Synthesis and catalytic activity of a fluorous-tagged TEMPO radical

Article abstract of DOI:10.1016/j.tetlet.2004.04.021

A fluorous-tagged TEMPO radical has been prepared and its catalytic activity in the chemoselective oxidation of alcohols to carbonyl compounds has been investigated. The new fluorous radical proved to be an efficient, selective and easily recoverable catalyst, which can be conveniently used in standard organic solvents and then isolated and recycled by fluorous liquid-liquid extraction.

Full text of DOI:10.1016/j.tetlet.2004.04.021

Tetrahedron
Letters
Tetrahedron Letters 45(2004) 4249–4251
Synthesis and catalytic activity of a fluorous-tagged
TEMPO radical
Gianluca Pozzi,* Marco Cavazzini, Orsolya Holczknecht, Silvio Quici and Ian Shepperson
CNR-Istituto di Scienze e Tecnologie Molecolari (ISTM), via Golgi 19, 20133 Milano, Italy
Received 25March 2004; revised 5April 2004; accepted 6 April 2004
Abstract—A fluorous-tagged TEMPO radical has been prepared and its catalytic activity in the chemoselective oxidation of alcohols
to carbonyl compounds has been investigated. The new fluorous radical proved to be an efficient, selective and easily recoverable
catalyst, which can be conveniently used in standard organic solvents and then isolated and recycled by fluorous liquid–liquid
extraction.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The original Fluorous Biphase System (FBS) concept1
has expanded to include many other separation tech-
niques based on the phase behaviour of molecules con-
taining at least one highly fluorinated domain (fluorous
molecules).2 Fluorous catalytic oxidation reactions,
where the substrates are converted to products of
greater polarity, which are easily expelled from the flu-
orous phase, were one of the first targets of the FBS
approach and still attract a lot of interest. Metal com-
plexes of (among others) porphyrins,3 b-diketonates,4
polyazamacrocycles5 and bipyridines,6 have been thus
immobilised in perfluorocarbons by modifying the
ligand structure with long perfluoroalkyl chains. Their
use as catalysts in several FBS oxidation processes,
including alkene epoxidation, alkane hydroxylation,
selective oxidation of organic sulfides to sulfoxides and
oxidation of alcohols to carbonyl compounds, has been
demonstrated.7 These organometallic complexes can
effectively operate in perfluorocarbons and then be
easily recovered by simple phase separation from reac-
tion products showing the usual affinity for organic
solvents. In comparison, fluorous metal-free oxidation
catalytic systems have received little attention, despite
their obvious potential for environmentally friendly
processes. Examples are limited to epoxidation reactions
promoted by fluorous ketones in the presence of H2O2
or Oxone.8–10 Here, we report the synthesis of 1 (Scheme
1), a fluorous derivative of the stable free radical 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO), and its use as
catalyst for the metal-free, chemoselective oxidation of
primary and secondary alcohols to aldehydes and
ketones, respectively.
1,3,5-Trichlorotriazine 2 was reacted with the commer-
cially available 4-hydroxy-2,2,6,6-tetramethylpiperidine-
1-oxyl radical 3 in dry toluene at room temperature, in
the presence of powdered KOH as a base (step i), to give
Keywords: Alcohols; Aldehydes; Ketones; Oxidation; Biphasic
catalysis.
* Corresponding author. Tel.: +39-2-503-14159; fax: +39-2-503-141459;
e-mail: gianluca.pozzi@istm.cnr.it
Scheme 1. Synthesis of 1.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.021

