A Practical, Large-Scale Synthesis of p -(Difluoroiodo)toluene (p -TolIF 2)

Article abstract of DOI:10.1055/s-0037-1611526

p -(Difluoroiodo)toluene (p -TolIF ₂) is a versatile fluorinating agent that acts as both a surrogate for elemental fluorine, and as a source of 'electrophilic' fluorine. Described here is a detailed three-step synthesis of p -TolIF ₂

Full text of DOI:10.1055/s-0037-1611526

SYNTHESIS
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Georg Thieme Verlag Stuttgart · New York
2019, 51, A–E
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Synthesis
J. Tao, G. K. Murphy
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A Practical, Large-Scale Synthesis of p-(Difluoroiodo)toluene
p-TolIF2)
(
Jason Tao
Graham K. Murphy*
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Department of Chemistry, University of Waterloo, 200 University
Ave. W., Waterloo, ON, N2L 3G1, Canada
graham.murphy@uwaterloo.ca
Received: 06.03.2019
Accepted after revision: 26.03.2019
Published online: 25.04.2019
which resulted in a gem-difluoride synthesis via the de-
nitrogenation of diazo compounds. This strategy was ex-
7
DOI: 10.1055/s-0037-1611526; Art ID: ss-2019-m0153-psp
panded by Gouverneur and co-workers to include -trifluo-
8
romethyl diazo compounds, and by Wang and co-workers
Abstract p-(Difluoroiodo)toluene (p-TolIF ) is a versatile fluorinating
9
2
to include -diazophosphonates. In all three reports, the
agent that acts as both a surrogate for elemental fluorine, and as a
source of ‘electrophilic’ fluorine. Described here is a detailed three-step
synthesis of p-TolIF was accomplished by titrating p-iodo-
2
sotoluene with aqueous HF, and in each instance the prod-
uct was described as a pale-yellow or off-white solid. Given
that a significant part of our research program is devoted to
developing new HVI-mediated fluorination reactions,
developing a scalable, detailed and reproducible synthesis
synthesis of p-TolIF , carried out on a 50 mmol scale, that consistently
2
provides high-quality product that is suitable for long-term storage. The
reactions employ inexpensive, readily available starting materials and
reagents, and uses the commodity chemical 48% aqueous HF as the
source of fluorine atoms.
6b,10
of p-TolIF was essential.
Key words hypervalent iodine, p-(difluoroiodo)toluene, fluorination,
2
synthetic methodology, oxidation
Previously reported syntheses of 1 include the direct ox-
idative fluorination of p-iodotoluene (2) using fluorine gas
(Scheme 1a).11 Working with fluorine gas, however, re-
quires a specialised laboratory setup, and the administra-
The organic chemistry of hypervalent iodine (HVI) has
been known for over 130 years, and in addition to their
common use as oxidising agents, these species also serve as
tive barriers to securing fluorine in an academic lab can be
12
‘
electrophilic’ sources of a variety of functional groups.1
onerous. Variations on this strategy include using XeF or
2
13
This latter reactivity derives from the 3c-4e bonding within
the hypervalent ligand sphere of aryl- -iodanes, which
SF4 as fluorine sources, but these have drawbacks related
to cost or hazardousness of the reagents. Shreeve and co-
workers reported a related synthesis of 1 from p-iodotolu-
ene (2), using Selectfluor® (electrophilic fluorine) and
3
renders the iodine atom electrophilic and susceptible to nu-
cleophilic attack. Exploitation of this reactivity has led to
tremendous growth in the field of hypervalent iodine
chemistry over the past two decades. This is due to the new
reactivity patterns offered by these reagents, to the typical-
ly mild reaction conditions and to the environmentally be-
nign, recyclable reaction by-products.
The hypervalent iodine reagent p-TolIF (1) was among
the first hypervalent iodine reagents reported, and it
serves as a stable, solid surrogate for elemental fluorine. It
has found great success as a source of ‘electrophilic’ fluo-
rine or as a fluorine transfer agent, and its many uses in-
14
Et N·3HF (Scheme 1a). They further developed a tandem
3
iodination/oxidative fluorination reaction, and Gilmour and
co-workers showed that CsF was also an effective fluoride
source.15 The weakness in these strategies is the use of 2.6–
4 equivalents of Selectfluor to deliver a single fluorine atom
which, as the costliest reagent, is at significant expense.
