Recent advances in electrophilic CF3-transfer using hypervalent iodine(III) reagents

Article abstract of DOI:10.2533/chimia.2008.260

The development of new methodologies for an efficient introduction of CF₃ groups into complex molecules constitutes one of the most challenging tasks of modern organic chemistry. Recently, we reported the access to a new class of electrophilic CF₃-transfer reagents based on hypervalent iodine. The versatile application of these reagents to C-centred nucleophiles, such as β-keto esters, silyl enol ethers and α-nitro esters, as well as to thiols and primary and secondary phosphines is described. Experiments with phenols afforded corresponding trifluomethylethers in very low yields. Schweizerische Chemische Gesellschaft.

Full text of DOI:10.2533/chimia.2008.260

LAUREATES: AWARDS AND HONORS SCS FALL MEETING 2007
260
doi:10.2533/chimia.2008.260
CHIMIA 2008, 62, No. 4
Chimia 62 (2008) 260–263
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
Recent Advances in Electrophilic
CF3-Transfer Using Hypervalent Iodine(III)
Reagents
Iris Kieltsch§*, Patrick Eisenberger, Kyrill Stanek, and Antonio Togni
§SCS Poster Prize Winner
Abstract: The development of new methodologies for an efficient introduction of CF3 groups into complex mol-
ecules constitutes one of the most challenging tasks of modern organic chemistry. Recently, we reported the ac-
cess to a new class of electrophilic CF3-transfer reagents based on hypervalent iodine. The versatile application
of these reagents to C-centred nucleophiles, such as β-keto esters, silyl enol ethers and α-nitro esters, as well as
to thiols and primary and secondary phosphines is described. Experiments with phenols afforded corresponding
trifluomethylethers in very low yields.
Keywords: Electrophilic trifluoromethylation · Fluorinated compounds · Hypervalent iodine ·
Trifluoromethylthio ether · (Trifluoromethyl)phosphine
Introduction
is commonly used to introduce the CF3-
F C
I
O
moiety. To circumvent this building block
3
1
There is a great demand for organofluorine
approach and for economical, ecological
CF X
3
R
1
R
compounds in a wide range of applications. and technical feasibility the development
Fluorinemodifiesthephysicalandchemical of stable, and selective trifluoromethyla-
properties of compounds that contain it in a tion agents that allow a direct introduction
E
R
R
R
unique manner. The trifluoromethyl unit as
at a late stage of a multi-step sequence has
1
1R=H, R =Me
1
drug component affects nearly all physical, received considerable attention. Although
adsorption, distribution, metabolism and the radical and nucleophilic methods seem
excretion properties of a lead compound.[1] to have been harnessed, electrophilic tri-
E=S, Se,Te, O
X=BF ,OTf,SbF
2R=H, R =O
1
4
6
3R=H, R =CF
3
1
4R=Me,R=CF
3
Therefore the building block approach
fluoromethylation still poses a challenge.
The commercial availability of Me3SiCF3
Fig. 1. Reagents for electrophilic trifluoromethy-
lation
(known as Ruppert-Prakash reagent) and
its ease of handling turned the anionic tri-
fluoromethylation reaction into one of the
the application of these compounds for a
mild and selective transfer of a CF3 group
toward selected nucleophiles, such as car-
bonyl compounds, thiols, phosphines and
phenols.
most powerful strategies and has led to
the development of other nucleophilic tri-
fluoromethylation reagents.[2] On the other
hand, only a few reagents are capable of
performing electrophilic trifluoromethy-
lation. One class of electrophilic reagents
are the trifluoromethylchalcogenium salts
(oxonium, sulfonium, selenonium, telluro-
nium) (Fig. 1), devised by Umemoto and
co-workers and based on seminal work by
Yagupol’skii.[3]
We recently succeeded in preparing
a new family of hypervalent iodine com-
pounds showing promising potential for the
trifluoromethylation of several types of nu-
cleophiles.[4] Here we highlight two mem-
bers of this reagent class, their improved
scalable syntheses and the advantage of
each reagent. Additionally, we summarize
Results and Discussion
The
I-based
trifluoromethylating
agents are accessible from cheap com-
mercial chemicals upon oxidation to 5 or
7 (Scheme 1), followed by a consecutive,
nucleophilic ligand substitution at the I(III)
*Correspondence: I. Kieltsch
Department of Chemistry and Applied Biosciences
Swiss Federal Institute of Technology
ETH Zurich
center using KOAc and Ac2O, respectively.
