Hypervalent iodine(III)/Et4N+Br- combination in water for green and racemization-free aqueous oxidation of alcohols

Article abstract of DOI:10.1016/j.tetlet.2009.02.020

We have found that the use of the PhI(OAc)₂/Et₄N⁺Br^- combination in water can significantly enhance its oxidation ability and oxidize a wide range of alcohols 1 to carbonyl compounds 2 in good to excellent yields. This clean aqueous oxidation method shows no detectable racemization processes, and even an enolizable ketone 2m could be obtained in an optically pure form from the corresponding chiral alcohol 1m. Utilization of the recyclable reagent 3 as a more practical alternative to PhI(OAc)₂ is also successful in these reactions.

Full text of DOI:10.1016/j.tetlet.2009.02.020

Tetrahedron Letters 50 (2009) 3227–3229
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
+
ꢀ
Hypervalent iodine(III)/Et N Br combination in water for green
4
and racemization-free aqueous oxidation of alcohols
Naoko Takenaga, Akihiro Goto, Misaki Yoshimura, Hiromichi Fujioka, Toshifumi Dohi , Yasuyuki Kita *,
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
+
ꢀ
Article history:
2 4
We have found that the use of the PhI(OAc) /Et N Br combination in water can significantly enhance its
Received 13 January 2009
Accepted 2 February 2009
Available online 8 February 2009
oxidation ability and oxidize a wide range of alcohols 1 to carbonyl compounds 2 in good to excellent
yields. This clean aqueous oxidation method shows no detectable racemization processes, and even an
enolizable ketone 2m could be obtained in an optically pure form from the corresponding chiral alcohol
1
m. Utilization of the recyclable reagent 3 as a more practical alternative to PhI(OAc)
2
is also successful in
Keywords:
these reactions.
Alcohol oxidation
Hypervalent compounds
Iodine
Ó 2009 Elsevier Ltd. All rights reserved.
Aqueous-phase syntheses
+
ꢀ
The oxidation of alcohols to carbonyl compounds is one of the
pivotal transformations in the area of organic synthesis. In view
4
Et N Br would suppress the undesired racemization processes
1
caused by the metal bromides, and would allow the efficient utili-
zation of the recyclable iodine reagent 3 during the aqueous
reaction.
9
of the recent strong demand for establishing greener synthetic pro-
2
cesses, the aqueous-phase oxidation of alcohols has been exten-
3
sively studied these days, as it surely reduces environmental
The PIDA/tetraalkylammonium bromides combination is
and economical issues caused by the use of organic solvents as
the reaction media.
known to induce the oxidation of benzyl alcohols in CH
2 2
Cl , but
the method is not broadly applicable for the oxidation of aliphatic
1
0
Hypervalent iodine reagents are now widely accepted as a
promising synthetic tool for the development of environmentally
benign oxidations due to their mild reactivities, low toxicity,
safety, ready availability, easy handling, etc.4 Both iodine(V) and
iodine(III) compounds have been successfully utilized for alcohol
alcohols such as cyclohexanol 1a.
hypervalent iodine(III)
+
-
OH
Et N Br
O
4
2 2
oxidations in organic solvents such as DMSO, CH Cl , and acetone,
R1
R2
R1
R2
H O, r.t.
2
and have already been applied in the key synthetic steps of natural
products and other related complex molecules.5 However,
examples of the effective oxidation of alcohols in water are rather
1
2
2
1
R , R = alkyl, aryl
6
–8
limited
because the solubilities and reactivities of the organoio-
dine compounds are quite low in water. To overcome this problem,
we have previously reported that the activation of iodosobenzene
hypervalent iodine(III)
OAc
I(OAc)2
(
n 2
[PhIO] ) or phenyliodine diacetate (PhI(OAc) , PIDA) by metal bro-
I
mides, that is, potassium bromide (KBr), in water is a solution that
enhances the solubilities and reactivities of the hypervalent iodine
reagents in aqueous alcohol oxidations.6 As part of our study, we
now report the practical metal-free aqueous oxidation of alcohols
with the combination of the trivalent iodine reagents and tetrae-
OAc
PIDA
O
I
I(OAc)2
+
ꢀ
(AcO)2I
4
thylammonium bromide (Et N Br ) (Scheme 1). The selection of
n
(
AcO)2I
3
*
Corresponding author. Tel./fax: +81 77 561 5829.
