Electrophilic fluorination using a hypervalent iodine reagent derived from fluoride

Article abstract of DOI:10.1039/c3cc44792h

The air and moisture stable fluoroiodane 8, readily prepared on a 6 g scale by nucleophilic fluorination of the hydroxyiodane 7 with TREAT-HF, has been used as an electrophilic fluorinating reagent for the first time to monofluorinate 1,3-ketoesters and d

Full text of DOI:10.1039/c3cc44792h

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: G. C. Geary, E. G. Hope, K. Singh and A.
M. Stuart, Chem. Commun., 2013, DOI: 10.1039/C3CC44792H.
This is an Accepted Manuscript, which has been through the RSC Publishing peer
review process and has been accepted for publication.
Accepted Manuscripts are published online shortly after acceptance, which is prior
Chemical Communications
www.rsc.org/chemcomm
Volume 46 | Number 32 | 28 August 2010 | Pages 5813–5976
to technical editing, formatting and proof reading. This free service from RSC
Publishing allows authors to make their results available to the community, in
citable form, before publication of the edited article. This Accepted Manuscript will
be replaced by the edited and formatted Advance Article as soon as this is available.
To cite this manuscript please use its permanent Digital Object Identifier (DOI®),
which is identical for all formats of publication.
More information about Accepted Manuscripts can be found in the
Information for Authors.
Please note that technical editing may introduce minor changes to the text and/or
graphics contained in the manuscript submitted by the author(s) which may alter
content, and that the standard Terms & Conditions and the ethical guidelines
that apply to the journal are still applicable. In no event shall the RSC be held
responsible for any errors or omissions in these Accepted Manuscript manuscripts or
any consequences arising from the use of any information contained in them.
ISSN 1359-7345
COMMUNICATION
FEATURE ARTICLE
J. Fraser Stoddart et al.
Directed self-assembly of a
ring-in-ring complex
Wenbin Lin et al.
Hybrid nanomaterials for biomedical
applications
1359-7345(2010)46:32;1-H
www.rsc.org/chemcomm
Registered Charity Number 207890

ChemComm
Page 1 of 4ChemComm
Dynamic Article Links ►
View Article Online
DOI: 10.1039/C3CC44792H
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
COMMUNICATION
Electrophilic Fluorination Using A Hypervalent Iodine Reagent Derived
From Fluoride†
Gemma C. Geary, Eric G. Hope, Kuldip Singh and Alison M. Stuart*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
The air and moisture stable fluoroiodane 8, readily prepared
on
a 6 g scale by nucleophilic fluorination of the
hydroxyiodane 7 with TREAT-HF, has been used as an
electrophilic fluorinating reagent for the first time to
10 monofluorinate 1,3-ketoesters and difluorinate 1,3-diketones
in good isolated yields.
In late 2011, Ritter reported the first electrophilic fluorination
using the fluoride anion in a transfer fluorination between two
palladium species.1 An alternative, nonꢀmetal based strategy
15 could be envisaged using cyclic hypervalent iodine(III)
compounds which have been shown to be mild, nonꢀtoxic and
selective reagents for halogenation.2ꢀ4 These reagents are
normally prepared by oxidation of iodine(I) species with
electrophilic reagents such as tertꢀbutyl hypochlorite (1 → 3) and
20 Nꢀbromosuccinimide (1 → 2),2 but Togni cleverly designed the
synthesis of the electrophilic trifluoromethylated hypervalent
iodine reagent 5 using a formal umpolung of the trifluoromethyl
group (Scheme 1).3a Ruppert’s reagent was used as the
nucleophilic source of the trifluoromethyl anion in order to
50
Scheme 1 Syntheses of hypervalent iodine reagents
Alternative reagents such as (difluoroiodo)arenes have been
prepared from aqueous HF, but they are extremely moisture
sensitive and are commonly used as a freshly prepared solution,
without isolation, or they can be generated in situ.9 Inspired by
25 displace
the
acetate
and
form
an
electrophilic
55 Togni’s seminal work on electrophilic trifluoromethylation,3 we
were interested in developing a new class of stable fluorinating
reagents based on the cyclic hypervalent iodine(III) skeleton, but
generated from cheap sources of fluoride. Here, we will report
three different methods for the preparation of an air and moisture
60 stable fluorinated hypervalent iodine reagent 8 and preliminary
results on its’ fluorination of a series of 1,3ꢀdicarbonyl substrates.
