Polymer-supported IBX-amide reagents: Significant role of spacer and additive in alcohol oxidation

Article abstract of DOI:10.1055/s-2005-872259

We found that the spacer and additive play a significant role in the oxidation of alkyl alcohols using polymer-supported IBX-amide reagents. The introduction of the spacer between the polymer support and IBX-amide group improved the initial conversion rate (up to 60% conversion). Furthermore, various alcohol compounds, when reacted with IBX-amide resin in the presence of BF₃·OEt₂, were effectively converted into the corresponding aldehydes or ketones within 5-30 minutes in high purities (>94%) at room temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872259

LETTER
2175
Polymer-Supported IBX-Amide Reagents: Significant Role of Spacer and
Additive in Alcohol Oxidation
P
olymer-SupportedIBX
o
-Amide
R
ea
o
gents -Jae Chung, Duk-Ki Kim, Yoon-Sik Lee*
School of Chemical & Biological Engineering, Seoul National University, Seoul 151-744, Korea
Fax +82(2)8769625; E-mail: yslee@snu.ac.kr
Received 12 April 2005
series of alcohols to the corresponding aldehydes or
ketones. However, as in previous studies, the oxidation of
long chain alkyl alcohols proved to be more difficult than
that of electronically active alcohols such as benzyl alco-
Abstract: We found that the spacer and additive play a significant
role in the oxidation of alkyl alcohols using polymer-supported
IBX-amide reagents. The introduction of the spacer between the
polymer support and IBX-amide group improved the initial conver-
sion rate (up to 60% conversion). Furthermore, various alcohol hol derivatives. In this regard, we suspected that the poly-
compounds, when reacted with IBX-amide resin in the presence of
mer matrix suppressed the diffusion of long chain alkyl
BF3·OEt2, were effectively converted into the corresponding alde-
alcohols into the reactive sites (IBX reagents), or that the
hydes or ketones within 5–30 minutes in high purities (>94%) at
hydroxy group of the alcohols was not so reactive to the
room temperature.
electrophilic iodine center of the IBX reagents. Despite
these plausible postulations, to the best of our knowledge,
Key words: spacer, additive, IBX-amide resin
there have been no previous reports on attempts to en-
hance the reactivity of supported IBX reagents.
Polymer-supported reagents have gained wider accep-
Herein, we report on the significant role of spacers in in-
tance in organic synthesis since the development of the
creasing the reactivity of IBX-amide resins in the oxida-
solid-phase and combinatorial high throughput synthesis
tion of 1-decanol as a model substrate. In addition, we
techniques.1 The application of polymer-supported
investigated whether additives such as trifluoroacetic acid
reagents to solution-phase organic synthesis combines the
7,8
(TFA),7 BF3·OEt2 and tetraethylammonium bromide
advantages of simple work up by filtration and fast reac-
(TEAB)9 could promote the oxidation of the alcohol,
tion optimization.2
since these agents were previously reported to activate
The oxidation of alcohols to ketones or aldehydes is an
important process in organic chemistry, because these
compounds represent important intermediates for the
preparation of various other compounds.3 The ensuing
continuous interest in developing new methods of mildly
and selectively oxidizing alcohols has prompted numer-
ous reports on solid-supported reagents.4 Especially, sev-
eral solid-supported o-iodoxybenzoic acid (IBX) reagents
have been developed, and these reagents were shown to
convert a series of alcohols to the corresponding alde-
hydes and ketones in excellent yield with high purity.5 In
contrast to most of the previously reported supported oxi-
dants, these IBX reagents do not rely on heavy metal salts
or additional co-oxidants, therefore meeting the industrial
needs for environment-friendly chemistry. However, their
preparation necessitates several elaborate or time-con-
suming steps.
conventional hypervalent iodine reagents by polarizing
the I=O bond and facilitating the nucleophilic attack of the
substrate to the polarized iodine center.
Firstly, we prepared four types of IBX-amide resin with
spacers of different lengths between the polymer matrix
and the IBX-amide group (Figure 1). b-Alanine (b-Ala),
e-aminohexanoic acid (e-ACA) or w-aminoundecanoic
acid (w-AUA) were separately employed as a spacer that
contains amino-group via Fmoc chemistry.
O
O
O
O
O
I
O
O
I
N
N
N
n
H
H
H
2 (n = 1)
3 (n = 4)
4 (n = 9)
1
Accordingly, we previously reported a very simple
method of preparing polymer-supported IBX amides
(IBX-amide resin) in two steps, involving the coupling of
2-iodobenzoic acid to amino functionalized polystyrene
beads, followed by their subsequent activation.6 Also, we
proved that these polymer-supported reagents were mild
and efficient oxidants by the successful conversion of a
Figure 1 Structure of IBX-amide resin with spacers of different
lengths: 1 (0.59 mmol/g); 2 (0.60 mmol/g); 3 (0.57 mmol/g); 4 (0.54
mmol/g).
