Direct electrophilic N-trifluoromethylation of azoles by a hypervalent iodine reagent

Article abstract of DOI:10.1002/anie.201201572

Effective CF₃ transfer: Various electron-rich nitrogen heterocycles (pyrazoles, triazoles, and tetrazoles) can be directly N-trifluoromethylated by a hypervalent iodine reagent in an efficient manner. The optimized procedure, which includes an in situ silylation of the substrate followed by an acid-catalyzed CF₃ transfer, provides ready access to a series of new and previously challenging or inaccessible NCF₃ compounds. Copyright

Full text of DOI:10.1002/anie.201201572

Angewandte
Chemie
DOI: 10.1002/anie.201201572
Direct N-Trifluoromethylation
Direct Electrophilic N-Trifluoromethylation of Azoles by
a Hypervalent Iodine Reagent**
Katrin Niedermann, Natalja Frꢀh, Remo Senn, Barbara Czarniecki, Renꢁ Verel, and
Antonio Togni*
The importance of fluorinated molecules in the chemical
sciences has been rapidly increasing in recent years. It is
estimated that the share of active ingredients containing at
least one fluorine atom in newly marketed crop protection
agents and pharmaceuticals amounts to 30–40% and nearly
20%, respectively. Furthermore, half of the top ten best-
selling prescription drugs in 2005 are fluorinated molecules.[1]
However, an extended database search showed that less than
ten N-trifluoromethylated compounds have been tested as
biologically active compounds for humans,[2] and the CCDC
reveals only 54 crystallographically characterized NCF3
derivatives,[3] most of which are perfluorinated alkyl amines.
In view of the strongly electron-withdrawing nature of the
trifluoromethyl group, trifluoromethylamines are anticipated
to be much less basic and less nucleophilic than the
corresponding methylamines.[4] Hence, their physical, chem-
ical, and/or biological properties should be remarkably
different.
In a stand-alone medicinal chemistry contribution Asa-
hina et al.[5] formally replaced the alkyl substituent on the 4-
quinolone nitrogen atom of Norfloxacin and Ciprofloxacin,
two important chemotherapeutical antibacterial agents, by
a CF3 group, thereby showing that, in this case, the trifluor-
omethyl group exerts an effect comparable to that of a simple
methyl group with respect to the antibacterial properties. The
CF3 substituent was introduced by an oxidative desulfuriza-
tion–fluorination procedure on a corresponding dithiocarba-
mate (see Scheme 1).
Scheme 1. A rare example of an N-trifluoromethyl intermediate used in
the preparation of corresponding derivatives of biologically active
compounds.
scarcely studied. In 2007 Umemoto and co-workers reported
the direct trifluoromethylation of amines, anilines, and
pyridines[7] as the first example of a direct N-trifluoromethy-
lation. However, the electrophilic CF3 source used in such
reactions is an unstable and very reactive O-(trifluorome-
thyl)dibenzofuranium salt with inherent shortcomings.
We recently reported the discovery of a Ritter-type
reaction leading to the formation of N-trifluoromethylated
imines by the acid-catalyzed electrophilic trifluoromethyla-
tion of nitriles in the presence of azoles such as benzotriazole
(1), indazole, and pyrazoles.[8] The trifluoromethyl group is
transferred by a hypervalent iodine reagent (2) under
straightforward reaction conditions, as illustrated by the
example in Scheme 2. Compounds of type 2 have been
This method, first described by Hiyama et al.,[6] is rather
convenient for the generation of the NCF3 unit because it uses
fluoride sources as mild as TBAH2F3 (TBA = tetrabutylam-
monium), though more aggressive reagents such as HF/
pyridine may be required. However, it is safe to say that N-
trifluoromethylated compounds are still rather rare and
[*] K. Niedermann, N. Frꢀh, R. Senn, B. Czarniecki, Dr. R. Verel,
Prof. Dr. A. Togni
Scheme 2. Synthesis of 3 under acid-catalyzed conditions.
Departement Chemie und Angewandte Biowissenschaften
Eidgençssische Technische Hochschule (ETH) Zꢀrich
8093 Zꢀrich (Switzerland)
E-mail: atogni@ethz.ch
previously shown to be the reagent of choice for the electro-
philic trifluoromethylation of a variety of substrates[9] and are
being used increasingly by several research groups.[10]
The observation of N-trifluoromethylbenzotriazole
(4a)[11] as a side product of the Ritter-type reaction indicates
that the direct N-trifluoromethylation of an azole with
reagents of type 2 is indeed possible. Such a reaction is
potentially useful and desirable, but still unknown as a viable
synthetic protocol.
