A New Polymer-attached Reagent for the Oxidation of Primary and Secondary Alcohols

Article abstract of DOI:10.1021/ol006483t

formula presented A new, polymer-bound reagent system for the efficient oxidation of primary alcohols to aldehydes and secondary alcohols to ketones in the presence of a catalytic amount of 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) is described. In most cases, workup of this heavy metal-free oxidation is achieved by simple filtration followed by removal of the solvent. In selected examples this reagent was compared with the known polymer-bound permanganate and chromium(VI) reagents.

Full text of DOI:10.1021/ol006483t

ORGANIC
LETTERS
2000
Vol. 2, No. 24
3781-3784
A New Polymer-Attached Reagent for
the Oxidation of Primary and Secondary
Alcohols
,‡
Georgia Sourkouni-Argirusi† and Andreas Kirschning*
Institut fu¨r Organische Chemie der UniVersita¨t HannoVer, Schneiderberg 1B,
D-30167 HannoVer, Germany, and Institut fu¨r Organische Chemie der TU Clausthal,
Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Germany
andreas.kirschning@oci.uni-hannoVer.de.
Received August 18, 2000
ABSTRACT
A new, polymer-bound reagent system for the efficient oxidation of primary alcohols to aldehydes and secondary alcohols to ketones in the
presence of a catalytic amount of 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) is described. In most cases, workup of this heavy metal-free
oxidation is achieved by simple filtration followed by removal of the solvent. In selected examples this reagent was compared with the known
polymer-bound permanganate and chromium(VI) reagents.
After an incubation time of more than 25 years, polymer-
supported reagents have seen renewed interest lately.1 Indeed,
the dramatic developments in the need for compound libraries
in pharmaceutical and agrochemical research has moved
functionalized polymers from an academic curiosity to a
widely recognized synthetic technique. The intrinsic advan-
tage of this hybrid solid/solution phase technique lies in the
simple purification and the possibility of using these reagents
in excess to drive reactions in solution to completion.
Furthermore, they may be adapted to continuous flow
processes and hence used in automated synthesis.2
and widely used examples are polymers that are function-
2- 4
alized with heavy metals such as CrO3 (2),3 Cr2O7
,
- 5
-
-
- 8
ClCrO3 , HCrO4 (3),5a,6 MnO4 (4),7 and RuO4
ions
(Scheme 1).9
Scheme 1
Oxidation of alcohols is a process which has been achieved
with various polymer-bound reagents.2 The most prominent
† Technische Universita¨t Clausthal.
‡ Universita¨t Hannover.
(1) Reviews: (a) Kirschning, A.; Monenschein, H.; Wittenberg, R.
Angew. Chem., Int. Ed. In press. (b) Drewry, D. H.; Coe, D. M.; Poon, S.
Med. Res. ReV. 1999, 19, 97-148. (c) Pittman Jr.; C. U. Polym. News 1998,
23, 416-418. (d) Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis
1998, 1217-1239. (e) Kaldor, S. W.; Siegel, M.; G. Curr. Opin. Chem.
Biol. 1997, 1, 101-106.
(2) Taylor, R. T. In Polymer reagents and catalysts; Ford, W. T., Ed.;
ACS Symposium Series 308; American Chemical Society: Washington,
DC, 1986; pp 132-154.
Typically, these oxidants are attached via different N-
heterocycles or simple quarternary ammonium cations to the
polymeric backbone.
(3) Brunelet, T.; Gelbard, G. NouV. J. Chim. 1983, 7, 483-490.
10.1021/ol006483t CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/10/2000