E-mail address: kita@ph.ritsumei.ac.jp (Y. Kita).
[PhIO]
n
Present address: College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-
Nojihigashi, Kusatsu, Shiga 525-8577, Japan.
Scheme 1. Aqueous alcohol oxidation with the combination of hypervalent
iodine(III) and Et N Br .
4
+
ꢀ
1
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.020

3
228
N. Takenaga et al. / Tetrahedron Letters 50 (2009) 3227–3229
+
ꢀ
OH
O
PIDA (1.2 equiv.)
Et4N Br (1.0 equiv.)
H2O, 13 h, r.t.
4
As the ammonium bromides, we chose Et N Br because of the
+
-
several following reasons: it is not only readily available and low-
cost, but also easily removable from the product mixture after the
ð1Þ
+
ꢀ
reactions. Indeed, the separation of Et
4
N Br from the product 2a
Cl
extraction), taking advantages of the unique high partition coef-
1a
2a
could be easily attained by a simple workup (AcOEt or CH
2
2
76%
1
1
+
ꢀ
12
4
ficient of Et N Br to water at ambient temperature.
We have now determined that the reactivity of the PIDA/ammo-
To confirm the scope of the aqueous system, we next examined
the reactions using several types of alcohols, and the results are
summarized in Table 1. The aliphatic secondary alcohols 1a–f gen-
erally afforded the corresponding ketones 2a–f in good to excellent
yields (entries 1–6). The yields of 2c–f were higher than the results
in cyclohexanol 1a and a sterically hindered alcohol 1b. In an ester
nium bromides is significantly enhanced in water, and the aqueous
oxidation of an aliphatic alcohol 1a to the corresponding ketone 2a
could smoothly occur at room temperature (Eq. 1). In this oxida-
tion, the effect of water is remarkable, and the oxidation of 1a
did not effectively proceed in organic solvents.
1
e, no hydrolysis of 1e and the product 2e was observed (entry 5).
Table 1
Furthermore, benzyl alcohols 1g–k also gave the aryl ketones 2g–k
in good yields (entries 7–11). Due to the mild reaction nature of the
present system, a nitrogen atom containing substrate 1k was
applicable for the reactions (entry 11). Unfortunately, when we
tried to perform the oxidation of primary alcohols under the same
reaction conditions, the formation of small amounts of ester prod-
ucts was detected by GC analysis as a result of the oxidative con-
densation between two molecules of the starting primary
alcohols. An intramolecular fashion of this type of condensation
rapidly occurred in the diol 1l to exclusively produce the corre-
sponding five-membered lactone 2l in a good yield (entry 12).
The important synthetic merit of the present method is featured
in the case of the oxidation of an optically active alcohol 1m (Scheme
+
ꢀa
4
Aqueous oxidation with the combination of PIDA and Et N Br
Yieldb (%), time (h)
Entry
1
Substrate
Product
OH
O
76, 13
1a
2a
1
3
2
3
4
5
6
7
8
9
72, 4
90, 4
90, 6
HO
1b
c
O
2b
OH
O
2). The chiral alcohol 1m is a challenging substrate, which produces
C6H13
C H
1
6
13
2c
an enolizable -aryl ketone 2m as a result of the oxidation. With the
a
+
ꢀ
14
OH
O
n 4
[PhIO] /Et N Br combination, the oxidation of an alcohol 1m
could proceed in a good yield and notably, the optical activity of
the ketone 2 was well maintained throughout the reaction. We have
clarified the racemization-free evidence by confirming the no in situ
1
d
2d
OH OBz
2
O
OBz
2
H/D exchange of deuterium at the acidic
a
-position of the resulting
89,c
5
1
a
-aryl ketone 2m based on H NMR and GC–Mass analyses. In con-
1e
2e
6
+
ꢀ
4
trast, the use of KBr instead of Et N Br was found to somewhat re-
duce the ee value of 2m (85% yield and 73% ee), indicating that even
the weak Lewis acidity of the potassium ion is enough to cause the
OH
O
O
81, 6
Ph
1f
Ph
2f
undesired enolization process of the
The racemization-free oxidation of 1m to 2m was also difficult using
the metal-catalyzed aqueous oxidation strategy such as Na WO
a-aryl ketone 2m in water.
