A facile strategy to a new fluorous-tagged, immobilized TEMPO catalyst using a click reaction, and its catalytic activity

Article abstract of DOI:10.1055/s-2006-950256

A new fluorous-tagged TEMPO catalyst was prepared by a facile approach using the copper-catalyzed azide-alkyne cycloaddition as the ligation method. A fluorous F₁₇-CLICK-TEMPO showed excellent activity and selectivity in the oxidation of alcohols to aldehydes using bleach as the terminal oxidant. Moreover, the catalyst could be easily recovered using silica gel 60 and recycled in four cycles without loss of activity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950256

LETTER
2767
A Facile Strategy to a New Fluorous-Tagged, Immobilized TEMPO Catalyst
Using a Click Reaction, and Its Catalytic Activity
F
acile Strategy to a
l
Ne
w
Fluorous
T
a
x
gged Immob
a
ilized TEM
n
PO dru Gheorghe,a Erick Cuevas-Yañez,a Joachim Horn,b Willi Bannwarth,b Banda Narsaiah,*c Oliver Reiser*a
a
Institut für Organische Chemie der Universität Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany
Fax +49(941)9434121; E-mail: Oliver.Reiser@chemie.uni-regensburg.de
b
c
Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, 79104 Freiburg, Germany
Indian Institute of Chemical Technology, Division of Fluoro Organics, Uppal Road, Hyderabad 500007, AP, India
Received 4 August 2006
Although a strong synergy in both fluorous and click
chemistry is perceived, surprisingly there are few exam-
ples which report a convergence between these two
fields.11,12 We wanted to take the advantages offered by
Abstract: A new fluorous-tagged TEMPO catalyst was prepared
by a facile approach using the copper-catalyzed azide-alkyne cy-
cloaddition as the ligation method. A fluorous F17-CLICK-TEMPO
showed excellent activity and selectivity in the oxidation of alco-
hols to aldehydes using bleach as the terminal oxidant. Moreover, fluorous and click chemistry and apply them to the devel-
the catalyst could be easily recovered using silica gel 60 and recy-
opment of a novel perfluorinated TEMPO catalyst that
could be efficiently recovered.13
cled in four cycles without loss of activity.
Key words: catalyst immobilization, fluorous, oxidation, click
Recently, Pozzi and co-workers14 described the synthesis
chemistry, TEMPO
and catalytic activity of fluorous-tagged TEMPO re-
agents, using perfluoroacylchlorides to achieve the con-
nection with 4-hydroxy-TEMPO (1). Our own attempts to
The use of fluorous biphasic separations has increased in
realize a direct attachment of the commercially available
recent years as a consequence of these technologies pro-
viding an attractive combination of simplicity of opera-
perfluorinated alkyliodide 3 to 1 using NaH were not suc-
cessful, even at long reaction times and elevated tempera-
tion, easy scale-up and ease of separating the
tures (Scheme 1).
perfluorinated-tagged compound exclusively from a com-
plex reaction mixture.1 This last property has provided an
O
OH
attractive method for catalyst recovery and recycling.
Thus, perfluorinated tags have been attached to several
metal-based catalysts2 and organocatalysts.3 However, an
inherent problem in this kind of compound is that the flu-
orous chains confer a highly hydrophobic character to the
rest of the molecule, so that handling and purification of
reaction products is complicated and sometimes low
yields are reported in these processes. For this reason, an
ideal synthetic route should attach the flourous tag in the
final step,4 ideally in a high-yielding reaction. This, how-
ever, can also be problematic as many of the perfluorinat-
ed precursors used for this purpose have low reactivity.
Br
NaH, DMF
78%
N
O
N
O
1
2
NaN3
F17C8
F17C8
I
N3
acetone–H2O (5:1)
quant.
3
4
C8F17
The copper-catalyzed azide-alkyne cycloaddition
(CuAAC; a click reaction) represents a simple method for
the regioselective synthesis of 1,4-substituted 1,2,3-triaz-
oles in almost quantitative yields with a high efficiency in
terms of atom economy.5 This process allows the forma-
tion of a thermally and hydrolytically stable linkage be-
tween two different molecules. Moreover, the CuAAC
has been demonstrated to be a powerful tool in preparing
building blocks6 and dendrimers,7 as well as supporting
functionalized molecules, diverse scaffolds and catalysts.8
In this regard, our group has reported the successful liga-
tion of azabis(oxazoline)9 and TEMPO10 catalysts to poly-
meric supports using the CuAAC approach.
