Facile and efficient oxidative transformation of primary alcohols to methyl esters in water using hypervalent iodine(III) reagents

Article abstract of DOI:10.1055/s-2003-38373

A facile and direct oxidative esterification of primary alcohols in water using a combination of the hypervalent iodine(III) reagent, iodosobenzene (PhIO), and KBr has been developed. This methodology is expected to be environmentally benign since it uses a recyclable polymer-supported iodine(III) reagent in water.

Full text of DOI:10.1055/s-2003-38373

LETTER
723
Facile and Efficient Oxidative Transformation of Primary Alcohols to Methyl
Esters in Water Using Hypervalent Iodine(III) Reagents
O
xidation of Prima
i
ry Alc
r
ohols to
o
M
ethyl
E
ster
f
s
umi Tohma, Tomohiro Maegawa, Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan
Fax +81(6)68798229; E-mail: kita@phs.osaka-u.ac.jp
Received 9 January 2003
We report herein a direct and efficient oxidative methyl
esterification of primary alcohols in aqueous MeOH using
hypervalent iodine(III) reagents.
Abstract: A facile and direct oxidative esterification of primary al-
cohols in water using a combination of the hypervalent iodine(III)
reagent, iodosobenzene (PhIO), and KBr has been developed. This
methodology is expected to be environmentally benign since it uses
a recyclable polymer-supported iodine(III) reagent in water.
In our previous paper, we reported on the intramolecular
esterification of diols leading to lactones in the presence
of water.9b As a practical extension of this reaction, we
planned to examine the intermolecular esterification be-
tween different alcohols. Our working hypothesis is as
follows: initially, oxidation of the hydrophobic alcohol
with PhIO–KBr occurs in water by the hydrophobic ef-
fect, then nucleophilic attack of the hydrophilic alcohol to
the aldehyde formed in situ, followed by further oxidation
yields the corresponding ester. Accordingly, we examined
the oxidation of 1-hexanol (1a) with PhIO–KBr in hydro-
philic alcohol (i.e. MeOH, EtOH, i-PrOH, and t-BuOH)–
H2O (1:1). Consequently, the best result was obtained
when using MeOH, which is a highly hydrophilic, hardly
oxidizable, and nucleophilic alcohol (entry 1, Table 1).
On the other hand, in the presence of other hydrophilic al-
cohols, the desired esters (2) were not obtained in good
yields, but several by-products involving other alkyl es-
ters were obtained (entries 2–4, Table 1).
Key words: alcohols, oxidations, esterification, hypervalent io-
dine, polymers
Esterification is one of the most important reactions in or-
ganic synthesis. The traditional approach to the prepara-
tion of esters is the simple condensation between a
carboxylic acid and an alcohol, and a number of such
methods have been reported.1 On the other hand, oxida-
tive esterification of an aldehyde with an alcohol has also
been established,2 yet, only limited methods have been re-
ported for the direct conversion of primary alcohols into
esters, mostly methyl esters, using oxidants including
MnO2–NaCN,3 chromium(VI) oxide-pyridine,4 t-butyl
hypochlorite,5 N-iodosuccinimide (NIS),6 and calcium
hypochlorite7 in the presence of MeOH. These direct es-
terifications still have several drawbacks from a practical
point of view. That is, i) anhydrous reaction conditions are
required, ii) excess amounts of reagents (normally, > 10
equiv) are needed, iii) generality of the reaction is limited,
and iv) toxic oxidants and additives are used. As a contin-
uation of our studies on hypervalent iodine chemistry,8 we
recently reported a mild and efficient oxidation of alco-
hols leading to the corresponding ketones, carboxylic ac-
ids, and lactones using iodosobenzene (PhIO) with KBr in
water under neutral conditions and its extension to a clean
oxidation process using poly(diacetoxyiodo)styrene
(PDAIS) (Scheme 1).9
Table 1 Oxidation of 1-Hexanol to Esters Using PhIO–KBr in
ROH–H2O (1:1)
O
3
3.5 equiv. PhIO
1.0 equiv. KBr
OH
OR
3
ROH-H2O (1:1)
r.t., 12h
1a
2
Entry
R
Yield (%)a
1
2
3
4
Me (2a)
Et
75
15
R1R2CHOH
R3CH2OH
R1R2C=O
R3CO2H
i-Pr
t-Bu
7
(PDAIS)
PhIO or
I(OAc)2
not detected
KBr in H2O
CH2OH
OH
O
O
a Yields were determined by GC.
