One-pot synthesis of hypervalent iodine reagents for electrophilic trifluoromethylation

Article abstract of DOI:10.1021/jo400774u

Simplified syntheses suited for large scale preparations of the two hypervalent iodine reagents 1 and 2 for electrophilic trifluoromethylation are reported. In both cases, the stoichiometric oxidants sodium metaperiodate and tert-butyl hypochlorite have been replaced by trichloroisocyanuric acid. Reagent 1 is accessible in a one-pot procedure from 2-iodobenzoic acid in 72% yield. Reagent 2 was prepared via fluoroiodane 11 in a considerably shorter reaction time and with no need of an accurate temperature control.

Full text of DOI:10.1021/jo400774u

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Note
One-Pot Synthesis of Hypervalent Iodine
Reagents for Electrophilic Trifluoromethylation
Václav Matoušek, Ewa Pietrasiak, Rino Schwenk, and Antonio Togni
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400774u • Publication Date (Web): 04 Jun 2013
Downloaded from http://pubs.acs.org on June 5, 2013
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One-Pot Synthesis of Hypervalent Iodine Reagents for
Electrophilic Trifluoromethylation
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Václav Matoušek, Ewa Pietrasiak, Rino Schwenk and Antonio Togni*
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Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology,
ETH Zürich, CH-8093 Zürich, Switzerland
Corresponding author : atogni@ethz.ch
TCICA, KOAc,
CF3SiMe3
I
O
I
F3C
O
OH
O
One-pot
in MeCN
72%
1
Abstract: Simplified syntheses suited for large scale preparations of the two hypervalent
iodine reagents 1 and 2 for electrophilic trifluoromethylation are reported. In both cases the
stoichiometric oxidants sodium metaperiodate and t-butyl hypochlorite, respectively, have
been replaced by trichloroisocyanuric acid. Reagent 1 is accessible in an one-pot procedure
from 2-iodobenzoic acid in 72% yield. Reagent 2 was prepared via fluoroiodane 11 in a
considerably shorter reaction time and no need of an accurate temperature control.
In recent years, the arena of synthetic organic chemistry has witnessed a vigorous
development of various synthetic methods for the introduction of polyfluorinated groups into
a plethora of molecular targets.1 The growing demand of such methods is intimately
associated with the benefits deriving from new molecules having remarkable properties such
as altered metabolic behavior, resistance towards chemical and enzymatic degradation, strong
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impact on acid-base equilibria,2 and enhanced lipophilicity.3 Consequently, fluoroalkylated
compounds are highly desirable targets mostly in the context of medicinal, crop protection,
and materials chemistry.
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Several years ago, our research group reported a conceptually new family of formally
electrophilic CF3 transfer reagents based on a cyclic hypervalent iodine(III) core,4 the most
successful ones being the "acid reagent" 1 and the "alcohol reagent" 2 (Figure 1).5
F3C
I
O
F3C
I
O
O
2
1
"Acid reagent"
"Alcohol reagent"
Figure 1. Hypervalent iodine reagents for electrophilic trifluoromethylation.
Recently, the substrate scope and general applicability of these reagents has been considerably
expanded thanks to significant contributions from several research groups. The original notion
that these reagents are primarily suited for trifluoromethylation of soft phosphorus-, sulfur-
and carbon-centered nucleophiles such as phosphines,6 thiols, α-nitroesters, β-ketoesters,7
phosphorothioates,8 and aromatics9 was soon to be overcome since even hard O-centered
nucleophiles such as alcohols,10 sulfonic acids,11 and hydrogen phosphates12 undergo
trifluoromethylation under proper Lewis or Brønsted acid activation. The concept of Lewis
acid activation of the CF3 reagents analogously demonstrated its utility in the
trifluoromethylation of nitrogen nucleophiles, such as in Ritter type functionalizations of
nitriles13 and trifluromethylations of trimethylsilylated azoles.14 Transition-metal promoted
transformations have provided a facile entry into selective trifluoromethylation of aromatic
cores,15 allylic trifluoromethylation of alkenes,16 trifluoromethylation of terminal alkynes,17
allylsilanes,18 and oxidative functionalization of alkenes.19 Substrates bearing enolizable
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carbon centers were shown to be good candidates for the stereoselective introduction of the
CF3 moiety, including α-trifluoromethylation of aldehydes using cooperatively Lewis acid
activation and organocatalysis,20 or enantioselective trifluoromethylation of cyclic β-keto
esters in the presence of chiral Cu-complexes.21 Finally, chiral enolates featuring the
acyloxazolidinone motif were trifluoromethylated in a diastereoselective fashion.22
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Based on this rapid progress, it is reasonable to assume that these hypervalent CF3 iodine
reagents might find in the near future further applications in late steps of syntheses as well as
in the production of valuable trifluoromethylated products on a multikilogram scale in the fine
chemical industry.
We were therefore motivated to reexamine the current syntheses of 1 and 2 and subject them
to a careful redesign and optimization for them to meet standards typical for larger scale
preparations, such as scalability, reproducibility, reduction of manipulation steps, use of less
hazardous reagents, lower production of toxic aqueous streams and finally reduction of the
amounts of costly reagents.