The subsequent introduction of the CF3
group corresponds to a formal ‘Umpolung’
of the CF3 fragment. This is delivered as
a nucleophile using Me3SiCF3, but shows
CH-8093 Zürich
Tel.: +41 44 632 4679
Fax: + 41 44 633 1032
E-mail: kieltsch@inorg.chem.ethz.ch

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CHIMIA 2008, 62, No. 4
its electrophilic character once bound to io-
dine. Thus, starting from readily available
I
O
H
Cl
I
O
AcO I
O
(CH 3) 3SiCF
3
cat. F /MeCN
F C I
3
O
-
iodobenzoic acid, 2 is synthesized in 74%
overall yield. Compound 1 is also derived
from iodobenzoic acid upon an esterifica-
tion and conversion to the alcohol. Follow-
ing the one-pot procedure, without isolation
of the acetoxy-intermediate, 1 is accessible
in an overall four-step-procedure in 62%
isolated yield (Scheme 1). Both crystalline
reagents can be exposed to and manipulated
in moist air for short periods of time with-
out any apparent alteration in the case of 1.
t--BuOCl
KOAc
–(CH3) 3SiOAc
5
6
1
one-potprocedure,93% yield
(CH 3) 3SiCF
-
I
OH
HO I
O
AcO I
O
3
cat. F /MeCN
F C I
3
O
Ac O
2
NaIO
4
O
O
O
O
reflux
–(CH3) 3SiOAc
The acid-derived reagent 2 is bench stable
7
2
for months.[4]
74%overall yield
The benefit of trifluoromethylating re-
agent 1 compared to the previous ones, is
the ‘dormant’ incorporated base. After the
CF3 transfer an alkoxide is formed, thus
Scheme 1. Improved synthesis of trifluoromethylation reagents 1 and 2
+
making any additional, stoichiometric
amount of base superfluous. However, the
less reactive and in this case, more selective
acid-derived trifluoromethylating agent 2
requires contingently a base, therefore it
excels as the reagent for sensitive substrates
F C I
3
O
I
OH
R
R
R
+
R
+
NuH
NuCF
3
1R=Me, 2R=O
suchasphosphines.Theremainingiodoben-
zoic acid can be removed easily by filtration
or extraction to prevent loss in product puri-
recyclable
fication by column chromatography. More-
over, after the delivery of the CF3 group to
a nucleophile the primary starting material
Scheme 2. General straightforward stoichiometry for electrophilic
trifluoromethylations using 1 and 2, respectively
(iodobenzoic acid and alcohol, respective-
ly) is formed as a byproduct in both cases.
Therefore, our system allows the recovery
1-tetralonederivatives:
1.5eq. 1
0.1eq. NBuI
3.0eq. K 2CO3
O
O
n=1, R=Me:42%
n=2, R=Me:40%
n=1, R=Et: 67%
n=1, R=t Bu:66%
1-indalone derivative:
n=1, R=Et:46%
of the CF3-carriers (Scheme 2).
O
O
4
Electrophilic trifluoromethylation of
carbonyl compounds, such as β-keto esters,
silyl enol ethers, silyl ketene acetals and
α-nitro esters, represents a novel example
of a C−C bond forming process. More-
over, this method gives a possible access to
the enantioselective trifluoromethylation,
which Billard branded the new ‘grail quest’
for chemists.[2b]
O
R
OR
H
CF
3
n
n
MeCN,r.t.
