Denitrogenative hydrofluorination of aromatic aldehyde hydrazones using (difluoroiodo)toluene

Article abstract of DOI:10.1039/c6ob02074g

An operationally simple conversion of aromatic aldehyde hydrazones to monofluoromethylated arenes is reported. The hypervalent iodine reagent TolIF₂ serves as an oxidant, converting the hydrazone to the corresponding diazo compounds. The by-product of the oxidation process, HF, is consumed in situ by a denitrogenative hydrofluorination reaction of the diazo group.

Full text of DOI:10.1039/c6ob02074g

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DOI: 10.1039/C6OB02074G
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Denitrogenative Hydrofluorination of Aromatic Aldehyde Hydra-
zones Using (Difluoroiodo)toluene
Kaivalya G. Kulkarni, Boris Miokovic, Matthew Sauder and Graham K. Murphy*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An operationally simple conversion of aromatic aldehyde sources of electrophilic “F+”, the S-F and I-F compounds (
4-8)
hydrazones to monofluoromethylated arenes is reported. The have umpolung reactivity: attack of the hypervalent sulphur or
hypervalent iodine reagent TolIF2 serves as an oxidant, converting iodine atom by a Lewis base expels fluoride, and generates an
the hydrazone to the corresponding diazo compounds. The electrophilic adduct to be displaced by the fluoride anion.
byproduct of the oxidation process, HF, is consumed in-situ by a
Figure 1: Fluorine transfer reagents based on N-F, S-F or I-F bonds.
denitrogenative hydrofluorination reaction of the diazo group.
PhO2S
SO2Ph
N
Cl
X
N
F
N
SF3
N
F
N
2 BF4
Introduction
F
1 SelectFluor
2 NFSI
3 N-fluoropyridinium salts 4 DAST
There are only a handful of naturally occurring fluorocarbons,
so fluorine’s use in medicinal chemistry might never have come
to pass had chemists limited themselves to naturally-inspired
pharmaceuticals.1 As fluorine is small, univalent and makes very
strong bonds to carbon, it is now routinely employed as a bio-
stere for hydrogen.2 Over the past few decades, site-specific
fluorination has become an essential tool to medicinal chemists
due to fluorine’s ability to act as a biostere, and because of its
desirable effects on the lipophilicity, metabolic stability and bi-
oavailability of pharmaceutical and agrochemical agents.3
X=BF4, OTf, F
MeO
OMe
F
O
N
I
N
I
Tol
F
BF4
SF2
SF3
F
7 TolIF2
5 Deoxo-Fluor
6 XtalFluor-E
8
Benzylic fluorides, represented by the ArCH2F, ArCF2H and ArCF3
groups,10 are common synthetic targets and strategies towards
the ArCH2F and ArCF2H functional groups have received consid-
erable attention in the literature.5a,5j,11 General strategies to-
wards their synthesis include deoxygenative fluorination of
Given the breadth of biologically active fluorinated com-
pounds,4 the development of new fluorination strategies and
reagents remain an important field of research.5 As a comple-
ment to nucleophilic fluorination strategies, a large body of re-
search developing electrophilic fluorinating reagents has been
completed. While elemental fluorine is the simplest and most
direct source of electrophilic fluorine, it is toxic, explosively re-
active with organic compounds, and cannot be used without
specialized laboratory equipment. To mitigate fluorine’s reac-
tivity, chemists have synthesized designer electrophilic fluori-
nating reagents based on N-F,6 S-F,7 and I-F bonds8,9 (Figure 1).
benzyl alcohol (using 4-6
),12 substitution reactions of benzyl hal-
ides,13 metal-catalyzed cross-coupling of fluorine-containing
units,3a,14 or radical-based fluorination reactions.15 The ArCH2F
group might also be synthesized by the hydrofluorination reac-
tion of diazo compounds, simply by treating them with HF
sources (Et3N•3HF, Py•
HF, HBF4, etc).16 This reaction is highly
effective for stabilized diazo compounds (eg. flanked by two Ar,
carbonyl, CF3 groups); however, the aryldiazomethanes re-
quired to synthesize benzylic monofluorides are unstable, rarely
isolable, and cannot easily serve as hydrofluorination precur-
sors. Nonetheless, development of this methodology could of-
fer a mild, rapid, operationally-simple and metal-free approach
to benzylic monofluorides from simple starting materials.