O
NaH, DMF
r.t. or 50 °C
4 d
N
O
1
+ 3
no reaction
5
N
N
N
CuI (6 mol%)
THF
O
2
+ 4
80%
C8F17
N
O
SYNLETT 2006, No. 17, pp 2767–2770
1
7
.1
0
.2
0
0
6
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950256; Art ID: G26106ST
6
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Synthesis of fluorous F17-CLICK-TEMPO 6

2768
A. Gheorghe et al.
LETTER
The low reactivity of 3 towards nucleophilic substitution catalyst 6 is only slightly soluble in perfluoromethylcy-
reactions has been noted before, calling for perfluorinated clohexane and perfluoro-1,3-dimethylcyclohexane at
alkyl iodides with an additional methylene group of type room temperature, preventing liquid–liquid phase separa-
Rf(CH2)3I, where Rf is a perfluorinated domain. These are tion. This behavior can be attributed to the relatively low
not, however, as readily available as molecules of type fluorine content (F = 46%), but also to the presence of a
Rf(CH2)2I.1a
polar linker in the molecule, namely the triazole ring. In
this respect, other authors22,23 have also reported discrep-
ancies between the fluorine content of a compound and its
solubility in fluorinated solvents. In general, it is assumed
that a high fluorine percentage is needed to gain differen-
tial solubility in fluorous solvents, but there is no clear
correlation between polarity and molecular weight of a
compound and its absolute solubility.1b
However, the new fluorous catalyst 6 could be prepared in
a three-step sequence starting from 1 and 1-iodo-
perfluorodecane (3) using the CuACC as the key step
(Scheme 1). The 4-propargylated TEMPO 210,15 was
smoothly ligated with 1-azido-perfluorodecane (4)16, ac-
cessible in quantitative yield from 3 by substitution with
sodium azide.17 The F17-CLICK-TEMPO 6 was obtained
in 80% yield upon reacting 2 and 4 in the presence of cat- However, the triazole moiety present in catalyst 6, beyond
alytic amounts of CuI, proving the high efficiency of this its chemical stability, could shift the overall polarity of the
ligation method.18
molecule and therefore, allow a better separation from the
reaction mixture through other techniques. We were
pleased to discover that silica gel 60 provides an easier
and less expensive solution. Thus, the crude product was
placed on a short bed of silica and eluted with dichlo-
romethane in order to obtain the pure oxidation product
with complete retention of 6 on silica (Rf £ 0.1). The cat-
alyst 6 (initial loading 75 mg, 1 mol%) was subsequently
recovered from the column by elution with diethyl ether
(Rf = 0.53) and reused in a total of four cycles, each time
oxidizing two grams of 4-bromobenzyl alcohol, without
loss of activity and selectivity (Table 2).24 Specifically,
the catalyst 6 was re-isolated with no observable degrada-
tion, emphasizing the stable linkage created through the
triazole moiety.
The catalytic activity of 6 was tested in the chemoselec-
tive oxidation of aliphatic and benzylic alcohols using so-
dium hypochlorite as the terminal oxidant and KBr as a
co-catalyst.19,20
The good solubility of 6 in dichloromethane at 0 °C makes
it a very effective catalyst. In all cases complete conver-
sion, high yield and excellent selectivity were observed
(Table 1).
We tried to recover the F17-CLICK-TEMPO 6 using fluo-
rous silica gel prepared using the procedure of Bannwarth
and co-workers.21 However, we were not able to get good
separation of the F17-CLICK-TEMPO 6 from the oxida-
tion products on this stationary phase. In addition, the
The good solubility of 6 in dichloromethane and at the
same time its high affinity to silica is striking. For exam-
ple, 25 mg of 6 readily dissolve in 10 mL of dichlo-
romethane. Upon addition of 1 g of silica, 6 is completely
adsorbed in less than one minute, analysis of the decanted
solvent showed only trace amounts of 6 still present. Upon
subsequent addition of 10 mL of ethyl acetate (Rf = 0.85)
to the silica, after stirring for 1 min 6 (19 mg) could be re-
covered from the solvent after decantation and concentra-
tion. In contrast, in an analogous experiment with fluorous
Table 1 Fluorous CLICK-TEMPO Oxidation of Alcohols to Carbo-
nyl Derivativesa
Entry Alcohol
Conversion Yield Purity
(%)b
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
(%)c
99
95
99
99
97
86
95
96
92
96
(%)b
>98
>98
>98
>98
>96
>96
>98
>98
>98
>95
1
2
benzyl alcohold
4-bromobenzyl alcohol
4-methylbenzyl alcohol
4-chlorobenzyl alcohol
2-phenylethanol
1-octanol
3
4
Table 2 Fluorous Click-TEMPO Oxidation of Alcohols to Carbonyl
Derivativesa
5
Entry
Conversion Yield
Purity
(%)b
Recovery of cata-
lyst 6 (mmol)
6
(%)b
>98
>98
>98
>98
(%)c
7
1-decanol
1
2
3
4
94
>98
>98
>98
>98
0.104
0.078
0.058
0.030
8
1-dodecanol
94
9
cyclohexanold
92
10
hexadecanole
90
a Alcohol (1 mmol) in CH2Cl2 (2 mL), KBr (0.2 mmol), F17-CLICK-
TEMPO 6 (1.0 mol%), NaOCl (0.8 mL, 1.3 mmol), NaHCO3 (40 mg,
50 mg·mL–1, bleach), 0 °C. Reaction time = 15 min.
