Oxidative detagging of fluorous organosilanes

Article abstract of DOI:10.1016/j.jfluchem.2009.05.017

We have validated a novel detagging strategy featuring the unmasking of a fluorous-tagged silane to a hydroxy moiety. The fluorous silylated bicyclononane, prepared from the titanium-mediated annulation of 1-acetylcyclohexene and a fluorous-tagged allylsi

Full text of DOI:10.1016/j.jfluchem.2009.05.017

Journal of Fluorine Chemistry 130 (2009) 1151–1156
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Oxidative detagging of fluorous organosilanes
a
b
a,
*
´
Sophie Boldon , Jane E. Moore , Veronique Gouverneur
a Chemical Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
b AstraZeneca UK, Alderley Park, Cheshire SK10 4TG, UK
A R T I C L E I N F O
A B S T R A C T
Article history:
We have validated a novel detagging strategy featuring the unmasking of a fluorous-tagged silane to a
hydroxy moiety. The fluorous silylated bicyclononane, prepared from the titanium-mediated annulation
of 1-acetylcyclohexene and a fluorous-tagged allylsilane, was successfully detagged under Fleming-type
oxidation conditions. The stereochemistry of the resulting hydroxylated product indicates retention of
configuration upon detagging in line with the non-fluorous variant of this transformation.
ß 2009 Published by Elsevier B.V.
Received 12 May 2009
Received in revised form 26 May 2009
Accepted 27 May 2009
Available online 6 June 2009
Keywords:
Fluorous
Silicon
Annulation
Oxidative detagging
1. Introduction
oxidative cleavage [6]. Since hydroxy groups are found ubiquitously
in natural products or drug-like targets, we identified the oxidation
The similaritiesanddifferencesbetweensolidphaseand fluorous
synthesis have been well-documented in the literature and have
stimulated the use of fluorous-based technology to facilitate small
molecule synthesis, library synthesis, peptide chemistry, micro-
arrays and more recently radiochemistry [1]. Amongst the
impressive number of fluorous linkers available to date, silyl linkers
have proved useful mainly in the context of protective group
chemistry [2]. Some rare examples of displaceable linkers have been
reportedsuchastheuseofaheavyfluoroussilyl-substitutedbenzoic
acid as a limiting reagent of the Ugi and Biginelli condensations [3].
The subsequent traceless cleavage of the silyl tag was performed
upon treatment with a nucleophilic fluoride source, tetrabutylam-
monium fluoride (TBAF). In recent work, we have reported a non-
traceless cleavage of light fluorous allylsilanes upon fluorodesilyla-
tion with an electrophilic fluorine source [4]. This reaction is a rare
example of a detagging process featuring a C–F bond-forming event,
indicating that the silicon group can be used as a masked fluorine
substituent. Pioneering work of Tamao, Kumada and Fleming has
demonstrated the utility of organosilanes for oxidative cleavage
with the replacement of a silyl group with a hydroxy functionality
[5]. The advantage of silicon versus boron as a disguised hydroxy
group is the fact that the Lewis acidity of boron requires immediate
oxidation after its introduction, a limitation contrasting with the
tolerance of a silyl group to various transformations prior to
of the carbon–silicon group of fluorous organosilanes as an
important transformation to be developed in the context of new
fluorous displaceable linkers (Fig. 1).
Mechanistically, two approaches may be considered for the
oxidative detagging, the Fleming oxidation of arylsilanes or the
Tamao–Kumada oxidation with silyl groups of general structure
SiR2X (withX = H, OR, NR2, Cl, F)[5]. Forproof ofconcept, wechoseto
study the synthesis of fluorous organosilanes for oxidative cleavage
under Fleming-type oxidation conditions. We opted for a light
fluorous approach typically requiring minimal optimisation studies
and allowing for both standard silica gel chromatography and
fluorous solid phase extraction (F-SPE) purification. The cyclopen-
tane annulation by [3 + 2] cycloaddition of fluorous allylsilanes to
1-acetylcyclohexene served as our model reaction [7]. In this
* Corresponding author. Tel.: +44 (0)1865 275644; fax: +44 (0)1865 275644.
E-mail address: veronique.gouverneur@chem.ox.ac.uk (V. Gouverneur).
Fig. 1. Detagging of fluorous silanes.
0022-1139/$ – see front matter ß 2009 Published by Elsevier B.V.
doi:10.1016/j.jfluchem.2009.05.017

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S. Boldon et al. / Journal of Fluorine Chemistry 130 (2009) 1151–1156
Scheme 1. Ring annulation of fluorous allylsilanes and oxidative hydroxy-detagging.
communication, we report the synthesis of various fluorous
allylarylsilanes and their reactivity in the context of annulation
chemistry. The first hydroxy-detagging of fluorous arylsilanes by
oxidation of the C–Si bond is also disclosed (Scheme 1).