4250
G. Pozzi et al. / Tetrahedron Letters 45 (2004) 4249–4251
4 in 45% yield. The fluorous secondary amine 5 was
conveniently prepared according to a modification of
the oxidation was carried out in pure CH2Cl2, fluorous
liquid–liquid extraction of the homogeneous mixture
allowed us to isolate 1 from the organic products in a
few minutes. The recovered catalyst was then reused five
times (entries 6–10), with a minor loss of catalytic
activity observed in the fifth recycle.
11
ꢀ
Rabai’s method. Selective dialkylation of benzylamine
(step ii) followed by hydrogenolysis of the N-benzyl
protective group (step iii) afforded 5 in 88% overall
yield. A two-fold excess of fluorous amine 5 was then
reacted with 4 in boiling THF (step iv). The ammonium
salt 5ꢀHCl formed thereby was easily recovered by
filtration of the cold reaction mixture, while 1 was
recovered from the liquid phase in 65% yield after flash
column chromatography on silica.12
We next examined the oxidation of a variety of alcohols
with BAIB (Table 2, entries 1–8). In a typical reaction, a
water-cooled jacketed vial fitted with a stirring bar was
charged with a solution of 4-bromobenzyl alcohol
(187 mg, 1 mmol) and n-decane (71 mg, 0.5mmol,
internal standard for GC) in CH2Cl2 (2 mL). To the
stirred solution thermostatted at 20 ꢁC, 1 (106 mg,
0.05mmol) was added. After 5min BAIB (354 mg,
1.1 mmol) was also added and the reaction mixture was
vigorously stirred. After 2 h a portion (10 lL) of the
solution was diluted with CH2Cl2 (0.1 mL) and analysed
by GC. The remaining solution was extracted with
The fluorous radical 1 is preferentially soluble in per-
fluorocarbons at room temperature, as indicated by
partition coefficients (P) measurements between perflu-
oro-1,3-dimethylcyclohexane (PDMC) and standard
organic solvents. For instance, PPDMC=Toluene is equal to
40. Fortunately, 1 is also readily soluble in ethers such as
tert-butyl methyl ether (MTBE) and, at low concentra-
tions, in CH2Cl2. This residual affinity for organic sol-
vents increases with the temperature and greatly
simplified both the preparation of 1 and the search for
convenient reaction conditions when it was tested as a
catalyst in the oxidation of alcohols.
perfluoro-1,3-dimethylcyclohexane
(3 · 2 mL).
The
combined fluorous extracts containing 1 were evapo-
rated to dryness under vacuum to recover the catalyst. 4-
Bromobenzaldehyde was obtained in 97% yield after
elution of the organic layer through a short silica pad
(light petroleum ether/CH2Cl2, 1:1).
As shown in Table 1, the fluorous-tagged radical 1
proved to be an effective catalyst for the selective oxi-
dation of the model substrate 1-octanol with various
inexpensive, safe and easy to handle stoichiometric
oxidants, such as trichloroisocyanuric acid (TCCA, en-
try 1),13 bleach (entries 2 and 3),14 and [bis(acet-
oxy)iodo]benzene (BAIB, entries 4–6).15 It has been
recently shown that alcohols are selectively oxidised
with oxygen under FBS conditions in the presence of
catalytic amounts of TEMPO and fluorous copper(I)
complexes at 90 ꢁC.16;17 A single homogeneous phase is
formed at such a temperature,17 overcoming mass
transfer limitations. The FBS oxidation of 1-octanol
catalysed by 1 in the presence of BAIB (entry 4) pro-
ceeded slower than the analogous reaction carried out in
CH2Cl2 (entry 5), because the present reaction system
remains biphasic at room temperature. However, when
The amount of 1 (5mol %) used in these experiments
was lower than that generally used in BAIB-promoted
oxidations catalysed by TEMPO (10 mol %).15 Never-
theless, primary and benzylic alcohols were smoothly
oxidised to the corresponding aldehydes under these
conditions (entries 1–4). The oxidation of secondary
alcohols (entries 5–8) was generally slower, reaction
rates depending on the steric hindrance of the substrate
analogously to what was found with TEMPO.15 When
quick oxidation of secondary alcohols is required, BAIB
can be conveniently replaced with bleach (entries 9–11).
In this case reactions are carried out with a catalyst
loading of 1 mol %.
In summary, we have developed a fluorous-tagged
TEMPO derivative, which is an efficient, selective cata-
Table 1. Oxidation of 1-octanol to octanal catalysed by 1
Entry
Oxidant
Solvent
T (ꢁC)
t (min)
Conv.a (%)
Sel.a (%)
94
1
TCCAb
NaOClc
NaOCld
BAIBf
CH2Cl2
MTBE
MTBE
0
0
15>99
10
30
87
>99
9596
56
2
3
0
4e
5BAIB
CH2Cl2/PDMC
2Cl2
20
20
20
20
20
20
20
120
120
120
120
120
120
120
>99
>99
>99
>99
>99
98
CH
93
92
6g
BAIB
BAIB
BAIB
BAIB
BAIB
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
7
93
87
8
9
10
91
8598
a Determined by GC (internal standard method).
b TCCA ¼ trichloroisocyanuric acid (1.05mol equiv with respect to the substrate, catalyst loading ¼ 1 mol %). Reaction conditions see Ref. 13.
c Aqueous NaOCl (1.25mol equiv with respect to the substrate, catalyst loading ¼ 1 mol %). Reaction conditions see Ref. 14. Co-catalyst ¼ KBr.
d Aqueous NaOCl (1.25mol equiv with respect to the substrate, catalyst loading ¼ 1 mol %). Bromide-free conditions.
e FBS conditions. PDMC ¼ perfluoro-1,3-dimethylcyclohexane.
f BAIB ¼ [bis(acetoxy)iodo]benzene (1.1 mol equiv with respect to the substrate, catalyst loading ¼ 5mol %). Reaction conditions see Ref. 15.
g Entries 6–10: Catalyst recycling. Each reaction was carried out with the catalyst recovered from the previous run.