b Determined by 1H and 13C NMR.
a Alcohol (10.7 mmol) in CH2Cl2 (20 mL), KBr (2.16 mmol), F17-
CLICK-TEMPO 6 (75 mg, 1.0 mol%, 0.107 mmol), NaOCl (8.6 mL,
14 mmol), NaHCO3 (430 mg, 50 mg·mL–1, bleach), 0 °C. Reaction
time = 15 min.
c Isolated yields.
b Determined by 1H- and 13C-NMR.
d Reaction time = 30 min.
c Isolated yields.
e Reaction temperature = from 0 °C to r.t.
Synlett 2006, No. 17, 2767–2770 © Thieme Stuttgart · New York

LETTER
Facile Strategy to a New Fluorous-Tagged Immobilized TEMPO
2769
silica21 most of 6 (>80%) could be recovered from the de-
canted dichloromethane phase.
(11) Wu, Y. M.; Deng, J.; Fang, X.; Chen, Q. Y. J. Fluorine
Chem. 2004, 125, 1415.
(12) Kaleta, Z.; Egyed, O.; Soos, T. Org. Biomol. Chem. 2005, 3,
2228.
In conclusion, we have developed a facile strategy for the
synthesis of a new fluorous tagged, immobilized TEMPO
catalyst from commercially readily available materials in
high yield using the simplicity of the copper-catalyzed
azide-alkyne cycloaddition. The new perfluorinated F17-
CLICK-TEMPO 6 proved to be very stable, highly effec-
tive in the chemoselective oxidation of alcohols with
bleach, and after recovery it was reused in four consecu-
tive cycles without loss of catalytic activity.
(13) For examples of immobilized TEMPO reagents, see:
(a) Bolm, C.; Fey, T. Chem. Commun. 1999, 1795. (b) Fey,
T.; Fischer, H.; Bachmann, S.; Albert, K.; Bolm, C. J. Org.
Chem. 2001, 66, 8154. (c) Brunel, D.; Fajula, F.; Nagy, J.
B.; Deroide, B.; Verhoef, M. J.; Veum, L.; Peters, J. A.; van
Bekkum, H. Appl. Catal. A 2001, 213, 73. (d) Ciriminna,
R.; Blum, J.; Avnir, D.; Pagliaro, M. Chem. Commun. 2000,
1441. (e) Ciriminna, R.; Bolm, C.; Fey, T.; Pagliaro, M. Adv.
Synth. Catal. 2002, 344, 159. (f) Ferreira, P.; Hayes, W.;
Phillips, E.; Rippon, D.; Tsang, S. C. Green Chem. 2004, 6,
310. (g) Benaglia, M.; Puglisi, A.; Holczknecht, O.; Quici,
S.; Pozzi, G. Tetrahedron 2005, 61, 12058. (h) Tanyeli, C.;
Gümüş, A. Tetrahedron Lett. 2003, 44, 1639. (i) Pozzi, G.;
Cavazzini, M.; Holczknecht, O.; Quici, S.; Shepperson, I.
Tetrahedron Lett. 2004, 45, 424. (j) Pozzi, G.; Cavazzini,
M.; Quici, S.; Benaglia, M.; Dell¢Anna, G. Org. Lett. 2004,
6, 441. (k) Gilhespy, M.; Lok, M.; Baucherel, X. Chem.
Commun. 2005, 1085. (l) Dijksman, A.; Arends, I. W. C. E.;
Sheldon, R. A. Chem. Commun. 2000, 271. (m) Weik, S.;
Nicholson, G.; Jung, G.; Rademann, J. Angew. Chem. Int.
Ed. 2001, 40, 1436.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(SPP 1179 Organokatalyse), the DAAD (fellowship for E.C.-Y.),
the DAAD-CSIR exchange program (fellowship for B.N.), and the
Fonds der Chemischen Industrie.
