PhI(OAc)2-mediated radical trifluoromethylation of vinyl azides with Me3SiCF3

Article abstract of DOI:10.1002/anie.201307846

The fluorine-containing organic motif is becoming privileged in pharmaceuticals, agrochemicals, and functional materials, owing to its unique properties such as electron-withdrawing character, metabolic stability, and lipophilicity. Described herein is the PhI(OAc)₂-mediated radical trifluoromethylation of vinyl azides with Me₃SiCF₃ to efficiently generate α-trifluoromethyl azines. The resulting α-trifluoromethyl azines were successfully transformed to valuable fluorine-containing molecules such as α-trifluoromethyl ketones, β-trifluoromethyl amines, 5-fluoropyrazoles, and trifluoroethyl isoquinolines. Trifluoromethylated diversity: The title reaction (see scheme) efficiently leads to α-trifluoromethyl azines, which were successfully transformed into valuable fluorine-containing molecules such as α-trifluoromethyl ketones, β-trifluoromethyl amines, 5-fluoropyrazoles, and trifluoroethyl isoquinolines. Copyright

Full text of DOI:10.1002/anie.201307846

Angewandte
Chemie
DOI: 10.1002/anie.201307846
Trifluoromethylation
PhI(OAc)2-Mediated Radical Trifluoromethylation of Vinyl Azides
with Me3SiCF3**
Yi-Feng Wang, Geoffroy Hervꢀ Lonca, and Shunsuke Chiba*
Abstract: The fluorine-containing organic motif is becoming
privileged in pharmaceuticals, agrochemicals, and functional
materials, owing to its unique properties such as electron-
withdrawing character, metabolic stability, and lipophilicity.
Described herein is the PhI(OAc)2-mediated radical trifluor-
omethylation of vinyl azides with Me3SiCF3 to efficiently
generate a-trifluoromethyl azines. The resulting a-trifluoro-
methyl azines were successfully transformed to valuable
fluorine-containing molecules such as a-trifluoromethyl
ketones, b-trifluoromethyl amines, 5-fluoropyrazoles, and tri-
fluoroethyl isoquinolines.
A
variety of methods for installation of the CF3 unit
(trifluoromethylation) have been developed to access CF3-
containing molecules because of their importance in pharma-
ceutical and material sciences.[1,2] Specifically, use of the CF3
radical[2e,f] has recently received considerable attention for
trifluoromethylation in which various CF3 radical precursors
have been utilized under redox reaction conditions (Sche-
me 1a), including CF3X (A: X = I or B: X = SO2Cl),[3] the
Togni reagent C,[4] Umemoto reagent D,[5] Ruppert–Prakash
reagent (Me3SiCF3) E,[6] and Langlois/Baran reagent
(CF3SO2M; F: M = Na or G: M = Zn).[7]
Scheme 1. Trifluoromethylation with the CF3 radical.
methods for the synthesis of aza-heterocycles based on MnIII-
mediated/catalyzed radical reactions of vinyl azides with
cyclopropanols or 1,3-dicarbonyl compounds.[11] The contin-
ued interest in radical reactions of vinyl azides motivated us to
investigate the reactions of the CF3 radical with vinyl azides,
and the CF3 radical generated oxidatively from Me3SiCF3
Among those radical trifluoromethylation reagents,
Me3SiCF3 has many advantages such as low cost, and easy
handling and storage.[8] Single-electron oxidation of Me3SiCF3
generates the CF3 radical. Most of the methods mainly rely on
the stoichiometric use of transition-metal complexes such as
silver[6a,e,f] and copper[6b] salts as the promoters, while a few
silver-catalyzed versions with PhI(OAc)2 as the stoichiometric
oxidant have recently been demonstrated by the groups of
Qing[6c] and Greaney.[6d] However, radical trifluoromethyla-
tion protocols with Me3SiCF3 in the absence of transition-
metals have rarely been achieved.[9]
=
adds to the C C bond of vinyl azides to form a-trifluor-
omethyl iminyl radicals. Subsequent conversions of the
transient iminyl radicals were envisioned. Herein, we disclose
a PhI(OAc)2-mediated oxidative trifluoromethylation of vinyl
azides with Me3SiCF3 to afford a-trifluoromethyl azines,
which could be readily transformed into valuable fluorine-
contatining synthons such as a-trifluoromethyl ketones, b-
trifluoromethyl amines, 5-fluoropyrazoles, and trifluoroethyl
isoquinoline (Scheme 1b). The present trifluoromethylation
with vinyl azides could be run in the absence of transition
metals, and the preliminary mechanistic investigation
revealed that the CF3 radical is likely involved in the
trifluoromethylation.