[**] This work was supported by ETH Zꢀrich and the Swiss National
Science Foundation. We thank Dr. M. Wçrle and R. Aardoom for
helpful advice concerning X-ray analysis, Dr. J. M. Welch and J.
Winkler for experimental assistance, and Dr. E. Zass for an
exhaustive literature search concerning NCF3 compounds.
Supporting information for this article (including experimental
procedures and characterization data for new compounds) is
available on the WWW under http://dx.doi.org/10.1002/anie.
201201572.
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We disclose here an efficient route for the direct N-
trifluoromethylation of azoles. Optimization of the reaction
conditions for benzotriazole (vide infra) led to the formation
of 4a as the main product in excellent yield. Optimized
conditions consist of the in situ silylation of the substrate by
1,1,1,3,3,3-hexamethyldisilazane (HMDS) in the presence of
catalytic silica sulfuric acid (SSA),[12] followed by trifluoro-
methylation in highly concentrated CH2Cl2 solution at 358C
in the presence of a catalytic amount of HNTf2 and LiNTf2
(Tf = trifluoromethanesulfonyl). These conditions were suc-
cessfully applied to a variety of different azoles, such as
indazoles, pyrazoles, triazoles, as well as tetrazoles, as shown
in Table 1.
Table 1: (Continued)
Entry Major product
Minor product
Yield[a] [%]
major/minor product
11
12
49:29
42:11
(30:12)[h]
(21:11)
13
46:10
42:18
(24:–)[i]
(18:10)
14[j]
Table 1: Product scope for the direct N-trifluoromethylation of azoles.
[a] Yields were calculated based on the integration of 19F NMR signals
using C6H5CF3 as an internal standard. Yields of isolated products are
given in brackets (significant differences are mainly due to losses during
isolation because of volatility). [b] 5 mol% BF3·Et2O instead of LiNTf2
and HNTf2. [c] 14 mol% HNTf2. [d] 7b contained 3% 7a, 15% yield as
single regioisomer after sublimation. [e] 8a contained 5% 8b. [f] Syn-
thesized from 1-trimethylsilyl-3,5-dimethylpyrazole. [g] 13a contained
<2% 13b. [h] 14b contained ꢀ5% 14a. [i] 16a contained 8% 16b. [j] RT
instead of 358C, no HNTf2 addition.
Entry Major product
Minor product
Yield[a] [%]
major/minor product
Thus, in the case of pyrazoles, the trifluoromethylation
reaction tolerates various substitution patterns and a range of
different substituents. Alkyl-, aryl-, and alkoxycarbonyl-
substituted pyrazoles all undergo the desired reaction. As
illustrated by the results in Table 1, entries 5–7, heterocycles
with electron-donating groups afford higher yields of N-
trifluoromethylated products, whereas electron-withdrawing
substituents lead to lower yields. This can be explained by the
fact that electron-poor groups lead to slower reactions,
allowing side-product formation, mainly decomposition of
the reagent, to predominate. Isomeric mixtures that can be
resolved by flash chromatography are typically obtained from
reactions of nonsymmetrically substituted pyrazoles. Inda-
zoles (Table 1, entries 10 and 11) are preferentially trifluor-
omethylated at the N2 position. Monocyclic triazoles
(Table 1, entries 12 and 13) with aryl or alkoxycarbonyl
substituents lead to isomeric mixtures when they are trifluor-
omethylated under the standard conditions. 5-Phenyltetrazole
can also be N-trifluoromethylated; however, the reaction
temperature should be lowered to room temperature, and no
acid is needed to obtain good yields (Table 1, entry 14).
The structures of the regioisomers of the newly prepared
compounds were assigned using 2D heteronuclear NMR
spectroscopic techniques. As a representative example, the
19F1H HOESY spectra of the major and minor isomer of N-
1
84:2
(64:–)
2[b]
48:46
(44:24)
3
69
(62)
4[c]
34:28
35:7
26
(30:25)[d]
(33:–)[e]
(<13)
(66)
5
6[b]
7
69
8[f]
68
(15)
trifluoromethylated
4,5,6,7-tetrahydro-1H-indazole
are
9
48:20
68:2
(40:12)
(39:–)[g]
shown in Figure 1. The spectrum of the major isomer 14a
shows the contact of the CF3 group with the unique proton of
the heteroaromatic ring, whereas in the case of the minor
regioisomer 14b, the contact between the trifluoromethyl
group and an aliphatic proton is observed.