References and Notes
(1) (a) Zhang, W. Chem. Rev. 2004, 104, 2531. (b) Tzschucke,
C. C.; Markert, C.; Bannwarth, W.; Roller, S.; Heber, A.;
Haag, R. Angew. Chem. Int. Ed. 2002, 41, 3964. (c)Curran,
D. P. Angew. Chem. Int. Ed. 1998, 37, 1174.
(2) (a) Dihn, L. V.; Gladysz, J. A. Angew. Chem. Int. Ed. 2005,
44, 4095. (b) Matsugi, M.; Curran, D. P. J. Org. Chem.
2005, 70, 1636. (c) Contel, M.; Izuel, C.; Laguna, M.;
Villuendas, P. R.; Alonso, P. J.; Fisch, R. H. Chem. Eur. J.
2003, 9, 3077. (d) Tzschucke, C. C.; Markert, C.; Glatz, H.;
Bannwarth, W. Angew. Chem. Int. Ed. 2002, 41, 4500.
(3) (a) Zu, L.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006, 8,
3077. (b) Dalicsek, Z.; Pollreisz, F.; Gomory, A.; Soos, T.
Org. Lett. 2005, 7, 3243.
(14) Holczknecht, O.; Cavazzini, M.; Quici, S.; Shepperson, I.;
Pozzi, G. Adv. Synth. Catal. 2005, 347, 677.
(15) Propargyl Ether TEMPO 2: To a stirring suspension of
NaH (60% in mineral oil, 830 mg, 20.75 mmol) in dry DMF
(10 mL), 4-hydroxy TEMPO (1, 3.0 g, 17.44 mmol) was
added portionwise at 0 °C and stirred at r.t. for 50 min.
Propargyl bromide (1.85 mL, 21.0 mmol) was added
dropwise at 0 °C over a period of 45 min. The resulting
mixture was stirred at r.t. overnight. The reaction mixture
was poured into ice water (80 mL) and was extracted with
EtOAc (4 × 25 mL). The combined organics were washed
with brine (2 × 30 mL), dried over MgSO4, filtered and
evaporated under reduced pressure. The residue was purified
by column chromatography (silica gel, hexanes–EtOAc, 9:1)
to give the title compound 2 (2.85 g, 78%) as an orange solid.
1H NMR and 13C NMR spectra were identical to those
previously reported.10
(16) Szonyi, F.; Cambon, A. J. Fluorine Chem. 1989, 42, 59.
(17) 1-Azidoperfluorodecane (4): 2-(n-perfluorooctyl) ethyl
iodide (3) was reacted with sodium azide in acetone–H2O
(5:1) under reflux conditions for 7 h, this gave 2-(n-
perfluorooctyl) ethyl azide (4) in quantitative yield. 1H NMR
and 13C NMR spectra were identical to those previously
reported.16
(18) F17-CLICK-TEMPO 6: To a stirred mixture of 1-azido-
perfluorodecane (4, 1.19 g, 2.43 mmol) and propargyl ether
TEMPO 2 (0.95 g, 4.54 mmol) in degassed THF (15 mL),
CuI (27 mg, 6 mol%) was added. The resulting mixture was
stirred under a nitrogen atmosphere at r.t. for 1 day. Then,
the solvent was removed in vacuo and the residue was
purified by column chromatography (silica gel, hexanes–
EtOAc, 5:1 → 1:1) to give some of the recovered TEMPO 2
(0.4 g, 42%) and the title compound 6 (1.35 g, 80% based on
4, 73% based on consumed 2) as a light orange solid. Mp
105–107 °C; IR (KBr): 2984, 1468, 1371, 1410, 1177, 1142,
1084, 1045, 989, 957, 661 cm–1; MS (PI-EI, 70 eV): m/z 699
[M+]; HRMS: m/z [M + H+] calcd for C22H24F17N4O2:
699.1628; found: 699.1620.
(4) Chen, W.; Xu, L.; Hu, Y.; Banet-Osuna, A. M.; Xiao, J.
Tetrahedron 2002, 58, 3889.
(5) (a) Rostovtsev, V. V.; Green, L. C.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2002, 41, 2596. (b) For a
recent review of the click reaction, see: Bock, D. P.;
Hiniestra, H.; Maarseveen, J. H. Eur. J. Org. Chem. 2006,
51.
(6) (a) Ryu, E. M.; Zhao, Y. Org. Lett. 2005, 7, 1035. (b)Kolb,
H. C.; Sharpless, K. B. Drug Discov. Today 2003, 8, 1128.
(7) (a) Lee, J. W.; Kim, B. K.; Kim, H. J.; Han, S. C.; Shim, W.