G. Pozzi et al. / Tetrahedron Letters 45 (2004) 4249–4251
Table 2. Oxidation of alcohols to carbonyl compounds catalysed by 1
4251
Entry
Oxidanta
Substrate
t (h)
Conv.b;c (%)
Sel.b (%)
1
BAIB
BAIB
BAIB
BAIB
1-Undecanol
4-Bromobenzyl alcohol
Benzyl alcohol
Cinnamyl alcohol
24
2
2
2
2
>99 (80)
>99 (97)
>99
>99
>99
>99
76
2d
3
4
>99
5BAIB
2-Octanol
92
>99
6d
7d
8d
9
BAIB
BAIB
BAIB
Cyclooctanol
2-Undecanol
1-Phenylethanol
2-Octanol
14
24
6
91 (78)
83
93 (88)
>99
>99
>99
NaOCl
NaOCl
NaOCl
0.2592
0.2599
0.595 >99
>99
>99
10
11
Cyclooctanol
2-Undecanol
a Reaction conditions: BAIB (catalyst loading ¼ 5mol %) see text; aqueous NaOCl (catalyst loading ¼ 1 mol %, co-catalyst ¼ KBr, T ¼ 20 ꢁC) see
Ref. 14.
b Determined by GC (internal standard method).
c Isolated yields in parentheses.
d Using catalyst 1 recovered from the reaction summarised in the previous entry.
6. Quici, S.; Cavazzini, M.; Ceragioli, S.; Montanari, F.;
Pozzi, G. Tetrahedron Lett. 1999, 40, 3647–3650.
7. For a recent review on fluorous technologies see: Dobbs,
A. P.; Kimberley, M. R. J. Fluorine Chem. 2002, 118, 3–17.
8. Van Vliet, M. C. A.; Arends, I. W. C. E.; Sheldon, R. A.
Chem. Commun. 1999, 263–264.
lyst for the oxidation of alcohols under mild, homoge-
neous reaction conditions. The new fluorous catalyst
offers the additional advantages of simplified workup
procedure and easy recovery and recycling, which are
usually associated with the use of heterogenised
TEMPO.18
9. Legros, J.; Crousse, B.; Bourdon, J.; Bonnet-Delpon, D.;
ꢀ
ꢀ
Begue, J.-P. Tetrahedron Lett. 2001, 42, 4463–4466.
ꢀ
10. Legros, J.; Crousse, B.; Bonnet-Delpon, D.; Begue, J.-P.
ꢀ
Tetrahedron 2002, 58, 3993–3998.
ꢀ
Rabai, J. J. Fluorine Chem. 2001, 108, 7–14.
Acknowledgements
ꢀ
ꢀ
€ €
11. Szlavik, Z.; Tarkanyi, G.; Gomory, A.; Tarczay, G.;
ꢀ
We gratefully acknowledge the European Union (Con-
tract no HPRN-CT-2000-00002, Development of Flu-
orous Phase Technology for Oxidation Processes) for
financial support.
12. Analytical data for 1. Mp 73–77 ꢁC. IR (KBr, selected
data): 1573, 1525 (C@N), 1366 (N–O) cmÀ1. Calcd C
31.70, H 1.95, N 3.96, found C 32.12, H 1.99, N 3.98.
HRSM (ESI): m=z found 2144.20114 ([M + Na]þ), calcd
for [(C56H41F68N6O2)Na]þ 2144.21027.
13. Jenny, C.-J.; Lohri, B., Schlageter, M. U.S. Patent 5821
374, 1998; Chem. Abstr. 1997, 127, P65794x.
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