Scheme 1
Further improvement of the reaction conditions,10 PhIO
(3.5 equiv)–KBr (0.5 equiv) in MeOH–0.5 N HCl aq (2:1)
was found to be the best for direct methyl esterification of
1a. The present reaction is applicable to the oxidation of
various primary alcohols, including aliphatic and benzylic
alcohols, to directly afford the corresponding methyl es-
ters in good yields as shown in Table 2. However, oxida-
tive condensation of primary alcohols 1 also occurred as
Synlett 2003, No. 5, Print: 10 04 2003.
Art Id.1437-2096,E;2003,0,05,0723,0725,ftx,en;U00203ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

724
H. Tohma et al.
LETTER
the hydrophobicity of 1 increased (entries 2 and 3, Next, we modified this system to develop a practical and
Table 2).
clean procedure for the methyl esterification of primary
alcohols using a polymer-supported hypervalent io-
dine(III) reagent. Polymer-supported hypervalent iodine
reagents are expected to be useful for pharmaceutical and
agrochemical industries due to their versatility, low toxic-
ity and high yields.11 Recently, Togo et al.,12 Ley et al.,13
and we9,14 demonstrated that PDAIS15 and poly bis(tri-
fluoroacetoxyiodo)styrene (PBTIS) show similar reactiv-
ities to (diacyloxyiodo)benzenes and utilized them as a
replacement for previously reported iodine(III) reagents.
Thus, we investigated the use of recyclable PDAIS for the
oxidative methyl esterification. As a result, methyl esters
were obtained in moderate to good yields (Table 3).
A plausible mechanism of this reaction is depicted in
Scheme 2. Polymeric iodosobenzene is initially depoly-
merized by the addition of KBr to form a highly reactive
intermediate 3, which could be detected by electrospray
ionization (ESI) mass spectroscopy.9b Intermediate 3 re-
acts with a hydrophobic alcohol 1, then in situ formation
of hemiacetal 5 by nucleophilic attack of MeOH to the al-
dehyde 4 followed by further oxidation affords the corre-
sponding methyl ester. Another mechanism via
carboxylic acid is also possible, but the mechanism via
hemiacetal is more likely since only 15% yield of 2a was
obtained from the reaction of 1-hexanoic acid and MeOH
even after 6 h under the same conditions (PhIO–KBr–0.5 The resin (poly iodostyrene) is readily recoverable and re-
N HCl aq–MeOH).
cyclable. The recovered resin was easily reoxidized by
peracetic acid (30% H2O2 and Ac2O) and the regenerated
PDAIS was found to maintain its activity (entries 1–3,
Table 3). In the present reaction, only a small amount of
the corresponding carboxylic acids were sometimes
formed together with 2, but they were easily removed by
simple filtration as described below.16
Table 2 Oxidative Methyl Esterification of Primary Alcohols Us-
ing PhIO–KBr
3.5 equiv. PhIO
O
0.5 equiv. KBr
R1
1a-j
OH
R1
2a-j
OMe
MeOH-0.5N HCl aq.
(2:1)
, r.t.
Entry
Substrate (R1 = )
n-C5H11 1a
Time (h)
Yielda (%)
84b
Table 3 Oxidative Methyl Esterification of Primary Alcohols (1)
Using PDAIS–KBr
1
2
6
12
12
4
(PDAIS)
I(OAc)2
1.0 equiv. KBr
MeOH-0.5N HCl aq.
(2:1)
3.0 equiv.
n-C7H15 1b
81b,c
56b,d
76b
2
1
3
n-C11H23 1c
cyclohexyl 1d
C6H5 1e
, r.t.
4
Entry
Substrate
Time (h)
Yielda (%)
75b [1st]
75b [2nd]
70b [3rd]
76b
5
6
90
1
2
3
4
5
6
1a
1a
1a
1d
1e
1h
4
4
6
4-MeC6H4 1f
3-pyridyl 1g
EtO2C(CH2)4 1h
N3(CH2)5 1i
C6H5C;C 1j
5
86
7
7
71
4
8f
9f
10
12
6
74 (86e)
68
3
5
68
6
52
12
61 (82c)
a Isolated yield unless otherwise noted.
b Yields were determined by GC.
a Isolated yield unless otherwise noted.
b Yields were determined by GC.
c n-Octyl n-octanoate also formed in 7% yield.
d Lauric acid laurylester also formed in 26% yield.
e Yield based on the reacted substrate.
f 4.0 equiv PhIO was used.
c Yield based on the reacted substrate.