Ac2O,
AcO
I
O
I
OH
HO
I
O
F3C
I
O
1.4 equiv CF3SiMe3
1) 1.5 equiv NaIO4,
reflux, H2O
140 °C, 5 min
O
O
O
O
1 mol% CsF
MeCN, rt, 24 h
2) H2SO4
3
4
5
1
96%
79%
Scheme 1. Current synthetic sequence leading to reagent 1.
The original synthesis of 1 (Scheme 1) commences with the aqueous oxidation of 2-
iodobenzoic acid 3 with 1.5 equivalents of sodium metaperiodate at reflux overnight
producing a suspension of hydroxyiodobenziodoxolone 4 in typical yields between 91-96%
after additional acidification with dilute sulfuric acid. The dry 4 is then acetylated in hot neat
acetic anhydride. The progress of this acetylation can be conveniently visually monitored as
the resulting acetoxy iodane 5 is well soluble in the mixture of hot acetic anhydride/acetic
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acid and finally a clear solution of 5 is obtained. Although we never experienced any accident,
the acetylation step has been always conducted behind a safety screen because of conceivable
adventitious traces of iodine(V) impurities or traces of sodium iodate contaminating the
starting material and possibly leading to violent decomposition processes.23 Cooling the
resulting solution to -20 °C brings about complete crystallization of 5 which is decanted from
the remaining mother liquor. For the final umpolung step, the crystalline 5 with acetic
anhydride/acetic acid mixture has to be thoroughly dried. Although this procedure is
acceptable for a small scale synthesis, the drying process becomes rather lengthy and often
incomplete as the batches exceed 30-40 g of material. The presence of acetic acid is
detrimental to the last step in which dry 5 is treated in acetonitrile suspension with 1.4 equiv
of the Ruppert-Prakash reagent (TMSCF3) and 1 mol% of cesium fluoride; in some cases it
was necessary to add cesium fluoride several times to initiate the umpolung reaction.
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During our initial attempts to find an alternative cheap non-aqueous oxidant capable of
selectively oxidizing 2-iodobenzoic acid to an appropriate iodine(III) intermediate, we were
pleased to find out that the use of stoichiometric 2,4,6-trichloro-triazin-1,3,5-trione,
commonly termed as trichloroisocyanuric acid (TCICA),24 gave a quantitative yield of the
corresponding chloroiodane 6 with concomitant precipitation of insoluble isocyanuric acid.
Heating the resulting suspension to reflux and filtration over a pad of Celite® while hot gave a
light yellow solution which upon concentration, filtration and washing with cold acetonitrile
provided free-flowing crystals of 6 in quantitative yield and excellent purity (Scheme 2).
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O
0.34 equiv TCICA
(= 1.02 Cl+ equiv.)
I
O
I
Cl
O
HN
NH
OH
O
+
O
N
H
O
MeCN, reflux, 5 min.
8
6
3
9
quantitative yield
200 g scale
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Scheme 2. Chlorination of 2-iodobenzoic acid 3 with trichloroisocyanuric acid.
Subsequent treatment of 6 with 2 equivalents of anhydrous KOAc in acetonitrile under reflux
for 2 h provided a fine suspension of KCl and acetoxyiodane 5 which was in situ treated with
1.1 equiv of TMSCF3 at room temperature overnight. The resulting suspension was quickly
heated to reflux and filtered over Celite® to give a brownish solution which after
concentration and cooling furnished crystals of 1 in 75-79% isolated yield (Scheme 3).
F3C
I
O
1) 2 equiv KOAc
2 h, 75 °C
Cl
I
O
O
O
2) 1.1 equiv CF3SiMe3
3.5 h
MeCN, rt
1
6
75-79% yield
30 g scale
Scheme 3. Preparation of reagent 1 from chloroiodane precursor 6.
During the scale up of this procedure to 30 g we have encountered difficulties in reproducing
yields and the product was often contaminated with the intermediate acetoxyiodane 5
indicating an incomplete umpolung step. We speculated that as the scale of the reaction was
increased, problems of efficient mass transfer in the reactor flask might have been responsible
for the lower yields. Indeed, using more vigorous and turbulent stirring conditions restored the
isolated yield. For larger scale work, the use of a mechanical propeller-shaped stirrer capable
of achieving high Reynolds number (> 10000), optionally combined with installed baffles on
the reactor walls is therefore highly recommended. Interestingly, the use of highly turbulent
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stirring on a 30 g scale considerably accelerated the umpolung step, since the reaction was
complete within 3.5 hours, a significantly shorter time than previously observed.25
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First experiments to unite all steps, i.e. chlorination of 2-iodobenzoic acid, chloride/acetate
exchange and CF3 umpolung met with failure. Upon mixing 2-iodobenzoic acid with dry
KOAc in acetonitrile, the rapid formation of a thick paste of potassium 2-iodobenzoate was
observed. However, after addition of trichloroisocyanuric acid, no chlorination took place.