trifluoromethylating reagent. Togni’s reagent now has
widespread applications including the electrophilic trifluoroꢀ
methylation of βꢀketoesters, αꢀnitroesters, thiols, phosphines and
heteroaromatic compounds.3 Using an analogous nucleophilic
30 route, Lu and Shen reported in 2013 the new electrophilic
hypervalent iodine reagent 6 for the trifluoromethylthiolation of
β
ꢀketoesters, alkynes, aryl and vinyl boronic acids.4
Our research group is interested in designing new methods for
introducing fluorine into organic molecules5 because of the
35 importance of incorporating fluorine into drug candidate
molecules.6 Since Banks first reported SelectFluor in 1992,7 the
fluoraza reagents have become increasingly popular electrophilic
fluorinating reagents because they are commerciallyꢀavailable,
shelfꢀstable powders that can be used to fluorinate a wide variety
40 of substrates.8 The main disadvantage of these electrophilic
fluorinating reagents, however, is that they are very expensive
because they are normally made from elemental fluorine.
____________________________________________________
Department of Chemistry, University of Leicester, Leicester, LE1 7RH,
45 UK. Fax: +44 (0)116 2523789; Tel: +44 (0)116 2522136; E-mail:
Alison.Stuart@le.ac.uk
† Electronic Supplementary Information (ESI) available: Experimental
procedures, NMR spectra and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b000000x/
Scheme 2 Synthesis of the fluoroiodane 8 using TREATꢀHF
[journal], [year], [vol], 00–00 | 1
This journal is © The Royal Society of Chemistry [year]

ChemComm
Page 2 of 4
View Article Online
DOI: 10.1039/C3CC44792H
Table 1 Optimisation of fluorination of ethylꢀ3ꢀoxoꢀ3ꢀphenylpropanoate
Entry Concenta Temp TREATꢀHF Yield of 12b,c Yield of 13b,c
[M]
0.12
0.12
0.12
0.12
0.12
0.12
0.12
0.12
0.24
0.24
0.24
(oC)
60
60
60
60
60
60
40
80
40
40
60
(no. equiv.)
(%)
8
30
48
65
54
0
54
(%)
0
4
7
19
28
0
4
36
1
2
3
0
0.9
1.8
2.7
2.7
2.7
2.7
2.7
2.7
2.7
2.7
4
5d
6e
7
8
49
89 (63)
83
Scheme 3 Syntheses of the fluoroiodane 8 using TBAF
9
6
11
25 (13)
10d
11
The fluoroiodane 8 was first prepared in 2012 by the electrophilic
fluorination of 2ꢀ(2ꢀiodophenyl)propanꢀ2ꢀol 1 with 1.3 equivꢀ
alents of Selectfluor in acetonitrile.10 Whilst this manuscript was
in the final stages of preparation, Togni reported a nucleophilic
route to the fluoroiodane 8 by halogen exchange of the
67(49)
a
b
Concentration of substrate.
Determined by 1H and 19F NMR
c
d
spectroscopy. Isolated yield in parenthesis. Reaction time was 48 h.
5
e Control reaction without fluoroiodane 8.
chloroiodane 3 with 1.5 equivalents of sprayꢀdried potassium 50 form the fluoroiodane 8, the addition of TREAT.HF was
fluoride in acetonitrile,11 but both the reaction and the work up
were carried out under argon. We have developed an alternative
10 three step synthesis that also uses a nucleophilic fluorination
(Scheme 2). The bromoiodane 2, synthesised using Nꢀbromoꢀ
investigated. With just 0.2 equivalents of TREATꢀHF (Scheme 3)
the fluoroiodane 8 was isolated in a 63% yield on a 1.0 g scale.