10
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Figure 2. ORTEP representation of the structures of ethyl 8a (left) and
7b (right); thermal ellipsoids at the 50% probability level.
Table 2: Reaction optimization for product 4a.
Entry Molar ratio 1(18)/2
R
Solvent T [8C] Conc.[a][m] 4a[b] [%]
1[c]
2[c]
3
4
5
6
7
8
9
3
H
H
H
H
H
CH3CN 60 0.1
16
41
58
6
16
42
70
79
81
73
87[d]
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.1
1.1
DCE
60 0.1
60 1.5
35 0.1
35 1.5
35 0.1
35 0.5
35 1.0
35 1.5
35 1.5
35 1.5
CS2
CH2Cl2
CH2Cl2
TMS CH2Cl2
TMS CH2Cl2
TMS CH2Cl2
TMS CH2Cl2
TMS CH2Cl2
TMS CH2Cl2
10
11
[a] Concentration of reagent 2. [b] Yields were calculated based on the
integration of 19F NMR signals using C6H5CF3 as the internal standard.
[c] From Ref. [8]. [d] Addition of LiNTf2 before the addition of reagent and
with 12 mol% HNTf2 instead of 10 mol%.
In general, relatively high temperatures were needed for
the reaction of unactivated benzotriazole to occur. Thus,
moderate yields were observed when the reaction was carried
out in 1,2-dichloroethane at 608C (Table 2, entry 2). When
the reaction was conducted at the same temperature but with
high concentrations in CS2, up to 60% yield was obtained
(Table 2, entry 3). Given that reagent decomposition becomes
significant at elevated temperatures, it was important to find
conditions under which the reaction would still take place at
reasonable rates but at temperatures significantly below
608C. However, at 358C only low yields were observed when
the trifluoromethylation was carried out in CH2Cl2 (Table 2,
entry 4). Slightly higher yields were obtained when the
concentration of the reaction mixture was increased by
a factor of 15, while maintaining the initial substrate/reagent
molar ratio of 1.5 (Table 2, entry 5). Based on previous
findings concerning the reaction of silylated phosphines,[9n]
the reaction was carried out with silylated benzotriazole (18)
at 358C. This afforded 42% yield (Table 2, entry 6). Increas-
ing the concentration gradually improved the yield of 4a to an
excellent 81% (Table 2, entries 7–9). Finally, using only
a slight excess of substrate (1.1 equiv instead of 1.5) led to
a minor reduction in yield (Table 1, entry 10)
Figure 1. 400 MHz 19F1H HOESY spectrum (CD2Cl2) of major (14a)
and minor (14b) products from the N-trifluoromethylation of 1H-
tetrahydroindazole.
In addition to 19F1H HOESY spectra, 19F15N HMBC
spectra were measured to confirm the connectivity of the
trifluoromethyl group to a ring nitrogen. An added benefit of
this method was the unambiguous assignment of the
15N NMR chemical shifts to the corresponding nitrogen
atoms and the determination of the 2J(N,F) coupling constant
in the range of roughly 20 Hz (see the Supporting Informa-
tion). In some cases, in addition to the NMR analysis, the
structure of the products obtained was determined by single-
crystal X-ray analysis. This was the case, for example, for 8a
and 7b (Figure 2).
As mentioned above, the important steps in optimizing
this new direct electrophilic N-trifluoromethylation were
carried out using the model substrate benzotriazole (Table 2).
Obviously, to avoid the formation of Ritter-type products
nitrile solvents should not be used.
In order to further optimize the reaction conditions, we
monitored the reaction leading to 4a by 19F NMR spectros-
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tioned experiments demonstrated the beneficial effect of
a potential fluoride scavenger. Therefore, we used, as an
alternative, the lithium salt LiNTf2 as a less Lewis acidic
fluoride scavenger compatible with a wider range of sub-
strates. To this end, an experiment (Table 2, entry 11) was
carried out in which 2 mol% LiNTf2 was added to the solution
containing 18 prior to the addition of 2 and subsequently
HNTf2. The presence of LiNTf2 at the onset of the reaction
seems to be crucial for improving the overall yield of N-
trifluoromethylation and leads to the formation of 4a in
excellent 87% yield.