Recently Yadav and co-workers reported a novel reaction where
tosylhydrazone derivatives of aromatic aldehydes were con-
verted to diazo intermediates in situ, and then treated with
However, contrary to the N-F reagents (1-3) that serve as
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J. Name., 2013, 00, 1-3 | 1
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Et3N
•
3HF to produce hydrofluorination products 10 (Figure 2, Due to the increased stability of the putative intermediate diazo
View Article Online
a).17 In an earlier study, Myers reported the oxidation of TBS- compound, hydrazone 13a was used as our model substrate
hydrazones to aryldiazomethanes using (difluoroiodo)benzene, during the reaction optimization. We first studied the effects of
and their subsequent hydroacylation with carboxylic acids Lewis acid activators on the reaction, in both laboratory glass-
(Scheme 1, b).18 By combining these two concepts, we have de- ware and PFA vials, using the optimal conditions previously de-
veloped the first synthesis of benzyl fluorides where the hyper- termined in our gem-difluorination reactions.19c,21,22 Treating
DOI: 10.1039/C6OB02074G
valent iodine reagent, TolIF2, acts as both an oxidant and as the 13a with TolIF2 and 1 mol% BF3
•OEt2 generally failed in both
fluoride source, and gives 10 under mild and operationally sim- types of reaction vessel, and gave aldehyde 17a as the major
ple reaction conditions (Scheme 1, c).
product (Table 1, entries 1,2). The reactions were repeated us-
ing TiF3 as the activator, and while the reaction in glassware was
very low yielding, the reaction in PFA gave 10a in 48% yield,
along with 25% of aldehyde 17a (Table 1, entries 3,4). The ex-
periment conducted in glassware without a Lewis acidic activa-
tor was also very low yielding,21 but the analogous reaction in a
PFA vial proceeded in 47% yield (Table 1, entries 5, 6).
Figure 2: In situ synthesis of aryldiazomethanes with subsequent hydrofunction-
alization by acidic nucleophiles.
Hydrofluorination of p-tosylhydrazones:
NHTs
H
N
F
K2CO3, Et3N•3HF
toluene, reflux
(a)
H
9
R
10
R
Table 1: Optimization of the denitrogenative hydrofluorination reaction.
Hydroacylation of TBS-hydrazones
NHTBS
N
NH2
F
F
O
O2CR
H
N
TolIF2 (equiv.)
additive (mol%)
PhIF2
2-chloropyridine
F
H
(b)
H
H
solvent, T °C
vessel
CH2Cl2 then RCO2H
O2N
O2N
O2N
O2N
11
12
R
R
13a
entry
10a
16a
temp
17a
yielda yielda yielda
This work: Oxidation / hydrofluorination of hydrazones:
TilIF2
(equiv.)
additive
(mol%)
solvent
vessel
glassb
NH2
°C
10a
16a
17a
H
N
TolIF2
H
F
1
2
3
4
5
6
1.1
1.1
1% BF3•OEt2
1% BF3•OEt2
25% TiF3
5%
22%
10%
48%
71%
55%
34%
25%
18%
–
PhCl
DCM
DCM
DCM
110
40
(c)
PFAc
glass
13
R
10
R
40
19%
–
1.1
1.1
25% TiF3
40
PFA
–
glass
1.1
1.1
1.1
1.1
1.5
1.7
2.1
110
40
40
40
40
40
40
22%
47%
48%
60%
61%
74%
71%
10%
44%
6%
PhCl
DCM
DCM
DCM
DCM
DCM
DCM
–
–
–
PFA
PFA
PFA
PFA
PFA
PFA
7d
8d
25% TiF3
19%
12%
15%
12%
11%
Results and Discussion
–
–
–
–
5%
10%
11%
15%
Our studies of halogenation reactions using PhICl2 or TolIF2 as
halogen sources have led to the gem-dihalogenation of diazo-
carbonyl compounds19 and the oxidative dichlorination of isa-
tin-3-hydrazones.20 The gem-difluorination reactions of diaz-
oesters proceeded best using Lewis acid activation of TolIF2 with
9d
10d
11d
aIsolated yields. bReaction carried out in a borosilicate round bottom flask. cReac-
tion carried out in a 4 mL PFA vial. d Reverse addition of hydrazone to TolIF2.