Recently, Rychnovsky and co-workers10 showed that on
the basis of the work of Cella11 and Anelli12 the TEMPO-
catalyzed oxidation of alcohols is achieved in the presence
of m-CPBA and halide ions, where hypobromite was
postulated to be the effective oxidant which oxidizes the
nitroxyl radical to the N-oxo ammonium ion. Similarly,
Espenson et al. found that hydrogen peroxide and the
cocatalyst methyltrioxorhenium are only an efficient system
for the oxidation of alcohols if a catalytic amount of bromide
ions is added to the reaction mixture.13 Recently, Kita and
co-workers reported on polymer-bound (diacetoxy)iodo
benzene which in the presence of a catalytic amount of
bromide is an efficient oxidant for the transformation of
secondary alcohols into ketones. Furthermore, it was shown
that this reagent system oxidizes primary alcohols to the
corresponding carboxylic acids.14a Related to this oxidation
protocol is the use of (diacetoxy)iodo benzene and TEMPO.14b
These finding prompt us to disclose our results on the use
of polymer-bound bromite(I) complex 115 which is an
effective oxidant for primary and secondary alcohols in
particular when a catalytic amount of TEMPO is added.
However, from our earlier work on electrophilic bromite-
(I) complex 1, we knew that it promotes the 1,2-haloac-
etoxylation of various alkenes under very mild conditions
with high efficiency.15,16 Therefore, the reagent seemed to
be less well suited for the oxidation of alcohols.
major product. Presumably, 7 was generated from 6 by
double electrophilic bromination followed by nucleophilic
displacement of one bromine atom by the acetate ion. This
hypothesis was proven when acetophenone was subjected
to the same reaction conditions that gave ketone 7 with a
similar yield. Under these uncatalyzed conditions, benzyl
alcohols 8 and 9 were also converted into the corresponding
aldehydes 15 and 16 (Table 1).
Table 1. Oxidation of Primary Alcohols
Nevertheless, in initial experiments, we treated 1-phenyl-
ethanol 5 with polymer-attached reagent 1 which furnished
acetophenone 6 in very good yield (Scheme 2). When the
Scheme 2
solvent was changed to toluene and the temperature was
raised to 90 °C, R-acetoxy-R-bromo ketone 7 became the
(4) Yang, H.; Li, B. Synth. Commun. 1991, 21, 1521-1526.
(5) (a) Abraham, S.; Rajan, P. K.; Sreekumar, K. Polym. Int. 1998, 45,
271-277. (b) Fre´chet, J. M. J.; Warnock, J.; Farrall, M. J. J. Org. Chem.
1978, 43, 2618-2621. (c) Fre´chet, J. M. J.; Darling, P.; Farrall, M. J. J.
Org. Chem. 1981, 46, 1728-1730.
a For details refer to the Supporting Information. b Transformations were
quantitative and yields refer to isolated pure products. Values in parentheses
1
refer to purity of the crude product determined by H NMR spectroscopy
c
or Determined by GC. d The use of CDCl3 allowed for the determination
of the yield of the volatile product 18 by NMR spectroscopy.
(6) Cainelli, G.; Cardillo, G.; Orena, M.; Sandri, S. J. Am. Chem. Soc.
1976, 6737-6738.
(7) Caldarelli, M.; Habermann, J.; Ley, S. V. J. Chem. Soc., Perkin Trans.
1 1999, 107-110.
Although these results were promising, we were unable
to employ this procedure on less reactive secondary alcohols
(8) (a) Hinzen, B.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1997, 1907-
1908. (b) Hinzen, B.; Lenz, R.; Ley, S. V. Synthesis 1998, 977-979.
(9) Also the polymer-supported versions of the Swern oxidation: (a)
Harris, J. M.; Liu, Y.; Chai, S.; Andrews, M. D.; Vederas, J. C. J. Org.
Chem. 1998, 63, 2407-2409. (b) Liu, Y.; Vederas, J. C. J. Org. Chem.
1996, 61, 7856-7859. In addition, the Corey oxidation: (c) Crosby, G.
A.; Weinshenker, N. M.; Uh, H.-S. J. Am. Chem. Soc. 1975, 97, 2232-
2235.
(10) Rychnovsky, S. D.; Vaidyanathan, R. J. Org. Chem. 1999, 64, 310-
312.
(11) (a) Cella, J. A.; Kelley, J. A.; Kenehan, E. F. J. Org. Chem. 1975,
40, 1860-1862. (b) Cella, J. A.; McGrath, J. P.; Kelley, J. A.; El Soukkary,
O.; Hilpert, L. J. Org. Chem. 1977, 42, 2077-2080.
3782
Org. Lett., Vol. 2, No. 24, 2000

