Palladium-Catalyzed Iodofluorination of Alkenes Using Fluoro-Iodoxole Reagent

Article abstract of DOI:10.1021/acscatal.5b02022

The application of an air- and moisture-stable fluoroiodane reagent was investigated in the palladium-catalyzed iodofluorination reaction of alkenes. Both the iodo and fluoro substituents arise from the fluoroiodane reagent. In the case of certain palladi

Full text of DOI:10.1021/acscatal.5b02022

Research Article
pubs.acs.org/acscatalysis
Palladium-Catalyzed Iodofluorination of Alkenes Using Fluoro-
Iodoxole Reagent
Nadia O. Ilchenko, Miguel A. Cortes, and Kalman J. Szabo*
́
́
́
́
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: The application of an air- and moisture-stable
fluoroiodane reagent was investigated in the palladium-catalyzed
iodofluorination reaction of alkenes. Both the iodo and fluoro
substituents arise from the fluoroiodane reagent. In the case of certain
palladium catalysts, the alkene substrates undergo allylic rearrangement
prior to the iodofluorination process. The reaction is faster for electron-rich alkenes than for electron-deficient ones.
KEYWORDS: fluorination, hypervalent iodines, iodofluorination, palladium catalysis, alkenes, difunctionalization
this respect, transition-metal-catalyzed procedures offer attrac-
rganofluorine compounds are important synthetic targets
Oin the pharmaceutical and agrochemical industries tive solutions.
Hypervalent iodine 1 is an easily accessible reagent11 that is
because of their useful pharmacokinetic and metabolic
properties.1 In addition, the radiochemical properties of 18F
can be exploited in positron emission tomography (PET)
diagnostics.2 This latter application requires late-stage synthetic
methods for the introduction of fluorine to the organic
molecules because of the relatively short half-life of 18F.3 The
large interest by the chemical industry and medical diagnostics
has boosted the development of modern fluorine chemistry,
which has been signified by the appearance of new fluorinating
reagents, applications of catalysis, and reporting of new,
selective late-stage methodologies.3,4
Fluorination-based difunctionalization is a useful approach
for the synthesis of organofluorides. By related methods not
only a fluorine but also an additional functional group can be
introduced in the organic molecules.5 Subsequently, the second
functionality can be employed as a handle for additional
transformations of the organofluoro compounds. In this
respect, iodofluorination of alkenes is a particularly useful
approach for the simultaneous introduction of both iodo and
fluoro substituents to organic substrates.6 Classical iodofluori-
nation reactions are usually based on the use of a strong oxidant
in connection with a reactive fluorine source.7 Barluenga and
co-workers8 employed bis(pyridine)iodide tetrafluoroborate
(IPy2BF4) for iodofluorination of alkenes. Another usual
approach for iodofluorination of alkenes is the application of
the N-iodosuccinimide (NIS)/HF system, often in the presence
of a base (e.g., Et3N, pyridine, imidazole derivatives).9 The
same type of iodofluorination can be achieved using an
oxidative fluorine reagent such as ArIF2 or MeIF2 together with
HF or I2 as an additive.10 These species are very reactive
fluorinating and iodinating reagents that are often difficult to
access, highly toxic, and hazardous to use. It would be desirable
to replace the corrosive, strongly oxidizing reagents with
nonhazardous stable species as well as to avoid using HF as an
essential component or possible byproduct of the reaction. In
thermostable up to 100 °C.12 At moderate temperatures, 1 is
completely inert toward olefins in the absence of transition-
metal-based or other activators. However, with suitable
activation 1 can be applied to fluorinations of 1,3-diketones
and 1,3-keto esters,11a,13 in difluorination of styrenes,14 and in
fluorocyclization reactions.12,15 A further attractive feature of
this electrophilic fluorinating reagent is that it can be easily
obtained from nucleophilic fluorinating reagents such as KF,11b
which is a potentially useful feature in the synthesis of PET
radioligands.2
During our studies of difluorination of styrenes,14 we found
that when certain palladium catalysts in the presence of 1 were
used, styrenes underwent iodofluorination instead of difluori-
nation. Expecting the above-mentioned benefits of a mild
palladium-catalyst-controlled iodofluorination method, we
decided to fully develop such a new synthetic transformation
(Table 1). When allylbenzene (2a) was reacted with 1 in the
presence of 5 mol % Pd(BF4)2(MeCN)4 (4a), the iodofluori-
nated product 3a was formed in 61% yield (Table 1, entry 1).