BF3Ÿ
OEt219c or borosilicate glass21 (eq. 1). Similarly, the oxidative
difluorination reactions of benzaldehyde hydrazone 13a pro-
ceeded best with TiF3 activation of the iodane (eq. 2).22 During
these latter studies, we observed for the first time traces of hy-
drofluorination by-product 10a, which we attributed to the HF
generated during the oxidation23 competing with TolIF2 as an
electrophilic partner for the diazo intermediate. We believed
that this intermediate could be induced to react preferentially
to give 10a by undertaking chemoselectivity-guided modifica-
tion of the reaction conditions.
Mass spectrometry analysis of the crude reaction mixtures of
these preliminary trials by revealed the occasional occurrence
of a hydrofluorinated dimerization product. To preclude dimer
formation by minimizing the concentration of substrate relative
to electrophile, the two most promising trial reactions (entries
4 and 6) were repeated using reverse addition of the hydrazone.
The reaction using TiF3 was unchanged (entry 7), but the reac-
tion without a Lewis acid activator gave 10a in 60% yield (entry
8). These two trials (entries 6,8) were to first examples of fluor-
ination reactions occurring in a PFA vessel in the absence of a
Lewis-acidic activator. Presumably this is due to TolIF2 acting
solely as an oxidant, instead of as an electrophilic fluorine
source, for which Lewis acid activation is unnecessary.18 We
completed our reaction optimization by varying the loading of
the TolIF2 (entries 9-11). While the production of the aldehyde
by-product 17a was unchanged with increasing TolIF2 loading,
the amount of benzylic difluoride (16a) increased with increas-
ing TolIF2 loading. This is consistent with our expectation that
O
O
1.1 eq TolIF2
PhCl, 110 °C
(1)
OMe
OMe
F
F
N2
15
1 mol% BF3•OEt2 : 66%
borosilicate glass : 81%
14
NH2
H
F
F
2.3 eq. TolIF2
25 mol% TiF3
N
F
+
(2)
CH2Cl2, 0 °C
O2N
O2N
O2N
16a, 76% yield
10a, trace
13a
2 | J. Name., 2012, 00, 1-3
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NH2
H
1.7 equiv. TolIF2
CH2Cl2, 40 °C
the gem-difluorination reaction should compete with hydro-
fluorination in the presence of excess TolIF2. The highest yield
(74%) of the desired benzylic fluoride 10a was achieved when
1.7 equivalents of iodane was used.
N
View Article Online
DOI: 10.1039/C6OB02074G
F
5 -10 min
PFA vial
R
R
13
10
F
F
F
F
Having demonstrated that benzaldehyde hydrazones could be
induced to react selectively via the denitrogenative hydrofluor-
ination reaction, we next investigated the reaction efficacy on a
variety of substituted benzaldehyde hydrazone derivatives. The
para-, meta- and ortho-nitro substituted substrates all per-
formed well, as did the di-substituted derivatives having a meta-
O2N
NO2
10c 64%
H3C
NO2
NO2
10a 74%
10b 71%
10d 51%
F
F
F
F
Br
MeO2C
10f 64%
NC
NO2 substituent, giving the products 10a
para-carbomethoxy and para- or meta-cyano substituted ben-
zylic fluorides (10f ) were isolated in good yield, as were the
benzylic fluorides of the para-tosylate, para-phenyl and 3,4-di-
chloro substrates (10i ). The para-methoxy and para-dimethyl-
-e in 51-74% yield. The
NO2
CN
10g 71%
10e 71%
10h 73%
-
h
F
F
F
F
TsO
Ph
Cl
MeO
MeO
-
k
10i 64%
10j 68%
Cl
10k 68%
10l 0%
amino benzaldehyde hydrazones substrates were consumed by
the action of TolIF2; however, no traces of the benzylic fluorides
(
10l,m) were observed. Interestingly, when the electron-releas-
F
F
F
F
ing -OMe functional group was in the meta-position, the hydro-
fluorination reaction gave 10n in 45% NMR yield, and 33% iso-
lated yield. Presuming the volatility of 10n to be problematic,
we investigated the bulkier substrates 13o and 13p, which also
possessed electron releasing -OBn and -OMe groups in their re-
Me2N
10m 0%
Br
OMe
OBn
10p 47%
10n 33%
10o 45%
Scheme 1: Denitrogenative hydrofluorination of benzaldehyde hydrazone deriva-
tives.