primary as well as secondary alcohols are converted into the
corresponding aldehydes and ketones, respectively. Oxidation
proceeds by treatment of alcohols 8-14 with a 3- to 6-fold
excess of reagent 117 (based on the amount of bromide18
attached to the commercial resin) in the presence of TEMPO.
Quantitative transformation of alcohols is achieved in di-
chloromethane. Toluene is also a suitable solvent. Except
for partially protected D-galactose 14, primary aldehydes are
oxidized to aldehydes at room temperature. Considering that
a polymer-bound reagent is employed, the reactions proceed
rather rapidly (e.g., refer to alcohols 12 and 13, Table 1).
Importantly, we did not observe over-oxidation to the
corresponding carboxylic acids.
Table 2. Oxidation of Secondary Alcohols
Decisive for applications in natural product syntheses, we
considered studies on the configurational integrity of a chiral
center in the R-position during the reaction process and
workup. On the basis of our earlier work on the asymmetric
acylation of aldehydes,19 we converted alcohol 12 into
aldehyde 19 and reacted the crude product (>95% purity)
with lithiated phosphine oxide 22 (Scheme 3). Elimination
Scheme 3
followed by asymmetric Sharpless dihydroxylation of the
intermediate O,O-ketene acetal afforded R-hydroxy ester 23
in excellent yield as the only diastereomer, a clear indication
of the high efficiency of the oxidation process. Furthermore,
upscaling to 10 mmol was possible without causing reduced
(15) Preparation of reagent 1 was achieved by oxidative, iodine(III)-
promoted ligand transfer onto polystyrene-bound bromide: Monenschein,
H.; Sourkouni-Argirusi, G.; Schubothe, K. M.; O’Hare, T.; Kirschning, A.
Org. Lett. 1999, 1, 2101-2104.
(16) (a) Kirschning, A.; Monenschein, H.; Schmeck, C. Angew. Chem.
1999, 111, 2720-2722; Angew. Chem., Int. Ed. 1999, 38, 2594-2596. (b)
Kirschning, A.; Jesberger, M.; Moneneschein, H. Tetrahedron Lett. 1999,
40, 8999-9002.
(17) Polymer-bound bromide was purchased from Fluka (3.5 mmol/g
bromide). Polymer-bound reagent 1 is also available from Novabiochem
(Switzerland).
(18) The need for an excess of 1 may be rationalized by assuming that
only a proportional amount of immobilized halide was transformed into
the hypervalent species or that only the most accessible haloate(I) anions
are involved in the cohalogenation process. A 3-fold excess was sufficient
in most cases but led to considerably longer reaction times as was shown
by a series of oxidations of alcohol 8 to benzaldehyde 15 under varying
conditions (equiv of 1, reaction time; % transformation to 15): 1, 24 h,
34%; 2, 24 h, 69%; 3, 24 h, >95%; 4, 2 h, >95%; 5, 1 h, >95%; 6, 30
min, >95%.
(19) (a) Kirschning, A.; Dra¨ger, G.; Jung. A. Angew. Chem. 1997, 109,
253-255; Angew. Chem., Int. Ed. Engl. 1997, 36, 253-255. (b) Monen-
schein, H.; Dra¨ger, G.; Jung, A.; Kirschning, A. Chem. Eur. J. 1999, 5,
2270-2280.
a For details refer to the Supporting Information. b Yields refer to isolated
pure products. Values in parentheses refer to purity of the crude product
determined by 1H NMR spectroscopy. c Values in parentheses refer to purity
of the crude product determined by GC. d 5% transformation as judged by
GC. e Decomposition during chromatographic purification on silica gel.
such as cyclohexanol 25 (Table 2). However, addition of a
catalytic amount of TEMPO (1-5 mol %) accelerated the
oxidation process dramatically (Tables 1 and 2). Here,
(12) (a) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem.
1987, 52, 2559-2562. (b) Anelli, P. L.; Banfi, S.; Montanari, F.; Quici, S.
J. Org. Chem. 1989, 54, 2970-2972.
(13) Espenson, J. H.; Zhu, Z.; Zauche, T. H. J. Org. Chem. 1999, 64,
1191-1196.
(14) (a) Tohma, H.; Takizawa, S.; Maegawa, T.; Kita Y. Angew. Chem.,
Int. Ed. 2000, 39, 1306-138. (b) De Mico, A.; Margarita, R.; Parlanti, L.;
Vescovi, A.; Piacantelli, G. J. Org. Chem. 1997, 62, 6974-6977.
Org. Lett., Vol. 2, No. 24, 2000
3783