The aryl-substituted allylsilanes 1b–d were deemed suitable for
the replacement of the silyl group with a hydroxy group after
annulation. The ethylene spacer insulating the aryl group from the
tag should minimise the electronic perturbation that could
otherwise affect the efficiency of the electrophilic displacement
step. Starting from commercially available 4-bromo-1H,1H,2H,2H-
perfluorodecylbenzene, allylsilanes 1b–d were accessed in mod-
erate to excellent yields (50–91%) in a two-step reaction. Lithiation
of the starting material was achieved at ꢀ30 8C with n-butyl
lithium in a 1:1 mixture of Et2O and THF. Subsequent addition of
commercially available chloro(dimethyl)allylsilane or freshly
distilled chloro(diisopropyl)allylsilane or chloro(methyl)(pheny-
l)allylsilane (prepared in one step from dichloro(diisopropyl)silane
or dichloro(methyl)(phenyl)silane respectively [8]) led to the
formation of the desired products 1b–d after stirring at room
temperature typically for 4 h (entries 1–3, Table 1). Despite
extending the reaction time to 16 h, 1c could not be accessed in a
higher yield than 50% (Scheme 3, Table 1, entry 2).
2. Results and discussion
In previous studies, the fluorous allylsilane 1a was prepared by
reacting the commercially available fluorous-tagged dimethyl-
chlorosilane 2 with allylmagnesium bromide (79% isolated yield,
Scheme 2) [4]. Although this substrate is useful to probe the
annulation process, it is likely not to be suitable for the subsequent
oxidative cleavage. The Fleming oxidation typically requires aryl-
substituted silyl groups which undergo an electrophilic aromatic
substitution prior to oxidative cleavage.
With the fluorous-tagged allylsilanes 1a–d in hand, attention
was turned to the ring [3 + 2] annulation (Scheme 4). We first
investigated the reactivity of allylsilane 1a. Following the reaction
conditions reported in the literature for non-fluorous allylsilanes,
1-acetylcyclohexene was stirred at ꢀ78 8C in CH2Cl2 with
1.1 equiv. of TiCl4 for 15 min before adding the allylsilane 1a
[7b]. After 19 h at ꢀ20 8C, the desired cycloadduct 3a was isolated
in an unoptimised yield of 33%. Previous studies have shown that
the efficacy of the annulation increased with the steric bulk at the
silicon atom of the allylsilane [7b,d]. Significantly, annulations of
non-fluorous allylsilanes, where the silicon is substituted with a
combination of methyl and alkyl or phenyl groups, are reported to
afford the product of allylation 4 as the major product. Since only
trace amounts of 4 were observed when using the fluorous
allylsilane 1a, it appears that the presence of the fluorous tag
favours annulation over the competitive allylation process.
Separation of the desired product and the non-fluorous by-product
was achieved using a combination of standard flash column
chromatography followed by F-SPE. Following the annulation
reaction, no unreacted starting material was recovered [9].
Having established that 1a can undergo an annulation, we
focussed on the reactivity of the novel fluorous allylarylsilanes 1b–
d (Scheme 5, Table 2).
Scheme 2. Synthesis of the fluorous allylsilane 1a.
Scheme 3.
Table 1
Synthesis of the fluorous aryl-substituted allylsilanes 1b–d.
Entry
R1
R2
Time (h)
Product
Yield (%)
1
2
3
Me
Me
iPr
Me
Ph
4
16
4
1b
1c
1d
91
50
90
iPr
Optimisation studies revealed that the [3 + 2] annulations gave a
higheryieldofthedesiredcycloadductwhenanadditional0.5 equiv.
of allylsilane was added to the reaction mixture after 16 h, and the
reaction stirred for a further 24 h. The dimethylarylallylsilane 1b,
withincreasedstericbulkaroundthesiliconanddifferingfrom1aby
the presence of an aryl group to insulate the silyl centre from the
fluorous tag, did undergo annulation in the presence of 1-
acetylcyclohexene but 3b was isolated in significantly lower yield
than 3a (entries 1 and 2, Table 2). This result, compared to the non-
fluorous variant, indicates that the remote tag in 1b does not affect
the course ofthis reaction [7b]. The replacement of one of the methyl
groups by a phenyl group on the silicon centre was sufficient to
increase the yield of the annulation process since 3c was isolated in
36% yield (entry 3, Table 2). As anticipated, the highest yield was
obtained where the steric bulk of the fluorous-tagged allylsilane was
maximised. The diisopropyl-substituted allylsilane 1d (entry 4,
Scheme 4. [3 + 2] Annulation of the fluorous allylsilane 1a.

S. Boldon et al. / Journal of Fluorine Chemistry 130 (2009) 1151–1156
1153
Scheme 5.
Scheme 6.
Table 2
[3 + 2] Annulation of fluorous allylsilanes 1a–d.
Table 3
Oxidative cleavage of fluorous cycloadducts 3a–d.
Entry
Allylsilane
Cycloadduct
Yield (%)
38
Entry
Cycloadduct
HBF4ꢁOEt2 (equiv.)
