Radical Carbofluorination of Alkenes with Arylhydrazines and Selectfluor: Additives, Mechanistic Pathways, and Polar Effects

Article abstract of DOI:10.1002/chem.201805256

Radical carbofluorination reactions starting from arylhydrazines and nonactivated alkenes, in which the C?F bond is formed through the use of Selectfluor, can be improved through the addition of anisole. Because direct trapping products could be detected only in trace amounts, anisole does primarily act as a reversible scavenger for the highly reactive ammonium radical dication released from Selectfluor in the C?F bond-forming step. As shown for three diverse substitution patterns, the main role of anisole is to prevent, or at least reduce, the undesired addition of the ammonium radical dication to the alkene, which in turn leads to an unfavorable consumption of the arylhydrazine-derived precursors required for carbofluorination. Moreover, besides the remarkable polar effects in radical trapping, this study shows that the Selectfluor-derived nitrogen-centered radical dication may add directly to alkenes, which has not been described so far.

Full text of DOI:10.1002/chem.201805256

A Journal of
Accepted Article
Title: Radical carbofluorination of alkenes with arylhydrazines and
Selectfluor: Additives, mechanistic pathways and polar effects
Authors: Anna Pirzer, Eva Maria Alvarez Pari, Heike Friedrich, and
Markus Rolf Heinrich
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To be cited as: Chem. Eur. J. 10.1002/chem.201805256
Link to VoR: http://dx.doi.org/10.1002/chem.201805256
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Chemistry - A European Journal
10.1002/chem.201805256
FULL PAPER
Radical carbofluorination of alkenes with arylhydrazines and
Selectfluor: Additives, mechanistic pathways and polar effects
Anna S. Pirzer, Eva-Maria Alvarez, Heike Friedrich and Markus R. Heinrich*
Dedication ((optional))
Abstract: Radical carbofluorination reactions starting from
arylhydrazines and non-activated alkenes, in which the C-F bond is
formed through the use of Selectfluor, can be improved through the
addition of anisole. Since direct trapping products could be detected
only in trace amounts, anisole does primarily act as a reversible
scavenger for the highly reactive ammonium radical dication released
from Selectfluor in the C-F bond forming step. As shown for three
diverse substitution patterns, the main role of anisole is to prevent, or
at least reduce, the undesired addition of the ammonium radical
dication to the alkene, which in turn leads to an unfavorable
consumption of the arylhydrazine-derived precursors required for
carbofluorination. Besides the observation of remarkable polar effects
in radical trapping, this study moreover shows that the Selectfluor-
derived nitrogen-centered radical dication may add directly to alkenes,
which has not been described so far.
fluorinations with Selectfluor (2), in contrast, do not directly
depend on the high reactivity of 3, and for such cases, one can
assume that a rapid reduction of radical dication 3 to cation 4, or
at least a deactivation of 3, should be beneficial to avoid side-
reactions.
A) radical C-F bond formation with Selectfluor[9]
R1
C
R1
C
N
Cl
N
Cl
N
Cl
red.
F
R3
+
R2
+
N
R2
N
N
R3
F
2 BF4
(BF4 )
1
2
3
4
B) radical carbofluorination [12a]
(2 BF4
)
R1
R1
Selectfluor
(2)
F
R2
+
2
+ side product
NH
R2
N
5
H
R
1
6
R
1
7
N
Cl
ox. 2
N
6
R2
3
9
8
2
C) para-selective C-H functionalization [
17]
Introduction
Pd/Ru
Cl catalysis
N
Cl
H
N
N
+
N
R
F
Fluorinated organic compounds are of importance in many fields
of application, including agrochemistry, medicinal chemistry and
materials.[ Consequently, the development of efficient synthetic
11
10
2
2 BF
4
R
red.
