A ritter-type reaction: Direct electrophilic trifluoromethylation at nitrogen atoms using hypervalent iodine reagents

Article abstract of DOI:10.1002/anie.201006021

Acid-catalyzed electrophilic trifluoromethylation of nitriles in the presence of azoles leads to N-(trifluoromethyl)imine derivatives. The source of the trifluoromethyl group is a readily prepared and easy-to-handle hypervalent iodine(III) reagent (see sc

Full text of DOI:10.1002/anie.201006021

DOI: 10.1002/anie.201006021
N-Trifluoromethylation
A Ritter-Type Reaction: Direct Electrophilic Trifluoromethylation at
Nitrogen Atoms Using Hypervalent Iodine Reagents**
Katrin Niedermann, Natalja Frꢀh, Ekaterina Vinogradova, Matthias S. Wiehn, Aitor Moreno,
and Antonio Togni*
The unique features the trifluoromethyl group imparts to
pharmaceuticals, crop-protection agents, and functional mate-
rials emphasize the necessity to design and develop new
reagents and methods for the direct trifluoromethylation of a
wide range of organic substrates. Electrophilic trifluorome-
thylation, that is, the reaction of a suitable reagent capable of
corresponding functional-group interconversions in the near
future.
We have shown that a new generation of readily accessible
trifluoromethylation reagents based on hypervalent iodine,
such as compounds 1 and 2 (Scheme 1), display the desired
+
formally transferring an intact CF3 unit, has been shown to
be one of these methods.[1] However, despite the availability
of several such effective reagents, the electrophilic trifluoro-
methylation of hard nucleophiles, for example, oxygen- or
nitrogen-centered ones, remains challenging. In particular,
À
the formation of a N CF3 bond by such a reaction is still
Scheme 1. Trifluoromethylation reagents based on hypervalent iodine.
extremely rare. In fact, the NCF3 unit is usually constructed by
the interconversion of suitable functional groups. Thus,
fluorination of N-formylamines,[2] thiuram sulfides,[3] isocya-
nates,[4] and trichloromethylamines,[5] the reaction of secon-
dary amines with CBr2F2 and tetrakis(dimethylamino)ethy-
lene,[6] and the electrochemical fluorination of alkylamines[7]
constitute the still relatively modest set of methods. Of these,
the most frequently used approach is the oxidative desulfur-
ization–fluorination of dithiocarbamates first described for
the generation of NCF3 groups by Hiyama and Kuroboshi.[8]
The single, still very recent report of a direct trifluoromethy-
lation at nitrogen is due to Umemoto and co-workers.[9] They
describe the direct N-trifluoromethylation of amines, anilines,
and pyridines under very mild conditions achieved with in situ
generated and thermally unstable O-(trifluoromethyl)diben-
zofuranium salts (corresponding reactions of alcohols and
phenols are also known). However, this type of reagent
suffers from several shortcomings. The active CF3 source is
obtained by photochemical decomposition of diazonium salts
at very low temperature, and the synthesis requires several
steps including the construction of a CF3O–aryl moiety. It is
therefore likely that this methodology will not replace the
reactivity towards a number of C-, S-, P-, and O-centered
nucleophiles. Despite their purported soft nature, reagents 1
and 2 do trifluoromethylate alcohols and sulfonic acids upon
activation with Lewis[10] and Brønsted acids,[11] respectively,
thus significantly expanding their application range.
During a recent investigation of the direct electrophilic
trifluoromethylation of heteroarenes[12] using reagent 1 and
catalytic amounts of bis(trifluoromethanesulfonyl)imide
(HNTf2) in acetonitrile, we surprisingly found that benzo-
triazole (3) is converted to the corresponding N-substituted
N-trifluoroimidoyl derivative 4, as shown in Scheme 2. The
generation of compound 4 corresponds to a novel Ritter-
type[13] reaction during which a new N CF3 bond is formed.
À
[*] K. Niedermann, N. Frꢀh, E. Vinogradova, Dr. M. S. Wiehn,
Dr. A. Moreno, Prof. Dr. A. Togni
Scheme 2. Formation of N-(trifluoromethyl)imine 4 by a new Ritter-
type reaction.