Timea
Yield of 5 (%)
t1 (d)
t2 (h)
c
1
2
3
4
5
3a
3b
3c
3d
3d
10
5
7b
1
16
4
–
1
1a
95 (56)d
72
5
1
16
16
16
5
7
4b
58
7
61
a
t1 refers to step (i); t2 refers to step (ii).
Refluxing in CH2Cl2.
b
c
Decomposition of starting material.
Purification using F-SPE.
2
3
4
1b
1c
1d
22
36
56
d
turned to the oxidative cleavage of the C–Si bond (Scheme 6,
Table 3).
All cycloadducts 3a–d were examined to determine which
fluorous silyl group is best suited for the Fleming-type oxidative
detagging event [10]. As anticipated, 3a was found to be unreactive
under the conditions employed. This was expected since the silicon
is not activated to undergo any further transformation (entry 1,
Table 3). Refluxing the cycloadduct in CH2Cl2 and 10 equiv. of
HBF4ꢁOEt2 for 7 days led to decomposition of the starting material.
Protodesilylation of the aryl group of 3b–d was achieved using
Flemingconditions,withtetrafluoroboricaciddiethylethercomplex
serving as a fluoride source. Complete conversion of the starting
material was observed within 24 h when the cycloadduct 3b or 3c
wasmixedwith5 equiv. ofHBF4ꢁOEt2 atroomtemperatureinCH2Cl2
(entries 2 and 3, Table 3). The increased steric bulk of 3d caused the
reaction to progress more slowly and complete conversion was
achieved after 7 days at room temperature. If the reaction was
heated to reflux, conversion was complete within 4 days (entries 4
and 5, Table 3). In all cases, the crude activated intermediate product
was subjected immediately to the next step without purification of
the intermediate detagged silyl fluoride. Employing Tamao condi-
tions(H2O2, TBAFandKHCO3 ina 1:1 mixtureof MeOH/THFat65 8C)
the oxidation afforded 5 in moderate yields indicating that the
overall transformation could be successfully performed. Impor-
tantly, the yields are comparable to those found in the non-fluorous
series (Table 3) [11]. Purification of the final carbinol 5 could be
achieved either through flash column chromatography or a standard
F-SPE protocol. In this latter case, the fluorous by-products resulting
from the initial cleavage of the aryl group could be separated from
non-fluorous desired product 5. The anti relationship of the acetyl
and hydroxy group was confirmed through kinetic NOE studies. It is
known that the oxidative cleavage of C–Si bonds is a stereospecific
reaction proceeding with retention. The stereochemical outcome of
this novel oxidative detagging process is therefore not affected by
the use of fluorous tagged silyl groups.
Table 2) led to the silylated bicyclo[4.3.0]nonane 3d in 56% isolated
yield. For these transformations, the product of allylation 4 was
either not seen (entries 3–4, Table 2) or only observed in a trace
amount (entries 1–2, Table 2). No other fluorous product could be
detected in the crude reaction mixture [9]. Kinetic NOE studies
performed on 3a indicated that the relative stereochemistry
between the acetyl and silyl groups was anti, which corroborate
data previously reported for annulations performed with non-
fluorous allylsilanes (Fig. 2) [7b].
Once the cycloadducts had been accessed with the optimum
fluorous allylsilane identified for the annulation process, focus was
3. Conclusions
In summary, we have validated a novel detagging strategy
featuring the unmasking of a fluorous-tagged silane to a hydroxy
moiety. A range of arylallylsilanes with a suitable light fluorous
moiety was prepared and their subsequent cycloannulation
Fig. 2. NOE studies on 3a.

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S. Boldon et al. / Journal of Fluorine Chemistry 130 (2009) 1151–1156
provided tagged cycloadducts susceptible to oxidative detagging.
The release of the hydroxylated product from the tagged
precursors was successfully performed using a sequential proto-
desilylation–oxidation. Importantly, our work demonstrates that
retention of configuration is maintained upon oxidative cleavage of
fluorous-tagged silyl groups.
4.2.2. Allyl(4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,
10-heptadecafluorodecyl)phenyl)(methyl)(phenyl)silane (1c)
Following the general procedure, and after additional stirring at
room temperature for 16 h before quenching, 1c was obtained
from
1-bromo-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptdeca-
fluorodecyl)-benzene (1.95 g) as a colourless oil (1.11 g) in 50%
yield following flash chromatography with hexanes (100%) as the
eluent. 1H NMR (500 MHz, CDCl3, ppm)
d 0.58 (s, 3H, SiCH3), 2.10
4. Experimental
(d, J = 8.0 Hz, 2H, SiCH2CH), 2.33–2.47 (m, 2H, CH2CH2CF2), 2.90–
2.98 (m, 2H, CH2CH2CF2), 4.87–4.98 (m, 2H, CH55CH2), 5.76–5.87
(m, 1H, CH55CH2), 7.24 (d, J = 7.4 Hz, 2H, Ar-H), 7.35–7.46 (m, 3H,
Ar-H, Ph-H), 7.47–7.58 (m, 4H, Ph-H); 13C NMR (126 MHz, CDCl3,
4.1. General experimental procedures
Reactions were carried out in flame-dried apparatus under an
argon atmosphere unless otherwise indicated. Commercial reagents
were used as received and solvents were purified prior to use by
passing through a column of activated alumina under inert
atmosphere or by distillation according to standard procedures.
