Novel light-fluorous TEMPO reagents and their application in oxidation reactions

Article abstract of DOI:10.1016/j.tetlet.2008.09.092

The synthesis of two light-fluorous TEMPO derivatives is reported, along with their application in oxidation reactions.

Full text of DOI:10.1016/j.tetlet.2008.09.092

Tetrahedron Letters 49 (2008) 6955–6958
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel light-fluorous TEMPO reagents and their application
in oxidation reactions
Adrian P. Dobbs , Mark J. Penny , Peter Jones b
a,*
a
a
School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, UK
Discovery Chemistry, Pfizer Global R&D, Sandwich, Kent CT13 9NJ, UK
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 July 2008
Revised 11 September 2008
Accepted 15 September 2008
Available online 19 September 2008
The synthesis of two light-fluorous TEMPO derivatives is reported, along with their application in oxida-
tion reactions.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Fluorous-TEMPO
Fluorous solid-phase extraction
Oxidation reaction
The ‘fluorous’ concept has rapidly expanded in recent years,
with many novel fluorous-tagged reagents reported and many
reactions being adapted for use in conjunction with the fluorous
biphase concept. There are now many excellent reviews of this
These were designed to be smaller and simpler than the alternative
tagged-TEMPO reagents. The compounds were prepared starting
from 4-oxo-TEMPO 5, itself prepared from 2,2,6,6-tetramethyl-4-
oxopiperidine 4 by oxidation with OxoneÒ (Scheme 1). With
the aim of attaching two simple fluorous ponytails by a reduc-
tive-type amination approach, we next prepared the fluorous-
amine 6 from the commercially available fluorous alcohol 7, via
15
1
–5
emerging area.
One of the most widely used stable free radicals is 2,2,6,6-tetra-
methylpiperidine-1-oxyl or TEMPO 1. In order to assist in the puri-
fication of reactions containing TEMPO, there have been several
1
6,17
18
tosylation,
azidation and reduction with lithium aluminium
6
18
reports of tagged TEMPO-type reagents, including resin-bound
hydride (56% over three steps). Reductive amination gave the
mono-tagged TEMPO 8. All attempts at alkylation of this secondary
amine failed. However, formation of the fluorous amide proved to
be more successful. Starting from the same fluorous alcohol 7, oxi-
and polymer-supported7 TEMPO-derivatives; an ionic liquid-
–9
based TEMPO system by Jiang and Ragauskas1
0,11
and, concurrent
with our own work, two reports of heavy fluorous-based TEMPO
12,13
19
derivatives by Pozzi and co-workers
workers.
and Reiser and co-
dation using Jones’ reagent gave the carboxylic acid, which was
1
4
converted into the acid chloride with thionyl chloride and triethyl-
amine. Amide formation proceeded in good yield to give the fluor-
Herein, we report the synthesis, characterisation, properties and
reactions of two light fluorous-TEMPO reagents, 2 and 3 (Fig. 1).
2
0
ous-TEMPO reagent 2
in 16% overall yield over the five steps
O
O
F C(F C)
(CF ) CF
F C(F C)
(CF ) CF
3
3
2
5
2 5
3
3
2
3
2 3
N
N
N
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
N
N
O
2
O
1
O
3
Figure 1.
*
Corresponding author. Tel.: +44 0207 882 5251; fax: +44 0207 882 7427.
E-mail address: A.Dobbs@qmul.ac.uk (A. P. Dobbs).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.092