spective meta- positions, and in both cases, the products 10o,p
were recovered in moderate yield.24
Figure 3: Plausible mechanistic pathway for the conversion of hydrazones to ben-
zylic fluorides.
N2
H
F
H
N2
H
These experiments indicate that substrates bearing electron-
neutral or electron-withdrawing substituents are well-tolerated
in the hydrofluorination reaction. And while substrates with
electron-releasing substituents at the para- position were not
compatible, substrates with the same electron-donating groups
in the meta- position were moderately effective in the reaction.
We attribute this trend to the destabilizing effect of electron-
donating groups on the aryldiazomethane intermediates, and
the decreased stability of the benzyl fluoride products that bear
an electron-donating group at the para- position. Our experi-
mental observations, coupled with the unlikelihood of free car-
bene formation at this low reaction temperature, led us to pro-
pose an ionic mechanism for the oxidative hydrofluorination re-
action (Figure 3). Upon oxidation of hydrazone 13 to aryldiazo-
F
TolIF2
H
H
H
13
N2
A
B
10
TolI
2 equiv. HF
G
G
G
destabilizing the diazo intermediate. This reaction is a mild,
rapid, metal-free and operationally simple alternative to the use
of alternative deoxygenative fluorinating strategies in the syn-
thesis of benzyl fluorides. Further exploration of this reaction,
including expanding the substrate and functional group scope,
is underway and will be disclosed in due course.
Experimental
methane intermediate
generated as by-products. Protonation of the diazo group
would give diazonium ion , from which N2 gas could be ex-
A, iodotoluene and HF (excess) would be
A 4 mL PFA vial containing (difluoroiodo)toluene (1.7 equiv)
was placed under nitrogen and immersed in a pre-heated 40 °C
bath. To this was added a pre-made solution of hydrazone 13a
(50 mg, 1.0 equiv) in CH2Cl2 (1.5 mL) via a syringe pump over
~10 minutes. The reaction was monitored by TLC analysis, and
upon consumption of the hydrazone (5-10 min), the reaction
mixture was cooled to RT and concentrated by rotary evapora-
tion. The resulting crude reaction mixture was purified by flash
silica gel chromatography (10% EtOAc in hexanes) to provide
benzyl fluoride 10a (35 mg) in 74% yield.
B
pelled upon fluoride attack, leading to benzylic fluoride 10
.
Conclusions
In conclusion, we have developed the first use of a hyperva-
lent iodine reagent (TolIF2) as both an oxidant and source of flu-
orine in the hydrofluorination of aromatic aldehyde hydra-
zones. The one-pot reaction made use of the oxidative potential
of the iodane, converting the hydrazone to a diazo group, and
generated an excess of the HF by-product which was consumed
by a denitrogenative hydrofluorination reaction. The reaction
proceeded best with electron-neutral or -withdrawing substitu-
ents, and failed with electron-donating groups capable of
Acknowledgments
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10. a) X. Y. Yang, T. Wu, R. J. Phipps and F. D. Toste, Chem. Rev., 2015,
The Natural Sciences and Engineering Research Council
(NSERC) of Canada and the University of Waterloo provided fi-
nancial support for this work. We would like to thank the mass
spec facility of the University of Waterloo for sample analysis.
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DOI: 10.1039/C6OB02074G
24. Hydrazones of 1-naphthaldehyde, pentafluorobenzaldehyde and
3-bromo-4-methoxybenzaldehyde were also effective in the
reaction, proceeding in 40-50% NMR yield. The products were
not sufficiently purified to determine isolated yields.
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TOC Graphic with Text:
(Difluoroiodo)toluene acts as both the oxidant and the fluoride source in this one-
pot oxidation/denitrogenative hydrofluorination reaction.