The loading levels of the prepared IBX-amide resins were
in the range of 0.54–0.60 mmol/g, so that the amount of
resin needed for the oxidation became similar in each
case. The swelling volume of each resin was in the range
of 3.4–4.2 mL/g in CHCl3. We found that the swelling
volume slightly decreased as the spacer was introduced
(IBX-amide resins 2–4).10
SYNLETT 2005, No. 14, pp 2175–2178
0
2
.0
9
.2
0
0
5
Advanced online publication: 03.08.2005
DOI: 10.1055/s-2005-872259; Art ID: U10605ST
© Georg Thieme Verlag Stuttgart · New York

2176
W.-J. Chung et al.
LETTER
Prior to the thorough experiment, we performed oxidation the inner part of the polymer-supports still have less
of 1-decanol using IBX-amide resin 1 in the presence of chance to react with the substrate in solution, considering
amide compound in the solution to investigate any that the conversion did not exceed 42–71%, even two days
feasible role of additional amide bond in the spacer in after the initial burst reaction.
indirect manner.11 We found there were no significant dif-
In an additional attempt to improve the reactivity of the
ferences between the results of oxidation with and without
IBX-amide resins, we investigated the effect that an addi-
additional amide compound. Moreover, the amide com-
tive such as TFA, BF3·OEt2 and TEAB would have on 1-
pound was not affected by the oxidation using IBX-amide
decanol oxidation under the same reaction conditions as
resins. With these results, we considered that additional
those described above (Figure 3).
amide bond in the spacer would not play a significant role
in alcohol oxidation.
In order to investigate the effect of the spacers, the
time courses of the 1-decanol oxidation reactions using
each IBX-amide resin with spacers of different
lengths were evaluated under the same conditions
(oxidant:alcohol = 1:1; Figure 2). The comparison ex-
periment with the IBX-amide resins with different spacers
2–4, showed that the introduction of the spacer increased
the conversion rate compared to that of the IBX-amide
resin without a spacer, 1. In particular, while a moderate
rate enhancement was observed for the IBX-amide resins
with a short spacer (b-Ala, 2) and longer spacer (w-AUA,
4) in the case of the IBX-amide resin with the e-ACA
spacer (3) the conversion was significantly increased from
17% to 63% when the oxidation reaction was performed
for 12 hours.
Figure 3 Time courses for the oxidation of 1-decanol to 1-decanal
with IBX-amide resin 1 (1 equiv) and additive (1 equiv) in CHCl3 (1
mL/100 mg of resin) at 25 °C. The conversions were determined by
GC-MS: (Æ) without additive (r) TFA, (̈) BF3·OEt2, (O) TEAB.
The results of the 1-decanol oxidation reactions proved
that the addition of a Brønsted and Lewis acid such as
TFA and BF3·OEt2 significantly increased the conversion
rate. In particular, we were surprised to find that when
BF3·OEt2 was added, IBX-amide resin converted 1-de-
canol to 1-decanal quantitatively within one hour at
25 °C. To our knowledge, this is the first report of a sig-
nificant enhancement of the oxidation rate being obtained
when supported IBX reagents were used with an additive.
The bromide ion has previously been used as an effective
catalyst in the oxidation of alcohols with PhI=O,12 and
sulfides with IBX.9 However, in contrast to the remark-
Figure 2 Time courses for the oxidation of 1-decanol to 1-decanal
using IBX-amide resin with spacers of different lengths, 1–4 (1 equiv)
able rate enhancement effected by TFA and BF3·OEt2, no
such result was observed when TEAB was used as an ad-
in CHCl3 (1 mL/100 mg of resin) at 25 °C. The conversions were de-
ditive. On the contrary, the addition of TEAB strongly re-
termined by GC-MS: (Æ) 1, (r) 2, (̈) 3, (X) 4.
tarded the oxidation of 1-dencaol. Instead we found that
the IBX-amide resin facilitated the oxidation of the bro-
Thus, we confirmed that the observed spacer effects were
mide ion, leading to the formation of the tribromide ion
consistent with the hypothesis that the accessibility of the
IBX-amide toward 1-decanol is an important factor in in-
(lmax = 266 nm).13,14
Inspired by the positive effect of BF3·OEt2 on alcohol
creasing the reaction rate.
oxidation with IBX-amide resins, we thoroughly investi-
However, despite the significant increase in the initial
gated the effects of the addition of BF3·OEt2 on other
conversion rate (<6 h), which was dependant on the length
alcohol oxidations. As shown in Table 1, all of the tested
of the spacer, it seemed that the reactive sites located at
alkyl and benzylic alcohols were cleanly converted to the
Synlett 2005, No. 14, 2175–2178 © Thieme Stuttgart · New York

LETTER
Polymer-Supported IBX-Amide Reagents
2177
corresponding aldehydes or ketones within 5–30 minutes tion of an IBX-amide resin and an additive such as
at room temperature.