H
N
Cl
1]
N
[
2]
strategies for their preparation is an attractive field of research,
R
3
10
[
3,4]
whereat the well-known approaches comprise nucleophilic and
electrophilic fluorinations[
or -mediated reactions.[
2,5,6]
Scheme 1. C-F bond formation (A), carbofluorination (B) and C-H
functionalization (C) with Selectfluor (2).
as well as transition metal-catalyzed
This variety of methods was recently
7,8]
complemented by radical fluorinations,[9] in which the C-F bond is
Our deeper interest in this topic arose from a recently developed
alkene functionalization (Scheme 1B).[12a] Starting from phenyl-
formed in a fluorine atom transfer step between a fluorine atom
donor, such as Selectfluor (2),[10] and carbon-centered radical 1
hydrazines
5
and alkenes 6, the first Meerwein-type
(
Scheme 1A).
carbofluorination could be put into practice, whereat the desired
arylation products 7[ were obtained via trapping of alkyl radical
8 by Selectfluor (2). In this reaction, the fluorine source 2
previously also serves as an oxidant to generate aryl radicals 9
from 5. Besides 7, this reaction however led to an unknown by-
product, which we were unable to suppress during optimization,
and which, we reasoned, could be formed due the high reactivity
of 3. Further evidence for the reactivity 3 was provided by a report
by Ritter[17] on an attractive new type of para-selective arene
functionalization, in which radical dication 3 was assumed to play
a key role in the attack onto arene 10 to give 11 (Scheme 1C).
Against this background, it was interesting to investigate whether
a suitably substituted arene might be a beneficial additive in
radical fluorination reactions with Selectfluor (2), as such an arene
could act as a scavenger for the reactive radical dication 3. If
successful, it was our further intention to see in detail how the
aromatic additive can influence the reaction pathways leading to
the carbofluorination product and the related by-products.
Examples for radical reactions proceeding via C-F bond formation
16]
[11]
[12]
are decarboxylative fluorinations,
carbofluorina-tions,
and
whereat, among several
has evolved as the most widely
[13],[14]
oxidative C-H functionalizations,
reagents,[
15]
[10]
Selectfluor (2)
used fluorine source.
Depending on the reaction type, the highly reactive ammonium
radical dication 3 released in the fluorine atom transfer, may be
[
11b,13e-I,14b,14d]
required for further mechanistic steps,
e.g. the
homolytic cleavage of an aliphatic C-H bond.[
13]
Other radical
[
a]
Apothekerin A. S. Pirzer, E.-M. Alvarez, H. Friedrich, Prof. Dr. M. R.
Heinrich
Department of Chemistry and Pharmacy
Pharmaceutical Chemistry
Friedrich-Alexander-Universität Erlangen-Nürnberg
Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany
E-mail: Markus.Heinrich@fau.de
Supporting information for this article is given via a link at the end of
the document.
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Chemistry - A European Journal
10.1002/chem.201805256
FULL PAPER
Results and Discussion
N
Cl
2 BF
F
N
MeO
F
4
MeO
MeO
+
2
The present investigation was started with experiments in which
the carbofluorination of alkene 6a was carried out with a
sufficiently soluble, donor-substituted arene as additive (Table 1).
(
3 2
CD CN/D O)
F
12
15
16
Table 1. Evaluation of donor-substituted arenes as additives in the radical
carbofluorination of 3-buten-1-yl acetate (6a).
N
Cl
BF
(5 equiv)
N
2
4
F
2
F
NH
2
+
N
H
OAc
3 2
(CH CN/H O)
OAc
5a
6a
7aa
(slow add. over 1 h)
(12 equiv)
Scheme 2. The slow background reaction of Selectfluor (2) with anisole (12) to
give 2-fluoroanisole (15) (light blue) and 4-fluoroanisole (16) (orange).
yield 7aa
%/%)[b],[c]
(
entry
variation of reaction conditions
none (without additive)
anisole (12) (2 equiv)
1
2
3
4
5
6
7
8
9
62/57
41/---
With optimized conditions available, the effect of anisole (12) was
next evaluated in carbofluorination reactions starting from other
aryl hydrazines 5a-g and alkenes 6a-e (Scheme 3).