The reaction was carried out under mild and neutral conditions
without any additives. Increasing the catalyst loading to 20 mol
% also increased the yield to 76% (entry 2). Surprisingly, the
iodine substituent in 3a arises from reagent 1. This atom-
economical use of iodine involves cleavage of the C(sp2)−I
bond in 1 and formation of a C−I bond in 3. This also suggests
an intriguing mechanism for the process.
The iodofluorination with Pd(OCOCF3)2 resulted in
terminally substituted product 3a, but the yields were lower
than with 4a (Table 1, entries 3 and 4). The reaction with
Pd(OAc)2 (4b) proceeded slower than that with 4a. When the
reaction was conducted for 18 h at 40 °C, 3a was isolated in
Received: September 11, 2015
Revised: December 6, 2015
© XXXX American Chemical Society
447
DOI: 10.1021/acscatal.5b02022
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ACS Catalysis
Research Article
a
Table 1. Variation of the Reaction Conditions for
Table 2. Palladium-Catalyzed Iodofluorination with 1
Iodofluoration of Allylbenzene (2a)
entry
[Pd] catalyst
yield of 3a (%)
1
2
3
4
5
6
7
8
9
5 mol % Pd(BF4)2(MeCN)4 (4a)
20 mol % Pd(BF4)2(MeCN)4 (4a)
5 mol % Pd(TFA)2
61
76
41
68
15
<5
0
20 mol % Pd(TFA)2
20 mol % Pd(OAc)2 (4b)
PdCl2(tBuCN)2, PdCl2(DMSO)2, or PdCl2(dppe)
−
20 mol % 4a in dioxane instead of CDCl3
20 mol % 4a in THF, MeCN, or MeOH
38
<5
only 15% yield (entry 5). Other palladium catalysts such as
PdCl2(tBuCN)2, PdCl2(DMSO)2, and PdCl2(dppe) were
inefficient for the iodofluorination (entry 6). With these
catalysts or no palladium catalyst (entry 7), the starting
materials 2a and 1 remained unchanged. We employed CDCl3
as a solvent, which allowed analysis of the crude reaction
1
mixtures by H and 19F NMR spectroscopy. When the solvent
was changed to dioxane (entry 8), the yield of 3a decreased to
38%. When tetrahydrofuran (THF), MeCN, or MeOH was
used as the solvent, formation of the iodofluorinated product
was not observed (entry 9).
Subsequently, we investigated the synthetic scope of the
palladium-catalyzed iodofluorination reaction (Table 2). As
mentioned above, a 20 mol % loading of 4a gave the best yield
of 3a when 2a was used as the substrate (entry 1). When
PdCl2(MeCN)2 (4c) was used as the catalyst (5 mol %), 3b
was formed (as a single anti stereoisomer) from 2a (entry 2).
Styrene derivative 2b (entry 3), which is the allylic isomer of
2a, also gave 3b with catalyst 4c. Compound 2c (a structural
homologue of 2a) also gave the internal iodofluorination
product 3c with catalyst 4c (entry 4). In this case the
iodofluorination occurred at the homoallylic position with
respect to the original double bond. As mentioned above
(Table 1, entry 5), 4b also catalyzed the iodofluorination, but
the reaction was slower than with 4a. When alkene 2c was
reacted at 50 °C with 1 using 4b as the catalyst, product 3d was
formed (Table 2, entry 5). Apparently, this palladium catalyst
4b did not induce the same rearrangement as 4c did (cf. entries
4 and 5). The iodofluorination of allylbenzenes bearing
electron-donating substituents (OMe, Me) proceeded
smoothly in very clean reactions (entries 6−10). Because of
the high reactivity of substrates 2d−h, 4b was used as the
catalyst at 40 °C. The isolated yields varied between 48 and
78%. The lower yields were due to purification losses,
attributable to either the volatility of the products or separation
difficulties. The p-methoxy-substituted allylbenzene 2d under-
went iodofluorination with higher yield than its o-methoxy-
substituted counterpart 2e (entries 6 and 7). Fluorinated
derivatives of methyl eugenol (2f) are useful antiseptics and
anesthetics.16 The corresponding iodofluorinated product 3g
(entry 8) could also be obtained in good yield. The difference
in the isolated yields was relatively small for the p-methyl- (2g)
and o-methyl-substituted (2h) analogues (entries 9 and 10).
