Fluorinating cleavage of solid phase linkers for combinatorial synthesis

Article abstract of DOI:10.1002/anie.200802126

(Figure Presented) Multitasking: A new preparative route to fluorine-containing compounds combines the advantages ofsolid-phase synthesis with the incorporation off luorine at the end ofthe synthetic route. A sulfur linker enables simultaneous fluorination of the target structures in the cleavage step. As it is stable under different reaction conditions, the linker has potential in the combinatorial synthesis off luorinated drug structures.

Full text of DOI:10.1002/anie.200802126

Communications
DOI: 10.1002/anie.200802126
Synthetic Methods
Fluorinating Cleavage of Solid Phase Linkers for Combinatorial
Synthesis**
Matthias S. Wiehn, Stephen D. Lindell, and Stefan Brꢀse*
Organofluorine compounds play an increasingly important
role in the modern drug discovery process. While the first
fluorine-containing agent was developed in the late 1950s,[1]
today fluorinated pharmaceuticals and agrochemicals make
up about 20% and 30% of their respective global markets.[2]
In 2006 two fluorinated drugs, the cholesterol-reducer Lipitor
(1) and the asthma agent Advair, were the top-selling
prescription drugs.[3] Another fluorine-containing blockbuster
drug of the last years is the antidepressant Prozac (2).
changed electron density in the molecule. For example,
fluorine-containing substituents drastically lower the reactiv-
ity of aromatic systems in electrophilic substitution reactions,
and nucleophilic substitution on aliphatic carbon atoms
bearing fluorine groups is hardly possible.[7] Hence, it is
advantageous to introduce fluorine atoms into the target
structures at a late stage in the synthesis, if possible in the last
synthetic step.
We present herein a novel strategy for the preparation of
geminal difluoro compounds by using solid-phase synthesis
(SPOS) which combines the advantages of SPOS as a well-
established method in combinatorial chemistry with the
incorporation of fluorine substituents at the end of the
synthesis. For this purpose we have developed a linker system
that enables the release of the target structures from the resin
under simultaneous fluorination.[8]
Kollonitsch and Marburg as well as Katzenellenbogen and
ꢀ
co-workers first reported that C F bonds can be easily
ꢀ
generated starting from the corresponding C S units; an
Fluorinated compounds represent a class of particular
interest as dramatic changes in the physical properties, the
chemical reactivity, and especially the biological activity can
be achieved by the introduction of fluorine-containing sub-
stituents.[4] However, fluorinated compounds occur only very
rarely in nature. A few hundred chlorinated natural products
are known but there are only about a dozen fluorine-
containing natural products.[5] Therefore, interest in synthe-
sizing organofluorine compounds is steadily increasing and
several interesting methods have been developed, particularly
in the recent past, for the introduction of fluorine atoms into
organic molecules.[6]
oxidized sulfur species is formed as the leaving group which is
displaced by fluoride ion.[9] Based on these observations, we
synthesized a dithiane linker on which different aldehydes
and ketones were attached, modified, and finally cleaved
from the solid support to give gem-difluoro compounds.
The precursor 4 of the linker was synthesized starting
from 2-(bromomethyl)acrylic acid (3) in 99% yield over two
steps[10] and subsequently attached to aminomethyl polysty-
rene resin (5, loading 2.06 mmolgꢀ1, 1% DVB = divinylben-
zene) using bromotrispyrrolidinophosphonium hexafluoro-
phosphate (PyBrOP) and diisopropylethylamine (DIPEA;
Scheme 1). The conversion and the resultant loading of resin
6 with the linker molecule were determined by sulfur
elemental analysis. The resin is very stable and can be
stored at room temperature. As basic hydrolysis inevitably
leads to the formation of the disulfide, the two thioester
groups must be cleaved under acidic conditions. The cleavage
The incorporation of fluorine substituents often leads to
difficulties in subsequent synthetic steps as a result of the
[*] M. S. Wiehn, Prof. Dr. S. Brꢀse
Institute of Organic Chemistry
University of Karlsruhe (TH)
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
Fax: (+49)721-608-8581
E-mail: braese@ioc.uka.de
Dr. S. D. Lindell
Bayer CropScience AG
Industriepark Hoechst, G836
65926 Frankfurt am Main (Germany)
Fax: (+49)69-305-17768
E-mail: stephen.lindell@bayercropscience.com
[**] We thank Dr. Sergiy Pazenok and Dr. Wolfgang Giencke for helpful
discussions, and Bayer CropScience AG the Landesgraduiertenfꢁr-
derung Baden-Wꢂrttemberg for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802126.
Scheme 1. Synthesis of the dithiol linker 7 starting from 2-(bromo-
methyl)acrylic acid (3).
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Chemie
reaction proceeded readily in HCl/methanol at 508C to yield
the free dithiol linker 7 quantitatively (Scheme 1) and could
be monitored by gel-phase 13C NMR spectroscopy.[11]
Aromatic aldehydes and ketones 8a–h were attached to
the free dithiol unit furnishing the corresponding dithanes
9a–h under Lewis acidic conditions.[12] For cleavage with
fluorination, the resins were treated with a combination of N-
iodosuccinimide (NIS) as the oxidizing agent and HF/
pyridine (70%) as the fluoride source; the gem-difluoro
compounds 10a–e were obtained in up to 81% yield over
three steps based upon the loading of resin 6 (Scheme 2).
Scheme 3. Amide coupling and subsequent fluorinating cleavage.
Scheme 2. Attachment of various aldehydes and ketones to a solid
support and subsequent cleavage to give gem-difluoro compounds.
When NIS was replaced by N-bromosuccinimide (NBS) or by
