Ortho-Functionalized Aryltetrazines by Direct Palladium-Catalyzed C-H Halogenation: Application to Fast Electrophilic Fluorination Reactions

Article abstract of DOI:10.1002/anie.201601082

A general catalyzed direct C-H functionalization of s-tetrazines is reported. Under mild reaction conditions, N-directed ortho-C-H activation of tetrazines allows the introduction of various functional groups, thus forming carbon-heteroatom bonds: C-X (X=I, Br, Cl) and C-O. Based on this methodology, we developed electrophilic mono- and poly-ortho-fluorination of tetrazines. Microwave irradiation was optimized to afford fluorinated s-aryltetrazines, with satisfactory selectivity, within only ten minutes. This work provides an efficient and practical entry for further accessing highly substituted tetrazine derivatives (iodo, bromo, chloro, fluoro, and acetate precursors). It gives access to ortho-functionalized aryltetrazines which are difficult to obtain by classical Pinner-like syntheses.

Full text of DOI:10.1002/anie.201601082

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201601082
German Edition: DOI: 10.1002/ange.201601082
À
C H Activation
Ortho-Functionalized Aryltetrazines by Direct Palladium-Catalyzed
À
C H Halogenation: Application to Fast Electrophilic Fluorination
Reactions
Christelle Testa, Élodie Gigot, Semra Genc, Richard DecrØau, Julien Roger,* and Jean-
Cyrille Hierso*
À
Abstract: A general catalyzed direct C H functionalization of
s-tetrazines is reported. Under mild reaction conditions,
À
N-directed ortho-C H activation of tetrazines allows the
introduction of various functional groups, thus forming
À
À
carbon–heteroatom bonds: C X (X = I, Br, Cl) and C O.
Based on this methodology, we developed electrophilic mono-
and poly-ortho-fluorination of tetrazines. Microwave irradi-
ation was optimized to afford fluorinated s-aryltetrazines, with
satisfactory selectivity, within only ten minutes. This work
provides an efficient and practical entry for further accessing
highly substituted tetrazine derivatives (iodo, bromo, chloro,
fluoro, and acetate precursors). It gives access to ortho-
functionalized aryltetrazines which are difficult to obtain by
classical Pinner-like syntheses.
T
he chemistry of s-tetrazines (1,2,4,5-tetrazines) has
attracted increasing interest over the years owing to multiple
biochemical, materials, and energy applications resulting
from their unique physicochemical properties.[1,2,3] Accord-
ingly, many improvements in tetrazine synthesis have been
reported.[4,2a] The aryltetrazine framework is classically
derived from the Pinner-like synthesis using hydrazine
derivatives with either cyanoaryl or chlorobenzoyle co-
reagents. Because of sterics and other factors these syntheses
failed to give efficient access to ortho-functionalized arylte-
trazines. This lack of efficiency is well illustrated with the
tedious synthesis of the ortho-tetrafluoro tetrazine acaricide
B which was patented by Chinoin-Sanofi (Scheme 1; for
details see Scheme S1 in the Supporting Information).[5]
Following a similar multistep methodology, an ortho-dibro-
minated aryltetrazine (A), a useful precursor in the synthesis
of benzo[a]acecorannulene for making bowl-shaped fullerene
materials, was obtained in less than 10% yield (Scheme 1).[6]
New synthetic access to ortho-functionalized tetrazines is
Scheme 1. General multistep synthesis of ortho-functionalized aryltetra-
zines: Applied to haloaryltetrazines.
clearly desirable. The direct introduction of reactive halo
functionality to the ortho-position of a preformed tetrazine
skeleton, for instance diaryltetrazine, which is commercially
available on gram scale, would be a useful synthetic progress.
Palladium-catalyzed cross-coupling reactions of aromatics
À
for C C bond formation (Scheme 2a) were recently adapted
to the tetrazine series, but with a very limited scope.[1a,7] The
[*] C. Testa, É. Gigot, S. Genc, Dr. R. DecrØau, Dr. J. Roger,
Prof. Dr. J.-C. Hierso
UniversitØ de Bourgogne, Institut de Chimie MolØculaire de l’Uni-
versitØ de Bourgogne, UMR-CNRS 6302
UniversitØ de Bourgogne Franche-ComtØ (UBFC)
9, avenue Alain Savary 21078 Dijon (France)
E-mail: julien.roger@u-bourgogne.fr
jean-cyrille.hierso@u-bourgogne.fr
Prof. Dr. J.-C. Hierso
Institut Universitaire de France (IUF)
103 Boulevard Saint Michel, 75005 Paris Cedex (France)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601082.
Scheme 2. Palladium-catalyzed tetrazine functionalizations.
Angew. Chem. Int. Ed. 2016, 55, 5555 –5559
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5555