We commenced our study by using the vinyl azide 1a with
Me3SiCF3 (3 equiv) and CsF (2 equiv) in the presence of
AgOTf (5 mol%) and PhI(OAc)2 (1.5 equiv). The reaction
proceeded smoothly at 08C in CH3CN, thus providing the
azine 2a as a mixture of E/Z isomers in 80% yield,[12] and is
likely formed by dimerization of the transient a-trifluoro-
methyl iminyl radical (Table 1, entry 1).[13] Notably, 2a was
also formed in 84% yield even in the absence of the Ag
catalyst (entry 2). Switching the fluoride source from CsF to
KF resulted in a sluggish reaction (entry 3). Further screening
Vinyl azides have served as versatile materials for the
synthesis of various nitrogen-containing molecules, especially,
azaheterocycles.[10] Vinyl azides work as a radical acceptor.
Using this chemical reactivity, we have recently developed
[*] Dr. Y.-F. Wang, G. H. Lonca, Prof. S. Chiba
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University
Singapore 637371 (Singapore)
E-mail: shunsuke@ntu.edu.sg
[**] This work was supported by funding from the Nanyang Techno-
logical University and Singapore Ministry of Education (Academic
Research Fund Tier 2: MOE2012-T2-1-014). Y.-F.W. thanks Lee Kuan
Yew postdoctoral fellowship (the LKY PDF). G.H.L. is grateful for the
financial support from Ecole Polytechnique.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307846.
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Table 1: Optimization of the reaction conditions.[a]
tions implicated the presence of the CF3 radical in the present
reaction.[16] When the reaction was conducted in the presence
of 1,4-cyclohexadiene (5 equiv), 2a was obtained in only 8%
yield along with 38% yield of the a-trifluoromethyl ketone 4a
(Scheme 2c). The a-trifluoromethyl ketone 4a is formed
presumably by hydrolysis of the NH imine intermediate,
which is generated by H-radical abstraction of the putative a-
trifluoromethyl iminyl radical.
Based on these observations, a proposed reaction pathway
for the formation of 2a is depicted in Scheme 3. The reaction
of Me3SiCF3 with CsF forms the silicate,[17] which is oxidized
by PhI(OAc)2 by a single-electron transfer (SET) to generate
the trifluoromethyl radical (Scheme 3a). The resulting tri-
fluoromethyl radical adds to 1a to form the iminyl radical
intermediate, which immediately dimerizes to give 2a (Sche-
me 3b).
Entry
FÀ source [equiv]
Conditions
Yield [%][b]
1[c]
2
3
4
5
CsF (2)
CsF (2)
KF (2)
CsF (1.5)
CsF (1)
CsF (0.5)
–
08C, 2 h
08C, 2 h
08C–RT, 24 h
08C, 20 min
08C, 1 h
80
84
70
96
74
72
0[e]
6
08C, 3 h
08C–RT, 24 h
7[d]
[a] Unless otherwise noted, the reactions were carried out on a 0.3–
0.5 mmol scale of 1a with 3 equiv of Me3SiCF3 in CH3CN (0.1m) under
a nitrogen atmosphere. [b] Combined yields of E,E, E,Z, and Z,Z isomers
(1.8:1.2:1) of 2a determined by 19F NMR spectroscopy using a,a,a-
trifluorotoluene as an internal standard. The major isomer is E,E, while
the stereochemistry of the minor two isomers was not assigned. [c] The
reaction was carried out in the presence of 5 mol% of AgOTf. [d] Instead
of CsF, 2 equiv of NaOAc was utilized. [e] 1a was recovered in 70% yield.