Department Chemie und Angewandte Biowissenschaften
Eidgenꢁssische Technische Hochschule (ETH) Zꢀrich
Wolfgang-Pauli-Strasse 10, 8093 Zꢀrich (Schweiz)
Fax: (+41)44-632-1310
E-mail: togni@inorg.chem.ethz.ch
Subsequent substrate screening showed that other azoles
such as indazole and substituted pyrazoles also undergo this
reaction (see below). Encouraged by these results, we used
benzotriazole (3) as a model substrate to optimize the
reaction conditions. Reactions were carried out at 608C in
the presence of a Brønsted acid (see Table 1). At higher
temperatures the formation of HCF3 (dF = À79.9 ppm, d,
[**] This work was supported by the ETH Zꢀrich. M.S.W. thanks the
Karlsruhe House of Young Scientists for a fellowship. We thank Dr. J.
Welch for his help with the kinetic studies and R. Koller for helpful
discussions and advice.
Supporting information for this article (experimental procedures
and characterization of selected new compounds) is available on
the WWW under http://dx.doi.org/10.1002/anie.201006021.
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Table 1: Formation of 4 at various acid concentrations. Conversion and
yield after 3.5 h reaction time at 608C.
Entry[a]
Acid
mol%
Conv.[b] [%]
Yield[b] [%]
1
2
3
4
5
6
–
0
69
99
quant.
quant.
quant.
0
HNTf2
HNTf2
HNTf2
(CF3)3COH
TFA
5
44
68
70
68[c]
60
10
15
10
10
[a] Reaction conditions: Reagent 1 and benzotriazole (3) (1.5 equiv) in
CH3CN were stirred after addition of acid (0.1m in CH2Cl2) at 608C for
3.5 h. [b] Calculated based on 19F NMR spectroscopic analysis using
C6H5CF3 as an internal standard. [c] Yield after completion (1 day).
2J(F,H) = 79.5 Hz) was observed by 19F NMR spectroscopy,
indicating reagent decomposition. HNTf2, a strong Brønsted
acid with an innocent conjugate base,[14] acts as a catalyst,
(Table 1, entries 2–4), while in its absence no reaction is
observed (Table 1, entry 1). Though higher catalyst loadings
accelerate the reaction, only a minor effect on the yield is
observed. The reactions can also be performed using
10 mol% of TFA or (CF3)3COH. However, TFA leads to
slightly lower yields, whereas (CF3)3COH is much less
efficient in promoting the reaction, presumably because of
its weaker acidity (Table 1, entries 5 and 6).
As depicted in Scheme 2, the side products 5 and 6 are
also formed. The former is a N-(trifluoromethyl)acetimidate
corresponding to the Ritter addition product of reagent 1 to
acetonitrile. The second, N1(trifluoromethyl)benzotriazole
(6), is the product of the direct trifluoromethylation of
benzotriazole. Their formation is influenced by the ratio
between substrate and reagent as shown in Table 2. When
reagent 1 is used in excess, more side product 5 is formed,
whereas an excess of substrate 3 leads to benzotriazole 6 to a
greater extent. The best results in terms of product yield and
suppression of side products are obtained using reagent 1 as
the limiting species and 1.5 equiv of benzotriazole (3)
(Table 2, entry 3).
Figure 1. Profile for the reaction of 0.1m 1 with 0.15m 2 and 6.8 mm
HNTf2 in CD3CN as monitored by 19F NMR spectroscopy (C6H5CF3
&
*
^
internal standard). 1, 4, 5, ꢂ 6.
of 4 were observed, implying that substrate 3 is not involved in
the rate-determining step of the reaction. If this were not the
case and since the concentration of 3 changes over time, one
would expect an exponential decrease of the concentration of
1 as well as an exponential rise to a maximum concentration
of 4. Additionally, under the reaction conditions, the concen-
trations of CD3CN and of the Brønsted acid are essentially
constant. Therefore, it is reasonable to assume that the rate-
determining step of the reaction involves the protonated form
of reagent 1 and CD3CN. This is in line with our previous
observations concerning the trifluoromethylation of THF[15]
and toluenesulfonic acid.[11]
On the basis of these rate studies and our previous
experience with these systems, we propose the mechanism
shown in Scheme 3. The protonated form of reagent 1 is the
reactive species. That such a protonation is indeed taking
Table 2: Distribution of product and side products depending on the
starting ratio of benzotriazole (3) and reagent 1.
