Oxidizing polymers: A polymer-supported, recyclable hypervalent iodine(V) reagent for the efficient conversion of alcohols, carbonyl compounds, and unsaturated carbamates in solution

Article abstract of DOI:10.1002/1521-3773(20011203)40:23<4395::AID-ANIE4395>3.0.CO;2-R

The oxidation of various alcohols and cyclization of an olefinic carbamate succeeds with the first polymer-supported iodine(v) reagent (see scheme). The novel oxidizing polymer oxidizes sensitive and complex alcohols, including protected amino alcohols, efficiency in good excellent yields. In addition, the α,β-dehydration of a ketone is demonstrated.

Full text of DOI:10.1002/1521-3773(20011203)40:23<4395::AID-ANIE4395>3.0.CO;2-R

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the iodoso and not to the iodoxo derivative.[9] Methyl
5-hydroxy-2-iodobenzoate (2) was obtained in two steps from
2-amino-5-hydroxybenzoic acid (1) by a Sandmeyer reac-
tionfollowed by esterificationwith thioynl chloride in
methanol (Scheme 1).[10] Compound 2 was coupled to chloro-
methylpolystyrene cross-linked with 1% divinylbenzene
Oxidizing Polymers: A Polymer-Supported,
Recyclable Hypervalent Iodine(v) Reagent for
the Efficient Conversion of Alcohols, Carbonyl
Compounds, and Unsaturated Carbamates in
Solution**
Gerhard Sorg, Anne Mengel, G¸nther Jung, and
Jˆrg Rademann*
1. NaNO2, KI
O
I
O
2. SOCl2, MeOH
HO
HO
OMe
OH
Polymer-supported reagents and reactive intermediates can
be applied successfully to the parallel conversion of single
compounds as well as for the construction of chemical
libraries by exploiting the advantages of solution-phase
synthesis in combination with those of synthesis on a solid
phase.[1 3] The oxidation of alcohols to carbonyl compounds is
one of the key transformations in organic synthesis because of
the diversity of products that canbe obtained from aldehyde
and ketone precursors. Recently, polymer-supported oxoam-
NH2
2
1
O
1. 2, Cs2CO3
2. KOSiMe3
O
OH
Cl
1.2 mmol g
I
-1
3
monium salts were demonstrated to be reactive and versatile
[3a]
O
oxidationreagents.
Incontrast to previous methods, oxo-
NBu4SO5H, MeSO3H, RT
O
ammonium salts do not rely on heavy metal salts[3b,c] or on
additional co-oxidants.[3d,e] The reactive intermediates derived
from 4-alkoxy-2,2,6,6-tetramethylpiperidine-1-oxide (4-TEM-
PO) were used to oxidize a diverse collectionof alcohols,
mostly in excellent purity and yield. An extension to even
more complex and sensitive substrates, preferably including
those with nitrogen functionalities, would be highly desirable.
The chemistry of hypervalent iodine compounds has been
reviewed extensively.[4] Iodinanes, that is, iodoso and io-
dine(iii) reagents, have been prepared in a supported fashion
by several research groups mainly as the bisacetoxyiodoso
derivative[5] or as the respective dihalogeno compounds.[6]
Iodoso reagents, however, cannot be used for a general
transformation of alcohols to carbonyl compounds. On the
contrary, periodinanes (namely, iodoxo and iodine(v) re-
agents) are widely employed in the oxidation of sensitive and
complex alcohols, usually as the 1-hydroxy-(1H)-benzo-1,2-
O
I
O
HO
4
0.80 mmol g-1
Scheme 1. Preparationof polymeric iodine reagent 4.
(1.20 mmolgÀ1) by using cesium carbonate as a base. The
loading of the resin was determined by elemental analysis and
was close to the theoretical loading (98%). Saponification to
yield resin 3 was effected by treatment with potassium
trimethylsilanoxide in THF.[11] Oxidationof 3 to resin 4 was
investigated under various conditions; initial screening for
oxidizing activity was conducted by HPLC analysis of the
reactionwith piperonyl alcohol ( 5a) as the test substrate. The
[8]
reactionwith potassium bromate
as well as potassium
monopersulfate triple salt[12] (oxone) failed in aqueous solvent
mixtures. Traces of the aldehyde 6b were detected whenthe
phase-transfer catalyst [18]crown-6 was used together with
oxone in a triphase system. Tetrabutylammonium oxone[13] in
dichloromethane (DCM) was used to avoid the presence of
iodoxol-3-one 1-oxide (2-iodoxybenzoic acid, IBX)[7] or its
[8]
acetylationproduct, the Dess Martinreagetn.