BF3·OEt2 and TFA resulted in a further rate enhancement.
Furthermore, we expect that the two methods presented
herein will extend the range of application of supported
IBX reagents.
In particular, we found that the conversion was completed
within five minutes when benzyl alcohol was subjected to
the oxidation reaction (Table 1, entry 4). In contrast, with-
out additive the conversion of benzyl alcohol was com-
pleted after 90 minutes under the same condition (data not
shown), thereby we confirmed that BF3·OEt2 also signifi-
cantly increased the conversion rate of benzylic alcohol.
Preparation of IBX-Amide Resin with Spacers of Different
Lengths
Amino PS resin (BTCore EM NH2 100–200 mesh, 1.5 mmol/g,
from BeadTech, Inc.) was pre-swollen with N-methylpyrrolidone
(NMP) at r.t. for 30 min. Various Fmoc-protected spacers (2 equiv),
viz. N-Fmoc-b-alanine, N-Fmoc-e-ACA or N-Fmoc-undecanoic ac-
id, BOP (2 equiv), HOBt (2 equiv), and DIEA (2.5 equiv) were add-
ed to the resin suspension in NMP (10 mL per 1 g of resin). The
resultant mixture was shaken at r.t. for 2 h (2×). The resins were fil-
tered, washed with NMP, MeOH, and CH2Cl2 (3 × 10 mL each) and
treated with 20%(v/v) piperidine/NMP (30 min) to afford the ami-
no-alkylated resins. To the spacer containing resins or initial resins
suspension in NMP, 2-iodobenzoic acid (2 equiv), BOP (2 equiv),
HOBt (2 equiv), and DIEA (2.5 equiv) were added and the suspen-
sion mixture was shaken at r.t. for 2 h (2×). The resins were filtered,
washed with NMP, MeOH, and CH2Cl2 (3 × 10 mL each) and dried
In addition, the IBX-amide resin 1 consumed in oxidation
with BF3·OEt2 was collected and reactivated using the
previously reported procedure6 affording the resins with a
restored oxidation activity.15
In conclusion, we presented two methods of improving
the oxidation of long chain alkyl alcohols by IBX-amide
resins, which was known to be difficult to accomplish us-
ing conventional polymer-supported IBX reagents. First-
ly, we found that extending the chain length of the spacer
between the polymer-support and IBX-amide group im-
proved the initial conversion rate. Secondly, the combina-
a
Table 1 Oxidation of Alcohols Using IBX-Amide Resin 1–4 with BF3·OEt2 in CHCl3
OH
O
IBX-amide resin, BF3·OEt2
CHCl3, r.t.
R
R'
R
R'
Entry
1
IBX-amide resin (equiv)
Time (min)
Product
Purity (%)b
>97
1 (1.1)
30
O
O
2
3
1 (1.5)
1 (1.1)
30
30
99
94
O
4
5
1 (2.0)
1 (1.1)
5
99
O
10
>95 (91)c
O
NO2
6
2 (1.5)
20
98
NO2
O
MeO
OMe
7
8
3 (1.1)
4 (1.5)
10
20
99
99
O
Cl
O
a Reactions run at r.t. using an equimolar mixture of IBX-amide resin and BF3·OEt2 in CHCl3.
b Determined by GC-MS.
c Yield of isolated product.
Synlett 2005, No. 14, 2175–2178 © Thieme Stuttgart · New York

2178
W.-J. Chung et al.
LETTER
overnight under vacuum at 30 °C. The completion of each coupling
step was confirmed by the ninhydrin color reaction.16 The resins
were activated by reacting them with an equimolar mixture of tet-
rabutylammonium oxone (5 equiv) and methylsulfonic acid in
CHCl3 at r.t., for 18–20 h. The activated resins were washed several
times with CH2Cl2, Et2O, and dried overnight under vacuum at
30 °C. The loading levels of the resulting resins were determined by
benzyl alcohol oxidation.6
(4) (a) Fréchet, J. M. J.; Darling, P.; Farrall, M. J. J. Org. Chem.