anisole (12) (3 equiv)
73/69
anisole (12) (4 equiv)
anisole (12) (3 equiv), traces of oxygen[d]
Selectfluor (2) (3 equiv), anisole (12) (3 equiv)[d]
alkene 5a (6 equiv), anisole (12) (3 equiv)[d]
add. of 4a over 30 min, anisole (12) (3 equiv)[d]
1,4-dimethoxybenzene (13) (3 equiv.)[d]
1,3-dimethoxybenzene (14) (3 equiv.)[d]
54/---
74/75
33/---
N
Cl
OMe
70/71
R1
N
R1
69/---
0/---
F
2 BF4
2 (5 equiv)
(CH CN/H O)
12
(3 equiv)
F
NH
2
+
R
2
10
0/---
N
H
3
2
R2
[
a] General reaction conditions: 5a (1.0 mmol) in CH
3
CN/H
2
O (5:1, 4 mL) added
5a-g
6a-e (12 equiv)
7aa-ae-ga
by syringe pump over 1 h to a mixture of 6a (12.0 mmol) and 2 (5.0 mmol) in
1
from 5a (R1 = H) and 6a-e:
from 5b-g and 6a (R2 = (CH
2 2
) OAc):
3
CH CN/H
2
O
(5:1,
5
mL) under argon. [b] Yield determined by H-NMR
7aa: R2 = (CH ) OAc
7ba: R1 = 4-Cl
spectroscopy. [c] Yield after purification by column chromatography. [d] Traces
of oxygen present due to incomplete degassing.
75% (57%)
40% (43%)
60% (45%)
60% (39%)
55% (42%)
23% (11%)
48% (29%)
51% (47%)
59% (49%)
2
2
2
7ca: R1 = 4-Br
7ab: R = (CH
2
)
2
OH
7
7
ac: R2 = (CH
2
)OAc
7da: R = 4-OMe
1
2
7ea: R1 = 4-CN
ad: R = (CH
2 2
) COMe 50% (30%)
Initial experiments showed that there is indeed a beneficial effect
of anisole (12) compared to the additive-free reaction (entries 1-
), but only at a defined excess of 3 equivalents of 12. Whereas
the amount of scavenger is probably not sufficient at 2 equivalents
7ae: R
2
= (CH ) COOH 48% (40%)
7fa:
7
R
1
= 3-Cl
2
2
ga: R1 = 3-Br
Scheme 3. Effect of added anisole on other substitution patterns. Yields after
4
purification by column chromatography. Yields in brackets refer to reactions
[12a]
without anisole.
(
entry 2), anisole (12) might start to compete as an aryl radical
[
18]
acceptor at 4 equivalents (entry 4),
so that lower yields are
In the first series of experiments, in which the alkene 6 was varied,
only 3-buten-1-ol (6b) led to a slightly lower yield of 7ab when
anisole was present. Anisole being ineffective in this case
suggests that alcohols such as 6b are even more reactive
scavengers for radical dication 3, however at the price of some
obtained in that case, too. A slight further improvement was
achieved through incomplete degassing, which leaves traces of
oxygen in the reaction mixture (entry 5). This effect can be
rationalized by the facilitated generation of aryl radicals from 5a,
as oxygen readily decomposes phenyldiazene (ArN=NH)
[21]
destruction of reactants and related products. For 5-hexen-2-
[19]
occuring as intermediate. Whereas the optimized conditions of
entry 5 do not allow a decrease of the amount of Selectfluor (2) to
one (6d), on the other hand, an increase in yield of 6ad from 30%
to 50% was observed upon the addition of anisole. In the second
series, and under variation of the aryl hydrazine 5, all experiments
led to higher yields when anisole was present. The highest
absolute increase by 21% was observed for 7ba, the highest
relative increase was determined for 7da with a factor of 2.1.
