Manganese-catalyzed oxidative benzylic C-H fluorination by fluoride ions

Article abstract of DOI:10.1002/anie.201301097

An efficient protocol for the selective fluorination of benzylic C-H bonds is described. The process is catalyzed by manganese salen complexes and uses nucleophilic fluorine sources, such as triethylamine trihydrofluoride and KF. Reaction rates are sufficiently high (30min) to allow adoption for the incorporation of ¹⁸F fluoride sources for PET imaging applications. Copyright

Full text of DOI:10.1002/anie.201301097

Angewandte
Chemie
DOI: 10.1002/anie.201301097
Fluorinated Compounds
Manganese-Catalyzed Oxidative Benzylic C–H Fluorination by
Fluoride Ions**
Wei Liu and John T. Groves*
[
11]
Fluorinated organic compounds are extremely important as
methylquinoline derivatives by using silver fluoride. How-
[
1]
pharmaceuticals, fine chemicals, and materials. In addition,
ever, this approach requires a directing group on the arene
ring.
1
8
18
radioactive F-labeled imaging agents, such as 2-[ F]fluoro-
-deoxyglucose, are widely used for positron emission tomog-
2
Given the potential importance of benzylic fluorides and
the paucity of current preparative methods, a general, tran-
sition-metal-catalyzed direct C–H fluorination at benzylic
positions with a nucleophilic fluorine source would be highly
desirable. Such a method could be of great value for both
radiolabeling applications of biomolecules and structure–
activity relationship (SAR) studies of drug candidates.
Recently, we reported an efficient process for the
conversion of unactivated aliphatic CÀH bonds into CÀF
[
2]
raphy (PET) in oncology and imaging the brain. The
transformation of CÀH bonds into CÀF bonds within organic
molecules can have profound effects on biological activity,
[
3]
phase 1 metabolism, and hydrophobicity. However, despite
the increasing importance of fluorine-containing molecules
and their applications, the development of synthetic methods
to form CÀF bonds selectively, under mild conditions is still
[4]
challenging. Conventional fluorination reactions developed
in the twentieth century are generally limited to simple
molecules and involve the use of difficult-to-handle reagents,
bonds that employed a manganese porphyrin catalyst (1,
Scheme 1) with silver fluoride/tetrabutylammonium fluoride
trihydrate (TBAF·3H O) as the fluorine source.
[
5]
[6]
[12]
such as elemental fluorine and various metal fluorides.
The
2
Although chemists have developed a variety of new methods
reaction is believed to proceed through a catalytic cycle
for the fluorination of organic molecules over the past five
3
years, general methodologies for forming C(sp )ÀF bonds are
[7]
still limited, in contrast to the comparatively well-developed
2
[8]
methods for aryl C(sp )ÀF bond formation. In particular,
there are relatively few methods available that can selectively
3
3
convert unactivated C(sp )ÀH bonds to C(sp )ÀF bonds by
direct C–H activation, particularly in chemically inaccessible
[
9]
carbocyclic rings.
3
In the context of C(sp )–F-containing molecules, the
benzylic fluoride fragment could be an effective substitute
for benzylic C–H groups in many bioactive molecules.
Traditionally, benzylic fluorides can be prepared by halogen
exchange, electrochemical methods, and the dehydroxyfluori-
nation of benzylic alcohols with diethylaminosulfur trifluor-
ide (DAST) and bis(2-methoxy-ethyl)aminosulfur trifluoride
Scheme 1. Manganese C–H fluorination catalysts used.
involving a novel trans-difluoro manganese(IV) species,
which efficiently transfers a fluorine atom to short-lived
[
10]
(
Deoxo-Fluor). However, these methods require prefunc-
V
tionalization at the benzylic positions and often suffer from
elimination by-products. Further, the fluorine source is often
alkyl radicals generated by a reactive oxoMn intermedi-
[
13]
ate. An intriguing and particularly useful aspect of this C–H
1
8
incompatible with the preparation of F-labeled compounds.