2
2
Hara reported the electrochemical oxidation of p-iodotolu-
+
ene (1.5 V vs. Ag/Ag ), using Et N·5HF as the source of fluo-
3
ride,16 but such electrochemical methods are not widely
employed. An alternate approach to 1 involves displacing li-
gands on an existing iodine(III) compound by fluoride, such
3
4
clude the synthesis of -fluoro carbonyl compounds, de-
5
sulfurative fluorinations and fluorinative rearrangements
as treating p-TolICl2 (3) with yellow mercuric oxide and
6
6a,17
of styrenes and related compounds. In 2013, we reported
aqueous HF (Scheme 1b).
At scale, however, this would
the reaction between p-TolIF2 and phenyldiazoacetates,
be discouraged due to environmental concerns. The original
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–E

B
Synthesis
J. Tao, G. K. Murphy
PSP
synthesis of 1 by Weinland and Stille was accomplished by
accomplished on a 50 mmol scale within 2 hours. The re-
sulting wet filter cake could be carried on without purifica-
tion or characterization, thus minimising the potential for
decomposition due to instability or light/heat sensitivity. If
desired, intermediate 3 can be dried by the procedure de-
2
treating p-iodosotoluene (4) with aqueous HF, and this re-
4c,18
mains the main method for preparing 1.
a) p-TolIF2 synthesis via oxidative fluorination:
20
Selectfluor (2.6 equiv)
Et3N•3HF
scribed for the synthesis of (dichloroiodo)benzene. The
chlorination procedure is a significant improvement over
F
I
F2 or
I
2
XeF2, SF4
or
1
F
synthesis involving p-TolI(OAc) , which requires strict tem-
2
2
Selectfuor (4 equiv)
CsF (5 equiv)
perature control over a longer period of time; however, if
one wishes to store an intermediate at this stage of the syn-
thesis, p-TolI(OAc) is recommended over p-TolICl .
b) p-TolIF2 synthesis via fluorinative ligand transfer on iodanes:
2
2
Cl
HgO
48% HF aq.
CHCl3
O
I
1
aq. HF
I
Cl
3
4
c) This work: Large-scale, three-step synthesis of p-TolIF2 (1):
F
i) concd HCl, NaOCl aq. (gives 3)
I
I
ii) 3 N NaOH (gives 4)
iii) 48% aq. HF
F
1
2, 50 mmol
Scheme 1 Synthetic strategies towards p-(difluoroiodo)toluene
We set the goal of developing a reproducible, large-scale
and expeditious synthesis of high-quality p-TolIF that can
2
be accomplished by a single individual in one day. Our plan
was to optimise a large-scale process involving the chlori-
nation of p-iodotoluene (2) to give 3, hydrolyzing this to 4,
and then treating with aqueous HF to give 1 (Scheme 1c).
We tested the need for isolating and purifying intermedi-
ates 3 and 4, and we used repeated experimentation and
detailed observation to develop a precise purification se-
quence for 1. The result is a three-step procedure using in-
expensive, commodity chemicals, that gives high-quality p-
Figure 1 Chlorination of p-iodotoluene by adding concd HCl to aque-
ous NaOCl and acetonitrile
The conversion of p-TolICl (3) to p-iodosotoluene (4)
2
was readily accomplished using a simplified variant of a
previously reported procedure.18 Dropwise addition of 3 N
NaOH to 3 in THF leads to the iodoso compound 4. This re-
action is exothermic, and slow addition of NaOH is needed
so that the resulting exotherm can be suppressed by the
cooling bath. After various modifications to this procedure
were tested, we found that effective cooling of the large-
scale reaction could be achieved by pre-suspending the wet
filter cake of 3 in THF (Figure 2a).18 So long as the reaction
mixture is adequately cooled in a –10 °C ice-saltwater bath,
this obviates the need for ice within the reaction vessel.
The resulting precipitate is very fine, and removal of
THF and water via filtration could be very laborious. The
following steps were developed to expedite the filtration
process, while minimising the need for specialised lab
equipment and transfers between vessels: the filtration
flask is supported at ca. 40° angle, and the reaction mixture
is poured such that a small portion of the sintered glass sur-
face remained dry (and thus unplugged).22 Filtration yielded
a wet cake of 4 that was again carried forward without pu-
rification or characterization, so as to minimise the poten-
tial for decomposition by disproportionation or explosion
upon drying. If desired, p-iodosotoluene can be isolated by
using a procedure described for the related compound iodo-
TolIF that can be stored long-term. Using aqueous HF as
2
our fluorine source offers a significant financial advantage
over other direct syntheses, but as this is highly corrosive
and a contact poison, appropriate care must certainly be
taken when working with this reagent.