Having observed the beneficial effect of anisole in the Meerwein-
type carbofluorination, the yet unknown hydrophilic by-product
was reinvestigated using the reaction of 5b and 6a to give 7ba
3
equivalents (entry 6), lower amounts of the alkene (entry 7) and
a faster addition of 5a over 30 minutes (entry 8) were tolerated at
an only minor drop in yield.
In further attempts, the 1,4-dimethoxybenzene (13) and 1,3-
dimethoxybenzene (14) proved unsuitable, as these additives
reacted readily with Selectfluor (2) in an electrophilic fluorination
20]
(
entries 9 and 10).[ The background reaction of anisole (12) with
Selectfluor (2), on the other hand, was found to proceed quite
slowly under our reaction conditions. After 1 h reaction time, which
was also applied for the carbofluorinations reported in Table 1,
just small amounts of 2-fluoroanisole (15) (2%) and 4-
Scheme 4).[12a]
(
1
fluoroanisole (16) (4%) could be detected by H-NMR analysis
(
Scheme 2). When running the experiment over a longer period
of 4 h, the yield of 2-fluoroanisole (15) increased to 11% and the
amount of 4-fluoroanisole (16) finally increased to 9%.
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Chemistry - A European Journal
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The assumed conversion of 19ba to 21ba did indeed occur and
could also be reproduced for the by-product 19ea (previously
formed along with 7ea) to give vinyldiazene 21ea. Investigation of
N
Cl
N
2
BF
4
Cl
F
Cl
F
2
(5 equiv)
NH
2
+
1
N
OAc
(CH CN/H O)
OAc
the vinyldiazenes 19ba and 19ea by H-NMR spectroscopy
3
2
H
5b
6a
7ba
revealed that both compounds exhibit only a very low stability,
which was found to be even lower for the acceptor-substituted
cyano derivative 21ea.[22] Due to the fact that the diazabicycle 20
is already formed in reasonable amounts during the
carbofluorination reaction, and cannot be removed from the
aqueous phase, which also contains 19, it is not possible to
distinguish analytically in between the previously formed
diazabicycle 20 and one that is newly formed during the
elimination of 19 to give 21.
(
slow add. over 1 h)
(12 equiv)
+ side-product (hydrophilic)
Cl
Cl
Cl
Cl
2
BF
N
4
2
BF
4
N
2 BF4
Cl
N
N
N
N
N
N
N
Cl
N
OAc
17 (not formed)
18 (not formed)
19ba (= side-product)
Scheme 4. Identification of the hydrophilic key by-product of the
carbofluorination reaction.[
12a]
As the structure of the key by-product had been determined, it is
now possible to give a more complete ovierview over the multiple
pathways occurring during carbofluorination (Scheme 6). Starting
from phenylhydrazine 5, oxidation by Selectfluor (2) at first
provides the phenyldiazene 22 (step (A)). The formation of 22
under the typical carbofluorination conditions could be confirmed
through trapping of 22b with 2,5-dimethylfuran (23), which led to
the pyridazinium salt 24b in 51% yield (Scheme 7).[ The further
oxidation of 22 to 9 under loss of dinitrogen represents one of the
critical steps in the carbofluorination (step (B), Scheme 6), as it is
greatly facilitated by the presence of dioxygen,[ but a large
amount dioxygen would later on promote the undesired formation
of the hydroperoxide 25 from 8 (step (E)).[12a,23] This background
thus explains why partial degassing, so that a limited but defined
amount of dioxygen is available, was found to be beneficial.
Addition of aryl radical 9 to the alkene 6 furnishes the central and
typical intermediate 8 of Meerwein arylation reactions (step (C)).
Besides the desired trapping of 8 by fluorine atom transfer from 2
to give 7 (step (D)), 8 may also react with dioxygen (step (E)), see
above), or it be trapped by a diazonium ion 26 or diazene 22 to
finally give azo compound 27 (step (F)).[22] Both 26 and 27 could
be identified as by-products, whereat 26 most likely results from
over-oxidation of 22 by Selectfluor (2) (step (G)).