O
OTMS
41%
1.5eq. 1
CF
3
MeCN,80°C
Under conditions of phase-transfer ca-
talysis the CF3-transfer to β-keto esters
succeeded to give the products shown in
Scheme 3, although the yields do not reach
those obtained using the previously report-
ed systems.[5] At elevated temperature, silyl
enol ethers and silyl keten acetals exposed
to 1 or 2 in MeCN give the corresponding
α-CF3 substituted carbonyl compounds in
respectable yields.
On the other hand, one of the cleanest
trifluoromethylation reactions we were
able to perform so far involves α-nitro es-
ters as substrates (Scheme 4). In the pres-
ence of catalytic amounts of Cu(I ) or Cu(II)
salts (15 mol%) the reaction proceeds
smoothly at room temperature with high
O
OTMS
OEt
1.0eq. 2
a
65%
OEt
F C
3
[D ]-MeCN,80°C
3
Scheme 3. Electrophilic α-trifluoromethylation of β-keto esters, silyl enol ether and silyl ketene
acetals; ayields determined by 19F NMR spectroscopy.
of unnatural α-amino acid precursors were ment to the sulfur atom in a nucleophilic,
obtained using enantiopure chiral copper or primarily radical fashion.[7] Electrophilic
complexes; optimization of the enantiose- S-trifluoromethylation using Umemoto’re-
lectivity is the subject of active research.
agents requires preformed sodium thiolates
to obtain product formation along with a
The high lipophilicity and the electronic
properties of the trifluoromethanethioether considerable amount of the corresponding
group make it a useful unit for pharmaceuti- disulfide byproduct.[3,8]
cals and agrochemicals. The introduction of
We found that both aromatic and ali-
conversion in CH2Cl2. The products are
an SCF3 substituent into organic molecules phatic thiols will selectively and smoothly
has been previously achieved either by us- undergo S-trifluoromethylation in the pres-
ing harsh functional group interconversion ence of 1.1 equivalents of the reagent 1 af-
reactions, by direct transfer of the SCF3 fording the products in good to excellent
moiety, or by the delivery of a CF3 frag- yields, as shown in Fig. 2.
obvious precursors of the corresponding
α-trifluoromethyl-α-amino acids,[6] which
can be obtained upon selective reduction of
the nitro group (Scheme 5). Promising re-
sults for an asymmetric catalytic synthesis

LAUREATES: AWARDS AND HONORS SCS FALL MEETING 2007
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CHIMIA 2008, 62, No. 4
The transformation shows a remarkably
high functional group tolerance. Therefore
it allows a diversified application in syn-
thesis at late stages of a given sequence.
1
2
a
R =Et, R =H: 89%
a
1.1eq. 1
0.15 eq.CuX
O
O
1
2
R =Et, R =Me: 99%
2
O N
2
O N
2
1
1
1
OR
CF
OR
H
R =Et, R =Bn: 69%
1
2
2
R
DCM,r.t.