Allylbenzene substrates with electron-withdrawing groups
(2i−k) reacted very slowly with 1 in the presence of 4b.
a
Unless otherwise stated, substrate 2 (0.1 mmol), 1 (0.1 mmol), and
the appropriate palladium catalyst (0.02 mmol, 20 mol %) in CDCl3
b
c
(0.5 mL) were stirred at 40 °C for 18 h. Isolated yields. 0.005 mmol
d
(5 mol %) of PdCl2(MeCN)2 (4c). The reaction was performed at 50
e
f
°C. The yield was determined by 19F NMR spectroscopy. The
reaction was performed at 60 °C.
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Therefore, catalyst 4a was used for these substrates, as it has a
higher catalytic activity than 4b (cf. Table 1, entries 2 and 5).
Even with the more active catalyst, the yields for iodofluori-
nation of fluoro- (2i) and trifluoromethyl-substituted (2j)
allylbenzenes were significantly lower than for the methoxy
analogue (Table 2, entries 11 and 12 vs 6). o-Bromo substrate
2k also underwent catalytic iodofluorination using 1 (entry 13)
to afford 3l, which contains three different halogenide handles
(F, Br, I), making it a useful synthetic intermediate for
substitution, elimination, and Suzuki−Miyaura coupling re-
actions.17 It is noteworthy that the C(sp2)−I bond of 1 was
cleaved but the C(sp2)−Br bond of 2k remained intact in the
catalytic iodofluorination process.
take place by the PdX2 catalyst 4. The activated complex 5
(Figure 1) undergoes electrophilic addition to the alkene to
Figure 1. Plausible mechanism for the iodofluorination reaction.
α-Methylstyrenes 2l−n also underwent iodofluorination
smoothly (Table 2, entries 14−16). In these reactions, catalysts
4b and 4c performed well, but the reaction temperature was
raised to 50−60 °C to get full conversion of the starting
materials. The lower reactivity is apparently due to the more
sterically hindered double bonds in 2l−n than in the linear
analogues, such as in 2a. Because of the mild reaction
conditions, elimination of the tertiary fluorine functionality in
products 3m−o could be avoided. Like 3l, product 3o also has
three different halogen functionalities. Simple cycloalkenes 2o
and 2p underwent iodofluorination with 1 in the presence of
catalyst 4c (entries 17 and 18). The reaction proceeded with
clean anti selectivity. Product 3p is volatile and was isolated in
only 40% yield, but the corresponding NMR yield was 96%.
We carried out mechanistic studies to understand the
regioselectivity of the reaction and investigate the fate of
reagent 1. As mentioned above (Table 2, entry 2), 2a and 1
gave internally iodofluorinated product 3b in the presence of
PdCl2(MeCN)2 (4c). It is well-documented that allylbenzene
derivatives can easily undergo allylic rearrangement in the
presence of 4c or other Pd(II) catalysts.18 Indeed, when we
reacted 2a with 4c in the absence of 1, allylic rearrangement of
2a occurred, resulting in 2b (Scheme 1). As we have shown
give iodonium ion 6. The electrophilic addition is in line with
our findings that the reaction proceeds faster in the presence of
electron-supplying substituents (OMe, Me) in the aromatic
ring of the allylbenzene substrate (e.g., Table 2 entries 6−10)
than in case of electron-withdrawing substituents (F, CF3;
entries 11 and 12). The next step is opening of the iodonium
ring, resulting in 7. The most intriguing process of the reaction
is the cleavage of the C(sp2)−I bond, which is most probably
catalyzed by palladium. Our GC/MS studies indicated that the
deiodinated aromatic ring of 1 underwent dimerization to give
8. The molecular peaks indicating the formation of 8 could be
found in the MS spectrum of the GC-separated reaction
mixture. Most probably the primary product was 8a, which
underwent water elimination to give 8b. Biphenyls with both
dimethyl hydroxy and α-methyl ethyl substituents are also
possible.