Reactions were monitored by thin layer chromatography (TLC) on
Merck aluminium-backed silica gel sheets and visualised with a UV
lamp (254 nm) or with potassium permanganate stain. Flash
chromatography was carried out using Merck silica gel (0.040–
0.063 mm) and eluents as indicated. Fluorous solid phase extrac-
tions were carried out using FluoroFlashTM silica gel cartridges from
Fluorous Technologies Inc. NMR spectra were recorded in deuter-
ated solvents as indicated using Bruker or Varian spectrometers. 1H
and 13C spectra are internally referenced to residual undeuterated
solvent. 13C and 19F NMR spectra are proton-decoupled. IR spectra
were recorded as thin films on NaCl plates using a Bruker Tensor 27
FT-IR spectrometer. Mass spectra were recorded on a Bruker
MicroTof (ESI) or on a Micromass GC-ToF (EI, CI, FI). Compounds 1a
[4] and 5 [7d] have previously been described.
ppm)
d
ꢀ4.8 (SiCH3), 22.1 (SiCH2CH), 26.4 (CH2CH2CF2), 32.8 (t,
JCF = 22.2 Hz, CH2CH2CF2), 114.3 (CH55CH2), 127.8 (HC-Ar), 127.9
(HC-Ph), 129.3 (HC-Ar), 134.0 (CH55CH2), 134.5 (HC-Ph), 134.8 (HC-
Ph), 135.0 (HC-Ph), 135.2 (HC-Ph), 135.7 (C-Ph), 136.4 (C-Ar), 140.2
(C-Ar); 19F NMR (377 MHz, CDCl3, ppm)
d
ꢀ80.7 (t, J = 10.0 Hz, 3F,
CF3CF2), ꢀ114.6, ꢀ121.6, ꢀ121.9, ꢀ122.7, ꢀ123.5, ꢀ126.1; IR (thin
film) 3072, 2974, 1631 (C55C), 1603, 1429, 1211, 1113, 703 cmꢀ1
;
HRMS (ESI) C26H21F17KSi calcd: 723.0773, found 723.0769.
4.2.3. Allyl(4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
heptadecafluorodecyl)phenyl)diisopropylsilane (1d)
Following the general procedure 1d was obtained from
1-bromo-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptdecafluorode-
cyl)-benzene (5.0 g) as a colourless oil which solidified on standing
(5.05 g) in 90% yield following flash chromatography with hexanes
(100%) as the eluent. 1H NMR (500 MHz, CDCl3, ppm)
d 1.02 (d,
J = 7.4 Hz, 6H, Si(CH(CH3)(CH3))), 1.05 (d, J = 7.4 Hz, 6H,
Si(CH(CH3)(CH3))), 1.29 (sept, J = 7.4 Hz, 2H, Si(CH(CH3)2), 1.95
(dt, J = 8.0 and 1.2 Hz, 2H, SiCH2CH), 2.34–2.47 (m, 2H, CH2CH2CF2),
2.86–2.97 (m, 2H, CH2CH2CF2), 4.88 (dm, J = 10.1 Hz, 1H,
CH55CHaHb), 5.00 (dq, J = 16.9 and 1.6 Hz, 1H, CH55CHaHb), 5.86–
5.96 (m, 1H, CH55CHaHb), 7.21 (d, J = 8.0 Hz, 2H, Ar-H), 7.47 (d,
J = 8.0 Hz, 2H, Ar-H); 13C NMR (126 MHz, CDCl3, ppm)
d 10.9
(Si(CH(CH3)2)), 17.2 (SiCH2CH), 17.9 (Si(CH(CH3)2)), 26.3
(CH2CH2CF2), 32.8 (t, JCF = 22.2 Hz, CH2CH2CF2), 113.7 (CH55CH2),
127.5 (HC-Ar), 133.1 (HC-Ar), 135.2 (CH55CH2), 135.3 (C-Ar), 139.6
4.2. General procedure for the preparation of fluorous
allylsilanes (1b–d)
nBuLi (2.5 M solution in hexanes, 1.05 equiv.) was added
dropwise to a solution of 1-bromo-4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,
10,10,10-heptadecafluoro-decyl)-benzene (1.0 equiv.) in a mixture
of THF and Et2O (1:1, 0.35 M) cooled to ꢀ30 8C. The resulting
mixture was stirred at this temperature for 30 min before the
dropwise addition of a solution of chloro(dialkyl)allylsilane in Et2O
(1.05 equiv., 0.73 M). The reaction mixture was allowed to warm to
room temperature and stirred for 4 h. The reaction was then
quenched with saturated aqueous NH4Cl solution (20 mL). The
aqueous phase was extracted with Et2O (3 mL ꢂ 20 mL) and the
combined organic phase washed with brine (3 mL ꢂ 20 mL), dried
(MgSO4) and concentrated in vacuo. Purification by flash column
chromatography eluting with hexanes (100%) afforded the desired
product.