The synthesis begins with the oxidation of p-iodotolu-
ene (2). This reagent is obtained in varying degrees of co-
louration from commercial suppliers, and it should be puri-
fied to a white crystalline state prior to use. We decolorized
it by dissolving in hexanes, treating with aqueous sodium
thiosulfate solution until colourless, and then concentrating
the organic layer under vacuum. We observed that if this
pre-purification is omitted, the contaminant will be carried
through the synthesis and the resulting p-(difluoroiodo)tol-
uene will be faint yellow in colour. The oxidation of p-io-
dotoluene is commonly accomplished by two methods: oxi-
dation to p-TolI(OAc) or oxidation to TolICl , both of which
2
2
are viable in this synthesis. We found that the latter oxida-
tion could be rapidly and reproducibly accomplished by the
Zhang protocol of treating 2 with chlorine gas generated in
situ by the addition of concd HCl to 5.25% aqueous NaOCl
19
and acetonitrile (Figure 1). Other than cooling, this re-
quired no stringent reaction conditions, and was generally
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J. Tao, G. K. Murphy
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final transformation is reduced,4c so we employed continu-
ous dropwise addition of aqueous HF in this step (Figure
3a). Once the suspended solid had been consumed, the two
resulting phases were separated by removal of the top,
aqueous layer. One must ensure that all the aqueous drop-
lets are removed, or else the subsequent purification will be
compromised (Figure 3b).23 Concentrating the mixture to a
7
reduced volume, instead of to dryness, was critical to re-
covering high quality product. Also, the use of a mild heat-
ing bath helped keep the temperature stable, giving more
consistent reaction outcomes. When following purification
protocols that involved concentrating to dryness and re-
crystallising from hexanes,18 the product rapidly yellowed
in colour upon storage, consistent with the many reports of
Figure 2 (a) Reaction setup for hydrolysis of 3 and (b) filter flask setup
that minimises the time required for filtration of 4 as fine particulates.
1
being an off-white or pale-yellow solid. By following our
new purification sequence, in which direct crystallisation
of 1 is achieved from the reaction solvent, we can recover
8.2–9.2 grams (64–72% yield over three steps) of p-TolIF2.
The white, crystalline solid could be stored in a –20 °C
freezer under inert atmosphere for a year without discolor-
ation or a notable loss of reactivity.
sobenzene,21 and although we did not experience any diffi-
culties using 4 as a wet paste, iodosoarenes are known to
detonate when heated and especially when dried.
The procedure for converting 4 into p-TolIF uses 48%
2
aqueous HF, and is adapted from various syntheses report-
ed in the literature. The wet p-iodosotoluene filter cake is
immediately slurried in chloroform in a Teflon vessel,
cooled, and treated with aqueous HF. A large excess of HF
was needed to drive the reaction to completion, and we
found that using less HF led to an incomplete reaction, even
with prolonged stirring. As this is an inexpensive reagent,
the cost associated with this is minimal. Earlier reports sug-
gested that if the HF is added in one portion, the yield of the
In conclusion, we have developed an optimised proce-
dure for conducting a three-step synthesis of p-TolIF (1) on
2
a 50 mmol scale. The reactions involve the use of inexpen-
sive and readily available starting materials, and the com-
plete synthesis can be accomplished in a single day by one
experimentalist. This detailed synthesis provides high puri-
ty, crystalline product that is stable to prolonged storage,
and we believe that this procedure will be of interest to
practitioners of hypervalent iodine mediated fluorination.
Figure 3 (a) Setup for dropwise addition of 48% aq. HF to 4; (b) removal of the aqueous layer by transfer pipette; (c) setup for concentrating the organic
phase under a stream of nitrogen gas; and (d) a view inside the reaction vessel while partially concentrating the crude product.
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J. Tao, G. K. Murphy
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tained at ambient temperature. The flask was cooled to <–10 °C in an
ice-salt-water bath and equipped with a 125 mL pressure-equilibrat-
ing addition funnel charged with 3 N NaOH (50 mL, 150 mmol, 3
equiv). The NaOH was added to the flask dropwise over 5 minutes,
and then stirred for an additional 30 min, yielding an off-white solid
suspended in a colourless solution. Dichloromethane (100 mL) was
added to the reaction flask and the resulting suspension was stirred
for an additional 2 minutes prior to being filtered through a 350 mL
medium porosity sintered glass funnel (pore size: 10–15 microns, 9
cm diameter). The off-white filter cake was washed with water
Reactions were carried out using borosilicate glassware or in a 250
mL Teflon beaker. p-Iodotoluene [CAS Reg. No. 624-31-7] was pur-
chased from Aldrich Chemical Company, Inc., Oakwood Products, Inc.,
or Matrix Scientific. Acetonitrile (>99.5%), hexanes (98.5%), THF
(>99.5%), chloroform (>99.8%, stabilised with amylene), hydrochloric
acid (37%), NaOH pellets (97%), and hydrofluoric acid (48%) were pur-
chased from Aldrich Chemical Co., Inc. and were used as received. The
5.25% aq. NaOCl [CAS Reg. No. 7681-52-9] solution used was common
household bleach, specifically without hydroxide additives.