6
956
A. P. Dobbs et al. / Tetrahedron Letters 49 (2008) 6955–6958
+
-
1
. nBu N Br
4
O
O
Na HPO aq. buffer pH 7.5-8.0
2
4
DCM, acetone
Me
Me
Me
Me
Me
Me
Me
Me
2. Oxone® , H O
N
O
N
H
2
4
5
1
. Et N, TsCl, DMAP 86%
3
2
. NaN , DMF, 84%
2. NaBH4
52 % (2 steps)
3
(
2 5
CF ) CF3
OH
H N
2
CF (CF )
3
2 5
3. LiAlH , THF 77%
4
7
6
(
CF ) CF
2 5 3
HN
(
F C) F C
(CF ) CF3
2
5
3
2 5
N
Me
Me
Me
Me
1
. NaH
N
O
Me
Me
Me
Me
(
CF ) CF
2 5 3
2
. I
N
O
8
9
1
. CrO , H O, conc. H SO
3 2 2 4
diethyl ether/acetone 57%
Cl
Et N, THF
OH
3
CF (CF )
CF (CF )
3
2 5
55%
3
2 5
2. Thionyl chloride 95%
O
1
0
O
O
F C(F C)
(CF ) CF3
F C(F C)
(CF ) CF3
2 5
3
2
3
2 3
3
2
5
N
N
N
Me
Me
Me
Me
Me
Me
Me
Me
N
O
2
O
3
Scheme 1. Synthesis of light-fluorous TEMPO reagents.
starting from 7. Initially, the synthetic sequence was performed
using two CF (CF fluorous ponytails; the sequence was later re-
peated with two shorter CF (CF ponytails to give 3, which
three additional times for the same reaction, also using Method A,
with no deterioration of reaction yield and only small loss in %
recovery of the fluorous-TEMPO on each occasion (ca. 10%). Double
oxidation of diols (Table 1, entries 6 and 7) gave the cyclic lactones
in very good yields. The reagent could also be employed for the
oxidation of secondary alcohols to ketones, albeit in lower yields
(Table 1, entry 5). Given their remoteness from the radical centre,
it was not surprising that similar yields for the oxidation reactions
were obtained for both the lighter and heavier Rf-TEMPO reagents.
All reaction mixtures were easily purified by fluorous solid-phase
extraction (SPE): the reaction mixture was extracted with water,
dried and concentrated and immediately loaded on to the fluorous
silica. This was eluted first with 10% water in methanol, to elute
the organic product(s), followed by 100% methanol to elute the
Rf-TEMPO. This ease of recycling offers a considerable advantage
over the current alternative fluorous-based TEMPOs, which require
lengthier purification processes.
In conclusion, we have prepared two light fluorous-TEMPO re-
agents and employed them as effective reagents for oxidation reac-
tions. The rapid synthesis of these compounds, their comparatively
low molecular weight and ease of recycling via fluorous solid-
phase purification give these fluorous-TEMPO reagents, we believe,
a considerable advantage over alternative fluorous and solid-sup-
ported TEMPO reagents.
3
2 5
)
3
2 3
)
proved to be equally effective and in comparable yield.
The partition coefficients for the two fluorous-TEMPO reagents
were determined by stirring 25 mg of the fluorous-TEMPO in a
mixture of 1 ml of an organic solvent and 1 ml of a fluorous solvent
thermostated at 25 °C for 24 h. The best ratio obtained for 2 was
3
9:61 for dichloromethane: FC-72; all other fluorous/organic sol-
vent combinations for 2 and also for the lighter fluorous analogue
were less successful, suggesting that fluorous-organic liquid–
3
liquid extraction would not be possible for reactions containing
these reagents. Therefore, it was necessary to use fluorous solid-
21–23
phase extraction employing fluorous-silica
to utilise, separate
and recycle these light-fluorous-TEMPO reagents.
Both fluorous-TEMPO reagents were used in a variety of oxida-
tion reactions, initially with the heavier Rf-TEMPO 2 and later with
the lighter Rf-TEMPO 3. Two different methods were employed for
the selective and high yielding oxidation of primary alcohols to
aldehydes and both methods gave good results.2 Both aromatic
and aliphatic alcohols were oxidised in excellent yields to the alde-
hyde, with no overoxidation to the carboxylic acid observed in any
case. The fluorous-TEMPO 3 recovered from the oxidation of p-
nitrobenzyl alcohol (Table 1, entry 1, method A) was re-employed
4