OH
2
4
/
77,c
4
+
ꢀ
3a,3b
[
(C
8
H
17
)
3
NMe] HSO in 30% H
2
O
2
aq.
4
1
g
2g
In the present iodine(III)-mediated oxidation method, iodoben-
OH
Et
O
zene (PhI) was typically co-produced together with the desired
oxidation products 2. This forces the removal of the organic con-
taminant from the products 2 by tedious chromatographic workup.
To make the purification step simpler, we therefore planned to ap-
ply a recyclable hypervalent iodine(III) reagent as a useful alterna-
Et
84, 4
1h
2h
OH
O
78, 8
tive to PIDA or [PhIO]
n
.
The use of 1,3,5,7-tetrakis[4-
c
7
5,
8
Br
1i
Br
2i
(diacetoxyiodo)phenyl]adamantane 3 (Fig. 1), a recyclable iodi-
9
ne(III) reagent developed by us, met this purpose, and ketones 2
OH
O
were obtained by a simpler experimental operation (see below).
Typically, the recyclable reagent 3 could afford the ketones 2 in
better yields than PIDA, except for the alcohols 1c and 1j (Table 2).
In all the experiments listed in Table 2, the reagent 3 could
easily be removed from the reaction mixtures by simple filtration,
tBu
tBu
1
0
1
88, 3
1j
2j
OH
Ph
O
1
Ph
75, 12
N
N
1k
2k
Ph
Ph
O
Ha
Ha
[
PhIO]
n
-
(1.1 eq.)
OH
OH
OH
2d
66,c
+
O
1
9
Et
4
N Br (0.2 eq.)
O
1l
2l
D O, 12 h, r.t.
2
a
+
ꢀ
1m
2m
Reactions were performed using PIDA (1.2 equiv) and Et
O (0.1 M) at room temperature unless otherwise noted.
GC yield.
4
N Br (1.0 equiv) in
H
2
b
83%, >98% ee
(H /D 100)
a
c
Isolated yield after purification.
d
2
.5 equiv of PIDA was used.
Scheme 2. Recemization-free oxidation of an optically active alcohol 1m.

N. Takenaga et al. / Tetrahedron Letters 50 (2009) 3227–3229
3229
X
racemization process of the enolizable
a
-aryl ketone product 2m.
In addition, effective utilization of the recyclable hypervalent iodi-
+
ꢀ
4
ne(III) reagent 3 is possible when using Et N Br as the bromide
source, enhancing the practicability of the aqueous method.
Further investigations on the scope of the functional group com-
patibility and availability of chiral compounds will lead to applica-
tion of the method to more complex molecules such as natural
products.
X
3
4
: X = I(OAc)2
: X = I
X
X
Acknowledgments
Figure 1. Adamantane-type recyclable hypervalent iodine(III) reagent.
This work was supported by a Grant-in-Aid for Scientific
Research (S and A) and for Young Scientists (B), and a grant for
Scientific Research on Priority Areas ‘Advanced Molecular Trans-
formations of Carbon Resources’ from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan. T.D. also acknowl-
edges support from the Industrial Technology Research Grant Pro-
gram from the New Energy and Industrial Technology
Development Organization (NEDO) of Japan. N.T. thanks research
fellowship of J.S.P.S. for Young Scientists.