of the reaction parameters revealed that the amount of CsF
and the reaction time are crucial to obtaining higher yields of
2a. The yield of 2a was dramatically improved to 96% by
using 1.5 equivalents of CsF and quenching the reaction
immediately upon the consumption of 1a within 20 minutes
(entry 4).[14] Reducing the amount of CsF to 1 equivalent led
to the longer reaction time and lowered the yield of 2a
(entry 5). Even by using 0.5 equivalents of CsF, 1a could be
consumed within 3 hours (entry 6), thus affording the product
2a in 72% yield. However, no reaction took place in the
absence of CsF, only with 2 equivalents of NaOAc
(entry 7).[15]
To gain insight into the reaction mechanism of the
trifluoromethylation of 1a for the formation of 2a, control
experiments with TEMPO (2,2,6,6-tetramethylpiperidin-1-
oxyl) were examined (Scheme 2a,b). The reaction of
Me3SiCF3 under the present oxidative reaction conditions in
the presence of TEMPO afforded the TEMPO-CF3 adduct 3
in 57% yield (determined by 19F NMR spectroscopy);
Scheme 2a).[4h,6c,f] Moreover, the formation of 2a was com-
pletely inhibited when TEMPO (2.5 equiv) was added to the
reaction mixture, and the formation of 3 was instead observed
along with 74% recovery of 1a (Scheme 2b). These observa-
Scheme 3. A proposed reaction mechanism.
Having developed a method for construction of 2a, we
next explored molecular transformations of 2a into valuable
fluorine-containing materials. At first, we aimed to develop
a facile procedure for the synthesis of 4a by hydrolysis of
2a.[3c,f–h,5f,7a,18] Indeed, the crude reaction mixture containing
2a was treated with 3N HCl (3 equiv) in THF, thus affording
4a in 81% yield (Table 2, entry 1). Following the established
procedure, the generality of this a-trifluoromethyl ketone
synthesis was examined using a series of vinyl azides (1). a-
Aryl-substituted vinyl azides were readily transformed into
the corresponding a-trifluoromethyl ketones 4 in good yields
(Table 2, entries 2–8). The addition of the CF3 radical to
trisubstituted vinyl azides (1i, 1j, and 1p) proceeded
smoothly to give the corresponding ketones 4 in good
yields. Notably, heteroaryl motifs such as benzothiophene
(1k), benzofuran (1l), and oxazole (1m) were compatible
under the present reaction conditions, thus furnishing the
desired ketones 4. a-Alkyl-substituted vinyl azides (1n–p)
were also capable of coupling with the CF3 radical efficiently,
thus demonstrating the broad applicability of the present
process.
We next turned our attention to the reduction of the
azines 2 to prepare b-trifluoromethyl amine derivatives.[4f,5a]
The azine 2a was subjected to a suspension of Zn dust in
AcOH,[19] which was then treated with Ac2O, thus delivering
the acetamide 5a in 61% yield (Scheme 4). The reduction of
the azine 2i derived from the trisubstituted vinyl azide 1i
resulted in the acetamide 5i in 65% yield as a mixture of
diastereomers (d.r. = 1.3:1). Similarly, the benzofuranyl vinyl
azide 1l as well as alkyl vinyl azide 1n could be converted into
Scheme 2. Investigation of the reaction mechanism.
