Combination of perfluoroalkyl and triazole moieties: A new recovery strategy for TEMPO

Article abstract of DOI:10.1021/ol801555f

(Chemical Equation Presented) The attachment of multiple triazole moieties and perfluoroalkyl chains to TEMPO promotes emulsion formation in dichloromethane/water, giving a highly active and easily recoverable catalyst for the oxidation of alcohols.

Full text of DOI:10.1021/ol801555f

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4171-4174
Combination of Perfluoroalkyl and
Triazole Moieties: A New Recovery
Strategy for TEMPO
Alexandru Gheorghe, Tamilselvi Chinnusamy, Erick Cuevas-Yañez,
Petra Hilgers, and Oliver Reiser*
Institut fu¨r Organische Chemie, UniVersita¨t Regensburg,
UniVersita¨tsstr. 31, 93053 Regensburg, Germany
oliVer.reiser@chemie.uni-regensburg.de
Received July 9, 2008
ABSTRACT
The attachment of multiple triazole moieties and perfluoroalkyl chains to TEMPO promotes emulsion formation in dichloromethane/water,
giving a highly active and easily recoverable catalyst for the oxidation of alcohols.
The use of perfluorinated alkyl chains as tags has been
broadly applied to impose fluorous properties onto a given
molecule. Arguably the most important application of this
strategy is to separate a perfluorinated compound from a
complex reaction mixture by fluorous biphasic separations,
for example, by extraction or retention of the tagged molecule
with a perfluorinated solvent, fluorous silica, or perfluorinated
polymers.1 As this property provides an attractive method
for catalyst recovery and recycling, perfluorinated tags have
been attached to several metal-based catalysts2 and organo-
catalysts.3 Thus, homogeneous catalysis is achieved in an
organic solvent due to the good solubility perfluorinated
tagged compounds still have, but easy and selective recovery
of the catalyst by a phase switch to a perfluorinated medium
is possible.
A well-known alternative approach for the development
of recyclable catalysts is their attachment to a polymeric
support that is insoluble in the reaction medium, allowing
its recovery by simple filtration. An inherent disadvantage
of this strategy is the generally reduced reactivity of such
modified catalysts due to the heterogeneous nature of the
reaction.4
We report here the combination of multiple perfluoroalkyl
chains and triazole moieties, leading to a new kind of
building block that can be used for the tagging of TEMPO.
The resulting reagent promotes the oxidation of alcohols to
aldehydes in organic solvent/water mixtures with reaction
(1) Leading reviews: (a) Gladysz, J. A.; Curran, D. P. Tetrahedron 2002,
58, 3823. (b) Tzschucke, C. C.; Markert, C.; Bannwarth, W.; Roller, S.;
Hebel, A.; Haag, R. Angew. Chem., Int. Ed. 2002, 41, 3964. (c) Curran,
D. P. In Handbook of Fluorous Chemistry; Gladysz, J. A., Curran, D. P.,
Horva´th, I. T., Eds.; Wiley-VCH, Weinheim, 2004; p 101.
(2) Leading examples: (a) Dinh, 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.; Fish, R. H. Chem. Eur. J. 2003, 9, 4168. (d) Tzschucke, C. C.; Markert,
C.; Glatz, H.; Bannwarth, W. Angew. Chem., Int. Ed. 2002, 41, 4500.
(3) Leading examples: (a) Zu, L.; Wang, J.; Li, H.; Wang, W. Org.
(4) Leading reviews: (a) De Vos, D. E.; Sels, B. F.; Jacobs, P. A. AdV.
Catal. 2001, 46, 1. (b) Gladysz, J. A. Pure Appl. Chem. 2001, 73, 1319.
(c) Oehme, G. In ComprehensiVe Asymmetric Catalysis I-III; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, Germany,
1999; Vol 3, p 1377.
´
Lett. 2006, 8, 3077. (b) Dalicsek, Z.; Pollreisz, F.; Go¨mo¨ry, A.; Soo´s, T.
Org. Lett. 2005, 7, 3243.
10.1021/ol801555f CCC: $40.75
Published on Web 08/28/2008
2008 American Chemical Society

rates comparable to homogeneous TEMPO reagents, but can
be easily recovered by liquid/emulsion filtration.