Benziodoxoles (such as 1) are very unusual iodine sources in
synthetic transformations. Mechanistic studies of these trans-
formations are encumbered by the fact that the iodine transfer
from the benziodoxole ring to the organic substrate occurs in a
late stage of the reaction, as the I−F and I−O bonds have to be
cleaved before the C(sp2)−I bond cleavage. Except for our early
report,14 we found only a single recent study in which
benziodoxoles were used for iodination. In that study, Rao and
co-workers20 showed that the MeO analogue of 1 can be used
for Pd-catalyzed aromatic iodination. Those authors suggested
an oxidative addition−reductive elimination sequence for
introduction of the iodine atom to the substrate. According
to Rao and co-workers,20 this sequence may involve a Pd(II) to
Pd(IV) oxidation step. We believe that a similar process may
occur in the above iodofluorination reaction as well. Several
studies21 have shown that hypervalent iodines (structurally
similar to 1) are able to oxidize Pd(II) species. Mechanistic and
density functional theory modeling studies to obtain a deeper
understanding of this interesting C(sp2)−I bond cleavage
process are underway in our laboratory.
Scheme 1. Isomerization of Allylbenzene
(Table 2, entry 3), 2b smoothly underwent iodofluorination
with 1 to afford 3b. Considering this, we concluded that 2a
undergoes allylic rearrangement (to 2b) in the presence of 4c,
after which iodofluorination of 2b gives product 3b (Table 2
entry 2). Accordingly, catalyst 4c performs a tandem catalytic
rearrangement−iodofluorination sequence when 2a is reacted
with 4c. Interestingly, under identical reaction conditions 2a
underwent allylic rearrangement even with 4a as a catalyst.
However, the reaction of 2a and 1 in the presence of 4a gave
the terminal iodofluorinated product 3a (Table 2 entry 1). The
above results indicate that in the presence of 4a the
iodofluorination of 2a with 1 is much faster than the
rearrangement to 2b. Conversely, in the presence of 4c the
rearrangement is faster than the iodofluorination. Both
reactions are very selective, as none of these reactions resulted
in mixtures of 3a and 3b.
In conclusion, we have shown that the air- and moisture-
stable fluoroiodine reagent 1 is suitable for iodofluorination of
alkenes in the presence of palladium catalysts. Reagent 1 is the
source of both the fluorine and iodine substituents. The
reaction involves a palladium-catalyzed C−I bond formation−
C(sp2)−I cleavage sequence. For some catalysts a clean allylic
rearrangement precedes the iodofluorination reaction. The
presented reaction is suitable for iodofluorination of alkenes
under mild neutral conditions and potentially applicable in PET
diagnostics.
Our previous studies indicated that 1 can be activated by
Lewis acid catalysts14,15 similarly to the trifluoromethyl
analogue of 1.19 In the present reaction this activation may
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Research Article
(13) Geary, G. C.; Hope, E. G.; Singh, K.; Stuart, A. M. RSC Adv.
2015, 5, 16501−16506.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.5b02022.
■
S
(14) Ilchenko, N. O.; Tasch, B. O. A.; Szabo,
Ed. 2014, 53, 12897−12901.
(15) Yuan, W.; Szabo, K. J. Angew. Chem., Int. Ed. 2015, 54, 8533−
8537.
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K. J. Angew. Chem., Int.
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Detailed experimental procedures, compound character-
1
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AUTHOR INFORMATION
Corresponding Author
*E-mail: kalman@organ.su.se.
Notes
■
(19) Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.; Niedermann, K.;
Togni, A. Angew. Chem., Int. Ed. 2009, 48, 4332−4336.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Support from the Swedish Research Council and the Knut och
Alice Wallenbergs Foundation is gratefully acknowledged.
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