Changing the order of addition appeared to solve the problem - chlorination of 2-iodobenzoic
acid and subsequent addition of KOAc followed by stirring at 75 °C for 2 hours gave a
suspension of 5 accompanied by insoluble isocyanuric acid and KCl. To this vigorously
stirred suspension was added at room temperature 1.4 equiv. of TMSCF3 and the resulting
mixture was vigorously stirred overnight. Subsequent quick heating to reflux, filtration over
Celite® and crystallization provided reagent 1 in 72% isolated yield, demonstrating that all
three steps can be conveniently united into a one-pot protocol (Scheme 4). The presence of
practically insoluble isocyanuric acid seemed to somewhat decrease the rate of the CF3
umpolung as compared to the previous variant starting from 6.
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1) 0.34 equiv TCICA, 5 min, reflux
I
O
F3C
I
O
2) 2 equiv KOAc, 2 h, 75 °C
3) 1.4 equiv CF3SiMe3, rt, 12 h
OH
O
MeCN
1
3
72% yield
15 g scale
Scheme 4. One-pot preparation of reagent 1 from 2-iodobenzoic acid.
The optimization of the synthesis of reagent 226 started with a more cost-effective synthesis of
methyl 2-iodobenzoate 8. Instead of esterification of relatively expensive 2-iodobenzoic acid,
much cheaper methyl anthranilate was diazotized in aqueous diluted sulfuric acid and the
resulting cold solution of diazonium salt was slowly cannulated into an acidified solution of
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potassium iodide with 0.28 equivalents of sodium hydrogensulfite. The presence of
hydrogensulfite anion in substoichiometric amounts ensures that all iodine, which is a side
product of radical decomposition of the diazonium salt, is reduced back to iodide allowing to
use only near-stoichiometric quantity of potassium iodide. The resulting methyl 2-
iodobenzoate 8 can be readily separated from the aqueous phase without the need of
extraction (Scheme 5).
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1) H2SO4, 1.01 equiv NaNO2, 0-5°C
NH2
O
I
O
2) 1.02 equiv KI,
0.28 equiv NaHSO3, 40°C to 80°C, 1 h
O
O
H2O
7
8
150 g scale
93% in 95% purity
Scheme 5. Cost-effective synthesis of methyl 2-iodobenzoate.
The following addition of methylmagnesium iodide to methyl 2-iodobenzoate to form alcohol
9, was performed according to the literature procedure26 with a minor modification of the
quench step, i.e. an inverse mode of quenching was preferred. With larger batches this
becomes especially convenient as compared to the original procedure where stirring problems
were often encountered because the partially hydrolyzed magnesium salts hampered regular
stirring and proper heat exchange. To transform the tertiary iodoalcohol 9 into the
corresponding chloroiodane 10, t-butyl hypochlorite was used in the previous synthesis.
However, the latter light-sensitive reagent has several disadvantages. It is a potent
lachrymator and its shelf life is short. Furthermore, it is linked to a history of documented
violent decompositions27 and the commercial availability is restricted. To our delight, the
same transformation could be effected in acetonitrile with stoichiometric amounts of
trichloroisocyanuric acid in comparable yield (Scheme 6).
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O
0.34 equiv TCICA
(= 1.02 Cl+ equiv.)
I
OH
Cl
I
O
HN
NH
+
O
N
H
O
MeCN, reflux, 5 min.
8
9
10
9
89% yield
190 g scale
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Scheme 6. Oxidation of alcohol 9 with TCICA.
In the previous synthesis of 2,26 the final umpolung starting from 1-acetoxy-3,3-dimethyl-1,2-
benziodoxole had to be performed using a carefully controlled temperature gradient and
required more than 20 h in order to obtain high yields. We were therefore prompted to look
for a more suitable hypervalent iodine precursor that does not necessitate such a strict control
of reaction conditions. We were very pleased to find that the use of fluoroiodane intermediate
11 is a very good alternative to the corresponding acetate. The halogen exchange with 1.5
equiv. of spray-dried KF goes to completion overnight at room temperature, giving a clear
white suspension of fluoroiodane 11. The addition of 1.1 equiv of TMSCF3 to this cooled
suspension led to a smooth umpolung in one hour affording 2 in 85-91% isolated yield
(Scheme 7).
1) 1.5 equiv spray dried KF, rt, 12 h
Cl
I
O
F3C
I
O
2) 1.1 equiv CF3SiMe3, -10 °C to rt, 1 h
MeCN
10
2
85-91% yield
F
I
O
11
Scheme 7. Fluoroiodane 11 as intermediate in the synthesis of reagent 2.
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The intermediate fluoroiodane 11 could be eventually isolated in sufficiently pure form and
excellent yield. X-ray quality crystals were grown by slowly cooling a corresponding solution
in pentane/dichloromethane. The crystallographic analysis revealed, as already noted,28 a I-O
bond shortening in comparison to the related chloroiodane 10 due to an altered trans effect of
the fluorine atom.29 Studies directed towards the use of this relatively easily accessible
fluoroiodane as an electrophilic fluorinating reagent are ongoing in our group.
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In conclusion, both syntheses of the hypervalent iodine reagents 1 and 2 were subjected to a
careful optimization. In the synthesis of reagent 1 a one-pot protocol could be devised, while
in the synthesis of reagent 2 several important improvements could be made, particularly in
terms of safety and operational simplicity. We hope this work will stimulate further interest
from the organofluorine community in these already popular reagents.