Since silylated heterocycles are moisture sensitive, we
opted for an in situ reaction sequence in order to avoid having
to isolate the silylated intermediates. Thus, 1 was heated at
reflux in HMDS with a catalytic amount of silica sulfuric acid
(SSA).[12] After this treatment, full derivatization was con-
firmed by NMR analysis. SSA was readily removed by
filtration and the solvent was replaced with CH2Cl2 prior to
trifluoromethylation. Only a minor decrease in the yield of 4a
was observed when the in situ silylation procedure was used
(compare entry 1 in Table 1 to entry 11 in Table 2). On a small
scale, the second reaction step was usually carried out in
a glovebox for convenience. This simplified the addition of
hygroscopic HNTf2 to water-sensitive silylated azoles. How-
ever, on a larger scale the reaction may be conducted using
standard Schlenk techniques and HNTf2 stock solutions
affording similar results.
In conclusion, we have developed a mild and effective
method for the direct electrophilic N-trifluoromethylation of
a series of variously substituted electron-rich nitrogen hetero-
cycles. Higher yields are obtained when TMS-activated azoles
are used as substrates. In situ silylation is a viable simplifi-
cation, thus allowing the synthesis of the desired N-trifluor-
omethyl products in moderate to high yields without the
isolation of the silylated intermediates. The novel compounds
were fully characterized inter alia by 2D NMR spectroscopic
methods in order to ascertain the isomeric distribution and, in
cases where crystalline products were obtained, X-ray dif-
fraction studies were carried out. We now have ready access
to a wide variety of stable NCF3 compounds which may be of
significant interest across the chemical sciences.
Figure 3. 19F NMR reaction profile (arbitrary integral units) for the
electrophilic trifluoromethylation of 18 with 1.5m 2 in CD2Cl2 using
12 mol% HNTf2 as the catalyst.
copy (Figure 3). Thus, both the exponential decay of the
reagent as well as the exponential formation of the product
were observed. On the basis of the 19F NMR chemical shifts,
a species suspected to be protonated or silylated, that is,
activated reagent 2, is present in catalytic amounts during the
reaction. A diminishing concentration of this species seems to
be related to the formation of trimethylsilyl fluoride (TMSF).
Further side products formed during the reaction include
HCF3 as well as the unstable trifluoromethylated benzyl
alcohol 19 formed as a decomposition product of 2. Finally,
the concentration of the acid catalyst HNTf2 slightly
decreases over the course of the reaction.
Based on the likely correlation between the decay of the
activated reagent and the generation of TMSF, we postulate
that the formation of fluoride might interfere with the
reaction. Therefore, we conducted additional 19F NMR
experiments in which the reaction was run using 5 mol%
BF3·Et2O as the catalyst instead of HNTf2 (see the Supporting
Information for the corresponding reaction profile). Again,
the exponential decay of reagent was observed but instead of
the exponential formation of only the N1-substituted product
4a also the N2-trifluoromethylated benzotriazole 4b was
observed. These two products form at essentially identical
rates and the overall yield of N-trifluoromethylated products
reached 94%, with less than 6% total yield of side products
(see Table 1, entry 2 for the in situ silylation experiment). The
most evident difference in the outcome of these trifluorome-
thylation reactions using different catalysts is the ratio of the
two isomeric products. This was to be expected since, in
general, the isomeric distributions observed in, for example,
alkylation reactions of heterocycles are highly sensitive to the
specific reaction conditions.[13,14]
Experimental Section
General procedure for the N-trifluoromethylation of azoles: A flame-
dried 25 mL two-neck flask with reflux condenser was charged with
silica sulfuric acid (SSA, 2.8 mg) and azole (0.55 mmol, 1.1 equiv).