(C-Ar); 19F NMR (377 MHz, CDCl3, ppm)
d
ꢀ80.7 (t, J = 10.0 Hz, 3F,
CF3CF2), ꢀ114.7, ꢀ121.6, ꢀ121.9, ꢀ122.7, ꢀ123.4, ꢀ126.1; IR (thin
film) 3072, 2950, 2867, 1631 (C55C), 1602, 1462, 1206, 1115, 910,
734 cmꢀ1
717.1239.
; HRMS (ESI) C25H27F17KSi calcd: 717.1242, found
4.3. General procedure for preparation of cycloadducts (3) [7c]
To a precomplexed solution of 1-acetylcyclohexene in CH2Cl2
(1.0 equiv., 1.8 M) and titanium (IV) chloride (1.0 M solution in
CH2Cl2,1.1 equiv.)cooledtoꢀ78 8Cwasaddeddropwiseasolutionof
allylsilane1inCH2Cl2 (1.3 equiv., 0.78 M). Theresultingmixturewas
allowed towarm toꢀ20 8C slowly and stirredat thistemperature for
16 h. A further solution of allylsilane in CH2Cl2 (0.5 equiv., 0.78 M)
was added and the reaction stirred at ꢀ20 8C for 24 h. The reaction
wasquenchedwithsaturatedaqueousNH4Clsolution(5 mL)andthe
aqueousphaseextractedwithCH2Cl2 (3 mL ꢂ 10 mL).Thecombined
organic phase was dried (Na2SO4) and concentrated in vacuo.
Purification by flash column chromatography eluting with hex-
ane:Et2O (99:1) afforded the desired product.
4.2.1. Allyl(4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,
10-heptadecafluorodecyl)phenyl)dimethylsilane (1b)
Following the general procedure 1b was obtained from 1-bromo-
4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptdecafluorodecyl)-ben-
zene (2.0 g) as a colourless oil (1.88 g) in 91% yield following flash
chromatography with hexanes (100%) as the eluent. 1H NMR
(500 MHz, CDCl3, ppm) d0.29 (s, 6H, Si(CH3)2), 1.76 (d, J = 8.0 Hz, 2H,
SiCH2CH), 2.32–2.46 (m, 2H, CH2CH2CF2), 2.89–2.96 (m, 2H,
CH2CH2CF2), 4.84–4.91 (m, 2H, CH55CH2), 5.73–5.84 (m, 1H, CH55
CH2), 7.23 (d, J = 7.9 Hz, 2H, Ar-H), 7.49 (d, J = 7.9 Hz, 2H, Ar-H); 13
C
NMR (126 MHz, CDCl3, ppm)
d
ꢀ3.5 (Si(CH3)2), 23.6 (SiCH2CH), 26.4
4.3.1. Trans-1-acetyl-8-((30,30,40,40,50,50,60,60,70,70,
80,80,90,90,100,100,100-heptadecafluorodecyl)dimethylsilyl)
bicyclo[4.3.0]nonane (3a)
(CH2CH2CF2), 32.9 (t, JCF = 22.2 Hz, CH2CH2CF2), 113.4 (CH55CH2),
127.7 (HC-Ar), 134.1 (HC-Ar), 134.5 (CH55CH2), 136.9 (C-Ar), 139.9
(C-Ar); 19F NMR (377 MHz, CDCl3, ppm)
CF3CF2), ꢀ114.6, ꢀ121.7, ꢀ121.9, ꢀ122.7, ꢀ123.5, ꢀ126.1; IR (thin
film) 3075, 2959, 1632 (C55C), 1604, 1211, 838, 657 cmꢀ1; HRMS
(ESI) C21H19F17 KSi calcd: 661.0616, found 616.0620.