Period-
inanes have not been prepared on a polymer support so far.
In order to obtain a functional iodine(v) reagent a
derivative of 2-iodobenzoic acid was required that was
suitable for immobilizationadn that still retaiend similar
oxidationproperties as the parent compound. 4-Hydroxy-2-
iodobenzoic acid esters permit efficient immobilization to
chloromethyl polystyrene through a phenoxide linker. The
alkoxy derivatives have thus beenprepared and oxidized to
water and to assure proper swelling of the resin. This
À1
procedure yielded a low resinactivity of 0.05 0.1 mmolg
.
Peroxymonosulfonic acid (Caro×s acid) is a stronger oxidant
than its anion that is present in oxone and was therefore
examined infurther oxidationexperiments. Anequimolar
mixture of tetrabutylammonium oxone with methylsulfonic
acid (DCM, RT, 3 h) furnished resin 4 with a high activity of
0.8 mmolgÀ1. Resin 4 was characterized by IR spectroscopy,
elemental analysis, and MAS-NMR spectroscopy.[14] Elemen-
tal analysis indicated a loading of 0.84 mmolgÀ1, which
corresponded to a yield of 94% in respect to the initial
loading and taking into account the mass increase of the resin.
No loss of iodine was observed under the strongly acidic
reaction conditions. The oxidizing polymer 4 was stable
towards air and moisture and it could be stored without loss of
activity.
[*] Dr. J. Rademann, Dipl.-Chem. G. Sorg, Prof. Dr. G. Jung
Institute f¸r Organische Chemie
Universit‰t T¸bingen
Auf der Morgenstelle 18, 72076 T¸bingen (Germany)
Fax : (‡49)7071-295560
E-mail: joerg.rademann@uni-tuebingen.de
Dr. A. Mengel
Schering AG, 13342 Berlin (Germany)
[**] J.R. gratefully acknowledges generous support from Prof. M. E.
Maier, T¸bingen, the Strukturfonds of the University of T¸bingen, the
Fonds der Chemischen Industrie, and the DFG. We thank Graeme
Nicholson, Dietmar Schmid, and Daniel Bischoff for analytical
support.
The oxidation properties of periodinane reagent 4 were
investigated by reaction with a diverse collection of benzylic,
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Table 1. Results of the treatment of various alcohols with polymeric
reagent 4.
allylic, primary as well as secondary alcohols 5a 22a,
including the terpene alcohols 11a, 13a, an d17a 19a, an d
the carbamate-protected aminoalcohols 21a and 22a (Ta-
ble 1). All reactions were followed by GC-MS (Figure1) or by
HPLC (214 and 280 nm). The products were identified by
NMR spectroscopy and by mass spetrometry (EI, 70 eV);
yields were determined by weight. Most alcohols were
converted into the respective aldehyde or ketone products
in good to excellent yields and purities. Resin 4 that had not
beenused at elevated temperatures could be recycled by
repeated oxidation following extensive washings.
Starting material
Product
Purity [%][a]
> 95 (84)[e]
> 95
> 95
> 95
95
> 95
Figure 1. The oxidationof alcohols 5a 22a by polymer 4 (0.8 mmolgÀ1).
The oxidative activity of the polymer reagent was determined using alcohol
5a as a test substrate; see gas chromatograms.
90[b]
Inadditionto the oxidationof alcohols, further important
transformations effected by IBX were investigated with resin
4.[15] Cyclohexanol (16a) reacted with 4 ina closed vessel
(2.3 equiv, DCM, 2 h, 658C) to yield the a,b-unsaturated
cyclohexenone 16c via the cyclohexanone 16b and a postu-
lated iodine enol ether intermediate.[15a] The unsaturated
carbamate 23 was treated with reagent 4 (4 equiv, THF/
DMSO (10/1), 908C, 16 h) to effect radical cyclizationand
afforded product 24 in25% yield. [15b] It should be noted that
at elevated temperatures IBX canoxidize beznylic posi-
tions,[15c] which are abundant in the polystyrene backbone of 4
and might account for a competing reaction pathway.
Insummary, we have prepared resin 4 as the first polymer-
supported periodinane reagent. The resin was obtained with
high loading (0.8 mmolgÀ1) and was capable of converting a
diverse collection of alcohols, including complex and sensiti-
vestructures, efficiently and in good to excellent yields into
the respective carbonyl compounds. In addition, the a,b-
desaturation of carbonyl compounds and the radical cyliza-
tionof anunsaturated carbamate were demonstrated. The
novel reagent is likely to find broad application in polymer-
assisted solution-phase synthesis. Furthermore, the new
oxidizing resin should be suitable for integration into parallel
polymer-supported reaction sequences and for the conversion
of compound libraries.