Entry[a] 1 [equiv] 3 [equiv] Yield 4[b] [%] Yield 5[b] [%] Yield 6[b] [%]
1
2
3
4
5
1.5
1
1
1
1
1
1
1.5
2
3
65
55
68
67
64
28
11
8
5
3
5
5
7
11
16
[a] Reaction conditions: reagent 1 and benzotriazole (3) were stirred
after addition of HNTf2 (10 mol% based on 1, 0.1m in CH2Cl2) at 608C
for 3.5 h. [b] Calculated based on 19F NMR spectroscopic analysis using
C6H5CF3 as an internal standard.
We monitored the reaction of 1.5 equiv of benzotriazole
(3), 6.8 mol% HNTf2 as a 0.1m solution in CH2Cl2, and
reagent 1 in CD3CN (0.1m) by 19F NMR spectroscopy. The
corresponding reaction profile is shown in Figure 1. Thus,
nearly constant rates of both consumption of 1 and formation
Scheme 3. Proposed reaction mechanism for the acid-catalyzed Ritter-
type reaction of reagent 1 with benzotriazole.
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place is also indicated by a significant shift of the correspond-
ing CF3 signal in the 19F NMR spectrum to higher frequency.
Thus, whereas the resonance of the free reagent appears at
d = À40 ppm in CDCl3, the addition of 1 equiv of a strong
Brønsted acid shifts the signal to d = À20 ppm. This activation
analysis. However, the product slowly decomposes under the
reaction conditions and, hence, longer reaction times lead to a
significantly lower yield. Unfortunately, as the resulting
product and alcohol 7 are not separable using flash column
chromatography, the Burgess reagent[17] must be added after
the reaction is complete in order to dehydrate alcohol 7. This
allows the desired product to be isolated in 38% yield in pure
form after flash column chromatography.
Indazole reacts under the same reaction conditions to
afford N2-substituted product 8 in 57% NMR yield. The
formation of the N1-substituted product 9 accounts for less
than 5% yield. Derivative 8 is smoothly converted to its
regioisomer 9 in 79% yield (according to NMR analysis)
upon heating in acetonitrile and in the presence of a catalytic
amount of HNTf2, as shown in Scheme 4. Compound 8 is the
À
is likely to weaken the I O bond, thus making the iodine
atom more electrophilic (iodonium character); this is analo-
gous to the activation of reagent 2 by Zn2+, as previously
reported.[10] A coordinated acetonitrile subsequently under-
goes the formation of a N-trifluoromethyl nitrilium ion[16] by a
reductive-elimination process, as the rate-determining step.
The nitrilium ion is then rapidly trapped by benzotriazole (3)
to form product 4, thus releasing a proton and completing the
catalytic cycle.
The optimized reaction conditions were subsequently
applied to other azoles such as indazole and substituted
pyrazoles. The results of these reactions are shown in Table 3.
The trifluoromethylated products can easily be separated
from the much more polar azoles by simple flash column
chromatography. In the reaction using ethyl 4-pyrazolecar-
boxylate (Table 3, entry 8) the desired product is formed in
68% yield after complete conversion according to NMR
Scheme 4. Isomerization of N2-substituted indazole 8 to N1-substi-
tuted derivative 9.
Table 3: Ritter-type N-trifluoromethylation of nitriles using 1, azoles, and
HNTf2 as catalyst.
kinetic product of the reaction of indazole with reagent 1, and
slowly isomerizes to the thermodynamic product 9. This
Entry[a]
Substrate
Product
Yield[b] [%]
68 (63)
À
process is likely to involve heterolytic N C bond cleavage,
regenerating a trifluoromethyl nitrilium ion. A comparable
reaction concerning N-(a-aminoalkyl)tetrazoles has recently
been reported by Katritzky and co-workers.[18]
1
Given that the products of our Ritter-type reaction
contain the rather uncommon N-(trifluoromethyl)amidine
unit, we carried out thorough structural characterization, both
in solution and in the solid state. Thus, as an example, the
structure of compound 4 in solution was determined by
multinuclear NMR methods. Figure 2 shows sections of the
corresponding 19F,15N and 1H,15N HMQC spectra. The 19F,15N
correlation (Figure 2, left) shows only one correlation
between the trifluoromethyl resonance (dF = À53.5 ppm)
and the imido resonance at dN = À125.7 ppm. The splitting
in the direct dimension is due to the 2J(N,F) coupling of 20 Hz.
The assigned structure was confirmed by X-ray crystallog-
raphy (see the Supporting Information). On the other hand,
2[c]
60 (37)
3
4
57 (47)[d]
51 (45)
5
6
52 (47)[e]
59 (47)
1
in the H,15N correlation (Figure 2, right) the methyl reso-
nance (dH = 3.12 ppm) shows two crosspeaks to the azole and
imido resonances (dN = À134.9 ppm and dN = À125.7 ppm,
respectively).