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Table 2: Substrate scope on synthesis of a-trifluoromethyl ketones 4.[a]
Table 2: (Continued)
Entry
1
4
Yield [%][b]
16[c]
1p
4p: 70%
Entry
1
4
[a] The reactions were carried out by treatment of the vinyl azides
1 (0.5 mmol) and Me3SiCF3 (3 equiv) with PhI(OAc)2 (1.5 equiv) and CsF
(1.5 equiv) in CH3CN (5 mL) at 08C under a nitrogen atmosphere. After
aqueous work-up, the resulting crude reaction mixture was treated with
3n HCl (3 equiv) in THF at 808C for 12–30 h. [b] Yields of the products 4
upon isolation. [c] The corresponding azine 2p was treated with 6N HCl
(6.0 equiv) in THF at 808C for 30 h.
Yield [%][b]
1
2
3
4
5
6
7
1a (R=H)
4a: 81%
4b: 70%
4c: 91%
4d: 80%
4e: 81%
4 f: 86%
4g: 72%
1b (R=2-Me)
1c (R=4-Me)
1d (R=4-MeO)
1e (R=3-Br)
1 f (R=4-Br)
1g (R=3-NO2)
8
1h
4h: 85%
Scheme 4. Synthesis of b-trifluoromethyl amines 5. [a] The diastereo-
mer ratio was determined by 1H NMR spectroscopy.
9
1i
1j
4i: 82%
4j: 66%
the corresponding acetamides 5l and 5n in 40% and 51%
yields, respectively.
10
We further explored robust conversions of the a-trifluoro-
methyl azines 2 for synthesis of fluorine-containing azahe-
terocycles, which are of great importance from the stand
points of biological and medicinal applications.[1] In that
respect, treatment of the crude reaction mixture of 2a with
K2CO3 in DMF delivered N-trifluoromethylalkenyl-5-fluoro-
pyrazole (6a) in 72% yield based on 1a (Scheme 5).[20] The
alkyl vinyl azides 1n as well as heteroaryl-substituted vinyl
azides 1k and 1l could be converted into the corresponding 5-
fluoropyrazoles 6 in moderate to good yields.[21]
11
12
1k
1l
4k: 82%
4l: 62%
13
14
15
1m
1n
1o
4m: 62%
4n: 80%
4o: 70%
Scheme 5. Synthesis of the 5-fluoropyrazoles 6.
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Scheme 6. Synthesis of trifluoroethylisoquinolines.
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As another example, we found that the RhIII-catalyzed
À
aromatic C H alkenylation of 2a with internal alkynes
allowed the synthesis of the trifluoroethyl isoquinolines 7a–
c in moderate to good yields (Scheme 6).[22] In this process, the
nitrogen atom of 2a functioned as the intramolecular direct-
À
ing group to facilitate ortho-aryl C H bond rhodation. These
approaches associated with the present radical trifluoro-
methylation enable facile accesses to fluorine-containing aza-
heterocycles from readily available vinyl azides 1 and
Me3SiCF3.
In summary, we have developed PhI(OAc)2-mediated
radical trifluoromethylation of vinyl azides using Me3SiCF3,
and it allows construction of a-trifluoromethyl azines. More-
over, facile protocols were devised to convert a-trifluoro-
methyl azines into valuable fluorine-containing compounds
such as a-trifluoromethyl ketones, b-trifluoromethyl amines,
5-fluoropyrazoles, and trifluoroethyl isoquinoline. We expect
that the present radical trifluoromethylation of vinyl azides is
capable of supplying a new approach for synthesis of
biologically and medicinally important fluorine-containing
molecules.
Received: September 6, 2013
Revised: October 14, 2013
Published online: December 11, 2013
Keywords: fluorine · heterocycles · hypervalent iodine · radicals ·
synthetic methods
.
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by isolating the side products. The CF3 anion is very nucleophilic,
[18] For selected recent reports on synthesis of a-trifluoromethyl
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À
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=
which can add to the C N bond of imines. For the relevant
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831 – 841.
Angew. Chem. Int. Ed. 2014, 53, 1067 –1071
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