Scheme 1
.
Synthesis of Benzyl Azides with Multiple Triazole
and Perfluoroalkyl Moieties
Based on our interest in developing immobilized reagents
on organic and inorganic supports,5 we recently utilized the
copper-catalyzed6 alkyne azide cycloaddition7 (CuAAC)
reaction as a versatile method for the ligation of TEMPO to
polymers8 such as 19 or 2.10 In this context, we discovered
that 1 showed low solubility in perfluorinated, but good
solubility in organic solvents, and more strikingly, showed
little affinity to fluorous but high affinity to conventional
silica.9
To further investigate the combination of perfluorinated
alkyl chains and triazole moieties, we attempted to synthesize
azides 8 and 9-F, which should be suitable building blocks
for the attachment of catalysts and reagents modified by an
alkynyl group.
1). Ligation with azide 7-R using catalytic amounts of CuI12
followed by chloride azide exchange resulted in the target
compounds 8 and 9 in high yields.
The fluorous tagged azides 8 or 9-F were only slightly
soluble in organic solvents, nevertheless, they smoothly
underwent the CuAAC with 10 in high yields, again using
catalytic amounts of CuI in THF (Scheme 2). 11 and 12
precipitated from the reaction mixture and could be conve-
The benzyl chlorides 511 and 6 could be readily synthe-
sized in a three-step procedure starting from commercially
available benzoic acid esters 3 and 4, respectively (Scheme
(5) (a) Glos, M.; Reiser, O. Org. Lett. 2000, 2, 2045. (b) Fraile, J. M.;
Garc´ıa, J. I.; Herrer´ıas, C. I.; Mayoral, J. A.; Reiser, O.; Socue´llamos, A.;
Werner, H. Chem. Eur. J. 2004, 10, 2997. (c) Gissibl, A.; Finn, M. G.;
Reiser, O. Org. Lett. 2005, 7, 2325. (d) Werner, H.; Herrer´ıas, C. I.; Glos,
M.; Gissibl, A.; Fraile, J. M.; Pe´rez, I.; Mayoral, J. A.; Reiser, O. AdV.
Synth. Catal. 2006, 348, 125. (e) Gissibl, A.; Padie´, C.; Hager, M.; Jaroschik,
F.; Rasappan, R.; Cuevas-Yan˜ez, E.; Turrin, C.-O.; Caminade, A.-M.;
Majoral, J.-P.; Reiser, O. Org. Lett. 2007, 9, 2895.
(6) (a) Tornøe, C. W.; Meldal, M. In 17th American Peptide Symposium;
Lebl, M., Houghten, R. A., Eds.; American Peptide Society and Kluwer
Academic Publishers: San Diego, CA, 2001; p 263. (b) Rostovtsev, V. V.;
Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002,
41, 2596. (c) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057.
Scheme 2
.
Synthesis of Novel TEMPO Reagents with Multiple
Triazole and Perfluoroalkyl Moieties
(7) Huisgen, R. Pure Appl. Chem. 1989, 61, 613.
(8) Immobilized TEMPO reagents: (a) Bolm, C.; Fey, T. Chem.
Commun. 1999, 1795. (b) Dijksman, A.; Arends, I. W. C. E.; Sheldon, R. A.
Chem. Commun. 2000, 271. (c) Weik, S.; Nicholson, G.; Jung, G.;
Rademann, J. Angew. Chem., Int. Ed. 2001, 40, 1436. (d) Fey, T.; Fischer,
H.; Bachmann, S.; Albert, K.; Bolm, C. J. Org. Chem. 2001, 66, 8154. (e)
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. (f) Ciriminna,
R.; Pagliaro, M.; Blum, J.; Avnir, D. Chem. Commun. 2000, 1441. (g)
Ciriminna, R.; Bolm, C.; Fey, T.; Pagliaro, M. AdV. Synth. Catal. 2002,
344, 159. (h) Pozzi, G.; Cavazzini, M.; Quici, S.; Benaglia, M.; Dell’Anna,
G. Org. Lett. 2004, 6, 441. (i) Ferreira, P.; Hayes, W.; Phillips, E.; Rippon,
D.; Tsang, S. C. Green Chem. 2004, 6, 310. (j) Benaglia, M.; Puglisi, A.;
Holczknecht, O.; Quici, S.; Pozzi, G. Tetrahedron. 2005, 61, 12058. (k)
Tanyeli, C.; Gu¨mu¨s¸, A. Tetrahedron Lett. 2003, 44, 1639. (l) Holczknecht,
O.; Cavazzini, M.; Quici, S.; Shepperson, I.; Pozzi, G. AdV. Synth. Catal.