1,3-dibromo-5,5-dimethyl-hydantoin (DBH), additional bro-
mination, especially of electron-rich aromatic substrates, was
observed as a side reaction. Notable was the high purity of the
1
Scheme 4. Palladium-catalyzed cross-coupling reactions and subse-
quent cleavage: a) 13, [Pd(PPh3)4], K3PO4, DMF, 1008C, 2 d; b) 15 or
17, Pd(OAc)2, PPh3, Et3N, DMF, 1008C, 2 d; c) 19, [Pd(PPh3)4], CuI,
Et3N, DMF, 808C, 2 d; d) NIS, HF/py, ꢀ78!08C, 3 h (yields over 4
steps).
crude products (> 90%), which was quantified by H NMR
spectroscopy. Besides traces of the corresponding carbonyl
compound arising from hydrolysis, only small amounts of
succinimide could be detected as impurities. The crude
products could be easily purified by column chromatography
or by flash filtration when necessary.
To investigate the scope of the novel linker system,
compounds 9a and 9 f–h were modified in different reactions
on the solid support and then cleaved from the resin under
fluorinating conditions. Resin-bound 4-aminoacetophenone
(9 f) was treated with three different acid chlorides 11a–c to
yield the corresponding amides. As partial double acylation of
the amino group caused by an excess of acid chloride was
observed, the resins were shaken in methanol for 24 h at 608C
and the monoacylated products were obtained exclusively.
The successful course of the on-bead reactions was monitored
qualitatively by gel-phase 13C NMR spectroscopy. The gem-
difluorinated amides 12a–c were obtained in 40–60% yield
after cleavage from the resin (Scheme 3). The crude products
showed a high purity of 85–90%.
coupled successfully with terminal olefins in Heck reactions.
Olefins bearing electron-withdrawing substituents like a
carbonyl or a carboxy group (15a and 15b) proved to be
appropriate substrates. The corresponding gem-difluorinated
compounds 16a and 16b were obtained in yields of up to 21%
over four steps. With the olefin 17 bearing an electron-
donating phenyl substituent, a vicinal difluorination of the
double bond was also observed. Most likely, the electron-rich
double bond is initially iodofluorinated under the cleavage
conditions. In a second step the iodine exchanges quantita-
tively with the fluorine, since no iodofluorinated byproduct
could be detected in the crude product, which was analyzed
by 1H NMR spectroscopy and GC mass spectrometry.
The solid-supported alkynes obtained by a Sonogashira
coupling also underwent an additional iodofluorination
reaction to yield selectively the 1-fluoro-2-iodoolefins 20a
and 20b. These results are consistent with past reports about
the reactivity of double and triple bonds in the presence of
halogen cations and fluoride sources.[13] Generally the crude
products of the cross-coupling reactions showed lower purity
after cleavage than those of the amide formation (about 50–
Different palladium-catalyzed cross-coupling reactions
ꢀ
for the formation of C C bonds were also performed on the
dithiane linker system (Scheme 4). The Suzuki coupling was
demonstrated on resin-bound 4-iodoacetophenone (9g) with
the phenyl boronic acids 13a–c. Fluorinating cleavage
afforded the biphenyl derivatives 14a–c in 19–34% yield
over four steps. The same resin-bound aryl iodide 9g was
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Communications
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60%) because of residual palladium catalyst, but purification
was easily accomplished by using flash filtration.
As dithianes are well established for the umpolung of the
carbonyl C atom, this reaction was also investigated. Such
transformations on the solid support are quite difficult and
only a few examples have been reported.[14] After attachment
of 4-tert-butylbenzaldehyde to the resin, the resulting dithiane
9a was deprotonated with n-butyllithium and alkylated with
butyl bromide (21). The corresponding fluorinated compound
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ꢀ
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Scheme 5. Umpolung on the dithiane linker and HWE reaction fol-
lowed by fluorinating cleavage: a) 9a, nBuLi, THF, ꢀ50!ꢀ208C, 4 h,
then 21, ꢀ508C!RT, 15 h; b) 9h, 23, KHMDS, [18]crown-6, THF,
ꢀ78!408C, 15 h; c) NIS, HF/py, ꢀ78!08C, 3 h.
[9] a) J. Kollonitsch, S. Marburg, L. M. Perkins, J. Org. Chem. 1976,
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[11] P. Grice, A. G. Leach, S. V. Ley, A. Massi, D. M. Mynett, J.
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double bonds on the linker system, solid-supported 4-
acetylacetophenone (9h) underwent a Horner–Wadsworth–
Emmons (HWE) reaction with triethylphosphonoacetate
(23) in the presence of KHMDS and [18]crown-6. The
double bond is stable under the cleavage conditions because
of the electron-withdrawing carboxy substituent. The gem-
difluoro acrylate 24 was isolated in 21% yield over four steps.
In summary, a novel linker system for solid-phase syn-
thesis was developed that enables for the first time the
introduction of fluorine substituents into target structures
during the cleavage step. This dithiane linker proved to be
compatible with different important organic transformations
and hence has great potential for the combinatorial synthesis
of fluorinated drug structures. We are currently working on
the extension of our strategy to other linker systems.
[14] a) V. Bertini, F. Lucchesini, M. Porci, A. De Munno, J. Org.
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Bromfield, N. Kann, Top. Curr. Chem. 2007, 278, 89 – 134. For
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Received: May 6, 2008
Revised: June 27, 2008
Published online: September 15, 2008
Keywords: alkyl fluorides · combinatorial chemistry ·
.
dithiane linkers · fluorination · solid-phase synthesis
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