R
2
3
R =Ar, R =Me: 85%
In fact, amines, amides, carboxylic acids,
thioacetals, alcohols, and alkynes do not
interfere with the formation of the SCF3
Scheme 4. Electrophilic α-trifluoromethylation of α-nitro esters; areaction performed in CD2Cl2; yields
group. Moreover, the reactivity of com-
determined by 1H NMR spectroscopy
pound 1 does not appear to be particularly
solvent dependent, such that solvent choice
is mainly dictated by the solubility of the
thiol. In fact, the reaction seems to be very
robust. The two most important factors ap-
pear to be the control of the temperature
t Bu
t Bu
Zn,HCl
1,4-Dioxan
(−78 °C) to suppress disulfide formation
O
O
and the solubility of the starting material at
O N
2
H N
2
88%
O
t Bu
O
CF
3
t Bu
this temperature.[4b]
CF
3
Electrophilic trifluoromethylation of tri-
phenylphosphine to obtain P-trifluorometh-
yl triphenylphosphonium salts was already
carried out by Umemoto and coworkers us-
Scheme 5. Reduction of α-trifluoromethylated α-nitro esters
ing S-trifluoromethyldibenzothiophenium
salts (Fig. 1).[8] However, the same approach
has never been applied to the synthesis of
neutral phosphine compounds from sec-
ondary, or primary phosphines. However,
P-trifluoromethyl phosphines are of interest
SCF
3
SCF
3
SCF
3
SCF
3
SCF
3
SCF
3
O
H
CO2H
N
as ligands in transition metal chemistry be-
cause of their altered electronic characteris-
tics, in particular the weak σ-donating and
Br
NH2
NO2
N
HAc
a
82%
88%
72%
80%
95%
O
91%
strong π-accepting properties. Therefore,
these phosphines can serve as more stable
F CS
3
surrogates of CO, NO, or PF3 from an elec-
tronic perspective at the cost of an increased
N
O
N
N
steric demand.[9]
N
BocHN
H N
Cl
2
H
HO
O
Me
OEt
CF
N
SCF
3
Adaptation of the previous reaction
conditions for the reaction of secondary
O
O
SCF
3
S
3
phosphines with 1 equiv. of reagent 1 or 2
in degassed, dry CH2Cl2 at ambient or low
temperatures produced the desired tertiary
O
H O
H
58%
99%
82%
99%
trifluoromethylated phosphines (Table,
AcO
AcO
AcO
O SCF
3
entries 1 to 7). Diaryl(trifluoromethyl)
phosphines were found to be fairly stable
toward oxidation, whereas the more basic
dicyclohexyl(trifluoromethyl)phosphine
was susceptible to oxidation and therefore
isolated as the corresponding sulfide (entry
1). Interestingly, applying reagent 2 to pri-
mary phosphines provides solely the cor-
responding monotrifluoromethylated phos-
phines (entry 8).[10]
O
SCF
3
O
SCF
3
14
SCF
3
Ph
O
O
OAc
90%
81%
53%
51%
Fig. 2. Products of the S-trifluoromethylation of free thiols; ayields determined by 1H NMR
spectroscopy
The
trifluoromethylated phosphorus
Table. Electrophilic trifluoromethylation of phosphines
compounds were found to serve as suited
ligands for transition metals in several oxi-
Entry Substrate
Conditions
1, −78 °C → r.t.
2, r.t.
Product
Yielda
52%b
78%
50%
78%
58%
58%
63%
84%c
1
2
3
4
5
6
7
8
Cy2PH
Cy2P(S)(CF3)
Ph2P(CF3)
dation states and form stable, crystalline
complexeswithappropriatePd(II),[11] Ru(II),
Ph2PH
Rh(I ) and Ir(III) precursors. Nevertheless,
this is a valuable preparative method for the
synthesis of dialkyl- or diaryl-substituted
trifluoromethyl phosphines since it does not
(o-Tol)2PH
(p-Tol)2PH
(β-Np)2PH
(p-OMePh)2PH
1, −78 °C → r.t.
2, r.t.
(o-Tol)2P(CF3)
(p-Tol)2P(CF3)
(β-Np)2P(CF3)
(p-OMePh)2P(CF3)
rac-(o-anisole)PhP(CF3)
PhPH(CF3)
2, 0 °C → r.t.
1, −78 °C → r.t.
require the synthesis of elaborate starting
materials such as P-cyanophosphines[12] or
P-fluorophosphines.[13] These are not com-
rac-(o-anisole)PhPH 1, −78 °C → r.t.
PhPH2 1, r.t.
mercially available and have to be accessed
in multistep procedures.
At this point in time, it is not possible
to deduce a mechanistic framework un-
aisolated yields; bS8 as oxidant; cconversion calculated based on 19F NMR spectroscopy with
PhCF3 as an internal reference

LAUREATES: AWARDS AND HONORS SCS FALL MEETING 2007
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CHIMIA 2008, 62, No. 4
Langlois, Eur. J. Org. Chem. 2007, 891; c)
equivocally for these trifluoromethylation
reactions. However, it seems to be sub-
strate dependent. Nevertheless, the mecha-
B. R. Langlois, T. Billard, Synthesis 2003,
185.