HMDS (5.5 mL) was added and the mixture was heated at reflux for
2 h. To remove SSA, the mixture was cooled to 1008C and the
solution was filtered off into a 20 mLYoung Schlenk by using a filter
canula and the original reaction vessel was rinsed with toluene (3 ꢀ
0.5 mL). After the collected filtrate and rinses were cooled to room
temperature all volatile compounds were removed under reduced
pressure (15 mbar, 30 min 10À3 mbar). In a glovebox the intermediate,
usually a dynamic isomeric mixture of N-silylated heterocycles, was
redissolved in CH2Cl2 (0.33 mL) and LiNTf2 (2.9 mg, 0.01 mmol,
2 mol%) was added. After the reaction mixture was shaken, 2[9a]
(165 mg, 0.5 mmol) and subsequently HNTf2 (16.9 mg, 0.06 mmol,
12 mol%) were added and the neck of the vessel was rinsed with
CH2Cl2 (50 mL). The resulting clear solution was then stirred at 358C
As promising as BF3·Et2O was as a catalyst for the
reaction of 18 with 2, it was significantly less effective in
combination with other N-silylated nitrogen heterocycles.
Nevertheless, the application of BF3·Et2O in the aforemen-
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(bath temperature) in a closed Young Schlenk for 15 h. The solvent
was then removed under reduced pressure (650 mbar, 408C).
CCDC 841859, 841860, 841861, 841862 ,and 843429 (compounds
7b, 6, 8a, 12a, and 15a, respectively) contain the supplementary
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.
Bremi, I. Kieltsch, A. Togni, D. Monna, D. Langenegger, D.
Hoyer, Helv. Chim. Acta 2009, 92, 2577 – 2586; k) R. Koller, P.
Battaglia, Q. Huchet, J. M. Welch, A. Togni, Chem. Commun.
2009, 5993 – 5995; l) S. Capone, I. Kieltsch, O. Flçgel, G. Lelais,
A. Togni, D. Seebach, Helv. Chim. Acta 2008, 91, 2035 – 2056;
m) K. Stanek, R. Koller, A. Togni, J. Org. Chem. 2008, 73, 7678 –
7685; n) P. Eisenberger, I. Kieltsch, N. Armanino, A. Togni,
Chem. Commun. 2008, 1575 – 1577; o) I. Kieltsch, P. Eisen-
berger, A. Togni, Angew. Chem. 2007, 119, 768 – 771; Angew.
Chem. Int. Ed. 2007, 46, 754 – 757; p) P. Eisenberger, S. Gischig,
A. Togni, Chem. Eur. J. 2006, 12, 2579 – 2586.
Received: February 27, 2012
Published online: May 22, 2012
[10] See e.g.: a) T. Liu, X. Shao, Y. Wu, Angew. Chem. Int. Ed. 2012,
51, 540 – 543; b) X. Wang, Y. Ye, S. Zhang, J. Feng, Y. Xu, Y.
Zhang, J. Wang, J. Am. Chem. Soc. 2011, 133, 16410 – 16413;
c) A. T. Parsons, S. L. Buchwald, Angew. Chem. 2011, 123, 9286 –
9289; Angew. Chem. Int. Ed. 2011, 50, 9120 – 9123; d) T. Liu, Q.
Shen, Org. Lett. 2011, 13, 2342 – 2345; e) R. Shimizu, H. Egami,
T. Nagi, J. Chae, Y. Hamashima, M. Sodeoka, Tetrahedron Lett.
2010, 51, 5947 – 5949; f) A. E. Allen, D. W. MacMillan, J. Am.
Chem. Soc. 2010, 132, 4986 – 4987; g) Y. Ye, N. D. Ball, J. W.
Kampf, M. S. Sanford, J. Am. Chem. Soc. 2010, 132, 14682 –
14687; h) X. Wang, L. Truesdale, J.-Q. Yu, J. Am. Chem. Soc.
2010, 132, 3648 – 3649; i) C. Ausꢂn, J. S. Kaufmann, R. J. Duff, S.
Shivaprasad, S. L. Beaucage, Tetrahedron 2010, 66, 68 – 79.
[11] In 2000 Yagupolskii and co-workers reported one of the first
preparation of N-trifluoromethyl azoles, including derivative 4a,
Keywords: electrophilic addition · hypervalent compounds ·
nitrogen heterocycles · synthetic methods · trifluoromethylation
.
[1] A. M. Thayer, Chem. Eng. News 2006, 84(33), 15 – 24.
[2] Thomson Reuters Integrity http://integrity.thomson-pharma.
com Biologics Search Results, 07.03.2011.
[3] ConQuest 1.13 search of CSD version 5.32 updates May 2011, on
May 15, 2011, for “N-CF3”.