To obtain the by-product in high quantity, the reaction was now
again conducted in the absence of anisole (12). While the desired
carbofluorination product 7ba can easily be separated from the
reaction mixture by extraction with an organic solvent such as
diethyl ether, the by-product was always found in the aqueous
phase and could not be extracted due to its high polarity. Although
attempts to separate or purify the by-product failed due to a
19]
certain instability of the compound, some insight could be gained
by 1H-NMR analysis, which indicated the presence of an
19]
acceptor-substituted,
arylhydrazine-derived
4-chlorophenyl
moiety as well as a Selectfluor-derived diammonium unit as
structural elements. Combining these two substructures, our first
suggestion was compound 17, which could however readily be
[
17]
ruled out by the synthesis of an authentic sample. The next
candidate, which appeared plausible to due to its assumable
instability, and which might result from an undesired attack of
radical dication 3 on hydrazine 5b was compound 18. As 18
should however also be formed in the absence of the alkene 6a,
we conducted
a
control reaction comprising only 4-
chlorophenylhydrazine (5b) and Selectfluor (2). This control
reaction did not provide the sought-after by-product, nor
compound 18, so that it became clear that the former alkene 6a
needed to be a structural component of the by-product as well.
R1
ox. R1
R1
1
Based on what was known about the by-product from H-NMR
2
ox.
NH
2
(
A)
NH
(B)
analysis of the original reaction (Scheme 4), the 4-chlorophenyl
has to be bound to an electron-accepting unit, so that compound
N
N
22
5
H
9
ox.
2
6
(C)
19ba now appeared plausible. Reinvestigation of the aqueous
R1
(G)
R1
phase by HPLC-MS did indeed support this suggestion, and the
presence of the acetate unit could be confirmed by H-NMR. To
ox.
N
2
red.
R2
1
26
8
R1
2
O , [H]
unambiguously prove the formation of 19ba in the
carbofluorination reaction, the aqueous phase containing the by-
product was treated with sodium hydroxide (Scheme 5). In the
presence of a base, we reasoned that deprotonation should easily
occur at position 2, then leading to elimination of the single
(
F)
(D)
2
(E)
R1
R1
R1
N
Cl
N
OOH
R2
N
F
+
N
R2
R2
Cl
2
7
7
3
25
N
[22
Cl
charged diazabicycle 20 and formation of vinyldiazene 21.
6
(H)
MeO
N
(K)
N
Cl
ox.
or
N
20
R
R
R1
red.
N
+
N
without with
anisole anisole
R
(M)
OMe
red.
(I)
28
31
2
2 or 26
Cl
Cl
N
2
BF
N
4
(J)
2
(L) slow
BF
4
Cl
N
N
N
N
N
N
NaOH
O)
N
N
N
12
+
R
N
Cl
2
2
Cl
N
F
(
H
2
N
19
OAc
OAc
N
N
H
R
1
1
9ba: R = Cl
9ea: R = CN
20
21ba: R = Cl (20%)
21ea: R = CN (7%)
29 (not detected)
MeO
30 (detected)
Scheme 5. Conversion of by-products 19ba and 19ea to vinyldiazenes 21ba
and 21ea.
Scheme 6. Overview over mechanistic pathways.
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Chemistry - A European Journal
10.1002/chem.201805256
FULL PAPER
Cl
Cl
N
Cl
BF
(1 equiv)
(CH CN/H O)
F
Cl
N
OAc
N2
X
2
4
Cl
F
N
N+
7ba
26b
NH
2
O
N
N
Cl
2
+
5b
H
N
Cl
N
Cl
NH
2
2 BF4
N
F
X = F, BF4
3
2
(slow add. over 1 h)
H
2 (5 equiv)
5b
23
1 equiv)
Cl
24b
+
(
(CH CN/H O)
without or with
anisole (12) (3 equiv)
OAc
3
2
NH
+ H+
6a
2 X
N
N
ox.