S.; Jin, S. H. J. Org. Chem. 2006, 71, 4988. (b) Fernandez-
Megia, E.; Correa, J.; Rodriguez-Meizoso, I.; Riguera, R.
Macromolecules 2006, 39, 2113. (c) Wu, P.; Malkoch, M.;
Hunt, J. N.; Vestberg, R.; Kaltgrad, E.; Finn, M. G.; Fokin,
V. V.; Sharpless, K. B.; Hawker, C. J. Chem. Commun.
2005, 5775.
(8) (a) Font, D.; Jimeno, C.; Pericas, M. A. Org. Lett. 2006,
ASAP. (b) Opsteen, J. A.; van Hest, J. C. M. Chem.
Commun. 2005, 57. (c) Parrish, B.; Breitenkamp, R. B.;
Emrick, T. J. Am. Chem. Soc. 2005, 127, 7404. (d) Dolle,
R. E.; MacLeod, C.; Martinez-Teipel, B.; Barker, W.; Seida,
P. R.; Hebert, T. Angew. Chem. Int. Ed. 2005, 44, 5830.
(e) Bettinewtti, L.; Lober, S.; Hubner, H.; Gmeiner, P. J.
Comb. Chem. 2005, 7, 309. (f) Jang, H.; Fafarman, A.;
Holub, J. M.; Kirshenbaum, K. Org. Lett. 2005, 7, 1951.
(g) Lober, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett.
2003, 5, 1753.
(19) Anelli, P. L.; Montanari, F.; Quici, S. Org. Synth., Coll. Vol.
(9) Gissibl, A.; Finn, M. G.; Reiser, O. Org. Lett. 2005, 7, 2325.
(10) Gheorghe, A.; Matsuno, A.; Reiser, O. Adv. Synth. Catal.
2006, 348, 1016.
VIII 1993, 367.
(20) General Procedure for the Oxidation of Alcohols by
F17-CLICK-TEMPO 6/Bleach: Alcohol (1.0 mmol) in 2 mL
Synlett 2006, No. 17, 2767–2770 © Thieme Stuttgart · New York

2770
A. Gheorghe et al.
LETTER
(24) Aerobic Oxidation of 4-Bromobenzyl Alcohol by F17-
CH2Cl2, KBr (24 mg, 0.2 mmol) in H2O (2 mL) and
F17-CLICK-TEMPO 6 (7 mg, 1 mol%) were added to a
round-bottom flask. The reaction mixture was stirred at 0 °C
before addition of NaOCl (0.8 mL, 10%) and NaHCO3 (40
mg, 50 mg·mL–1, bleach). The resulting mixture was stirred
at 0 °C for 15 min. The reaction was quenched by the
addition of H2O (5 mL) and the organic layer was extracted
with CH2Cl2 (2 × 5 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated in vacuo to
give crude product, which was placed on a short bed of silica
and eluted with CH2Cl2 in order to obtain pure aldehyde.
CLICK-TEMPO 6; Recycling Experiments: 4-Bromo-
benzyl alcohol (2.0 g, 10.7 mmol) in CH2Cl2 (20 mL), KBr
(257 mg, 2.16 mmol) in H2O (2 mL) and F17-CLICK-
TEMPO 6 (75 mg, 1 mol%) were added to a round-bottom
flask. The reaction mixture was stirred at 0 °C before
addition of NaOCl (8.6 mL, 14 mmol), NaHCO3 (430 mg, 50
mg·mL–1, bleach), stirring then continued at 0 °C for 15 min.
The reaction was quenched by addition of H2O (10 mL) and
the organic layer was extracted with CH2Cl2 (2 × 10 mL).
The combined organic layers were dried over anhydrous
Na2SO4 and concentrated to give crude product, which was
placed on a short bed of silica (5 g) and eluted with CH2Cl2
in order to obtain 4-bromobenzylaldehyde. The catalyst was
recovered from the column by elution with Et2O and used in
the next cycle.
(21) Schwinn, D.; Glatz, H.; Bannwarth, W. Helv. Chim. Acta
2003, 86, 188.
(22) Aluey, L. S.; Rutherford, D.; Juliette, J. J. J.; Gladysz, J. A.
J. Org. Chem. 1998, 63, 6302.
(23) Richter, B.; de Wolf, E.; van Koten, G.; Deelman, B. J. J.
Org. Chem. 2000, 653, 3885.
Synlett 2006, No. 17, 2767–2770 © Thieme Stuttgart · New York