The reaction between the tosyliodane 10 and TBAF in the
presence of TREATꢀHF was also successful giving a 100%
succinimide, was reacted with potassium hydroxide at room 55 conversion to the fluoroiodane 8 and a 46 % yield after
temperature in order to produce the hydroxyiodane 7 under mild
reaction conditions. In the key step the hydroxyiodane 7 was
15 reacted with 1.2 equivalents of triethylamine tris(hydrogen
fluoride) (TREATꢀHF) at room temperature to give the
recrystallization from hexane. Neither the trifluoroacetoxyiodane
9 nor the tosyliodane 10 react with TREATꢀHF (1.2 equivalents)
at room temperature and in both cases unreacted starting material
was recovered at the end of the reaction showing that it is the
fluoroiodane 8 in a 94 % isolated yield after recrystallization 60 fluoride ion from the TBAF that is undergoing the nucleophilic
from hexane. This is an excellent method for the preparation of 8
because there are no timeꢀconsuming purifications by column
20 chromatography, each of the steps have been performed routinely
on a 6ꢀ10 g scale and the reactions do not require either dry or
inert conditions.
Since one of the long term aims of this project is to prepare a
new fluorinating agent that is suitable for the production of 18Fꢀ
25 labelled radiotracers for Positron Emission Tomography (PET)
imaging, we were also interested in developing a nucleophilic
substitution to form the fluoroiodane 8.
The reactivity of the fluoroiodane 8 as an electrophilic
fluorinating reagent was first investigated using ethyl 3ꢀoxoꢀ3ꢀ
phenylpropanoate 11 as the model substrate (Table 1). When 2
65 equivalents of the fluoroiodane 8 was reacted with ethyl 3ꢀoxoꢀ3ꢀ
o
phenylpropanoate 11 at 60 C for 24 hours (entry 1), only an 8%
conversion to the monofluorinated product 12 was obtained. The
addition of TREATꢀHF is essential for the fluorination and on
increasing the amount from 0.9 to 2.7 equivalents the conversion
route to the fluoroiodane 8 using sources of fluoride, such as 70 to both the monofluorinated and difluorinated products increased
potassium fluoride or tetrabutylammonium fluoride (TBAF), that
can be applied to PET chemistry. Our synthetic strategy was to
30 introduce a good leaving group onto the hypervalent iodine
reagent in order to facilitate nucleophilic displacement by
to 65% and 19% respectively (entry 4). On extending the reaction
time to 48 hours in entry 5, more of the difluorinated product 13
was produced. However, the fluorination of ethyl 3ꢀoxoꢀ3ꢀ
phenylpropanoate 11 with 2.7 equivalents of TREATꢀHF does
fluoride (Scheme 3). To this end, the new hypervalent iodine 75 not proceed in the absence of the fluoroiodane 8 (entry 6).
reagents, trifluoroacetoxyiodane 9 and tosyliodane 10, were
synthesised by the reaction of 2ꢀ(2ꢀiodophenyl)propanꢀ2ꢀol 1
35 with either PhI(OCOCF3)2 or PhI(OH)(OTs) following Koser’s
procedure12 and the solidꢀstate structures of both compounds are
presented in the supplementary information. When the
trifluoroacetoxyiodane 9 was reacted with 1.2 equivalents of
TBAF in dichloromethane, a mixture of the fluoroiodane 8 and
40 the hydroxyiodane 7 was obtained in a 3:1 ratio. Since neither 9
nor 8 are hydrolysed in the presence of water, the formation of
Interestingly, the temperature of the reaction is an important
factor with a more selective reaction towards the monofluorinated
product 12 observed at 40 C (entry 7), whilst the amount of the
o
competing difluorinated product 13 increased at 80 oC (entry 8).
The concentration of the reaction mixture is also an important
factor in these fluorinations. When the concentration of the
substrate was doubled from 0.12 M to 0.24 M, there was a
dramatic improvement in the fluorination performed at 40 oC and
the conversion to the monofluorinated product 12 increased from
80
the hydroxyiodane 7 is believed to be due to the presence of 85 54% (entry 7) to 89% (entry 9). The reaction was purified by
tetrabutylammonium hydroxide in the TBAF. Therefore, since
tetrabutylammonium hydroxide reacts with aqueous HF to give
45 TBAF13 and the hydroxyiodane 7 reacts with TREATꢀHF to
column chromatography and ethyl 2ꢀfluoroꢀ3ꢀoxoꢀ3ꢀphenylꢀ
propanoate 12 was isolated in 63% yield. When either the
reaction time was extended to 48 hours (entry 10) or the reaction
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

ChemComm
Page 3 of 4ChemComm
Dynamic Article Links ►
View Article Online
DOI: 10.1039/C3CC44792H
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
COMMUNICATION
product in 55% isolated yield. On the other hand, the fluorination
of ethyl 1ꢀindanoneꢀ2ꢀcarboxylate was much more efficient and
35 100% conversion to ethyl 1ꢀindanoneꢀ2ꢀfluoroꢀ2ꢀcarboxylate was
obtained in 48 hours (55% yield) because of its higher enol
content (17% in CDCl3 by 1H NMR spectroscopy).