Melting points were recorded with a MEL-TEMP II instrument and are
uncorrected. Infrared spectra were recorded with a Perkin Elmer FT-
(5 × 30 mL), then dichloromethane (3 × 30 mL), which resulted in a
wet, pale-yellow paste of p-TolIO 4 that was carried forward without
purification or weighing.
1
IR Spectrum Two with ATR Two. Proton NMR spectra ( H NMR) were
recorded at 500 MHz, and are reported (ppm) relative to the residual
chloroform peak (7.26 ppm), and coupling constants (J) are reported
13
Step 1c: Synthesis of p-TolIF (1)
2
in hertz (Hz). Carbon NMR spectra ( C NMR) were recorded at 125
MHz, and are reported (ppm) relative to the centre line of the triplet
The wet filter cake of p-TolIO (4) was transferred to a 250 mL Teflon
beaker (6 cm diameter) equipped with 5 cm long magnetic stir bar.
The beaker was charged with chloroform (80 mL) and the resulting
suspension was stirred. The reaction vessel was cooled in a 0 °C an
ice-water bath and six portions of concentrated hydrofluoric acid
19
from CDCl (77.16 ppm). F NMR spectra were recorded at 282 MHz,
3
and are reported relative to TFA. TGA Analysis was performed with a
TGA Q500 V20.13 Build 39.
CAUTION! Mixing hydrochloric acid and aqueous NaOCl (bleach) gen-
erates toxic chlorine gas. The chlorination of p-iodotoluene should be
performed in a well-ventilated fumehood.
(
(
6 × 2.5 mL, 6 × 69 mmol, 6 × 1.4 equiv) were continuously added
dropwise) to the beaker using a 3 mL polypropylene graduated pi-
pette. After the addition of HF, the mixture was stirred for 30 minutes,
after which the solid p-iodosotoluene was no longer visible and the
reaction mixture consisted of two colourless phases. The reaction
vessel was then removed from the cooling bath and the top layer of
the biphasic mixture was removed by using a 3 mL polypropylene pi-
pette. Ensuring complete removal of all the aqueous droplets was criti-
cal to the success of this reaction. The beaker was then placed in a pre-
heated to 40 °C water bath and stirred while being concentrated to
approximately 25% of its original volume by using a gentle stream of
nitrogen gas.
CAUTION! The intermediate compound p-iodosotoluene 4 is explosive.
The related compound iodosobenzene is known to detonate when
isolated, dried and heated to ca. 200 °C. This intermediate is carried
forward wet in this synthesis, and there have been no adverse events.
CAUTION! Hydrofluoric acid is extremely toxic. Consult standard oper-
ating procedures before handling, use only in a well ventilated fume-
hood and ensure that proper PPE is worn when using this reagent.
Consult institutional HF handling SOPs and ensure suitable training
prior to carrying out this synthesis.
Crystallisation of the crude p-iodotoluene difluoride was induced by
slowly adding hexanes (100 mL) from a graduated cylinder to the Tef-
lon beaker at 40 °C over 1 minute. The resulting mixture was concen-
trated to approximately 25% of its original volume with a gentle
stream of nitrogen gas. The resulting slurry was cooled to 0 °C and de-
canted, ensuring that the white solid adhering to the side of the Tef-
lon beaker was quickly scraped down into the bulk solid by using a
metal spatula. (If desired, a polypropylene funnel equipped with filter
paper can be used to collect any lost p-iodotoluene difluoride during de-
cantation.) This bulk solid was washed twice with hexanes (50 mL),
decanting between washes. The resulting white solid was transferred
to a 10 dram Teflon or polypropylene vial, placed into a 40 °C water
bath, and the excess hexanes was evaporated by concentration under
a gentle stream of nitrogen gas. The vial containing the solid was de-
posited into a vacuum chamber and dried under high vacuum (<0.1
torr) until a constant weight of 8.2–9.2 g (64–72% yield over three
steps) of p-iodotoluene difluoride (1) was achieved. The resulting sol-
id, white needles (mp 99–101 °C), were stored in a –20 °C freezer un-
der an atmosphere of nitrogen gas. The purity of the product was de-
Step 1a: Synthesis of p-TolICl (3)
2
In ambient atmosphere, a 1 L round-bottomed flask with a 29/34
ground glass joint was charged with a 6 cm long Teflon-coated, ellip-
soidal magnetic stir bar and p-iodotoluene (2, 10.9 g, 50 mmol, 1
equiv). The flask was then charged with acetonitrile (100 mL) and the
mixture was stirred to give a colourless solution. The flask was then
cooled in a 5 °C ice-water bath and charged with 5.25% aq. NaOCl (300
mL, 211 mmol, 4.2 equiv). The flask was then equipped with a 125 mL
pressure-equilibrating addition funnel charged with concentrated
HCl (100 mL, 1.2 mol, 24.8 equiv). The reaction mixture was stirred
vigorously and the HCl was then added dropwise over 30 minutes.