I
O
(PhIO)
n
Ph
via
hemiacetal
O
OH
H
KBr
R1
OMe
R1
H
O–
3
Br
MeOH
O–
4
5
Ph
I
H
Ph I
via
R1
OH
carboxylic
acid
O
C
R1
H
1
O
O
MeOH
2
OMe
R1
R1
OH
Scheme 2
Synlett 2003, No. 5, 723–725 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Oxidation of Primary Alcohols to Methyl Esters
725
(10) Among the typical hypervalent iodine(III or V) reagents,
PhIO gave the best yield [75% yield], while other reagents
such as phenyliodine diacetate (PIDA) [47% yield],
phenyliodine bis(trifluoroacetate) (PIFA) [40% yield],
Dess–Martin periodinane [trace], and o-iodoxybenzoic acid
[trace], were also examined under the reaction conditions
described in Table 1.
In summary, we developed a facile and direct oxidative
methyl esterification of primary alcohols using hyperval-
ent iodine(III) reagents. The environmentally benign pro-
cedure described herein16 will provide a new practical
method for methyl esterification because of its simple op-
eration and use of non-toxic reagents.
(11) Reviews see: (a) Drewry, D. H.; Coe, D. M.; Poon, S. Med.
Res. Rev. 1999, 19, 97. (b) Ley, S. V.; Baxendale, I. R.;
Bream, R. N.; Jackson, P. S.; Leach, A. G.; Longbottom, D.
A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J. Chem.
Soc., Perkin Trans. 1 2000, 3815. (c) Bhalay, G.; Dunstan,
A.; Glen, A. Synlett 2000, 1846. (d) Kirschning, A.;
Monenschein, H.; Wittenberg, R. Angew. Chem. Int. Ed.
2001, 40, 650. (e) Togo, H.; Sakuratani, K. Synlett 2002,
1966.
(12) (a) Togo, H.; Nogami, G.; Yokoyama, M. Synlett 1998, 534.
(b) Togo, H.; Abe, S.; Nogami, G.; Yokoyama, M. Bull.
Chem. Soc. Jpn. 1999, 72, 2351. (c) Abe, S.; Sakuratani, K.;
Togo, H. Synlett 2001, 22. (d) Abe, S.; Sakuratani, K.;
Togo, H. J. Org. Chem. 2001, 66, 6174.
(13) (a) Ley, S. V.; Thomas, A. W.; Finch, H. J. Chem. Soc.,
Perkin Trans 1 1999, 669. (b) Ley, S. V.; Schucht, O.;
Thomas, A. W.; Murray, P. J. J. Chem. Soc., Perkin Trans. 1
1999, 1251. (c) Baxendale, I. R.; Ley, S. V.; Piutti, C.
Angew. Chem. Int. Ed. 2002, 41, 2194. (d) Baxendale, I. R.;
Lee, A.-L.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 2002,
1850.
Acknowledgement
This work was supported by Grant-in-Aid for Scientific Research
(S) (No. 13853010) and for Encouragement of Young Scientists
(No. 13771331) from the Ministry of Education, Science, Sports
and Culture, Japan. H. T. also thanks Industrial Technology Rese-
arch Grant Program (No. 02A28004d) from New Energy and Indus-
trial Technology Development Organization (NEDO) of Japan.
References
(1) (a) Protective Group in Organic Synthesis, 3rd ed.; Greene,
T. M.; Wutz, P. G., Eds.; Wiley: New York, 1999, 149.
(b) Protective Group in Organic Synthesis, 3rd ed.; Greene,
T. M.; Wutz, P. G., Eds.; Wiley: New York, 1999, 373.
(2) (a) Larock, R. C. Comprehensive Organic Transformation,
2nd ed.; VCH: New York, 1999, 1656. (b) March, J.
Advanced Organic Chemistry; John Wiley & Sons: New
York, 1992, 1196.
(3) (a) Kaneko, R.; Seki, K.; Suzuki, M. Chem. Ind. (London)
1971, 1016. (b) Smith, A. B. III; Sulikowski, G. A.;
Sulikowski, M. M.; Fujimoto, K. J. Am. Chem. Soc. 1992,
114, 2567. (c) Foot, J. S.; Kanno, H.; Giblin, G. M. P.;
Taylor, R. J. K. Synlett 2002, 1293.