Experimental Section
General. All experiments were carried out under an Ar atmosphere with oven-dried (140 °C)
glassware and magnetic stirring if not otherwise stated. Acetonitrile (p.a.) and pentane (p.a.) was dried
for at least 24 h prior to use over activated 3Å molecular sieves. Potassium acetate (p.a.) was dried
under high vacuum (8 10-3 mbar) at 130 °C for 1-2 h prior to use (for one pot synthesis of reagent 1).
2-iodobenzoic acid (98%) was supplied by TCI Chemicals, GmbH. Grey samples of 2-iodobenzoic
acid obtained from some other suppliers gave inferior results. Other commercially available chemicals,
1
including trichloroisocyanuric acid (TCICA, 97%) and spray-dried KF were used as received. H, 19
F
and 13C NMR spectra were recorded on a spectrometer operating at 300.1 MHz, 282 MHz, and 75.5
MHz, respectively. Since all compounds reported here are known we do not describe corresponding
NMR spectra. However, copies of NMR spectra are provided in the Supporting Information. Melting
points are corrected.
Chlorination of 2-iodobenzoic acid (3) to 1-chloro-1,2-benziodoxol-3(1H)-one (6). A 3-liter
three-necked round-bottom flask equipped with a massive ellipsoidal magnetic stirring bar (6 cm
diameter), Ar inlet, Dimroth condenser and dropping funnel with pressure-equalizing side-arm was
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charged under Ar with solid 2-iodobenzoic acid (200 g, 0.7902 mol, 1 equiv) and anhydrous MeCN
(1.5 l) was added. The resulting stirred suspension was heated to 75°C in an oil bath. The dropping
funnel was charged with a solution of trichloroisocyanuric acid (63.7 g, 0.2660 mol, 1.02 Cl+ equiv) in
300 mL anhydrous MeCN. The solution of trichloroisocyanuric acid was dropped into the vigorously
stirred reaction mixture within 5 minutes. During the addition of trichloroisocyanuric acid, formation
of insoluble isocyanuric acid became apparent. The dropping funnel was rinsed with further anhydrous
MeCN (100 mL). After addition was complete, the reaction mixture was refluxed for further 5
minutes. The reaction mixture was vacuum-filtered over an oven-preheated sintered-glass funnel with
a tightly packed pad of Celite® (1 cm thick) and the filter cake was rinsed with additional hot MeCN
(100-200 mL). The combined filtrates were evaporated to near dryness, the resulting yellow solid was
filtered over a sintered-glass funnel and washed with little cold MeCN. The mother liquor from
filtration was partially concentrated on a rotavap giving a second crop of crystals. The combined crops
were dried for 2 hours under high vacuum to give product 6 as free flowing light yellow crystals in
quantitative yield. (223 g): mp 178.5-180 °C (partial dec.); δH (300 MHz, CDCl3, 23°C) 7.79 (m, 1H),
7.99 (ddd, J = 8.6, 7.2, 1.6 Hz, 1H), 8.23 (ddd, J = 14.0, 8.0, 1.3 Hz, 2H); δC (75.5 MHz, CDCl3, 23°C)
117.1, 126.9, 128.8, 131.9, 133.4, 136.6, 167.2; Anal. Calcd. for C7H4O2ClI: C 29.77, H 1.43; found C
29.84, H 1.60.
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Preparation of reagent 1 from 1-chloro-1,2-benziodoxol-3(1H)-one (6). A 500 mL two-
necked round-bottom flask equipped with a massive ellipsoidal-shaped magnetic stirring bar (4 cm
diameter), rubber septum and Ar inlet was charged with potassium acetate (21 g, 0.212 mol, 2 equiv).
This was heated with stirring under high vacuum (8 10-3 mbar) for 5 minutes, then cooled down to
room temperature under Ar. 1-Chloro-1,2-benziodoxol-3(1H)-one (6, 30 g, 0.106 mol, 1 equiv) was
added in counter-current flow of Ar followed by anhydrous MeCN (300 mL). The resulting
suspension was vigorously stirred under Ar at 75°C for 2 hours. The color went from slightly
yellowish to off-white. The suspension was cooled to room temperature and
trifluoromethyltrimethylsilane (17.3 mL, 16.57 g, 0.1166 mol, 1.1 equiv) was injected through the
septum in one portion and the resulting suspension was vigorously stirred for 3.5 h during which the
mixture turned brownish. A sample of the reaction mixture revealed by 19F NMR analysis that
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trifluoromethyltrimethylsilane was almost completely consumed. Further anhydrous MeCN (100 mL)
was added, the reaction mixture was heated to 75°C in an oil bath and filtered hot over a Celite® pad (1
cm thick). The Celite® pad was rinsed with additional hot MeCN (100 mL). The brown filtrate was
concentrated to approx. 80 mL end volume (whereby crystals of reagent 1 already formed) and stirred
at -20 °C to complete crystallization. The crystals were filtered off, rinsed with cold MeCN (-20 °C, 30
mL) and dried under vacuum. The mother liquor was again concentrated to ca. 25 mL end volume,
cooled to -20°C, the crystals were filtered off and washed with little cold MeCN. Both crystalline
fractions were dried under high vacuum to give the product as a white solid (24.5 g first crop, 1.57 g
second crop, combined yield 78%). Yields varied between 76 and 79%. mp 163 °C (dec.); δH (300
MHz, CDCl3, 23°C) δ 7.67 – 7.89 (m, 3H), 8.38 – 8.52 (m, 1H); δC (75.5 MHz, CDCl3, 23° C) 107.1
(q, J = 380.2 Hz), 114.8 (poorly resolved q, J = 1.1 Hz), 127.3 (q, J = 3.2 Hz), 131.9, 133.7, 135.7,
165.9; δF (282 MHz, CDCl3, 23 °C) -33.84; Anal. Calcd. for C8H4O2F3I : C 30.41, H 1.28; found C
30.40, H 1.48.