d
ꢀ80.7 (t, J = 10.0 Hz, 3F,
Following the general procedure 3a was obtained from 1-
acetylcyclohexene (88 mg) as a colourless oil (181 mg) in 38%
yield. 1H NMR (500 MHz, CDCl3, ppm)
d
0.03 (s, 3H, Si(CH3)(CH3)),
0.04 (s, 3H, Si(CH3)(CH3)), 0.72–0.78 (m, 2H, CH2–CH2CF2), 1.09–

S. Boldon et al. / Journal of Fluorine Chemistry 130 (2009) 1151–1156
1155
1.24 (m, 2H, H-8 and H-3a), 1.33–1.53 (m, 7H, H-2a, H-3b, H-4a,b, H-
5a, H-7a and H-9a), 1.55–1.63 (m, 1H, H-5b), 1.71 (ddd, J = 12.3, 8.4
and 6.5 Hz, 1H, H-7b), 1.85 (dm, J = 13.7 Hz, 1H, H-2b), 1.90 (dd,
J = 13.2 and 10.7 Hz, 1H, H-9b), 1.94–2.08 (m, 2H, CH2CH2CF2), 2.15
(s, 3H, C(O)CH3), 2.48 (dq, J = 10.0 and 5.1 Hz, 1H, H-6); 13C NMR
7b), 1.91–2.00 (m, 1H, H-9b), 2.12 (s, 3H, C(O)CH3), 2.32–2.46 (m,
3H, CH2CH2CF2 and H-6), 2.89–2.96 (m, 2H, CH2CH2CF2), 7.22 (d,
J = 7.9 Hz, Ar-H), 7.48 (d, J = 8.0 Hz, 2H, Ar-H); 13C NMR (126 MHz,
CDCl3, ppm)
d 11.3 and 11.4 (Si(CH(CH3)2)2), 18.6, 18,7, 18.9 and
18.9 (Si(CH(CH3)2)2) 19.9 (C-8), 21.9 (C-4), 23.4 (C-3), 25.5
(C(O)CH3), 26.3 (C-5), 26.4 (CH2CH2CF2), 31.1 (C-2), 32.6 (C-7),
32.8 (t, J = 21.9 Hz, CH2CH2CF2), 38.1 (C-9), 41.2 (C-6), 58.2 (C-1),
127.5 (HC-Ar), 132.9 (C-Ar), 135.8 (HC-Ar), 139.7 (C-Ar), 213.0
(126 MHz, CDCl3, ppm)
d
ꢀ5.3 (Si(CH3)(CH3)), ꢀ5.2 (Si(CH3)(CH3)),
3.7 (CH2CH2CF2), 22.0 (C-8), 22.0 (C-4), 23.4 (C-3), 25.4 (C(O)CH3),
25.9 (t, J = 22.2 Hz, CH2CH2CF2), 26.6 (C-5), 31.2 (C-2), 31.9 (C-7),
37.2 (C-9), 41.4 (C-6), 58.4 (C-1), 212.7 (C(O)CH3); 19F NMR
(C(O)CH3); 19F NMR (377 MHz, CDCl3, ppm)
d
ꢀ80.7 (t, J = 9.8 Hz,
(377 MHz, CDCl3, ppm)
d
ꢀ80.7 (t, J = 10.0 Hz, 3F, CF3CF2), ꢀ116.1,
3F, CF3CF2), ꢀ114.6, ꢀ121.7, ꢀ121.9, ꢀ122.7, ꢀ123.4 ꢀ126.1; IR
(thin film) 2941, 2866, 1701 (C55O), 1602, 1460, 1351, 1212,
656 cmꢀ1; HRMS (ESI) C33H39F17ONaSi calcd: 825.2391, found
825.2388.
ꢀ121.7, ꢀ121.9, ꢀ122.7, ꢀ123.2, ꢀ126.1; IR (thin film) 2935, 2864,
1702 (C55O), 1443, 1206, 1151, 1113, 836 cmꢀ1; HRMS (ESI)
C23H27F17ONaSi calcd: 693.1452, found 693.1460.
4.3.2. Trans-1-acetyl-8-((4-(30,30,40,40,50,50,60,60,
70,70,80,80,90,90,100,100,100-
4.4. Oxidative cleavage of carbocycles (3b–d)
heptadecafluorodecyl)phenyl)dimethylsilyl)bicyclo[4.3.0]nonane (3b)
Following the general procedure 3b was obtained from 1-
acetylcyclohexene (250 mg) as a colourless oil (326 mg) in 22%
4.4.1. Oxidative cleavage of trans-1-acetyl-8-((4-(30,30,40,40,50,50,60,60,
70,70,80,80,90,90,100,100,100-
heptadecafluorodecyl)phenyl)dimethylsilyl)bicyclo[4.3.0]nonane 3b
Tetrafluoroboric acid diethyl ether complex (0.20 mL,
1.47 mmol) was added to a stirred solution of 3b (219 mg,
0.29 mmol) in DCM (4.1 mL) at room temperature. The resulting
solution was stirred at room temperature for 16 h. The reaction