2005, 347, 677. (m) Pozzi, G.; Cavazzini, M.; Holczknecht, O.; Quici, S.;
Shepperson, I. Tetrahedron Lett. 2004, 45, 4249. (n) Luo, J.; Pardin, C.;
Lubell, W. D.; Zhu, X. X. Chem. Commun. 2007, 2136. (o) Gilhespy, M.;
Lok, M.; Baucherel, X. Chem. Commun. 2005, 1085. (p) Gilhespy, M.;
Lok, M.; Baucherel, X. Catal. Today 2006, 117, 114. (q) Karimi, B.; Biglari,
A.; Clark, J. H.; Budarin, V. Angew. Chem., Int. Ed. 2007, 46, 7210. (r)
Mason, B. P.; Bogdan, A. R.; Goswami, A.; McQuade, D. T. Org. Lett.
2007, 9, 3449.
(9) Gheorghe, A.; Cuevas-Yan˜ez, E.; Horn, J.; Bannwarth, W.; Narsaiah,
B.; Reiser, O. Synlett 2006, 2767.
(10) Gheorghe, A.; Matsuno, A.; Reiser, O. AdV. Synth. Catal. 2006,
348, 1016.
4172
Org. Lett., Vol. 10, No. 19, 2008

Table 1. Oxidation of Alcohols with 11 and 12a
Table 3. Oxidation of 4-Methylbenzyl Alcohol with TEMPO
12. Recovery and Recycling Experimenta
conversionb yield purityb
run
conversionb (%)
yield (%)
purityb (%)
entry
alcohol
catalyst
(%)
(%)
(%)
1
2
4-bromobenzyl alcohol
11
12
11
12
11
12
11
12
11
12
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
95
95
98
98
95
96
98
92
92
91
>98
>98
>98
>98
>97
>96
>96
>95
>98
>98
1
2
3
4
>98
>98
>98
>98
98
99
97
92
>98
>98
>98
>98
3
4-methylbenzyl alcohol
1-octanol
4
5
a Alcohol (2.5 mmol), CH2Cl2 (5 mL), KBr (0.5 mmol), 12 (1.0 mol
%,), NaOCl (2.0 mL, 2.8 mmol), NaHCO3 (1.3 mmol), 0 °C. Reaction time
15 min. 12 was recovered by filtration and reused after washing once with
6
7
1-decanol
8
9
cyclohexanolc
b
1
water and twice with CH2Cl2. Determined by H NMR.
10
a Alcohol (1.0 mmol) in CH2Cl2 (2 mL), KBr (0.2 mmol), catalyst (1.0
mol %), NaOCl (0.8 mL, 1.1 mmol), NaHCO3 (0.5 mmol), 0 °C. Reaction
b
time 15 min. Determined by H NMR. c Reaction time 1 h.
1
Notably, the activity of 12 (Table 2, entries 6-8) in the
oxidation of 4-methylbenzylalcohol on a 25 mmol scale in
CH2Cl2/water is about four times higher than polystyrene
supported TEMPO 2 (entries 4-5) and at least comparable
to that of TEMPO or fluorous tagged TEMPO 1 (entries
1-3), both being soluble in the solvent system employed
for the reaction.
niently isolated by simple filtration and purified from residual
copper by washing with aqueous EDTA (0.1 M) solution.
The absence of the typical azide band around 2100 cm-1 in
the IR-spectrum further indicated that the products were
obtained free from the starting materials 8 or 9-F, respec-
tively.