Cl
N
O
N
Cl
(12 equiv)
Cl
N
N
-
2
H O
OAc
OAc
22b
27ba
19ba
Scheme 7. Trapping of the phenyldiazene intermediate 22b by cycloaddition
to 2,5-dimethylfuran (23).
As mentioned in the introduction, and as verified by the structure
of the by-products 19ba and 19ea (Scheme 5), the reactivity of
the radical dication 3 does indeed play a major role in the
carbofluorination reaction described herein. In the absence of
anisole (12), 3 does readily attack alkene 6 to give 28 (step (H)).
Interestingly, alkyl radical 28 is then almost exclusively trapped by
Scheme 8. Influence of anisole (12) on the carbofluorination using 4-
chlorophenylhydrazine (5b).
22 or 26 to give 19 (step (I)), but not by Selectfluor (2) to provide
9 (step (J)), since 29 could not be detected among the
2
hydrophilic products by 19F-NMR or LC-MS. Given that the two
secondary alkyl radicals 8 and 28 should possess a comparable
reactivity, but 8 preferably reacts with 2 to give 7 (step (D)),
whereas 28 chooses 22 or 26 to give 19 (step (I)), we assume that
a strong polar effect (lipophilic phenyl group in 8 vs. doubly
charged diazabicycle in 28) is responsible for this remarkable
selectivity. At this point, it is worth to mention that the direct attack
of radical dication 3 onto an alkene has so far not been reported,
so that this observation could be an interesting starting point for
future developments.[
In the presence of anisole (12), 19 is most often formed in much
lower amounts, so that one can assume that the reactivity of
radical dication 3 gets reduced. Since no degradation products
related to anisole (12) could however be detected in the reaction
mixture besides a small amount of 30 (steps (K) and (L)) it
appears plausible that a reversible complex such as 31 is
responsible for the reduced reactivity of 3.[26] The substitution of
Regarding the formation of the carbofluorination product 7ba from
arylhydrazine 5b and alkene 6a (Scheme 8), a strong effect of
anisole (12) could be observed (bottom left), which resulted in an
almost doubled yield for the anisole-containing reaction. On the
part of the by-products (bottom right), and in agreement with the
above made assumptions, the presence of anisole led to sharp
drop in yield for the adduct 19ba arising from the addition of
radical cation 3 onto alkene 6a. The main damage to the reaction
related to adduct 19 is thereby generally not done due to the
incorporation of the alkene, which is present in sufficient excess,
but due to the consumption of diazene 22, which could otherwise
form the desired product 7. Regarding the further by-products in
the reaction of the 4-chloro-substituted phenylhydrazine 5b,
neither diazonium salts 26b nor the azo compound 27ba play a
major role.
24], [25]
MeO
MeO
F
MeO
1
2 to give 30 (step (L)), which is identical to one of the products
OAc
N
2
X
recently reported by Ritter,[17] obviously occurs slowly in
NH2
N
Cl
7da
26d
X = F, BF4
N
OMe
N
OMe
H
N
5
d
2 BF4
comparison to the reductive decay of the complex 31 leading to
F
(
slow add. over 1 h)
2
(5 equiv)
CN/H O)
without or with
anisole (12) (3 equiv)
12 and 20. The reductive step (M) is thereby most probably
+
(
CH
3
2
OAc
coupled to one of the oxidative steps (A), (B), (F) or (I).
MeO
2 X
N
N
6a
N
Cl
N
N
Against the background of these multiple pathways, we next
studied the particular influence of the substitution on the
arylhydrazine using the more or less electron-neutral
arylhydrazine 5b (4-Cl), the donor-substituted hydrazine 5d (4-
OMe) as well as the acceptor substituted hydrazine 5e (4-CN)
(12 equiv)
OAc
OAc
27da
19da
(
Schemes 8-10). Samples from the individual reaction mixtures
were drawn after 15, 30, 45 and 60 minutes to get insights into
product and by-product formation depending on the presence of
anisole (12). Note that, due to the multiple sample acquisitions,
the final yields in this study do not exactly match those of the
undisturbed reactions reported in Scheme 3. The resulting graphs
should thus be preferably seen as a qualitative than an absolutely
quantitative representation.