was then cooled to 0 8C and quenched by the addition of saturated
aqueous NaHCO3 solution (5 mL). The aqueous phase was
extracted with Et2O and the combined organic phase washed
with brine, dried (MgSO4) and concentrated in vacuo. The crude
residue was then redissolved in a mixture of MeOH and THF (1:1,
3.4 mL) and cooled to 0 8C before the addition of KHCO3 (58 mg,
0.58 mmol), tetrabutylammonium fluoride (1.0 M solution in THF,
0.87 mL, 0.87 mmol) and hydrogen peroxide (35 wt.%, 0.51 mL,
5.8 mmol). The resulting solution was heated to 65 8C and stirred
for 4 h. The reaction was then cooled to 0 8C and quenched by the
addition of an aqueous solution of Na2S2O3 (10 wt.%, 5 mL). The
aqueous phase was extracted with Et2O, and the combined organic
phase washed with brine, dried (MgSO4) and concentrated in
vacuo. Purification by flash column chromatography eluting with
hexanes/EtOAc (7:3) afforded the desired trans-1-acetyl-8-hydro-
xybicyclo[4.3.0]nonane 5 as a yellow oil (50 mg, 95%). 1H NMR
yield. 1H NMR (500 MHz, CDCl3, ppm)
d 0.28 (s, 6H, Si(CH3)2), 1.07–
1.16 (m, 1H, H-3a), 1.20–1.62 (m, 10H), 1.71 (ddd, J = 12.4, 8.2 and
6.6 Hz, 1H, H-7b), 1.76 (dm, J = 13.8 Hz, 1H, H-2b), 1.90 (dd, J = 13.1
and 10.6 Hz, 1H, H-9b), 2.12 (s, 3H, C(O)CH3), 2.31–2.48 (m, 3H,
CH2CH2CF2 and H-6), 2.89–2.95 (m, 2H, CH2CH2CF2), 7.22 (d,
J = 7.7 Hz, Ar-H), 7.47 (d, J = 7.9 Hz, 2H, Ar-H); 13C NMR (126 MHz,
CDCl3, ppm)
d
ꢀ4.6 and ꢀ4.5 (Si(CH3)2), 22.0 (C-4), 22.7 (C-8), 23.5
(C-3), 25.5 (C(O)CH3), 26.4 (CH2CH2CF2), 26.4 (C-5), 31.1 (C-2), 32.1
(C-7), 32.8 (t, J = 21.9 Hz, CH2CH2CF2), 37.6 (C-9), 41.4 (C-6), 58.5
(C-1), 127.7 (HC-Ar), 134.3 (HC-Ar), 136.7 (C-Ar), 139.9 (C-Ar),
212.9 (C(O)CH3); 19F NMR (377 MHz, CDCl3, ppm)
J = 10.0 Hz, 3F, CF3CF2), ꢀ114.6, ꢀ121.7, ꢀ121.9, ꢀ122.7, ꢀ123.4,
ꢀ126.1; IR (thin film) 2933, 2862, 1700 (C55O), 1602, 1456, 1212,
1151, 806 cmꢀ1; HRMS (ESI) C29H31F17ONaSi calcd.: 769.1765,
found 769.1766.
d
ꢀ80.7 (t,
4.3.3. Trans-1-acetyl-8-((4-(30,30,40,40,50,50,60,60,70,70,80,80,90,90,100,
100,100-heptadecafluorodecyl)phenyl)methylphenylsilyl)bicyclo
[4.3.0]nonane (3c)
Following the general procedure 3c was obtained from 1-
acetylcyclohexene (126 mg) as a colourless oil (292 mg) in 36%
(500 MHz, CDCl3, ppm)
d 1.17–1.27 (m, 1H, H-3a), 1.34–1.43 (m,
yield. 1H NMR (500 MHz, CDCl3, ppm)
d
0.57 (s, 3H, SiCH3), 1.05–
1H, H-4a),1.47–1.80 (m, 7H, H-2a, H-3b, H-4b, H-5a,b, H-7b and H-9a),
1.71 (br s, 1H, OH), 1.86-1.94 (m, 1H, H-2b), 2.07 (dt, J = 13.5 and
7.7 Hz, 1H, H-7b) 2.13 (s, 3H, C(O)CH3), 2.17 (dd, J = 13.8 and 8.4 Hz,
1H, H-9b), 2.34–2.41 (m, 1H, H-6), 4.35–4.42 (m, 1H, H-8); HRMS
(GCT, CI+) C11H22NO2 calcd: 200.1651, found 200.1653.