Table 2
Reactions using a recyclable iodine(III) reagent 3
a
Entry
Substrate
Product
Yield (%), time (h)
1
2
3
1a
1c
1e
1g
1h
1j
2a
2c
2e
2g
2h
2j
99, 4
88, 18
99, 2
99, 4
91, 5
82, 3
97, 24
b
4
5
6
References and notes
c,d
7
1l
2l
a
+
ꢀ
1. (a) Comprehensive Organic Functional Group Transformations; Katritzky, A. R.,
Meth-Cohn, O., Rees, C. W., Pattenden, G., Moody, C. J., Eds.; Elsevier Science:
Oxford, 1995; Vols. 3 and 5, (b) March, J. Advanced Organic Chemistry, 4th ed.;
John Wiley & Sons: New York, 1992. Chapter 19; (c) Caron, S.; Dugger, R. W.;
Ruggeri, S. G.; Ragan, J. A.; Ripin, D. H. B. Chem. Rev. 2006, 106, 2943.
Reactions were performed using 3 (1.1 ꢁ 1/4 equiv) and Et
4
N Br (0.5 equiv) in
H
4
2
O (0.1 M) at room temperature. The reagent 3 was recovered as its reduced form
in over 95% yields by filtration.
b
c
+
ꢀ
0
2
1
.2 equiv of Et
4
N Br was used.
.0 ꢁ 1/4 equiv of 3 was used.
2
.
(a) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751; (b) Klijn, J. E.; Engberts, J. B. F.
N. Nature 2005, 435, 746; (c) Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68.
Selected recent papers: (a) Sato, K.; Aoki, M.; Takagi, J.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 12386; (b) Sato, K.; Aoki, M.; Takagi, J.; Zimmermann, K.; Noyori,
R. Bull. Chem. Soc. Jpn. 1999, 72, 2287; (c) Brink, G.-J.; Arends, I. W. C. E.;
Sheldon, R. A. Science 2000, 287, 1636; (d) Figiel, P. J.; Leskela, M.; Repo, T. Adv.
Synth. Catal. 2007, 349, 1173; (e) Kon, Y.; Yazawa, H.; Usui, Y.; Sato, K. Chem.
Asian J. 2008, 3, 1642; (f) Tervekar, V. N.; Jadhav, N. C. Synth. Commun. 2008, 38,
d
+
ꢀ
4
.0 equiv of Et N Br was used.
3
.
utilizing the insolubility of the co-produced tetraiodide 4 in water
and methanol. Thus, after completion of the reactions, saturated
NaHCO aq and methanol were added to the reaction mixtures.
3
3107.
The resulting precipitates involving 4 were collected by filtration
and the residues were washed several times with small portions
of methanol. With this operation, the reagent 4 could be removed
from the mixtures in at least 95% recovered yields, which could be
4.
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) Kirschning,
A. Eur. J. Org. Chem. 1998, 2267; (d) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002,
1
02, 2523; (e) Hypervalent Iodine Chemistry; Wirth, T., Ed.; Springer: Berlin,
Heidelberg, 2003; (f) Zhdankin, V. V.; Stang, P. J. Chem. Rev 2008, 108, 5299.
reoxidized to the initial form 3 in nearly quantitative yields by the
5. (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277; (b) Frigerio, M.;
Santagostino, M.; Sputore, S.; Palmisano, G. J. Org. Chem. 1995, 60, 7272; (c)
Tohma, H.; Kita, Y. Adv. Synth. Catal. 2004, 346, 111.
treatment with m-chloroperbenzoic acid (mCPBA).9 On the other
hand, the crude products 2 could be obtained from the filtrates
by extraction with AcOEt or CH Cl and by evaporation of the sol-
2 2
vents. Isolation of the pure 2 could be easily achieved by short col-
6.
7.
8.
9.