A. P. Dobbs et al. / Tetrahedron Letters 49 (2008) 6955–6958
6957
Table 1
Oxidation reactions using fluorous-TEMPOs 2 and 3
Entry
Starting
material
Product
Methoda
Lighter Rf-TEMPO 3
Heavier Rf-TEMPO 2
Yieldb (%)
Yieldb
(%)
Recovered fluorous-
Recovered fluorous-
TEMPOc (%)
c
TEMPO (%)
O
OH
86 (89, 82)d
—
97 (94, 95)d
—
A
B
76
65
91
89
1
H
O N
2
O N
2
O
OH
2
3
4
5
6
7
A
B
89
69
94
95
—
—
—
—
H
O
A
B
87d
61
94
92
91
92
94
97
CH (CH )
OH
3
2 4
CH (CH )
H
3
2 4
O
OH
89d
75
A
B
96
93
H
OH
O
A
B
62
0
87
94
74
—
95
—
CH (CH )
CH (CH )
3
2 6
3
2 6
O
OH
A
B
71
64
89
88
—
—
—
—
HO
O
O
O
A
73 (1:1.3 mixture
product:SM)
92
—
HO
OH
OH
OH O
8
A
B
0
0
96
97
0
0
98
89
OH
H
a
Method A: alcohol (1 equiv), fluorous-TEMPO (0.03 equiv), 0.5 M KBr (0.3 equiv), NaOCl and NaHCO
NBr (0.4 equiv), Oxone (2.2 equiv).
Purified and isolated yields. All compounds gave satisfactory spectroscopic and analytical data.
Each reaction mixture was purified using fluorous solid-phase extraction using fluorous-silica: the organic material was first eluted using 10% water in methanol,
3
(aq Buffer). Method B: alcohol (1 equiv), fluorous-TEMPO (0.1 equiv),
Ò
Bu
4
b
c
followed by elution with 100% methanol to remove the fluorous-TEMPO.
d
Figures in parentheses are the yields and recovery for the second and third runs using the recycled Rf-TEMPO.
9
.
Pozzi, G.; Cavazzini, M.; Quici, S.; Benaglia, M.; Dell’Anna, G. Org. Lett. 2004, 6,
41–443.
0. Jiang, N.; Ragauskas, A. J. Tetrahedron Lett. 2005, 46, 3323–3326.
Acknowledgements
4
1
We wish to thank Pfizer (CASE award to MJP) and the EPSRC
11. Jiang, N.; Ragauskas, A. J. Org. Lett. 2005, 7, 3689–3692.
12. Holczknecht, O.; Pozzi, G.; Quici, S. Qsar Comb. Sci. 2006, 25, 736–741.
(
DTA award to MJP) for funding of the project and Dr. Peter Jones
13. Holczknecht, O.; Cavazzini, M.; Quici, S.; Shepperson, I.; Pozzi, G. Adv. Synth.
Catal. 2005, 347, 677–688.
and Dr. Peter Stephenson (both Pfizer) for helpful discussions. Fur-
ther, we wish to thank Mr. Greg Coumbarides for fluorine NMR
spectra. The EPSRC National Mass Spectrometry Service (Swansea,
UK) is gratefully acknowledged for running all high resolution
mass spectra.
14. Gheorghe, A.; Cuevas-Yanez, E.; Horn, J.; Bannwarth, W.; Narsaiah, B.; Reiser, O.
Synlett 2006, 2767–2770.
1
1
1
1
1
2
5. Brik, M. E. Tetrahedron Lett. 1995, 36, 5519–5522.
6. Elshani, S.; Kobzar, E.; Bartsch, R. A. Tetrahedron 2000, 56, 3291–3301.
7. Briza, T.; Kvicala, J.; Paleta, O.; Cermak, J. Tetrahedron 2002, 58, 3841–3846.
8. Porcherie, O.; Guari, Y.; Reye, C. New J. Chem. 2005, 29, 538–543.
9. Achilefu, S.; Mansuy, L.; Selve, C.; Thiebaut, S. J. Fluorine Chem. 1995, 70, 19–26.
References and notes
0
0
0
0
0
0
0
0
0
0
0
0
0. 3 ,3 ,4 ,4 ,5 ,5 ,6 ,6 ,7 ,7 ,8 ,8 -Tridecafluorooctanoic acid (1-hydroxyl-2,2,6,6-
0
0
00 00 00 00 00 00 00 00 00 00 00 00
tetramethylpiperidin-4-yl)-(3 ,3 ,4 ,4 ,5 ,5 ,6 ,6 ,7 ,7 ,8 ,8 ,8 -tridecafluoro-
1.
2.
3.
4.
5.
6.
7.
8.
Handbook of Fluorous Chemistry; Wiley-VCH, 2004.
Dobbs, A. P.; Kimberley, M. R. J. Fluorine Chem. 2002, 118, 3–17.
Zhang, W. Chem. Rev. 2004, 104, 2531–2556.
octyl)-amide 2: Orange/red solid; R 0.42 (4:1 [DCM/ether] 1% TEA); mp
f
48–49 °C (petrol) ; mMAX/cmꢀ1 (KBr disc) 2979 w, 2899 w, 1702 m, 1639 s
(amide), 1436 m, 1365 m, 1294 m (CF ), 1236 s (CF ), 1221-1159 br s (8 ꢁ CF ),
3
3
2
Dandapani, S. Qsar Comb. Sci. 2006, 25, 681–688.
2 2 H C 3
1144 s (CF ) and 1114 s (CF ); d could not be obtained; d (100 MHz: CDCl )
Gladysz, J. A.; Curran, D. P. Tetrahedron 2002, 58, 3823–3825.
Kashiwagi, Y.; Ikezoe, H.; Ono, T. Synlett 2006, 69–72.
Bolm, C.; Fey, T. Chem. Commun. 1999, 1795–1796.
Dijksman, A. E.; Arends, I.; Sheldon, R. A. Chem. Commun. 2000, 271–272.
2 2 2 2 2
161.9 (CH CON), 57.7 (CHN), 34.1 (CH CO), 33.9 (CH CH N), 30.5 (CH CHN),
30.3 (CH CHN), 28.2 (CH CH N), 21.8 (CH ), 19.6 (CH ), 11.9 (CH ) and 11.8
2
2
2
3
3
3
(CH ); d (282.4 MHz; CDCl ) ꢀ81.1 (CF ), ꢀ112.7 (CF ), ꢀ118.6 (CF ), ꢀ121.5
3
F
3
3
2
2
+
2
(CF ), ꢀ124.3 (CF ) and ꢀ126.5 (CF ); m/z (EI) 877 (M+H
2
2
, 100%) and 857