The pale-yellow solution became dark-yellow during the first half of
the addition, and the solution became less intensely coloured as the
addition neared completion and p-iodotoluene dichloride was ob-
served as a yellow solid suspended in a faintly yellow solution.
After the addition of HCl was complete, the reaction mixture was
stirred for an additional 30 minutes. The mixture was then filtered
through a 350 mL medium porosity sintered glass funnel (pore size:
1
termined by quantitative H NMR analysis using hexamethyldisilox-
ane (HMDSO) as internal standard.
10–15 microns, 9 cm diameter) and the filtrate was discarded. The fil-
ter cake was washed with deionised water (3 × 200 mL), followed by
hexanes (3 × 50 mL), to give a wet filter cake of 3, usually weighing
IR (ATR): 1478 (m), 1380 (w), 1208 (w), 1001 (m), 789 (s) cm–1
.
15.35–16.10 g, that was used without further purification.
1
H NMR (300 MHz, CDCl ):  = 7.83 (d, J = 8.6 Hz, 2 H), 7.38 (d, J =
3
8.4 Hz, 2 H), 2.46 (s, 3 H).
Step 1b: Synthesis of p-TolIO (4)
13
C (125 MHz, CDCl ):  = 142.3, 132.1, 130.2, 120.8 (t, 2J = 11 Hz),
3
The wet filter cake of 3 was immediately transferred into a 300 mL,
single-neck round-bottomed flask with a 24/40 joint, using THF (100
mL) to assist with the transfer. To this was further added a 4 cm long
Teflon-coated ellipsoidal magnetic stir bar and the flask was main-
21.1.
19
F (282 MHz, CDCl ):  = –177.22.
3
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J. Tao, G. K. Murphy
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Funding Information
Fukuhara, T.; Yoneda, N. Synlett 1998, 495. (d) Hara, S.;
Nakahigashi, J.; Ishi-i, K.; Fukuhara, T.; Yoneda, N. Tetrahedron
Lett. 1998, 39, 2589.
This work was supported by the Natural Sciences and Engineering Re-
search Council of Canada (NSERC; grant number 418602-2013) and
by the University of Waterloo. J.T. was supported by an NSERC PGS-D
(
7) Tao, J.; Tran, R.; Murphy, G. K. J. Am. Chem. Soc. 2013, 135,
16312.
award.
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(
8) Emer, E.; Twilton, J.; Tredwell, M.; Calderwood, S.; Collier, T. L.;
Liegault, B.; Taillefer, M.; Gouverneur, V. Org. Lett. 2014, 16,
6
004.
Acknowledgment
(
9) Zhou, Y.; Zhang, Y.; Wang, J. Org. Biomol. Chem. 2016, 14, 10444.
(
10) (a) Sinclair, G. S.; Tran, R.; Tao, J.; Hopkins, W. S.; Murphy, G. K.
Eur. J. Org. Chem. 2016, 4603. (b) Zhao, Z.; Kulkarni, K. G.;
Murphy, G. K. Adv. Synth. Catal. 2017, 359, 2222.
We would like to thank Dr. Léanne Racicot for her advice and sugges-
tions, as well as Dr. Thomas Wirth (Cardiff University) for helpful dis-
cussions.
(11) (a) Naumann, D.; Ruther, G. J. Fluorine Chem. 1980, 15, 213.
(b) Ruppert, I. J. Fluorine Chem. 1980, 15, 173.
(
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611526.
(
(
14) Ye, C. F.; Twamley, B.; Shreeve, J. M. Org. Lett. 2005, 7, 3961.
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S
u
p
p
orti
n
g Inform ati
o
n
S
u
p
p
orit
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g Inform ati
o
n
(
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(23) This aqueous layer contains extremely toxic hydrofluoric acid.
Appropriate protective equipment and handling procedures for
safe HF use should be adhered to. This aqueous hydrofluoric
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sium hydroxide.
(
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–E