Recently, Sanford and co-workers have reported a palladium-
catalyzed direct benzylic C–H fluorination on a variety of 8-
fluorination was a marked preference for methylene CÀH
bonds in carbocyclic rings, apparently owing to steric and
stereoelectronic effects. When we applied this fluorination
protocol to substrates containing benzylic CÀH bonds, such
as 4-ethylbiphenyl (3), we observed the formation of the
benzylic fluorinated product 3a in 44% yield as expected.
However, analysis of the reaction mixture revealed that
nearly equal amounts of oxygenated compounds (benzylic
alcohol and ketone) were also formed (Table 1, entry 1).
Since the reactions were conducted under anaerobic condi-
tions, the oxygen in these by-products must derive from the
oxidant, iodosylbenzene (PhIO), or water. Our rationale for
the formation of the oxygenation products is that the
relatively low ionization potential of the incipient benzylic
radical leads to a rapid carbon radical rebound to the
[*] W. Liu, Prof. J. T. Groves
Department of Chemistry, Princeton University
Princeton, NJ 08544 (USA)
E-mail: jtgroves@princeton.edu
[
**] This research was supported by the Center for Catalytic Hydro-
carbon Functionalization, an Energy Frontier Research Center, U.S.
Department of Energy, Office of Science, Basic Energy Sciences,
under award no. DE SC0001298. Fluorination of biomolecules was
supported by the US National Science Foundation (CHE-1148597).
We also thank Lotus Separations LLC and Prof. A. Doyle for chiral
analyses and Prof. D. Fiedler for flash column chromatography.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301097.
IV
[14]
Mn –OH intermediate.
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Table 1: Effects of catalysts and fluorine sources on the reactions.
[
a]
Entry Catalyst
F source
Conv. Yield -F/-O
[
a]
[b]
(
mol%) (equiv)
[%]
[%]
[
[
c]
c]
1
2
3
4
5
1 (10)
2 (10)
2 (10)
2 (20)
2 (20)
TBAF·3H O (0.2) AgF (3) 94
44
40
37
59
60
1:1
5:1
12:1
6:1
2
TBAF·3H O (0.2) AgF (3) 50
2
TREAT·HF (1.5)
TREAT·HF (1.5)
TREAT·HF (0.5) AgF (3)
42
75
81
[
d]
[
c]
5:1
[
a] The ratio of fluorinated to oxygenated compounds was determined by
1
9
GC/MS. [b] Determined by F NMR spectroscopy using fluorobenzene
as an internal standard. [c] Reactions were carried out under exclusion of
light. [d] Yield of isolated product based on starting material.
Accordingly, we sought a catalyst system that might
display complementary selectivity to that of the manganese
porphyrin catalysts and mediate benzylic C–H fluorinations.
Upon screening a number of other ligand systems, we found
that a manganese–salen complex (2; Scheme 1), originally
Scheme 2. Substrate scope of the benzylic fluorination. [a] Method A:
substrate (0.8 mmol), PhIO (6–9 equiv), TREAT·HF (1.2 mmol),
CH CN (0.5 mL), 508C, 6–9 h. Method B: substrate (0.8 mmol), PhIO
[15]
3
developed by Jacobsen and co-workers for oxygen transfer,
(
6–9 equiv), TREAT·HF (0.4 mmol), AgF (2.4 mmol), CH CN (0.5 mL),
3
did favor the efficient formation of benzylic fluorides while
effectively suppressing the oxygenation products observed
with 1, albeit in a relatively low conversion (Table 1, entry 2).
After further screening of reaction conditions, we discovered
that triethylamine trihydrofluoride (TREAT·HF) is a supe-
rior fluorine source for this reaction compared to the
5
08C, 6–9 h. [b] Yields of isolated products are indicated below each
product, unless otherwise noted. [c] Yields for volatile compounds
were determined by F NMR spectroscopy.