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One-pot preparation of reagent 1 from 2-iodobenzoic acid (3). A 250 mL three-necked
round-bottom flask equipped with a massive ellipsoidal-shaped magnetic stirring bar (4 cm diameter),
Dimroth condenser, dropping funnel with pressure-equalizing side-arm and Ar inlet was charged with
2-iodobenzoic acid (14.1 g, 55.7 mmol, 1 equiv) followed by dry MeCN (120 mL). The resulting
stirred suspension was heated to 75 °C. Meanwhile, the dropping funnel was charged with a solution
of trichloroisocyanuric acid (4.49 g, 18.75 mmol, 1.02 Cl+ equiv) in MeCN (30 mL). The solution of
trichloroisocyanuric acid was added within 5 minutes. After the addition was complete, the dropping
funnel was rinsed with dry MeCN (10 mL). The reaction mixture was cooled to r. t., dry potassium
acetate (10.95 g, 114.4 mmol, 2 equiv) was added under a counter-current flow of Ar and the resulting
suspension was again heated to 75 °C for 2 h and then cooled to r. t. Trifluoromethyltrimethylsilane
(11.5 mL, 11.1 g, 78 mmol, 1.4 equiv) was added at once and the resulting mixture was vigorously
stirred for 12 h. After this time, further dry MeCN (50 mL) was added, the resulting suspension
brought to reflux and filtered over a pad of Celite® (1 cm thick). The brown filtrate was concentrated
in a rotavap to ca. 1/3 of its original volume and cooled to -20 °C under stirring. The formed crystals
were filtered off and washed with little cold MeCN. The mother liquor from filtration was further
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concentrated in a rotavap to 1/3, cooled to -20 °C, and a second crop of crystals was isolated by
filtration. Both crystal crops were dried under high vacuum to give the product as white to off-white
solid. (11.9 g first crop, 0.8 g second crop, combined yield 72%).
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Synthesis of methyl-2-iodobenzoate (8) from methyl anthranilate (7).30 A 2-liter beaker
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equipped with an overhead mechanical stirrer was placed in a larger plastic bowl and secured in
position by symmetrically positioned pieces of elastic sponge placed between the external wall of the
beaker and the internal wall of the plastic bowl. The mechanical stirring rod should preferably have
rather smaller vanes (1 cm). The beaker, externally cooled with ice-salt mixture, was subsequently
charged with 300 g ice, 100 mL distilled water and concentrated sulfuric acid (83 mL, 153 g) and the
mixture was stirred. Methyl anthranilate (151 g, 1 mol, 1 equiv) was quickly poured into the beaker.
Within few seconds, full solidification of the reaction mixture to a white paste of the hydrogensulfate
salt occurred. The mixture was cooled to 0-5 °C and diluted with ice cold distilled water (100 mL). A
solution of sodium nitrite (70 g, 1.01 mol, 1.01 equiv) in water (100 mL) was injected slowly under
the surface of the stirred suspension to minimize losses of nitrite due to decomposition to nitrous
gases. During the addition of sodium nitrite, temperature of the reaction mixture should be held within
the range 0-7 °C. Occasionally, addition of crushed precooled ice (liquid N2-precooled) conveniently
lowers the temperature of the reaction mixture. After all sodium nitrite has been added, the reaction
mixture was stirred until it gave only a weak nitrite content as indicated by KI-starch paper. The
diazonium salt solution, cooled to -5°C, was then transferred during 30 minutes via Teflon cannula
into a well-stirred, warmed (40 °C) mixture of potassium iodide (170 g, 1.02 mol, 1.02 equiv), 300 mL
water, 40% solution of sodium hydrosulfite (75 g, 40% solution, 0.28 mol, 0.28 equiv) and sulfuric
acid (36 mL of concentrated sulfuric acid diluted in 75 mL distilled water) placed in a well-stirred 3-
liter three-necked round-bottom flask equipped with massive magnetic stirring bar, Dimroth condenser
and vacuum-inlet. The addition should be done preferably in small portions in order to prevent
excessive foaming during the decomposition. After the addition, the mixture was allowed to react at
40 °C for 5 minutes and then at 80 °C for 1 hour. The dark brown reaction mixture was then cooled to
r. t., the lower heavy organic phase was separated and washed subsequently with 20% diluted sulfuric
acid (150 mL), diluted sodium hydrogensulfite (150 mL), water (200 mL) and brine (200 mL). The
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organic phase was diluted with ethyl acetate (200 mL), dried over a mixture of anhydrous sodium
sulfate and potassium carbonate, filtered and concentrated to dryness to give orange-colored methyl-2-
iodobenzoate (8, 245 g, 93% yield in 95% purity, 88% yield corrected for purity). Analytically pure
material can be obtained by vacuum-distillation. δH (300 MHz, CDCl3, 23°C) 3.91 (s, 3H), 7.12 (m,
1H), 7.37 (m, 1H), 7.77 (dd, J = 7.8, 1.7 Hz, 1H), 7.96 (dd, J = 7.9, 0.9 Hz, 1H); δC (75.5 MHz,
CDCl3, 23°C) 52.5, 94.1, 127.9, 131.0, 132.7, 135.2, 141.3, 167.0; Anal. Calcd. for C8H7O2I : C 36.67,
H 2.69; found C 37.09, H 2.83.