[4] G. Klçter, W. Lutz, K. Seppelt, W. Sundermeyer, Angew. Chem.
1977, 89, 754 – 754; Angew. Chem. Int. Ed. Engl. 1977, 16, 707 –
708.
[5] Y. Asahina, I. Araya, K. Iwase, F. Iinuma, M. Hosaka, T. Ishizaki,
J. Med. Chem. 2005, 48, 3443 – 3446.
[6] a) M. Kuroboshi, T. Hiyama, Tetrahedron Lett. 1992, 33, 4177 –
4178; b) K. Kanie, K. Mizuno, M. Kuroboshi, T. Hiyama, Bull.
Chem. Soc. Jpn. 1998, 71, 1973 – 1991.
[7] T. Umemoto, K. Adachi, S. Ishihara, J. Org. Chem. 2007, 72,
6905 – 6917.
[8] K. Niedermann, N. Frꢁh, E. Vinogradova, M. S. Wiehn, A.
Moreno, A. Togni, Angew. Chem. 2011, 123, 1091 – 1095; Angew.
Chem. Int. Ed. 2011, 50, 1059 – 1063.
[9] a) P. Eisenberger, I. Kieltsch, R. Koller, K. Stanek, A. Togni,
Org. Synth. 2011, 88, 168 – 180; b) N. Santschi, A. Togni, J. Org.
Chem. 2011, 76, 4189 – 4193; c) J. Bꢁrgler, A. Togni, Chem.
Commun. 2011, 47, 1896 – 1898; d) L. K. Charkoudian, C. W.
Liu, S. Capone, D. E. Cane, A. Togni, D. Seebach, C. Khosla,
by
a sequence of functional-group interconversions. See:
a) L. M. Yagupolskii, D. V. Fedyuk, K. I. Petko, V. I. Troitskaya,
V. I. Rudyk, V. V. Rudyuk, J. Fluorine Chem. 2000, 106, 181 –
187. For further reports on the synthesis of NCF3 compounds, see
e.g.: b) G. Pawelke, J. Fluorine Chem. 1991, 52, 229 – 234; c) S. R.
Schow, R. L. Mackman, C. L. Blum, E. Brooks, A. G. Horshma,
A. Joly, S. S. Kerwar, G. Lee, D. Shiffman, M. G. Nelson, X.
Wang, M. M. Wick, X. Zhang, R. T. Lum, Bioorg. Med. Chem.
Lett. 1997, 7, 2697 – 2702; For a recent synthesis of N-(trifluor-
omethyl)amides using BrF3, see: d) Y. Hagooly, J. Gatenyo, A.
Hagooly, S. Rozen, J. Org. Chem. 2009, 74, 8578 – 8582.
[12] M. N. S. Rad, A. Khalafi-Nezhad, M. Divar, S. Behrouz,
Phosphorus Sulfur Silicon Relat. Elem. 2010, 185, 1943 – 1954.
[13] a) D. H. OꢃBrien, C. P. Hrung, J. Organomet. Chem. 1971, 27,
185 – 193; b) L. Birkofer, P. Wegner, Chem. Ber. 1967, 100, 3485 –
3494.
ˇ
Protein Sci. 2011, 20, 1244 – 1255; e) V. Matousek, A. Togni, V.
Bizet, D. Cahard, Org. Lett. 2011, 13, 5762 – 5765; f) N.
Armanino, R. Koller, A. Togni, Organometallics 2010, 29,
1771 – 1777; g) S. Fantasia, J. M. Welch, A. Togni, J. Org.
Chem. 2010, 75, 1779 – 1782; h) M. S. Wiehn, E. V. Vinogradova,
A. Togni, J. Fluorine Chem. 2010, 131, 951 – 957; i) R. Koller, K.
Stanek, D. Stolz, R. Aardoom, K. Niedermann, A. Togni, Angew.
Chem. 2009, 121, 4396 – 4400; Angew. Chem. Int. Ed. 2009, 48,
4332 – 4336; j) D. Seebach, H. Widmer, S. Capone, R. Ernst, T.
[14] For key references concerning silylated azoles, see: a) L.
Birkofer, P. Richter, A. Ritter, Chem. Ber. 1960, 93, 2804 –
2809; b) V. A. Lopyrev, L. I. Larina, M. G. Voronkov, Russ. J.
Org. Chem. 2001, 37, 149 – 193.
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