1
9
[16]
compounds. Several biologically active molecules were sub-
jected to this Mn(salen) fluorination procedure. In all cases,
highly selective benzylic fluorinations were observed
(Scheme 3). As examples, a nonsteroidal anti-inflammatory
drug (ibuprofen methyl ester), a vitamin E analogue (d-
tocopherol acetate), a commercial perfume component
(celestolide) and a non-natural amino acid derivative (homo-
phenylalanine), were each selectively fluorinated at a single
position with good efficiency. The fluorinated ibuprofen
derivative has also been prepared previously by a two-step
combination of TBAF·3H O and AgF in terms of the
2
selectivity for fluorination over oxygenation (Table 1,
entry 3). Upon optimizing the catalyst load, we found that
in the presence of 20 mol% 2, fluorination of 3 afforded the
benzylic fluoride 3a in 59% yield (Table 1, entry 4, Meth-
od A). The combination of TREAT·HF and AgF also served
as a good fluorine source, although slightly diminished
selectivity for fluorination was observed in this case
(
Table 1, entry 5, Method B). Control reactions in the absence
[17]
of the Mn(salen) catalyst showed none of the fluorinated
product. No aromatic fluorination was observed in any of the
cases examined. Approximately 5% of the gem-difluoride
product was observed in the crude reaction mixture for 3.
With the optimized reaction conditions in hand, we
investigated the scope of this fluorination protocol
enzymatic hydroxylation–chemical fluorination protocol.
1
8
For potential application of this C–H fluorination to
F
PET imaging it would be desirable to replace TREAT·HF or
(
Scheme 2). The method has a broad scope and exhibits
high functional-group tolerance. Substrates containing amide,
ether, ester, carbonyl, halide, imide, and aryl groups were
mono-fluorinated efficiently at the benzylic sites. For com-
pounds that contain electron-withdrawing groups, AgF was
found to be advantageous (Method B). The fact that a variety
of halogens was tolerated is of interest, because this strategy
could provide sites for further modification of the fluorinated
motif. Moreover, a wide array of ring systems, most of which
are important scaffolds in biologically active molecules, such
as tetrahydronaphtahlene, indan, tetrahydroquinoline, and
dibenzocycloheptene were all successfully fluorinated.
Encouraged by the generality of the reaction, we next
turned our attention to the late-stage fluorination of drug-like
Scheme 3. Results of benzylic fluorinations of bioactive molecules.
2
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[
2d,10f,18]
AgF with potassium fluoride.
Furthermore, short
(4.6 Æ 1.0) was observed by Katsuki and co-workers for
[20]
reaction times are required because of the short half-life of
a Mn(salen)-catalyzed C–H hydroxylation reaction, thus
1
8
V
F (110 min). We have found conditions that meet these two
important criteria. Treating ibuprofen methyl ester with 2
20 mol%) as the catalyst, potassium fluoride as the sole
fluorine source, [18]-crown-6 as the phase transfer catalyst, as
well as silver triflate, afforded the corresponding benzylic
fluoride analogue in 20% yield within 30 min (Scheme 4).
Further development along these lines and the application of
suggesting a common {Mn (O)(salen)} intermediate and
a similar transition state for the CÀH bond cleavage. Analysis
of compounds 8 and 18 by HPLC on a chiral stationary phase
(Figures S2 and S3 in the Supporting Information) showed
that readily detectable enantioselectivities were achieved
(11% and 20% ee, respectively). Compound 18 could be
obtained in 40% ee at À408C in approximately 5% yield. The
relatively low enantioselectivities observed are probably due
to a very early transition state for the fluorine transfer step
and a linear Mn–F–C geometry (top-on approach) as
indicated by DFT calculations on a related manganese
(
[
19]
flow techniques are under way.
[
12]
porphyrin system. C–H hydroxylations mediated by chiral
[
20]
Mn(salen) complexes also show modest ee values.