(a) Tohma, H.; Takizawa, S.; Maegawa, T.; Kita, Y. Angew. Chem., Int. Ed. 2000,
39, 1306; (b) Tohma, H.; Maegawa, T.; Kita, Y. Adv. Synth. Catal. 2002, 344, 328.
(a) Qian, W.; Jin, E.; Bao, W.; Zhang, Y. Tetrahedron 2006, 62, 556; (b) Su, W.;
Wang, H.; Xia, C.; Li, J.; Zhao, P. Angew. Chem., Int. Ed. 2003, 42, 1042.
Mu, R.; Liu, Z.; Yang, Z.; Lui, Z.; Wu, L.; Lui, Z.-L. Adv. Synth. Catal. 2005, 347,
1333.
(a) Tohma, H.; Maruyama, A.; Maeda, A.; Maegawa, T.; Dohi, T.; Shiro, M.;
Morita, T.; Kita, Y. Angew. Chem., Int. Ed. 2004, 43, 3595; (b) Dohi, T.; Maruyama,
A.; Yoshimura, M.; Morimoto, K.; Tohma, H.; Shiro, M.; Kita, Y. Chem. Commun.
2005, 2205.
umn chromatography on silica gel.
+
ꢀ
Another merit of choosing Et
that the former bromide source exhibits superior performance
4
N Br instead of KBr6 is the fact
+
ꢀ
4
when using the recyclable reagent 3. Et N Br is not only an effec-
tive bromide source, but also works as a phase transfer catalyst
permitting the high reactivity of the water-insoluble reagent 3 in
water. For example, the oxidation of 1a with the recyclable reagent
10. Brunjes, M.; Sourkouni-Argirusi, G.; Kirschning, A. Adv. Synth. Catal. 2003, 345,
35.
1. Typical experimental procedure in Table 1: To a suspension of 1e (33.3 mg,
6
1
3
and KBr (0.5 equiv) required a longer reaction time to reach the
0
Et
.150 mmol) in H
2
O (1.50 mL) were added PIDA (58.0 mg, 0.180 mmol) and
+
ꢀ
high conversion of the alcohol 1a (24 h, 76% yield) compared to
4
N Br (31.5 mg, 0.150 mmol). The mixture was then stirred for 5 h at room
+
ꢀ
ꢀ
temperature. AcOEt and solid sodium thiosulfate were successively added to
the reaction mixture. After stirring for 5 min, the organic layer was separated,
that using the same amount of Et
sult also implies that the use of Et
4
N Br (Table 2, entry 1). This re-
+
4
N Br enables the utilization of
dried with Na
residue by column chromatography on silica gel gave 2e (29.5 mg,
.134 mmol) in 89% yield.
4 2 2
2. It is known that the concentration of Et N Br in the same volume of CH Cl
4
SO , and evaporated to remove the solvent. Purification of the
2
a variety of alternative reagents, and will potentially contribute to
the development of new and green aqueous-phase oxidations.
In summary, we have demonstrated the facile and green aque-
ous oxidation of alcohols 1 to ketones 2 using the combination of
0
+
ꢀ
1
and water is in the ratio of 1/10,000: Pradines, V.; Despoux, S.; Claparols, C.;
Martins, N.; Micheau, J.-C.; Lavabre, D.; Pimienta, V. J. Phys. Org. Chem. 2006, 19,
350.
+
ꢀ
hypervalent iodine(III) reagents and Et
4
N Br . The present system
13. Direct oxidative esterification of alcohols, see: Tohma, H.; Maegawa, T.; Kita, Y.
Synlett 2003, 723. and references cited therein.
showed a broad generality of the substrates 1 including the ali-
+
ꢀ
phatic alcohols. The choice of Et
4
N Br is indispensable for the suc-
14. The use of PIDA caused partial racemization of 2m (3 h, 85% yield and 83% ee),
probably due to the in situ released acetic acid.
cessful reaction progress and suppression of the undesired