However, 12 can be recovered in a highly efficient manner
by simple filtration of the reaction mixture through a standard
sintered glass funnel (16-40 µm pore size) and reused
without further purification. For example, the oxidation of
4-methylbenzyl alcohol to the corresponding aldehyde was
carried out in four runs in 92-98% yield with no observable
loss of activity using an initial amount of 1 mol %
of catalyst 12 (Table 3). Analysis of the filtrates by NMR
gave no indication that 12 or fragments thereof due to
degradation were present. Moreover, the catalytic activity
of the filtrates for alcohol oxidations under the reaction
conditions was in the limits of the known13,15 background
reaction in the absence of any catalyst (see Supporting
Information). In contrast, 11, although also insoluble but
apparently more highly dispersed in CH2Cl2/water, was not
held back by a sintered glass funnel as described above for
12. Therefore, its recovery by filtration was not possible,
but could be readily achieved by chromatography due to its
high affinity to silica in a similar way as already noticed for
1.9 For practical purposes, 12 therefore seems to be the
catalyst of choice.
The new TEMPO derivatives 11 and 12 showed remark-
able properties: They are largely insoluble in organic or
fluorinated solvents (e1 mg/10 mL CH2Cl2 or perfluoro-
(methylcyclohexane) at 25 °C) as well as in water; neverthe-
less, oxidation of alcohols using Anelli’s conditions,13 calling
for KBr as the cocatalyst and NaOCl as the terminal oxidant,
or using Minisci’s conditions,14 calling for Mn(II) and Co(II)
nitrate as cocatalysts in acetic acid and oxygen as the terminal
oxidant, proceeded with high yields and selectivity. Under
both protocols, 12 could be recovered with high efficiency
and subsequently reused as such without loss of activity.
Oxidations of alcohols were carried out at 0 °C in the
presence of 1 mol % of catalyst and 1.1 equiv of NaOCl
(Table 1-3). Under these conditions, most alcohols were
quantitatively oxidized within 15 min, with the exception
of the more challenging cyclohexanol, which was smoothly
oxidized within 1 h. In all cases, the purity of the isolated
carbonyl derivatives was >95%.
The high activity of 12 can be most likely attributed to its
behavior to act like a surfactant by forming an emulsion
between the organic and aqueous phase, suggesting a
detergent effect that enhances catalysis (Figure 1).16 The
combination of multiple polar triazole and perfluoroalkyl
Table 2. Activity Comparison of Heterogeneous (2, 12) and
Homogeneous (TEMPO, 1, 13) TEMPO Catalysts in the Anelli
Oxidation of 4-Methylbenzyl Alcohola
entry catalyst (mol %) time (min) yieldb (%) TON TOF (h-1
)
1
2
3
4
5
6
7
8
9
TEMPO (0.2)
TEMPO (0.2)
1 (0.2)
2 (2.5)
2 (0.2)
12 (1.0)
12 (0.2)
12 (0.2)
13 (0.2)
40
15
40
15
40
15
40
15
40
g98
60
g98
68
58
g98
97
500
300
500
29
300
100
500
370
500
g750
1200
g750
116
(11) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.;
Voit, B.; Pyun, J.; Frechet, J. M. J.; Sharpless, K. B.; Fokin, V. V. Angew.
Chem., Int. Ed. 2004, 43, 3928.
(12) Lo¨ber, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5,
1753.
450
g400
g750
1480
g750
(13) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987,
52, 2559.
74
96
(14) (a) Cecchetto, A.; Fontana, F.; Minisci, F.; Recupero, F. Tetrahedron
Lett. 2001, 42, 6651. (b) Minisci, F.; Recupero, F.; Rodino, M.; Sala, M.;
Schneider, A. Org. Proc. Res. DeV. 2003, 7, 794.
(15) Huang, J.-Y.; Li, S.-J.; Wang, Y.-G. Tetrahedron Lett. 2006, 47,
5637.
a Alcohol (25 mmol, 1.0 equiv) in CH2Cl2 (50 mL), KBr (0.2 equiv),
TEMPO catalyst, NaOCl (1.1 equiv, 20 mL), NaHCO3 (0.5 equiv), 0 °C.
b Purity >98% in all cases.
(16) Dwars, T.; Paetzold, E.; Oehme, G. Angew. Chem., Int. Ed. 2005,
44, 7174.