Scheme 9. Influence of anisole (12) on the carbofluorination using 4-
methoxyphenylhydrazine (5d).
As shown in Scheme 9 (bottom left), the carbofluorination reaction
starting from 4-methoxyphenylhydrazine (5d) does not strongly
benefit from the addition of anisole (12). A closer inspection of the
by-products revealed that although anisole (12) can again
suppress the formation of the adduct 19da to a large extent, it is
however unable to inhibit the undesired over-oxidation of the
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Chemistry - A European Journal
10.1002/chem.201805256
FULL PAPER
diazene 22 to the diazonium salts 26d (Scheme 9, botton right).
Taking into account that the electron-donating character of the 4-
methoxy group does strongly facilitate the oxidation of diazene
OMe
N
Cl
N
F
2 BF4
2 (2 equiv)
AgNO
12 (1.2 equiv)
O
C
O
22d to diazonium salts 26d, it is not surprising that oxidative
3
(0.2 equiv)
F
+
R
(
CH Cl
2
2
/H O/AcOH)
2
carbofluorinations are difficult to carry out with electron-rich
arylhydrazines as starting materials.
EtO
2
EtO
2
C
R
50°C, Ar, 12 h
33c[[d]: R = (CH )OAc 71% (35%[ a[ c] ,] 40%[b]
32
6c,f,g
)
2
d]
NC
NC
33f : R = 4-C
6
H
4
Cl 79% (59%)
68% (23%)
F
[d]
NC
6 5
33g : R = C H
OAc
N
2
X
NH
2
Scheme 11. Effect of anisole on carbofluorination developed by Li.[12b] Yields
after purification by column chromatography. Yields in brackets refer to
reactions without anisole. [a] Yield determined by H-NMR spectroscopy. [b]
(1.00 mmol) added.[12b] [d] Product shows
2 2 8
Yield according to ref. 12b. [c] K S O
N
Cl
7ea
26e
X = F, BF
N
CN
N
CN
H
N
5
e
2 BF4
F
(
slow add. over 1 h)
4
1
2
(5 equiv)
+
(
CH
3
CN/H O)
without or with NC
anisole (12) (3 equiv)
2
OAc
2
X
N
cis/trans isomerism and keto-enol tautomerism.
6a
N
Cl
N
N
(
12 equiv)
N
OAc
OAc
27ea
19ea
With allyl acetate (6c), a remarkable increase in the yield of 33c
from 40% to 71% was observed upon the addition of anisole to
the reaction mixture. In contrast to that, the effect of anisole on
the carbofluorination of styrenes appears to be dependent on the
substitution pattern on the aromatic core. While only a smaller
raise of 20% was achieved for 33f, the yield of 33g could be
increased by 45%. Thus, the free para-position on styrene (6g)
plays a role in the sensitivity of this type of alkene towards the
[12]
reactive radical dication 3. Under the conditions of Li
the
background reaction of anisole (12) and Selectfluor (2) led to an
almost complete consumption of 12 with only 7% remaining after
the typical reaction time of 12 h. This shows that carbofluorination
reactions such as the one developed by Li should be completed
within a few hours to benefit from the addition of anisole (12), as
the negative effect of Selectfluor consumption will otherwise
prevail.
Scheme 10. Influence of anisole (12) on the carbofluorination using 4-
cyanophenylhydrazine (5e).
In the case of the acceptor-substituted 4-cyanophenylhydrazine
(
5e), the yield of the carbofluorination product 7ea could again be
considerably increased through the addition of anisole (12)
Scheme 10, bottom left). On the side of the by-products (bottom
(
right), it however became obvious that the amount of adduct 19
was not decreased to the same extent as it had been the case for
the 4-chloro- and the 4-methoxy derivatives (Schemes 8 and 9).