In summary, we have prepared fluoroiodane 8 by three
different methods using either TREATꢀHF or TBAF as the source
40 of the fluoride ion. Preliminary reactivity studies have revealed
that it can be used to fluorinate 1,3ꢀdiketones and 1,3ꢀketoesters
in good isolated yields and we are currently investigating further
applications of 8 as an electrophilic fluorinating reagent with a
range of different organic substrates.
Table 2 Fluorination of 1,3ꢀdicarbonyl compoundsa
Entry
Substrate
Temp Time Monofluoro
Difluoro
(oC) (h) Productb,c (%) Productb,c(%)
1
40
40
24
24
89 (63)
95 (67)
6
5
2
3
40
60
24
24
30
11
0
55
76
100 (71)
60d 24
60d 24
4
0
100 (45)
ꢀ
45 Notes and references
1
E. Lee, A. S. Kamlet, D. C. Powers, C. N. Neumann,. G. B.
Boursalian, T. Furuya, D. C. Choi, J. M. Hooker, T. Ritter, Science,
2011, 334, 639.
5e
60 168
62 (55)
2
3
D. C. Braddock, G. Cansell, S. A. Hermitage, A. J. P. White, Chem.
Commun., 2006, 1442.
50
55
60
65
70
75
80
85
90
(a) P. Eisenberger, S. Gischig, A. Togni, Chem. Eur. J., 2006, 12,
2579; (b) I. Kieltsch, P. Eisenberger, A. Togni, Angew. Chem. Int.
Ed., 2007, 46, 754; (c) P. Eisenberger, I. Kieltsch, N. Armanino, A.
Togni, Chem. Commun., 2008, 1575; (d) M. S. Wiehn, E. V.
Vinogradova, A. Togni, J. Fluorine Chem., 2010, 131, 951; (e) K.
Niedermann, N. Frueh, E. Vinogradova, M. S. Wiehn, A. Moreno, A.
Togni, Angew. Chem. Int. Ed., 2011, 50, 1059; (f) N. Santschi, A.
Togni, J. Org. Chem., 2011, 76, 4189; (g) K. Niedermann, N. Frueh,
R. Senn, B. Czarniecki, R. Verel, A. Togni, Angew. Chem. Int. Ed.,
2012, 51, 6511.
X. Shao, X. Wang, T. Yang, L. Lu, Q. Shen, Angew. Chem. Int. Ed.,
2013, 52, 3457.
(a) M. Fornalczyk, K. Singh, A. M. Stuart, Chem. Commun., 2012,
48, 3500; (b) M. Fornalczyk, K. Singh, A. M. Stuart, Org. Biomol.
Chem., 2012, 10, 3332.
6e
60
48
100 (55)
ꢀ
a Reaction conditions: substrate (0.72 mmol), fluoroiodane 8 (1.44 mmol),
Et3N.3HF (1.94 mmol) and dry CH2Cl2 (1.2 mL). b Determined by 1H and
19F NMR spectroscopy. c Isolated yield in parenthesis. d Fluoroiodane 8 (3
equiv). e No solvent.
5
was performed at 60 oC (entry 11), the amount of ethyl 2,2ꢀ
difluoroꢀ3ꢀoxoꢀ3ꢀphenylpropanoate 13 increased.
The scope of the reaction was established with a series of 1,3ꢀ
dicarbonyl compounds and the results are presented in Table 2.
10 The relative reactivity of the different substrates could be directly
correlated with their enol content as observed previously for
electrophilic fluorinations.7c,14 When ethyl 3ꢀ(4ꢀmethoxyphenyl)ꢀ
3ꢀoxoꢀpropanoate was reacted with the fluoroiodane 8 under the
optimum reaction conditions from Table 1 (entry 9: 40 C, 24
15 hours), the monofluorinated product was isolated in 67% yield
(entry 2). Under the same reaction conditions the more reactive
substrate, 1,3ꢀdiphenylꢀ1,3ꢀpropanedione (entry 3), gave
mixture of the monofluorinated (30%) and difluorinated (55%)
products. In order to convert the 1,3ꢀdiketone into the difluorinꢀ
4
5
6
7
(a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc.