Org. Lett., Vol. 10, No. 19, 2008
4173

Table 5. Oxidation of 4-Methylbenzyl Alcohol with TEMPO
12. Recovery and Recycling Experimenta
run
conversionb (%)
yield (%)
purityb (%)
1
2
3
>98
>98
97
98
99
96
>98
>98
>98
Figure 1. Reaction mixture containing 12 (left; Table 2, entry 7)
or 13 (right; Table 2, entry 9).
a Alcohol (3.0 mmol) in AcOH (3 mL), for conditions see Table 4,
reaction time ) 2 h. 12 was recovered by filtration and reused after washing
once with water and twice with CH2Cl2. Determined by H NMR.
b
1
chains seems to be decisive for this property since both, 1
or 13, the latter being analogous to 12 but having the
perfluoroalkyl chains replaced by benzyl groups, are readily
soluble in dichloromethane. Those display similar activities
as 12 (Table 2, entries 3 and 9) but cannot be recovered by
simple filtration from the reaction mixture.
than polystyrene supported TEMPO 2 and only slightly
reduced to that of unmodified TEMPO.
Table 6. Activity Comparison of Heterogeneous (2, 12) and
Homogeneous TEMPO Catalysts in the Aerobic Oxidation of
4-Methylbenzyl Alcohola
Alternatively, the TEMPO derivative 12 was investigated
under Minisci’s conditions, using Mn(II)- and Co(II)-nitrate
as cocatalysts in acetic acid oxygen as the terminal oxidant.14
Under these conditions benzylic alcohols were oxidized
within 2-4 h, while 1-octanol, cyclohexyl alcohol and
cinnamyl alcohol required 7-20 h (Table 4) to reach
conversions g90%.
catalyst
conversionb (%)
yield (%)
TEMPO
2
12
97
26
84
92
25
82
a For conditions, see Table 4, reaction time ) 1 h. b Determined by 1H
NMR.
In conclusion, we have developed a new TEMPO deriva-
tive that retains the activity of homogeneous TEMPO
catalysts for the oxidation of alcohols, but nevertheless allows
recovery by simple filtration. The fluorous/triazole building
blocks developed here should also be suitable for other
catalysts and reagents that are carried out in aqueous/organic
two-phase media, which is under investigation in our
laboratories.
Table 4. Aerobic Oxidation of Alcohols with TEMPO 12a
time conversionb yield
entry
alcohol
(h)
(%)
(%)
1
2
3
4
5
benzyl alcohol
2
2
3
90
>98
>98
95
>98
>98
90
89
98
96
92
90
93
82
91
4-methylbenzyl alcohol
4-methoxybenzyl alcohol
4-bromobenzyl alcohol
cinnamyl alcohol
cyclohexyl alcohol
1-octanol
3
20
12
7
Acknowledgment. This work was supported by the
Degussa foundation (fellowship for C.T.), the DAAD (fel-
lowship for E. C.-Y.), the DFG (HI-1329/1-1 and SPP 1179
Organokatalyse), and the Fonds der Chemischen Industrie.
We thank Dr. Marianne Engeser, University of Bonn, for
carrying out high-resolution mass spectra analyses on
compounds 11 and 12. Helpful comments from Prof. John
Gladysz, Texas A&M University, and the reviewers during
the preparation of this manuscript are gratefully acknowl-
edged.
6
7c
8
thiophen-2-yl-methanol
4
>98
a Alcohol (1.0 mmol) in AcOH (1 mL), Mn(NO3)2·4H2O (2.0 mol %),
Co(NO3)2 • 6 H2O (2.0 mol %), 12 (1.0 mol %,), oxygen atmosphere, 40
b
°C. Determined by H NMR. c 5.0 mol % of catalyst used.
1
In contrast to unmodified TEMPO, 12 can be also
recovered by simple filtration of the reaction mixture through
a standard sintered glass funnel (see above) and reused
without further purification. For example, the oxidation of
4-methylbenzyl alcohol to the corresponding aldehyde was
carried out in three runs in 96-98% yield with consistent
catalytic activity (Table 5).
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 8, 9, 11,
12, and 13; details on catalyzes performed and catalyst
recovery. This material is avaliable free of charge via the
Internet at http://pubs.acs.org.
Again, the activity of 12 (Table 6) in the oxidation of
4-methyl benzyl alcohol is about three to four times higher
OL801555F
4174
Org. Lett., Vol. 10, No. 19, 2008