A plausible explanation for the reduced effect of anisole (12) is,
that the anisole-radical cation complex 31 can no longer decay
rapidly enough to cation 20 and anisole (12) (Scheme 6, step (M))
as the available oxidation steps (A), (B), (F) and (I) have become
more difficult due to the presence of the cyano group on the
aromatic core. Complex 31 can thus reversibly give back radical
dication 3, which in turn limits the overall effect.
On the other hand, the electron-accepting cyano group turns
diazene 22 and diazonium 26 into very good scavengers for
nucleophilic alkyl radicals such as 8 (Scheme 6), now giving rise
to an increased amount of azo compound 27. The fact that the
formation of 27 is exclusively observed in the anisole-containing
reaction, whereat diazonium ions 26 were not detected, suggests
that especially the lifetime of the 4-cyanophenyldiazene 22 gets
increased through anisole addition.
Conclusions
In summary, it has been shown that carbofluorination reactions,
in which C-F bond formation is achieved through the use of
Selectfluor, benefit from the addition of anisole to the reaction
mixture. All obtained experimental results support the assumption
that the reactive ammonium radical dication 3, released in the
fluorine atom transfer step, is only trapped to a very minor extent
by anisole in an electrophilic aromatic substitution. Instead, a
complex of 3 with anisole is most likely formed, through which the
reactivity of radical dication 3 is sufficiently reduced to prevent its
undesired addition to the alkene. Anisole can thus be a useful
additive for all those radical fluorinations with Selectfluor that do
not further depend on the reactivity of the ammonium radical
dication 3. Moreover, the hitherto unknown ability of the
ammonium radical dication 3 to add onto alkenes can serve as a
promising starting point for future developments in the field of
alkene functionalization and related experiments are currently
underway in our laboratory.
As a concluding remark related to all six time course reactions
depicted in Schemes 8 to 10, it is worth to mention that product
as well as by-product formation mainly occurred in a linear fashion.
This means that inhibitory and accelerating effects of the newly
formed compounds do not play a major role in the reaction course.
Finally, we evaluated the effect of anisole (12) in another type of Experimental Section
carbofluorination that was recently reported by Li[ (Scheme 11).
12b]
In this reaction, radicals that are oxidatively generated from ethyl
acetoacetate (32), or similar compounds, add to alkenes 6, and
the related adducts are ultimately trapped by Selectfluor (2) to
give carbofluorinaton products 33.
General Procedure for carbofluorination reaction (GP1): To an
undegassed, stirred solution of Selectfluor (2) (1.77 g, 5.00 mmol) and the
alkene 6 (12.0 mmol) in a mixture of CH CN/H O (5:1, 5 mL), anisole (12)
3.00 mmol) was added at room temperature under argon atmosphere in
a Schlenk flask shortly before the next step. Subsequently an undegassed
solution of the aryl hydrazine 5 (1.00 mmol) in CH CN/H O (5:1, 4 mL) was
3
2
(
3
2
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Chemistry - A European Journal
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FULL PAPER
added dropwise to the reaction mixture over a period of 1 h. Stirring was
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2
O (10 mL).
2
O
(
2
4
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,
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Entry for the Table of Contents (Please choose one layout)
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Anna S. Pirzer, Eva-Maria Alvarez,
Heike Friedrich, Markus R. Heinrich *
Page No. – Page No.
Radical carbofluorination of alkenes
with arylhydrazines and Selectfluor:
Additives, mechanistic pathways and
polar effects
Tamed by anisole. Anisole was found to be a beneficial additive in two types of
radical carbofluorination reactions using Selectfluor. Given that the ammonium
radical dication arising from the fluorine atom transfer step is not required for the
reaction course, anisole can serve as a scavenger for this reactive intermediate to
prevent side-reactions such as the addition of the radical cation to the alkene.
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