Synlett 2013; 24(1): 135-136
DOI: 10.1055/s-0032-1317530
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© Georg Thieme Verlag Stuttgart · New York

The Mukaiyama Reagent: An Efficient Condensation Agent

Irina Novosjolova
Faculty of Material Science and Applied Chemistry, Riga Technical University, Azenes Str. 14/24, LV-1007 Riga, Latvia   Email: irina.novosjolova@gmail.com
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Further Information

Publication History

Publication Date:
04 December 2012 (online)

 
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Irina Novosjolova was born in Jēkabpils, Latvia, in 1986. She received her BSc and MSc in Chemical Engineering from Riga Technical University (RTU), Latvia. She is currently pursuing her doctoral degree under the supervision of Professor Maris Turks and Professor Erika Bizdena at RTU. Her research is focused on structure and reactivity studies of bis(triazolyl)purine nucleosides.

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]

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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 ]


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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.


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  • References

  • 1 Mukaiyama T. Angew. Chem., Int. Ed. Engl. 1979; 18: 707
  • 3 Yamano Y, Tsuboi K, Hozaki Y, Takahashi K, Jin X.-H, Ueda N, Wada A. Bioorg. Med. Chem. 2012; 20: 3658
  • 4 Mukaiyama T, Usui M, Saigo K. Chem. Lett. 1976; 49
  • 5 Kulikov OV, Incarvito C, Hamilton AD. Tetrahedron Lett. 2011; 52: 3705
  • 6 Huang H, Iwasawa N, Mukaiyama T. Chem. Lett. 1984; 1465
  • 7 Funk RL, Abelman MM, Jellison KM. Synlett 1989; 36
  • 8 Kong KH, Tan CK, Lin X, Lam Y. Chem. Eur. J. 2012; 18: 1476
  • 9 Mokhtari B, Azadi R, Mardani E. Tetrahedron Lett. 2012; 53: 491
  • 10 Mukaiyama T, Shimada E, Saigo K. Chem. Lett. 1975; 1045
  • 11 Crosignani S, Gonzalez J, Swinnen D. Org. Lett. 2004; 6: 4579
  • 12 Li P, Xu J. Tetrahedron 2000; 56: 8119
  • 13 Mazón A, Nájera C, Yus M, Heumann A. Tetrahedron: Asymmetry 1992; 3: 1455
  • 14 Motozaki T, Sawamura K, Suzuki A, Yoshida K, Ohara A, Munakata R, Takao K, Tadano K. Org. Lett. 2005; 7: 2265
  • 15 Punthasee P, Vanitcha A, Wacharasindhu S. Tetrahedron Lett. 2010; 51: 1713
  • 16 Vandromme L, Teulade-Fichou M.-P. Synlett 2006; 3423
  • 17 Barghash RF, Massi A, Dondoni A. Org. Biomol. Chem. 2009; 7: 3319
    • 18a Matsugi M, Hasegawa M, Sadachika D, Okamoto S, Tomioka M, Ikeya Y, Masuyama A, Mori Y. Tetrahedron Lett. 2007; 48: 4147
    • 18b Matsugi M, Suganuma M, Yoshida S, Kunda Y, Hagihara K. Tetrahedron Lett. 2008; 49: 6573
    • 18c Matsugi M, Nakamura S, Kunda Y, Sugiyama Y, Shioiri T. Tetrahedron Lett. 2010; 51: 133

  • References

  • 1 Mukaiyama T. Angew. Chem., Int. Ed. Engl. 1979; 18: 707
  • 3 Yamano Y, Tsuboi K, Hozaki Y, Takahashi K, Jin X.-H, Ueda N, Wada A. Bioorg. Med. Chem. 2012; 20: 3658
  • 4 Mukaiyama T, Usui M, Saigo K. Chem. Lett. 1976; 49
  • 5 Kulikov OV, Incarvito C, Hamilton AD. Tetrahedron Lett. 2011; 52: 3705
  • 6 Huang H, Iwasawa N, Mukaiyama T. Chem. Lett. 1984; 1465
  • 7 Funk RL, Abelman MM, Jellison KM. Synlett 1989; 36
  • 8 Kong KH, Tan CK, Lin X, Lam Y. Chem. Eur. J. 2012; 18: 1476
  • 9 Mokhtari B, Azadi R, Mardani E. Tetrahedron Lett. 2012; 53: 491
  • 10 Mukaiyama T, Shimada E, Saigo K. Chem. Lett. 1975; 1045
  • 11 Crosignani S, Gonzalez J, Swinnen D. Org. Lett. 2004; 6: 4579
  • 12 Li P, Xu J. Tetrahedron 2000; 56: 8119
  • 13 Mazón A, Nájera C, Yus M, Heumann A. Tetrahedron: Asymmetry 1992; 3: 1455
  • 14 Motozaki T, Sawamura K, Suzuki A, Yoshida K, Ohara A, Munakata R, Takao K, Tadano K. Org. Lett. 2005; 7: 2265
  • 15 Punthasee P, Vanitcha A, Wacharasindhu S. Tetrahedron Lett. 2010; 51: 1713
  • 16 Vandromme L, Teulade-Fichou M.-P. Synlett 2006; 3423
  • 17 Barghash RF, Massi A, Dondoni A. Org. Biomol. Chem. 2009; 7: 3319
    • 18a Matsugi M, Hasegawa M, Sadachika D, Okamoto S, Tomioka M, Ikeya Y, Masuyama A, Mori Y. Tetrahedron Lett. 2007; 48: 4147
    • 18b Matsugi M, Suganuma M, Yoshida S, Kunda Y, Hagihara K. Tetrahedron Lett. 2008; 49: 6573
    • 18c Matsugi M, Nakamura S, Kunda Y, Sugiyama Y, Shioiri T. Tetrahedron Lett. 2010; 51: 133

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Scheme 1