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Remarks for the synthesis of 2-(2-iodophenyl)-propan-2-ol (9). The synthesis was performed
as described in the literature,26 however with minor modifications: a) On a larger scale, addition of
methyl 2-iodobenzoate to the solution of methylmagnesium iodide in diethylether should be done with
careful temperature control. Preferably, the solution of methylmagnesium iodide should be precooled
to -30 °C. b) Frequently, the reaction mixture does not have be stirred overnight or refluxed. In most
cases TLC reaction control revealed the reaction to be complete within 6 hours after addition of
methyl 2-iodobenzoate. Longer ageing of the reaction mixture has been shown to lead to increased
formation of byproducts. c) On a larger scale, quenching of the reaction mixture is conveniently done
in an inverse manner - the reaction mixture is allowed to run via a Teflon cannula onto a well stirred
ice-slush-water mixture and then diluted with ethyl acetate. Insoluble magnesium salts are easily
dissolved by addition of formic acid until pH= 4-6 is reached. In this way, possible thermal stress and
stirring problems during the quench are eliminated.
Chlorination of 2-(2-iodophenyl)-propan-2-ol (9) to 1-chloro-3,3-dimethyl-1,2-
benziodoxole (10). A 2-liter three-necked round-bottom flask equipped with a massive ellipsoidal
magnetic stirring bar (8 cm diameter), Ar inlet, Dimroth condenser and dropping funnel with pressure-
equalizing side-arm was charged under Ar with crude 2-(2-iodophenyl)-propan-2-ol (191 g of 90%
purity, 0.656 mol, 1 equiv) and anhydrous MeCN (1.2 l) was added. The resulting stirred suspension
was heated to 75 °C in an oil bath. The dropping funnel was filled with a solution of
trichloroisocyanuric acid (52.9 g, 0.2207 mol, 1.02 Cl+ equiv) in anhydrous MeCN (200 mL). The
solution of trichloroisocyanuric acid was added to the well-stirred solution of 2-(2-iodophenyl)-
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propan-2-ol within 5 minutes. During addition, formation of insoluble isocyanuric acid was observed.
The resulting suspension was refluxed for further 5 minutes and then filtered hot over a preheated
sintered-glass funnel covered with a tightly pressed pad of Celite® (1 cm thick). The filter cake was
then washed with boiling MeCN (100 mL). The yellow-to-brown filtrate was concentrated in a
rotavap to 150 mL end volume, cooled to -20 °C, and the resulting yellow crystals were filtered off
and washed with a little cold MeCN. Concentration of the mother liquor gave a further crop of
crystals. The crystals were dried under high vacuum. (first crop 164 g, second crop 9 g, combined
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yield 89%). mp 145-147 °C; δH (300 MHz, CDCl3, 23 °C) δ 1.55 (s, 6H), 7.12 – 7.21 (m, 1H), 7.46 –
7.62 (m, 2H), 7.95 – 8.09 (m, 1H); δC (75.5 MHz, CDCl3, 23°C) 29.2, 85.2, 114.7, 126.1, 128.5, 130.5,
131.0, 149.5. Anal. Calcd. for C9H10OClI: C 36.45, H 3.40; found C 36.57, H 3.47.