Angewandte
Communications
Chemie
2
À
tetrazine ring is well-known to act as a ligand for metals, and
thus poisons the catalytic activity.[1d] Moreover, tetrazines can
be reduced by metals, and subsequent ring opening may
occur.[1a,8] Recent work from the group of Devaraj described
a practical palladium-catalyzed Heck-type reaction for pro-
ducing alkenyl tetrazines (Scheme 2b): the combination of
appended mesityl group and careful optimization of the
reaction conditions allow the palladium chemistry to proceed
with excellent functional-group tolerance.[2a]
may be affected by the presence of up to four sp C H bonds
at the ortho positions of the heteroaromatic ring. We achieved
selective monobromination of 1 using N-bromosuccinimide
(NBS) both as an oxidant and bromination agent, under mild
reaction conditions.[10] In the absence of palladium no
reaction occurred (entry 1). The reaction of equimolar
amounts of 1 and NBS in the presence of 10 mol% of
[Pd(OAc)2] in 1,2-dichloroethane (DCE) at 1008C for
17 hours led to 75% conversion of 1, and afforded the
expected monobrominated product 2a along with two
dibrominated side-products, 2b and 2c (3,6-bis(2-bromo-
À
Ligand-directed C H bond activation/functionalization
by a transition metal has emerged as a powerful method for
À
À
selectively creating C C and C X bonds (X = N, O, S,
phenyl)-1,2,4,5-tetrazine
and
3-(2,6-dibromophenyl)-6-
halogen).[9] We envisioned that nitrogen-directed C H bond
phenyl-1,2,4,5-tetrazine, respectively), in a 73:17:10 ratio
(entry 2). The compound 2a can be easily purified and
isolated in about 50% yield. Other palladium sources, such as
[PdCl2] and [Pd(dba)2] led to lower conversions (entries 3 and
4). Increasing the amount of NBS led to higher conversions
but was detrimental to the selectivity for 2a (entries 5 and 6).
Improvements were not observed upon replacing NBS with
other bromination agents, such as Br2 or Br2CHCHBr2
(entries 7 and 8). Improvements were also not observed
upon using other solvents (such as CH3CN; entry 9), ligands,
and additives (see Table S1).
Highly selective functionalization of 1 with a variety of
valuable functional groups was achieved by tuning our
protocol as follows. Iodination of 1 was achieved using
N-iodosuccinimide (NIS) in the presence of 10 mol% [Pd-
(dba)2] in DCE to afford 55% conversion and a 89:11 ratio of
the monoiodinated product 3a to the symmetrical diiodinated
À
activation/functionalization would be
approach, thus obviating prefunctionalization of tetrazine
substrates. Nitrogen donors in the skeleton are an opportunity
to achieve ligand-directed C H bond functionalization, as
long as the reaction conditions remain compatible with the
tetrazine nucleus.
a
very attractive
À
À
We now report a general and direct catalyzed C H
functionalization of tetrazines for the introduction of various
useful functional groups, such as halides. Introducing halogen
atoms on the aryl ring is a first step towards extending the
conjugation of the ring system and the construction of more
sophisticated structures through the use of metal-catalyzed
À
coupling reactions. Hence, we report the first efficient C H
functionalization of aryltetrazines. This reaction delivers
a straightforward general solution for accessing difficult
ortho-functionalized aryltetrazines with mono-, di-, tri-, and