7
8
62 (53)
47 (38)[f]
The structure of the two constitutional isomers 8 and 9
were determined in solution by analogous NMR methods and
confirmed by X-ray analysis. Corresponding ORTEP repre-
sentations and selected geometrical parameters are shown in
Figure 3. Both imidoyl groups have an E configuration, which
is common to all azole derivatives prepared in this study. Both
isomers are almost perfectly planar molecules, the imidoyl
group being only slightly twisted out of the indazole plane as
indicated by the torsion angles N1-N2-C8-N3 of 178.06(17)8
and 176.71(15)8 for 8 and 9, respectively. A further, more
notable deviation from the expected ideal geometry concerns
[a] Reaction conditions: HNTf2 (10 mol%, 0.1m in CH2Cl2) was added to
a solution of reagent 1 and azole (1.5 equiv) in CH3CN (6 mL), and the
reaction mixture was stirred for 3.5 h at 608C. [b] Yields were calculated
based on reagent 1 from the integration of the 19F NMR signals using
C6H5CF3 as internal standard. Yields of isolated products are given in
brackets. [c] C2H5CN instead of CH3CN. [d] N2-substituted product 8
was formed and isolated. [e] Reaction time 16 h. [f] Owing to separation
problems the Burgess reagent[17] (1.5 equiv in CH2Cl2) was added after
completion of the reaction, and the mixture was stirred for an additional
30 min at 608C.
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In conclusion, we have shown that N-substituted
N-(trifluoromethyl)imidoyl compounds are formed
in a Ritter-type reaction using an azole and reagent
1 as the trifluoromethylating agent in a nitrile under
HNTf2 catalysis. To the best of our knowledge such a
reaction is unprecedented and represents a funda-
mentally new access to NCF3 derivatives by forma-
À
tion of the N CF3 bond. Furthermore, it has been
shown that benzotriazole (3) can be directly N-
trifluoromethylated. We are currently improving
these new reactions further and also exploring the
reactivity and synthetic utility of the newly accessed
compounds.
Experimental Section
General procedure: A flame-dried 20 mL Young–Schlenk
flask was charged with 1-trifluoromethyl-1,3-dihydro-3,3-
dimethyl-1,2-benziodoxole (1; 198 mg, 0.60 mmol) and
azole (0.90 mmol, 1.5 equiv). CH3CN (6 mL) and HNTf2
(0.6 mL, 0.1m in CH2Cl2, 10 mol%) were added. The
mixture was stirred at 608C for 3.5 h. The mixture was extracted with
pentane (3 ꢀ 15 mL) and the pentane was removed under reduced
pressure.
Figure 2. Sections of the 19F,15N (left) and 1H,15N (right) HMQC spectra of
compound 4. Correlations found are indicated by arrows.
CCDC 792179 (compound 4), 792180 (compound 8), 7928181
(compound 9), and 792182 ((E)-N-(1-(3,5-diphenyl-1H-pyrazol-1-
yl)ethylidene)-1,1,1-trifluoromethanamine) contains the supplemen-
tary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: September 25, 2010
Published online: December 23, 2010
Figure 3. ORTEP representation of compounds 8 (left) and 9 (right).
Thermal ellipsoids are drawn at the 50% probability level; hydrogen
atoms are omitted for clarity. Selected bond lengths [ꢃ] and angles [8]
for 8: N1–N2 1.363(2), N2–C1 1.360(3), N2–C8 1.408(3), N3–C8
1.276(3), N3–C9 1.389(3), C8–C10 1.488(3), C1-N2-N1 113.52(17), N3-
C8-N2 115.38(18), N3-C8-C10 129.9(2), N1-N2-C8-N3 178.06(17).
Selected bond lengths [ꢃ] and angles [8] for 9: N1–N2 1.390(2), N2–C1
1.302(2), N1–C8 1.383(2), N3–C8 1.283(2), N3–C9 1.387(2), C8–C10
1.499(2); C1-N2-N1 105.69(15), N3-C8-N1 115.88(16), N3-C8-C10
128.52(17), N2-N1-C8-N3 176.71(15).
Keywords: electrophilic addition · hypervalent compounds ·
.
nitrogen heterocycles · synthetic methods · trifluoromethylation
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Scheme 5. Direct N-trifluoromethylation of benzotriazole.
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