1.15 (m, 2H, H-2a and H-3a), 1.21–1.40 (m, 3H, H-3b, H-4a and H-5a),
1.46–1.72 (m, 4H, H-2b, H-5b, H-7a and H-9a), 1.72–1.86 (m, 2H, H-
7b and H-8), 2.00 (dd, J = 13.1 and 10.4 Hz, H-9b), 2.13 (s, 3H,
C(O)CH3), 2.33–2.45 (m, 2H, CH2CH2CF2), 2.48 (dq, J = 10.0 and
5.1 Hz, 1H, H-6), 2.89–2.96 (m, 2H, CH2CH2CF2), 7.22 (d, J = 7.9 Hz,
Ar-H), 7.33–7.42 (m, 3H, Ar-H), 7.47–7.56 (m, 4H, Ar-H); 13C NMR
4.4.2. Oxidative cleavage of trans-1-acetyl-8-((4-(30,30,40,40,50,50,60,60,
70,70,80,80,90,90,100,100,100-heptadecafluorodecyl)phenyl)
(126 MHz, CDCl3, ppm)
d
ꢀ6.0 (SiCH3), 21.1 (C-8), 21.9 (C-4), 23.4
(C-3), 25.6 (C(O)CH3), 26.3 (C-5), 26.4 (CH2CH2CF2), 30.9 (C-2), 32.3
(C-7), 32.8 (t, J = 22.2 Hz, CH2CH2CF2), 37.7 (C-9), 41.3 (C-6), 58.5
(C-1), 127.8 (HC-Ar), 127.8 (HC-Ph), 129.3 (HC-Ar), 134.7 (HC-Ph),
134.8 (HC-Ph), 135.3 (HC-Ph), 135.3 (HC-Ph), 136.3 (C-Ph), 136.4
(C-Ar), 140.2 (C-Ar), 212.9 (C(O)CH3); 19F NMR (377 MHz, CDCl3,
methylphenylsilyl)bicyclo[4.3.0]nonane 3c
Tetrafluoroboric acid diethyl ether complex (0.18 mL,
1.30 mmol) was added to a stirred solution of 3c (211 mg, 0.26
mmol) in DCM (3.6 mL) at room temperature. The resulting
solution was stirred at room temperature for 16 h. The reaction
was then cooled to 0 8C and quenched by the addition of saturated
aqueous NaHCO3 solution (5 mL). The aqueous phase was
extracted with Et2O and the combined organic phase washed
with brine, dried (MgSO4) and concentrated in vacuo. The crude
residue was then redissolved in a mixture of MeOH and THF (1:1,
3.0 mL) and cooled to 0 8C before the addition of KHCO3 (52 mg,
0.52 mmol), tetrabutylammonium fluoride (1.0 M solution in THF,
0.78 mL, 0.78 mmol) and hydrogen peroxide (35 wt.%, 0.46 mL,
5.20 mmol). The resulting solution was heated to 65 8C and stirred
for 16 h. The reaction was then cooled to 0 8C and quenched by the
addition of an aqueous solution of Na2S2O3 (10 wt.%, 5 mL). The
aqueous phase was extracted with Et2O, and the combined organic
phase washed with brine, dried (MgSO4) and concentrated in
ppm)
d
ꢀ80.7 (t, J = 10.0 Hz, 3F, CF3CF2), ꢀ114.6, ꢀ121.7, ꢀ121.9,
ꢀ122.7, ꢀ123.4, ꢀ126.1; IR (thin film) 3070, 2934, 2862, 1699
(C55O), 1602, 1456, 1428, 1206, 786 cmꢀ1; HRMS (ESI) C34H33F17O-
NaSi calcd: 831.1921, found 831.1917.
4.3.4. Trans-1-acetyl-8-((4-(30,30,40,40,50,50,60,60,70,70,80,80,90,90,100,
100,100-heptadecafluorodecyl)phenyl)diisopropylsilyl)bicyclo
[4.3.0]nonane (3d)
Following the general procedure 3d was obtained from 1-
acetylcyclohexene (250 mg) as a colourless oil (898 mg) in 56%
yield. 1H NMR (500 MHz, CDCl3, ppm)
d 0.95–1.43 (m, 20H,
Si(CH(CH3)2)2, Si(CH(CH3)2)2, H-2a, H-3a,b, H-4a,b and H-5a), 1.43–
1.69 (m, 5H, H-2b, H-5b, H-7a, H-8 and H-9a),1.75–1.82 (m, 1H, H-

1156
S. Boldon et al. / Journal of Fluorine Chemistry 130 (2009) 1151–1156
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vacuo. Purification by flash column chromatography eluting with
hexanes/EtOAc (7:3) afforded the desired carbinol 5 as a yellow oil
(34 mg, 72%).
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diisopropylsilyl)bicyclo[4.3.0]nonane 3d
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starting material after a total of 4 days at reflux. The reaction was
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aqueous NaHCO3 solution (10 mL). The aqueous phase was
extracted with Et2O and the combined organic phase washed
with brine, dried (MgSO4) and concentrated in vacuo. The crude
residue was then redissolved in a mixture of MeOH and THF (1:1,
4.4 mL) and cooled to 0 8C before the addition of KHCO3 (74 mg,
0.74 mmol), tetrabutylammonium fluoride (1.0 M solution in THF,
1.11 mL, 1.11 mmol) and hydrogen peroxide (35 wt.%, 0.65 mL,
7.40 mmol). The resulting solution was heated to 65 8C and stirred
for 8 h. The reaction was then cooled to 0 8C and quenched by the
addition of an aqueous solution of Na2S2O3 (10 wt.%, 5 mL). The
aqueous phase was extracted with Et2O, and the combined organic
phase washed with brine, dried (MgSO4) and concentrated in
vacuo. Purification by flash column chromatography eluting with
hexanes/EtOAc (7:3) afforded the desired carbinol 5 as a yellow oil
(41 mg, 61%).
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