[ 3 ] Nucleophilic attack of the carboxylate anion on CMPI (1) produces pyridinium salt 2. Further reaction between 2 and an alcohol produces esters 3, 4 and 1-methyl-2-pyridone 5. The reagent is also useful for the kinetic resolution of racemic carboxylic acids and alcohols with enantiomerically pure alcohols or carboxylic acids, respectively.[ 13 ]
(B) Macrolactonization is very important for the total synthesis of macrolide antibiotics. Macrolactonization is possible in the presence of CMPI.[ 14 ] Synthesis of lactones from ω-hydroxy carboxylic acids (n = 5, 6, 7, 10, 11, 14) has been developed under mild conditions in good yields using the Mukaiyama reagent.[1] [4] Both small and large macrocycles can be obtained.
(C) The Mukaiyama reagent can also be used for C–N bond formation, for example for synthesis of 3-alkylquinazolin-4-ones. The latter are valuable molecular scaffolds in medicinal chemistry. Thus, a formal transamidation occurs under very mild reaction conditions.[ 15 ]
(D) CMPI is applicable for the construction of β-lactams from β-amino acids. When compared with the dicyclohexyl carbodiimid method and the Ph3P(PyS)2 method of β-lactam synthesis, the Mukaiyama method is often more effective. The reaction proceeds under mild reaction conditions which are compatible with the acid- and base-sensitive β-lactam ring.[ 6 ] For example, the use of Mukaiyama 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. The proposed mechanism involves the formation of 1-methyl-2-thiocyanatopyridinium iodide (MTPI) from the reaction of CMPI with NH4SCN as the first step. Next, the reaction of the alcohol with MTPI produces the desired alkyl thiocyanates.[ 9 ]
(F) When triethylammonium dithiocarbamate, easily prepared from amine, carbon disulfide, and triethylamine, is treated with 2-chloro-1-methylpyridinium iodide at room temperature, isothiocyanate is produced in a high yield.[ 17 ]
(G) 2-Chloro-1-methylpyridinium iodide is used in the synthesis of carbodiimides 3 from N,N’-disubstituted thioureas 2. The former can be transformed into derivatives 4 which upon treatment with CMPI and acetic acid provides 1,3,5-triazines 5.[ 8 ]
(H) After the discovery of the Mukaiyama reagent, various N-alkyl-2-halopyridinium salts were developed, with the purpose to achieve better yields in the condensation reactions. Recently, a number of fluorous tagged reagents have been developed.[18a] [b] [c] They are useful in ester- and amide-forming reactions.

• References

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