Preparation of reagent 2 from 1-chloro-3,3-dimethyl-1,2-benziodoxole (10). A 2-necked
500-ml round bottom flask equipped with a massive magnetic stirring bar was charged with anhydrous
spray dried potassium fluoride (8.71 g, 0.15 mol, 1.5 equiv) and flame-dried with vigorous stirring
under high vacuum (8·10-3 mbar) for 5 minutes. After cooling down to room temperature under Ar,
solid 1-chloro-3,3-dimethyl-1,2-benziodoxole (10, 29.65 g, 0.1 mol, 1 equiv) was added, followed by
anhydrous MeCN (300 mL). The resulting suspension was vigorously stirred for at least 8 h,
preferably 12 h during which the color changed from yellowish to white. (Alternatively, cheaper
ordinary grade anhydrous KF can also be employed, in which case at least 2 equiv and stirring for 20 h
is recommended to complete the halogen exchange). After the halogen exchange is finished, the
resulting suspension was cooled in an ice-salt bath to -10 °C and trifluoromethyltrimethylsilane (16.3
mL, 15.6 g, 0.11 mmol, 1.1 equiv) was injected in one portion. The resulting suspension was
vigorously stirred for 1 h allowing to warm up to r. t., filtered over a pad of Celite® (1 cm thick) (Note
1), and the filter cake was washed with little MeCN. The brown solution was concentrated to dryness
in a rotavap. The crystalline crude residue was redissolved in dry pentane (400 mL) at room
temperature and filtered over a pad of activated alumina (Note 2) (5 cm diameter,1.5 cm thick),
covered by a protective compressed Celite® layer into another 2-necked round bottom flask equipped
with magnetic stirring bar. The clear almost colorless filtrate was slowly cooled under Ar with stirring
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to -78°C causing full precipitation of reagent 2 (Note 3). The residual mother liquor was removed by
cannula with filter and the resulting white solid was dried in high vacuum with stirring to give the
target product (29.7 g, 90% yield). The yields varied between 85-91%.
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Note 1: Alternatively, the crude reaction mixture can be concentrated to dryness without filtration. The
resulting solid is then treated with pentane and processed as described above. No diminished yield was
observed.
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Note 2: Aluminum oxide of Brockmann activity I was heated with a heat gun in a 250 mL round
bottom flask under high vacuum (8·10-3 mbar) for 5-10 minutes and then allowed to cool to room
temperature under Ar. During the filtration, aluminum oxide with lower activation grade was shown to
retain considerable amounts of reagent 2 and thus led to lower isolated yields.
Note 3: Recrystallization from cold pentane is the preferred purification method for larger scale. As
opposed to that, sublimation leads to excessive thermal stress and gives lower recoveries and in some
cases inferior purity than samples purified by recrystallization. In view of the recent reports of its
potential exothermic decomposition,23b such practice should be discouraged.
Preparation of 1-fluoro-3,3-dimethyl-1,2-benziodoxole (11) from 1-chloro-3,3-dimethyl-1,2-
benziodoxole (10). 1-Fluoro-3,3-dimethyl-1,2-benziodoxole 11 was prepared following the previous
procedure, with the only modification that just 1/10 of the original scale was used. The reaction
mixture is filtered by cannula under Ar into another Schlenk flask and then concentrated to dryness
with an external cold trap. White crystalline material is obtained in 94% isolated yield and 92% purity.
X-ray quality crystals were obtained by slow cooling of the saturated solution of the title compound in
a pentane/dichloromethane solvent mixture. Alternatively, the crude product can be recrystallized from
boiling diisopropylether. δH (300 MHz, CDCl3, 23°C) 1.51 (d, J = 1.1 Hz, 6H), 7.16 (m, 1H), 7.42 –
7.59 (m, 2H), 7.77 (m, 1H); δC (75 MHz, CDCl3, 23 °C) 29.05 (d, J = 3.2 Hz), 85.20 (d, J = 2.6 Hz),
115.95 (d, J = 8.0 Hz), 125.93 (s), 128.58 (d, J = 8.5 Hz), 130.20 (s), 130.54 (s), 148.50 (d, J = 1.8
Hz); δF (282 MHz, CDCl3, 23°C) -142.93; HRMS (EI, EBE-triSector) calcd for C9H10FIO 279.9755
[M+], 264.9521 [M+-CH3], found 279.9731 [M+, 0.7%], 264.9522 [M+-CH3, 100%]. Anal Calcd for
C9H10FIO: C, 38.60; H 3.60. Found: C 38.68; H 3.69.
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Acknowledgement
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ETH Zurich is acknowledged for financial support. Dr. Thijs Braam, Dr. Gert Meijer and Dr.
Koji Kato (F-TOSOH Chemicals) are gratefully acknowledged for a generous gift of
trifluoromethyltrimethylsilane (Ruppert-Prakash reagent).
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Supporting Information. Copies of NMR spectra of the reported compounds and a cif file
for compound 11. This material is available free of charge via the Internet at
http://pubs.acs.org.
References and Notes
(1) For recent reviews and monographs, see: (a) Isanbor, C.; O’Hagan, D. J. Fluorine
Chem. 2006, 127, 303. (b) Müller K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320. (d) Furuya, T., Kamlet, A.S.; Ritter, T. Nature 2011, 473, 470. (e) Tomashenko,
O.A.; Grushin, V.V. Chem. Rev. 2011, 8, 4475. (f) Kirsch, P. Modern Fluoroorganic
Chemistry: Synthesis, Reactivity, Applications, Wiley-VCH, Weinheim, 2004. (g)
Uneyama, K. Organofluorine Chemistry, Blackwell Publishing, Oxford, 2006. (h)
Shibata, N.; Matsnev, A.; Cahard, D. Beilstein J. Org. Chem. 2010, 6, 65. (i) Ma, J.A.;
Cahard, D. Chem. Rev. 2008, 108, 9, PR1-PR43. (j) Mac, Y., Magnier, E. Eur. J. Org.