1981, 46, 1728. (b) Mohanazadeh, F.; Ghamsari, S. React.
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Chem. Soc., Perkin Trans. 1 1997, 1907. (d) Kessat, A.;
Babadjamian, A.; Iraqi, A. Eur. Polym. J. 2001, 37, 131.
(e) Tamami, B.; Karimi Zarchi, M. A. Eur. Polym. J. 1995,
31, 715.
(5) (a) Mülbaier, M.; Giannis, A. Angew. Chem. Int. Ed. 2001,
40, 4393. (b) Sorg, G.; Mengel, A.; Jung, G.; Rademann, J.
Angew. Chem. Int. Ed. 2001, 40, 4395. (c) Reed, N. N.;
Delgado, M.; Hereford, K.; Clapham, B.; Janda, K. D.
Bioorg. Med. Chem. Lett. 2002, 12, 2047. (d) Lei, Z.;
Denecker, C.; Jegasothy, S.; Sherrington, D. C.; Slater, N. K.
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2003, 44, 9251.
(7) Zhdankin, V. V.; Litvinov, D. N.; Koposov, A. Y.; Luu, T.;
Ferguson, M. J.; McDonald, R.; Tykwinski, R. R. Chem.
Commun. 2004, 106.
(8) (a) Moriarty, R. M.; Vaid, R. K.; Ravikumar, V. T.; Vaid, B.
K.; Hopkins, T. E. Tetrahedron Lett. 1988, 44, 1603.
(b) Ochiai, M.; Miyamoto, K.; Shiro, M.; Ozawa, T.;
Yamaguchi, K. J. Am. Chem. Soc. 2003, 125, 13006.
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Chem. 2003, 68, 5422.
(10) Swelling volume was determined using a column (ID 0.9
cm, length 40 cm) with sintered glass filter. Each resin (500
mg) was swollen in CHCl3 for 2 h. Thereafter, the solvent
was removed by filtration, and the swelling volume of each
resin was determined as: resin 1 (4.2 mL/g); resin 2 (3.9 mL/
g); resin 3 (3.4 mL/g); resin 4 (3.8 mL/g).
(11) Oxidation of 1-decanol (1 equiv) was performed using IBX-
amide resin 1 (1.3 equiv) with N-methyl hexanamide (1.3
equiv) in CHCl3 at r.t. The reaction mixture was analyzed by
GC-MS after 3 h and 6 h. The conversion of 1-decanol was
compared with that from the oxidation of 1-decanol without
N-methyl hexanamide (NMH) under the same condition;
37% (with NMH) and 34% (without NMH) after 3 h, 43%
(with NMH) and 44% (without NMH) after 6 h. No reaction
between NMH and IBX-amide resin 1 was detected.
(12) (a) Tohma, H.; Takizawa, S.; Watanabe, H.; Kita, Y.
Tetrahedron Lett. 1998, 39, 4547. (b) Tohma, H.;
Maegawa, T.; Takizawa, S.; Kita, Y. Adv. Synth. Catal.
2002, 344, 328.
Time Courses of 1-Decanol Oxidation
1-Decanol (1 equiv) and each IBX amide resin (1 equiv) were
mixed in CHCl3 (1 mL/100 mg of resin) and shaken at 25 °C for a
designated time. When investigating their effect, the additives (1
equiv) were also added to the reaction mixture. The reaction was
terminated by filtration and the filtered resin was washed (5 × 1 mL)
with CH2Cl2. The final conversion was determined from the com-
bined reaction and wash solution by GC-MS.
Long Alkyl Alcohol Oxidation Using IBX-Amide Resin and
BF3·OEt2
The alcohol (1 equiv), IBX-amide resin 1 (1.1 equiv), and BF3·OEt2
(1.1 equiv) were mixed in CHCl3 (3 mL/300 mg of resin) and shak-
en at 25 °C for a designated time. Thereafter, the reaction was ter-
minated by filtration and the filtered resin was washed (5 × 2 mL)
with CH2Cl2. The reaction and wash solution were combined,
passed through the short silica column, and analyzed by GC-MS.
Acknowledgment
The authors wish to acknowledge the financial assistance provided
by the Intelligent Microsystem Center, which carries out some of
the 21st century’s Frontier R&D Projects under the sponsorship of
the Korean Ministry of Science & Technology and the Brain Korea
21 Program supported by the Ministry of Education.
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Synlett 2005, No. 14, 2175–2178 © Thieme Stuttgart · New York