selectivity or efficiency. In contrast to this result, the
conventional Swern oxidation20 in solution led to partial
racemization of the intermediate aldehyde.
25 are not converted by this reagent. Therefore, it is obvious
that future applications of functionalized polymer 4 will only
be associated with these two groups of alcohols. This oxidant
as well as polymer-bound chromium(VI) reagents 2 and 3
may complement reagent 1 (Scheme 4) in the field of
unsaturated alcohols because the bromate(I) complex yields
complex product mixtures when reacted with unsaturated
alcohols such as 36. Obviously, the ability of reagent 1 to
add to alkenic double bonds15,22 is not suppressed when
TEMPO is used to initiate a radical-promoted oxidation.
In summary, we developed a new polymer-bound non-
heavy-metal-based oxidant.23 In the presence of a catalytic
amount of TEMPO, it is a powerful and generally applicable
reagent for the high-yielding oxidation of primary and,
importantly, secondary alcohols. The products isolated after
filtration and evaporation of the solvent are very pure and
can be used directly in the next step. These arguments along
with the fact that all transformations proceed in the same
solvent, dichloromethane, make this reagent potentially useful
for automated synthesis. As long as no additional alkene
functionality is present in the substrate, it is superior to
polymer-bound chromium(VI) and manganese(VII) reagents
in most respects.
It is important to note that this reagent system allows
oxidation of secondary aryl-substituted as well as aliphatic
alcohols 5 and 24-29 with efficiency similar to that of
primary alcohols. In general, the reaction times are prolonged
because of the reduced reactivity of secondary alcohols
toward polymer-bound oxidants. Still, only a few polymer-
attached oxidants have been developed so far which are able
to oxidize secondary alcohols. For example, solid-phase-
attached perruthenate is very efficient for oxidizing primary
and secondary benzylic alcohols, but it often fails to
quantitatively oxidize primary aliphatic alcohols and cannot
be employed for oxidizing secondary aliphatic alcohols.
Therefore, we turned our attention to the more “classical”
immobilized oxidants 2-4 and compared their properties
with those of reagent 1. Chromium(VI)-based reagents 2 and
3 are strong oxidants with reactivity comparable to that of
polymer-bound bromate(I) reagent 1 as exemplified for the
secondary alcohols indanol 24 and cyclohexanol 25 (Table
1).21
However, in our hands both reagents rapidly age within
days; therefore they cannot be stored and have to be freshly
prepared. This observation can be ascribed to possible self-
oxidation of the polymeric backbone by the chromium(VI)
species. Unlike reagent 1, chromium(VI) reagents 2 and 3
are not well suited for recycling. Additionally, we found that
polymer-bound permanganate 4 is a rather weak oxidant and
can basically only be used for the oxidation of benzylic
(Table 1; refer to indanol 24)7 and allylic alcohols such as
36 (Scheme 4). Secondary alcohols such as cyclohexanol
Acknowledgment. This work was supported by the Fonds
der Chemischen Industrie. We are grateful to M. Ries, M.
Siemers, and H. Monenschein for expert preparative as-
sistance.
Supporting Information Available: Spectra and descrip-
tions of experimental procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL006483T
Scheme 4
(20) Polymer-bound DMSO useful for the Swern oxidation may only
be prepared via multistep solid-phase synthesis. Furthermore, compared to
reagent 1 it is less easily recycled (refer to refs 9a and 9b).
(21) In our hands the chromium-based reagents 3 and 4 show the
tendency of over-oxidation of primary alcohols.
(22) Hashem, Md. A.; Jung, A.; Ries, M.; Kirschning, A. Synlett 1998,
195-197.
(23) The polymer-bound iodine-containing analogue of reagent 1 is also
able to promote these kinds of oxidations. However, in part iodine is released
into solution during the process, which can lead to byproducts.
3784
Org. Lett., Vol. 2, No. 24, 2000