70
56[c]
69
89
67
28[g]
Experimental Section
> 95
Attachment of 2 to the Merrifield resin: A solution of 2 (500.4 mg,
1.8 mmol) indry DMF (4 mL) was added to chloromethylated polystyrene
4396
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Angew. Chem. Int. Ed. 2001, 40, No. 23

COMMUNICATIONS
Table 1. (Continued)
Starting material
Oxidationof alcohols: Solutions of 5a 22a (1 equiv) indry DCM (15 m m)
were treated with resin 4 (1.75 equiv) for 3 h at RT. The resinwas filtered
off and washed with dry DCM. The volatile compounds in the filtrate were
analyzed by GC-MS. The nonvolatile compounds were analyzed by HPLC-
MS. For product isolation, the collected filtrates of several washings (DCM,
3 Â 2 mL) were evaporated to yield, for 5 mg of starting alcohols 5a and
22a: 5b (4.2 mg, 84%) and 22b (4.1 mg, 82%), respectively. The purity and
identity of the products were determined by GC or HPLC and by NMR
spectroscopy.
Product
Purity [%][a]
> 95
5b: 1H NMR (400 MHz, CD3CN): d ˆ 9.81 (s, 1H, CHO), 6.8 7.5 (m, 3H,
aromatic protons), 6.01 (s, 2H, CH2); 13C NMR (100.6 MHz, CD3CN): d ˆ
190.2, 153.6, 148.5, 131.7, 128.2, 108.0, 105.2, 102.3. 22b: 1H NMR, 1H
COSY (400 MHz, [D6]DMSO): d ˆ 9.65 (s, 1H, CHO), 7.0 8.0 (m, 13H,
aromatic protons), 7.90 (d, 3J ˆ 7.8 Hz, 1H, NH), 4.3 4.4 (m, 3H, Fmoc-9-
H, Fmoc-CH2), 4.25 (m, 1H, a-CH), 3.25 (dd, 3J ˆ 6.8, 2J ˆ 13.9 Hz, 1H, b-
26
66[d]
3
CH), 2.82 (dd, J ˆ 10.4 Hz, 1H, b-CH).
Resin recycling: The resin consumed in oxidations was collected, washed,
and dried. Oxidation following the procedure described above yielded resin
4 with a restored oxidationactivity of 0.8 mmolg À1. Three cycles of resin
recycling were investigated.
53[f]
Received: August 8, 2001 [Z17688]
[1] a) J. Rademann, W. Kraas, B. Dˆrner, Nachr. Chem. 2000, 48, 280
283; b) S. V. Ley, I. R. Baxendale, R. M. Bream, P. S. Jackson, A. G.
Leach, D. A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer, S. J. Taylor,
J. Chem. Soc. Perkin Trans. 1 2000, 23, 3815 4195; c) A. Kirschning,
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Weinheim, 1999.
> 95[f] (82)[e]
[2] J. Rademann, J. Smerdka, G. Jung, P. Grosche, D. Schmid, Angew.
Chem. 2001, 113, 390 393; Angew. Chem. Int. Ed. 2001, 40, 381 385.
[3] S. Weik, G. Nicholson, G. Jung, J. Rademann, Angew. Chem. 2001, 113,
1489 1492; Angew. Chem. Int. Ed. 2001, 40, 1436 1439; b) G.
Gardillo, M. Orena, S. Sandri, Tetrahedron Lett. 1976, 17, 3985-3988;
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Sourkouni-Argirusi, A. Kirschning, Org. Lett. 2000, 2, 3781 3784.
[4] a) P. J. Stang, V. V. Zhdankin, Chem. Rev. 1996, 96, 1123 1178; b) A.
Varvoglis, Hypervalent Iodine in Organic Synthesis, Academic Press,
SanDiego 1997; c) T. Wirth, U. H. Hirth, Synthesis 1999, 1271 1287;
d) T. Wirth, Angew. Chem. 2001, 113, 2893 2895; Angew. Chem. Int.
Ed. 2001, 40, 2812 2814.
[5] a) M. L. Hallensleben, Angew. Makromol. Chem. 1972, 27, 223 227;
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c) S. V. Ley, A. W. Thomas, H. Finch, J. Chem. Soc. Perkin Trans. 1
1999, 669 671; d) S. Ficht, M. M¸lbaier, A. Giannis Tetrahedron 2001,
57, 4863 4866.