By
contrast, the high enantioselectivities observed for olefin
epoxidation by manganese salen catalysts have been attrib-
uted to a side-on approach of the substrate p bond to the
manganyl group (Mn=O) of the catalyst, thus increasing the
Scheme 4. Fluorination of ibuprofen methyl ester using KF.
steric contacts during the oxygen atom transfer from
V
[21]
Mn =O. Despite the modest enantiomeric ratios for C–H
A
likely mechanism for this benzylic fluorination
fluorination, the observation that the asymmetric Mn catalyst
can afford the observed degree of stereoinduction provides
strong support for a manganese-bound fluorine source in the
fluorine transfer step.
In conclusion, we have presented here a general Mn-
catalyzed method for the formation of benzylic fluorides
directly from CÀH bonds. In contrast to previous efforts in
(
Scheme 5) is analogous to the Mn–porphyrin case we
[12]
III
recently described.
The starting [Mn (salen)F] or
III
À
[
[
Mn (salen)F ] catalyst, formed in situ, is oxidized to
2
V
Mn (O)(salen)F], which then abstracts a hydrogen atom
from the substrate, forming the benzyl radical and a manga-
nese(IV) species. In the fluorine transfer step, the radical
reacts with the [Mn (salen)F ] complex, thereby affording
IV
this area, the reaction does not require a directing group and
uses simple and easily handled nucleophilic fluoride reagents.
The success of this direct C–H fluorination reaction suggests
a general strategy for late-stage drug diversification and
building block construction. Ongoing efforts in our laboratory
seek to probe the mechanism of the current reaction and to
evaluate the potential of this transformation for PET imaging
applications.
2
the fluorinated products. This step also regenerates the resting
III
Mn catalyst. While further work is required to elucidate the
mechanistic aspects of this reaction more fully, several
preliminary observations warrant comment. The ESI mass
spectrum of the starting catalyst/fluoride mixture showed
a large peak at m/z 637.5 (Figure S1 in the Supporting
III
À
Information), which is the mass of the [Mn (salen)F ]
2
catalyst. A significant kinetic isotope effect (5.6 Æ 0.6) was
observed for 1:1 mixture of ethylbenzene and
D ]ethylbenzene as the substrate. A similar KIE value
a
[
1
0
Experimental Section
Representative procedure for the synthesis of fluorinated products:
An oven-dried, 5 mL Schlenk flask equipped with a stir bar was
placed under an atmosphere of N . Mn(salen)Cl (100 mg, 20 mol%),
2
substrate (0.8 mmol), and TREAT·HF (0.2 mL, 1.2 mmol, 1.5 equiv)
were then added, followed by degassed CH CN (0.5 mL). The
3
reaction mixture was then heated to 508C. Iodosylbenzene was
added slowly to the reaction mixture in solid form under a stream of
N over a period of 6–9 h. Significant decreases in yield were obtained
2
if the iodosylbenzene was added rapidly. After the reaction was
complete, the solution was allowed to cool to 258C and diluted with
hexanes (2 mL). Products were separated from the reaction residue
by column chromatography.
Received: February 6, 2013
Revised: March 13, 2013
Published online: && &&, &&&&
Keywords: C–H fluorination · manganese · porphyrins ·
.
Scheme 5. Proposed catalytic cycle for benzylic C–H fluorination.
positron emission tomography · synthetic methods
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Communications
Fluorinated Compounds
W. Liu, J. T. Groves*
An efficient protocol for the selective
fluorination of benzylic CÀH bonds is
described. The process is catalyzed by
manganese salen complexes and uses
nucleophilic fluorine sources, such as
triethylamine trihydrofluoride and KF.
Reaction rates are sufficiently high
&&&& — &&&&
Manganese-Catalyzed Oxidative Benzylic
C–H Fluorination by Fluoride Ions
(
30 min) to allow adoption for the incor-
1
8
poration of F fluoride sources for PET
imaging applications.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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These are not the final page numbers!