Chem. 2012, 2479.
(2) Leroux, F.R.; Manteau,B.; Vors, J.P. Pazenok, S.; Beilstein J. Org. Chem. 2008, 4, 13.
(3) Lintvedt, R.L.; Holtzclaw, H.F. J. Am. Chem. Soc. 1966, 88, 2713.
(4) Eisenberger, P.; Gischig, S.; Togni, A. Chem. Eur. J. 2006, 12, 2579.
(5) „Acid reagent“ and „alcohol reagent“ are the denominations routinely used in our
laboratory and stem from the starting materials used for the corresponding syntheses, an
acid and an alcohol, respectively. We are aware of the fact that they are often referred to
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in the literature as Togni’s reagents. The senior author, though, refrains from actively
attaching his name to these chemicals.
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(6) Eisenberger, P.; Kieltsch, I.; Armanino, N.; Togni, A. Chem. Commun. 2008, 1575.
(7) Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem. Int. Ed. 2007, 46, 754.
(8) Santschi, N.; Togni, A. J. Org. Chem. 2011, 76, 4189.
(9) Wiehn, M.S.; Vinogradova, E.V.; Togni A. J. Fluor. Chem. 2010, 131, 951.
(10) Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.; Niedermann, K.; Togni, A. Angew.
Chem. Int. Ed. 2009, 48, 4332.
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(11) Koller, R.; Huchet,Q.; Battaglia, P.; Welch, J.M.; Togni, A. Chem. Commun. 2009,
5993.
(12) Santschi, N.; Geissbühler, P.; Togni, A. J. Fluorine Chem. 2012, 135, 83.
(13) Niedermann, K.; Früh, N.; Vinogradova, E.; Wiehn, M.S, Moreno, A.; Togni, A.
Angew. Chem. Int. Ed. 2011, 50, 1059.
(14) Niedermann, K.; Früh, N.; Senn, R.; Czarniecki, B.; Verel, R.; Togni, A. Angew. Chem.
Int. Ed. 2012, 51, 6511.
(15) Liu T.; Shen, Q. Org Lett. 2011, 13, 2342.
(16) a) Xu, J.; Fu,Y.;Luo, D.F.; Jiang, Y.Y.;Xiao, B.; Liu, Z.J. ;Gong, T.J.; Liu,L. J. Am.
Chem. Soc. 2011, 133, 15300. b) Wang, X.;Ye,Y.; Zhang, S.; Feng, J.; Xu,Y.; Zhang,
Y.; Wang, J. J. Am. Chem. Soc. 2011, 133, 16410.
(17) Weng, Z.; Li, H.; He, W.; Yao, L.F.; Tan, J.; Yuan, Y.; Huang, K.W. Tetrahedron 2012,
68, 2527.
(18) Shimizu, R.; Egami, H.; Hamashima, Y.; Sodeoka, M. Angew. Chem. Int. Ed. 2012, 51,
4577.
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(19) a) Janson, P.G.; Ghoneim, I.; Ilchenko, N.O.; Szabó, K.J. Org Lett. 2012, 14, 2882. b)
Zhu, R.; Buchwald, S. J. Am. Chem. Soc. 2012, 134, 12462 c) Egami, H.; Shimizu, R.;
Kawamura, S.; Sodeoka, M. Angew. Chem. Int. Ed. 2013, 52, 4000.
(20) Allen, A.E.; MacMillan, D.W.C. J. Am. Chem. Soc. 2010, 132, 4986.
(21) Deng, Q.-H.; Wadepohl, H.; Gade, L. J. Am. Chem. Soc. 2012, 134, 10769.
(22) Matoušek, V.; Togni, A.; Bizet, V.; Cahard, D. Org. Lett. 2011, 13, 5762.
(23) (a) Plumb, J. B.; Harper, D. J. Chem. Eng. News 1990, 68, 3. (b) Very recently, a report
about the potential explosive properties of reagent 1, still prepared via the acetoxy route,
has appeared. See: Fiederling, N.; Haller, J.; Schramm, H. Org. Process Res. Dev. 2013,
17, 318.
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(24) For a review about the use of TCICA, see : Tilstam, U.; Weinmann, H. Org. Process
Res. Dev. 2002, 6, 384.
(25) Stanek, K.; Koller, R.; Togni, A. J. Org. Chem. 2008, 73, 7678.
(26) Eisenberger, P.; Kieltsch, I.; Koller, R.; Stanek, K.; Togni, A. Org. Synth. 2011, 88, 68.
(27) Bradshaw, C.P.C.; Nechvatal, A. Proc. Chem. Soc. 1963, 213.
(28) The crystal structure of 11 has been recently reported, see: Legault, C.Y.; Prévost, J.
Acta Cryst. 2012, E68, o1238.
(29) Ochiai, M.; Sueda, T.; Miyamoto, K.; Kiprof, P.; Zhdankin, V.V. Angew. Chem. Int. Ed.
2006, 45, 8203.
(30) Urbach, H. (BASF, Aktiengesellschaft, Germany), US4007221, A, February 8, 1977.
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