[6] a) M. Okawara, Y. Oiji, E. Imoto, Kogyo Kagaku Zasshi 1962, 65,
1647 1652 [Chem. Abstr. 1963, 58, 8051d]; b) M. Zupan, A. Pollak, J.
Chem. Soc. Chem. Commun. 1975, 715 716.
[7] a) C. Hartmann, V. Meyer, Chem. Ber. 1893, 26, 1727 1732; b) M.
Frigerio, M. Santagostino, Tetrahedron Lett. 1994, 35, 8019 8022.
[8] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155 4156.
[9] A. R. Katritzky, B. L. Duell, J. K. Gallos, H. D. Durst, Magn. Reson.
Chem. 1989, 27, 1007 1011.
[10] a) R. A. Moss, K. W. Alwis, J.-S. Shin, J. Am. Chem. Soc. 1984, 106,
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[11] H.-C. Zhang, B. E. Maryanoff, J. Org. Chem. 1997, 62, 1804 1809.
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4537 4538.
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[14] A. R. Katritzky, G. P. Savage, J. K. Gallos, H. D. Durst, J. Chem. Soc.
Perkin Trans. 2 1990, 1515 1518.
25[f, h]
[a] Determined by GC-MS. Reactions with 1.75 equiv of 4, DCM, 2 h. [b] By-
product: 7.5% Z isomer. [c] After reduced reactiontime (30 min); 36%
isopulegol is formed as major product after 2 h. [d] Obtained with 1 equiv of 4.
[e] Yield of isolated product. [f] Purity determined by HPLC. [g] 2.3 equiv of
4, DCM, 658C, 2 h; main product: cyclohexanone (16b, 78%). [h] 4 equiv of 4,
THF/DMSO (10/1), 908C, 16 h.
resin (0.5 g, 0.6 mmol, 200 400 mesh, cross-linked with 1% divinylben-
zene, loading 1.2 mmolgÀ1). Cs2CO3 (390 mg, 1.2 mmol) was added and the
reactionmixture was agitated for 3 h at 80 8C. The resinwas washed with
DMF, THF/AcOH (1/1), MeOH, DCM, MeOH, DCM, Et2O (six times
each) and dried in vacuo. IR: nÄ ˆ 1111, 1213, 1244, 1288, 1378, 1561, 1588,
1733 cmÀ1. Iodine content: 11.73%. Loading: 0.92 mmolgÀ1. This value
corresponds to 98% conversion when the mass increase is taken into
account.
Ester hydrolysis: Potassium trimethylsilanoxide in dry THF (4 mL,
saturated solution) was added to the resin product (ca. 0.6 mmol). After
shaking the resin for 1 h at room temperature and washing with MeOH
(5 times), a mixture of THF/AcOH (9/1, 4 mL) was added and the
suspension was agitated for 5 h at RT. Finally, the resin was washed (THF,
DCM, MeOH, and Et2O, seventimes each) and dried to yield product 3.
IR: nÄ ˆ 1707 cmÀ1, the ester band completely disappeared.
Oxidationof 3: Resin 3 (100 mg, 0.092 mmol) was treated with a solutionof
tetrabutylammonium oxone (460 mg, 0.46 mmol, active oxygen ca. 1.6%)
and methylsulfonic acid (30 mL, 0.46 mmol) indry DCM (1.2 mL), and
agitated for 3 h at RT. The product was washed thoroughly with DCM,
Et2O, DCM, Et2O, DCM, and Et2O (seventimes each). The product was
dried to yield resin 4. IR: nÄ ˆ 1578, 1602, 1655 cmÀ1. Iodine content: 10.8%.
Loading: 0.85 mmolgÀ1. This value corresponds to 93% conversion of the
chloromethyl groups over three steps when the mass increase is taken into
account. The oxidative activity of resin 4 (0.8 mmolgÀ1) was determined by
converting an excess of test substrate 5a.
[15] a) K. C. Nicolaou, Y.-L. Zhong, P. S. Baran, J. Am. Chem. Soc. 2000,
122, 7596 7597; b) K. C. Nicolaou, Y.-L. Zhong, P. S. Baran, Angew.
Chem. 2000, 112, 639 642; Angew. Chem. Int. Ed. 2000, 39, 625 628;
c) K. C. Nicolaou, Y.-L. Zhong, P. S. Baran, J. Am. Chem. Soc. 2001,
123, 3183 3185.
Angew. Chem. Int. Ed. 2001, 40, No. 23
¹ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4023-4397 $ 17.50+.50/0
4397