Rev., 2008, 37, 320; (b) D. O’Hagan, J. Fluorine Chem., 2010, 131,
1071.
o
(a) R. E. Banks, S. N. MohialdinꢀKhaffaf, G. S. Lal, I. Sharif, R. G.
Syvret, J. Chem. Soc., Chem. Commun., 1992, 595; (b) G. S. Lal, J.
Org. Chem., 1993, 58, 2791; (c) R. E. Banks, N. J. Lawrence, A. L.
Popplewell, J. Chem. Soc., Chem. Commun., 1994, 343.
(a) G. S. Lal, G. P. Pez, R. G. Syvret, Chem. Rev., 1996, 96, 1737;
(b) S. D. Taylor, C. C. Kotoris, G. Hum, Tetrahedron, 1999, 55,
12431; (c) R. P. Singh, J. M. Shreeve, Acc. Chem. Res., 2004, 37, 31;
(d) P. T. Nyffeler, S. G. Durón, M. D. Burkart, S. P. Vincent, C.ꢀH.
Wong, Angew. Chem. Int. Ed., 2005, 44, 192.
(a) S. Hara, M. Sekiguchi, A. Ohmori, T. Fukuhara, N. Yoneda,
Chem. Commun., 1996, 1899; (b) M. Sawaguchi, S. Ayuba, S. Hara,
Synthesis, 2002, 1802; (c) M. A. Arrica, T. Wirth, Eur. J. Org.
Chem., 2005, 395; (d) T. Kitamura, S. Kuriki, M. H. Morshed, Y.
Hori, Org. Lett., 2011, 13, 2392.
a
8
9
o
20 ated product, the reaction was repeated at 60 C for 24 hours but
there was still a small amount of the monofluorinated product
present (11%) at the end of the reaction. Finally, the reaction was
repeated with 3 equivalents of the fluoroiodane 8 at 60 oC
resulting in a 100% conversion to 1,3ꢀdiphenylꢀ2,2ꢀdifluoroꢀ1,3ꢀ
25 propanedione which was isolated in 71% yield. The other 1,3ꢀ
diketone, 1ꢀphenylꢀ1,3ꢀbutanedione (entry 4), was also reacted
10 C. Y. Legault, J. Prévost, Acta Cryst., 2012, E68, o1238.
11 V. Matoušek, E. Pietrasiak, R. Schwenk, A. Togni, J. Org. Chem.,
2013, 78, 6763.
12 G. A. Rabah, G. F. Koser, Tetrahedron Lett., 1996, 37, 6453.
13 I. Kuwajima, E. Nakamura, K. Hashimoto, Org. Synth., 1990, Coll.
Vol. 7, 512.
o
with 3 equivalents of the fluoroiodane 8 at 60 C for 24 hours
producing 1ꢀphenylꢀ2,2ꢀdifluoroꢀ1,3ꢀbutanedione in 45% yield.
Due to its extremely low enol content (100% ketone in CDCl3 by
30 1H NMR spectroscopy), the fluorination of the monosubstituted
1,3ꢀketoester, ethyl 2ꢀmethylꢀ3ꢀoxoꢀ3ꢀphenylpropanoate (entry 5)
took 7 days at 60 oC without solvent to give the fluorinated
14 L. Hintermann, A. Togni, Angew. Chem. Int. Ed., 2000, 39, 4359.
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 3

ChemComm
Page 4 of 4
View Article Online
Electrophilic Fluorination Using A Hypervalent Iodine Reagent Derived From Fluoride
DOI: 10.1039/C3CC44792H
Gemma C. Geary, Eric G. Hope, Kuldip Singh and Alison M. Stuart*
Department of Chemistry, University of Leicester, Leicester, LE1 7RH, UK.
Email: Alison.Stuart@le.ac.uk
Table of Contents Entry
The air and moisture stable fluoroiodane 8 has been used to monofluorinate 1,3-ketoesters and
difluorinate 1,3-diketones in good isolated yields.
1