(4) (a) Corey, E. J.; Samuelsson, B. J. Org. Chem. 1984, 49,
4735. (b) Guest, A. W. Tetrahedron Lett. 1986, 27, 3049.
(5) Milovanovic, J. N.; Vasojevic, M.; Gojkovic, S. J. Chem.
Soc., Perkin Trans. 2 1991, 1231.
(14) (a) Tohma, H.; Morioka, H.; Takizawa, S.; Arisawa, M.;
Kita, Y. Tetrahedron 2001, 57, 345. (b) Tohma, H.;
Morioka, H.; Harayama, Y.; Hashizume, M.; Kita, Y.
Tetrahedron Lett. 2001, 42, 6899.
(15) (a) Okawara, M.; Mizuta, K. Kogyo Kagaku Zasshi 1961, 64,
232. (b) Yamada, Y.; Okawara, M. Makromol. Chem. 1972,
152, 153. (c) Hallensleben, M. L. Angew. Makromol. Chem.
1972, 27, 223.
(16) General Experimental Procedure: Oxidation with PhIO-
KBr: To a stirred solution of 1 (1.0 mmol) and KBr (0.5
mmol) in MeOH (1 mL) was added dropwise 0.5 N HCl aq
(0.5 mL). PhIO (3.5 mmol) was added to the vigorously
stirred solution and stirring was continued for several hours
at room temperature while checking the reaction progress by
GC or TLC. After completion of the reaction, water (ca. 1.5
mL) was added to the mixture. The mixture was filtrated
through BOND ELUT C 18 (Varian), washed with a small
amount of water, and extracted with Et2O. The filtrate was
dried with MgSO4, and evaporated. The residue was purified
by column chromatography (SiO2/n-hexane–Et2O) to give
pure 2. Oxidation with PDAIS-KBr: To a stirred solution
of 1 (1.0 mmol) and KBr (1.0 mmol) in MeOH (2 mL) was
added dropwise 0.5 N HCl aq (1 mL). PDAIS (prepared by
the reported procedure9b) (3.0 mmol) was added to the
vigorously stirred solution and stirring was continued for
several hours at room temperature. After completion of the
reaction, water (ca. 3 mL) was added to the mixture. The
mixture was filtered through BOND ELUT C 18 (Varian)
and washed with a small amount of water to remove KBr.
The residue was extracted with Et2O, and the filtrate was
dried and evaporated. The residue was purified by column
chromatography to give pure 2.
(6) McDonald, C. E.; Holcomb, H. L.; Leathers, T. W.;
Kennedy, K. E. Microchem. J. 1993, 47, 115.
(7) McDonald, C. E.; Nice, L. E.; Shaw, A. W.; Nestor, N. B.
Tetrahedron Lett. 1993, 34, 2741.
(8) Recent reviews see: (a) Stang, P. J.; Zhdankin, V. V. Chem.
Rev. 1996, 96, 1123. (b) Kita, Y.; Takada, T.; Tohma, H.
Pure & Appl. Chem. 1996, 68, 627. (c) Varvoglis, A.
Hypervalent Iodine in Organic Synthesis; Academic Press:
San Diego, 1997. (d) Kitamura, T.; Fujiwara, Y. Org. Prep.
Proced. Int. 1997, 29, 409. (e) Ochiai, M. In Chemistry in
Hypervalent Compounds; Akiba, K., Ed.; Wiley-VCH: New
York, 1999, Chap. 12. (f) Wirth, T.; Hirt, U. H. Synthesis
1999, 1271. (g) Zhdankin, V. V.; Stang, P. J. Chem. Rev.
2002, 102, 2523. (h) Hypervalent Iodine Chemistry (Top.
Curr. Chem. 224); Wirth, T., Ed.; Springer-Verlag: Berlin,
Heidelberg, 2003.
(9) (a) Tohma, H.; Takizawa, S.; Maegawa, T.; Kita, Y. Angew.
Chem. Int. Ed. 2000, 39, 1306. (b) Tohma, H.; Maegawa,
T.; Takizawa, S.; Kita, Y. Adv. Synth. Catal. 2002, 344, 328.
Synlett 2003, No. 5, 723–725 ISSN 0936-5214 © Thieme Stuttgart · New York