6
958
A. P. Dobbs et al. / Tetrahedron Letters 49 (2008) 6955–6958
+
(
M+H , ꢀF, 58%). Found: C, 33.37; H, 2.22; N, 2.15; F, 56.28; C25
H
23
F
26
N
2
O
2
methanol to give the organic product(s), followed by elution with 100%
methanol to give, after removal of the methanol in vacuo, the recovered
fluorous TEMPO, which could be re-used without further purification.
requires C, 34.22; H, 2.64; F, 56.30; N, 3.19; O, 3.65.
1. Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 11837–11865.
2. Matsugi, M.; Curran, D. P. Org. Lett. 2004, 6, 2717–2720.
3. Curran, D. P. Synlett 2001, 1488–1496.
2
2
2
2
Method B: General procedure for the mild oxidation of alcohols using fluorous
Ò
TEMPO and Oxone :
4
A solution of the alcohol (1.0 equiv) and Bu NBr
4. Typical experimental procedures for oxidation reaction:
(0.4 equiv) in dry toluene was treated with a 0.1 M solution of fluorous
TEMPO (0.1 equiv) in dry toluene and Oxone (2.2 equiv) and stirred at room
temperature for 8–48 h. After TLC showed complete conversion, the solvent
Ò
Method A: General procedure for the mild oxidation of alcohols using fluorous
TEMPO and NaOCl: A solution of the alcohol (1 equiv) in CH Cl was cooled to
°C and treated with a solution of fluorous TEMPO (0.03 equiv) in CH Cl . The
reaction mixture was stirred at 0 °C for 5 min before being treated with a 0.5 M
solution of KBr (0.3 equiv) and NaOCl solution buffered with NaHCO . The
2
2
0
2
2
was removed in vacuo and the residue was suspended between CH
water (10 ml, 1:1). The aqueous phase was separated and extracted with
CH Cl
(3 ꢁ 10 ml). The organic phases were combined, washed with water
(15 ml), dried over MgSO , filtered and concentrated in vacuo. The residue was
2 2
Cl and
3
2
2
reaction mixture was stirred at 0 °C for 1 h before being allowed to warm to
4
room temperature over 20 min. The aqueous phase was separated and
purified by fluorous silica column chromatography, eluting first with 10%
water in methanol to give the organic product(s), followed by elution with
100% methanol to give, after removal of the methanol in vacuo, the recovered
fluorous TEMPO, which could be re-used without further purification.
extracted with CH
over MgSO , filtered and concentrated in vacuo. The residue was purified by
fluorous silica column chromatography, eluting first with 10% water in
2
Cl
2
(3 ꢁ 10 ml). The organic phases were combined, dried
4