SPOTLIGHT ██135

SYNLETT spotlight
The 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 re-
agent 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
thioureas8 and thiocyanates from alcohols.9 CMPI was in-

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activation of hydroxyl groups of carboxylic acids and
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
N Cl
N+ Cl able for peptide synthesis.12
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–
1 base⋅HCl 2
philic attack of the carboxylate anion on CMPI (1) produces
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–
good yields using the Mukaiyama reagent.1,4 Both small and large OH Et3N, MeCN O O
CO2H
macrocycles can be obtained. H ∆ H
96% yield

H H
OH OH

(C) The Mukaiyama reagent can also be used for C–N bond forma-
tion, 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 +
method and the Ph3P(PyS)2 method of β-lactam synthesis, the Mu- R2 O N Cl R3 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
R3 R2 R1
base-sensitive β-lactam ring.6 For example, the use of Mukaiyama 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 thiocya-

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

(F) When triethylammonium dithiocarbamate, easily prepared from OBn

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1. CS2 OBn
amine, carbon disulfide, and triethylamine, is treated with 2-chloro- O
2. Mukaiyama reagent O
1-methylpyridinium iodide at room temperature, isothiocyanate is BnO NH2
Et3N, CH2Cl2, r.t. BnO NCS
produced in a high yield.17 50–88% yield

(G) 2-Chloro-1-methylpyridinium iodide is used in the synthesis of S N

i ii R1 C
carbodiimides 3 from N,N’-disubstituted thioureas 2. The former can S C N
R1 N
be transformed into derivatives 4 which upon treatment with CMPI NH NH
1 2 3
and acetic acid provides 1,3,5-triazines 5.8
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)
better yields in the condensation reactions. Recently, a number of N Cl Tf2O N Cl 1b Rf = C8F17 (84% yield)
OH 1c Rf = C6F13 (60% yield)
fluorous tagged reagents have been developed.18a–c They are useful Rf CH2Cl2, 45 °C, 24–48 h TfO– 1d Rf = C4F9 (41% yield)
in ester- and amide-forming reactions. recrystallization
Rf 1e Rf = C10F21 (33% yield)
from EtOAc

References
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5892. (c) Khoroshilov, G.; Demchak, I.; Saraeva, T. (13) Mazón, A.; Nájera, C.; Yus, M.; Heumann, A. Tetrahedron:
Synthesis 2008, 1541. (d) Armstrong, A.; Wang, Y.; Wang, Asymmetry 1992, 3, 1455.
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(7) Funk, R. L.; Abelman, M. M.; Jellison, K. M. Synlett 1989, S.; Tomioka, M.; Ikeya, Y.; Masuyama, A.; Mori, Y.
36. Tetrahedron Lett. 2007, 48, 4147. (b) Matsugi, M.;
(8) Kong, K. H.; Tan, C. K.; Lin, X.; Lam, Y. Chem. Eur. J. Suganuma, M.; Yoshida, S.; Kunda, Y.; Hagihara, K.
2012, 18, 1476. Tetrahedron Lett. 2008, 49, 6573. (c) Matsugi, M.;
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Synlett 2013, 24, 135–136 © Georg Thieme Verlag Stuttgart · New York