[3] a) T. Umemoto, Chem. Rev. 1996, 96, 1757
nism most likely involves SET
processes.
and references cited therein; b) J.-J. Yang,
In fact, the best results for a CF3-transfer
using reagent 1 and 2 were achieved with
soft nucleophiles such as thiols.
R.L. Kirchmeier, J. M. Shreeve, J. Org.
Chem. 1998, 63, 2656; c) E. Magnier, J.-C.
Blazejewski, M. Tordeux, C. Wakselman,
Unfortunately, applying standard SN2
conditions for the reaction of hard oxygen
nucleophiles such as phenols with 2 gives
only traces (and 15% yield when the or-
tho and para positions are blocked) of the
desired O-trifluoromethylated product.[14]
Bearing these results in mind we endorse
the conclusion drawn by Cahard concerning
Angew. Chem., Int. Ed. 2006, 45, 1279;
d) T. Umemoto, K. Adachi, S. Ishihara, J.
Org. Chem. 2007, 72, 6905.
[4] a) P. Eisenberger, S. Gischig, A. Togni,
Chem. Eur. J. 2006, 12, 2579; b) I.
Kieltsch, P. Eisenberger, A. Togni, Angew.
Chem., Int. Ed. 2007, 46, 754.
[5] J.-A. Ma, D. Cahard, J. Org. Chem. 2003,
68, 8726.
+
the ‘real’ carriers of the electrophilic CF3
[6] V. P. Kukhar, V. A. Soloshonok, ‘Fluorine-
species.[2a] Further studies to find a thermal-
ly stable and easily accessible solution for
the challenges in O-trifluoromethylation
are under investigation in our laboratory.
In conclusion, we have shown recent
advances in electrophilic trifluoromethy-
lation using our mild and readily acces-
sible reagents 1 and 2. We demonstrated
the advantages of these reagents and their
versatile application in C-, S- and P-triflu-
oromethylation as well as their temporary
limitations.
Containing Amino Acids: Synthesis and
Properties’, John Wiley & Sons, New
York, 1995.
[7] a) T. Billard, N. Roques, B. R. Langlois, J.
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M. Medebielle, W. R. Dolbier, Jr., Org.
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Dolbier, Jr., M. Médebielle, J. Org. Chem.
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B. Hoge, Y. L. Yagupolskii, J. Fluorine
Chem. 2003, 119, 101 and references
cited therein.
[8] T. Umemoto, S. Ishihara, J. Am. Chem.
Soc. 1993, 115, 2156.
Acknowledgments
[9] S. P. Flanagan, P. J. Guiry, J.
Financial support from ETH Zürich (PhD
Organometallic Chem. 2006, 691, 2125.
grants to I.K., P.E. and K.S.) is gratefully
acknowledged.
[10] P. Eisenberger, I. Kieltsch, N. Armanino,
A. Togni, Chem. Commun. 2008, 1575.
[11] a) M. A. Beg, H. C. Clark, Can. J. Chem.
Received: February 25, 2008
1962, 40, 283; b) A. J. Rest, J. Chem. Soc.
1968, 2212.
[1] a)
K.
Uneyama,
‘Organofluorine
Publishing,
[12] P. Panne, D. Naumann, B. Hoge, J.
Chemistry’,
Oxford, 2006; b) K. Müller, C. Fäh, F.
Diederich, Science 2007, 317, 1881.
Blackwell
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[13] I.Tworowska,W. Dabkowski,J.Michalski,
Angew. Chem., Int. Ed. 2001, 40, 2898.
[14] K. Stanek, A. Togni, unpublished results.
[2] a) J.-A. Ma, D. Cahard, J. Fluorine
Chem. 2007, 128, 975; b) T. Billard, B. R.