tetrafunctionalization in a single well-controlled step.
analogue
3b
((3,6-bis(2-iodophenyl)-1,2,4,5-tetrazine;
À
The C H activation reaction of substituted tetrazines,
Table 1, entry 10). Chlorination of 1 was achieved using
N-chlorosuccinimide (NCS) and 10 mol% [PdCl2] in HOAc
at 1208C (entry 11) to afford the monochlorinated tetrazine
4a with 92% selectivity (see Tables S3 and S5). The scope of
such as 3,6-diphenyl-1,2,4,5-tetrazine (1), is challenging
(Table 1) because it can indeed be reduced by metals and
then undergo decomposition.[1a] Moreover, the selectivity
À
such an unprecedented C H functionalization of s-tetrazine
was extended to acetoxylation reactions using PhI(OAc)2 and
10 mol% [Pd(OAc)2] in HOAc to afford pure 5a in 51% yield
(entry 12).
À
Table 1: C H monofunctionalization of 3,6-diphenyl-1,2,4,5-tetrazine
(1).[a]
À
To demonstrate the power of direct C H halogenation of
aryltetrazine we optimized the synthesis of A (Scheme 1) to
involve a single step from the commercially available 1 by
using 3 equivalents of NBS. A was isolated in 47% yield after
work-up while the monobrominated species 2a (25%) was
recovered for additional selective bromination.
Entry [Pd]
Oxidant (equiv) Solvent Conv. [%]
Yield [%]
1
2
3
–
NBS (1.0)
Pd(OAc)2 NBS (1.0)
PdCl2 NBS (1.0)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH3CN
DCE
HOAc
0
75
26
67
87
96
0
0
0
55
48
84
0
À
The four C H functionalizations of s-tetrazine were also
2a: 55 (48)
2a: 26
2a: 54 (45)
2a: 57
examined. Tetrahalogenation of s-tetrazine was achieved
upon adjusting the amount of the halogenation reagent
(Table 2). By using 8 equivalents of NBS and 10 mol% of
a palladium catalyst, full conversion of 1 was achieved and
afforded the tetrabrominated tetrazine 2e in 98% yield upon
isolation (entry 1). The reaction was even faster when using
a smaller amount of NBS (entry 2) in the presence of
10 mol% of [Pd(OAc)2] in HOAc at 1208C. When using the
4
5
6
7
8
9
10
[Pd(dba)2] NBS (1.0)
[Pd(dba)2] NBS (1.7)
[Pd(dba)2] NBS (2.2)
[Pd(dba)2] Br2 (2.2)
[Pd(dba)2] (Br2CH)2 (2.2)
[Pd(dba)2] NBS (1.7)
[Pd(dba)2] NIS (1.0)
2a: 41
0
0
0
3a: 49 (33)
4a: 44 (32)
5a: 64 (51)
11[b] PdCl2
NCS (1.0)
À
same catalytic system, multiple C H halogenation reactions
12
Pd(OAc)2 PhI(OAc)2 (1.0) HOAc
were successfully achieved with other N-halosuccinimides
(10 equiv) albeit in lower yields (entries 3 and 4): the
tetraiodotetrazine 3e and tetrachlorotetrazine 4e were
obtained from NIS (71% yield) and NCS (80% yield),
respectively. Patents and reports have highlighted the acar-
[a] Reaction conditions: 1 (1 equiv), [Pd] (10 mol%), X source (1.0 to
2.2 equiv), solvent (0.125m), 1008C, under argon, 17 h. Yield determined
by 1H NMR spectroscopy. Yield of isolated product given within
parentheses. [b] 1208C. dba=dibenzylideneacetone, DCE=1,2-
dichloroethane.
5556
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 5555 –5559

Angewandte
Communications
Chemie
Table 2: Tetrafunctionalization of 1.[a]
Table 3: Fluorination of 1: Optimization for fast reaction time and good
selectivity in monofluorinated product.[a]
Entry [Pd]
Oxidant (equiv) Solvent T [8C]
Yield [%]
Entry [Pd]
NFSI (equiv) Solvent
T
Yield [%]
1
2
3
4
[Pd(dba)2] NBS (8.0)
HOAc
HOAc
HOAc
HOAc
100
120
120
120
2e: 99 (98)
2e: 99 (89)
3e: 71 (64)
4e: 80 (34)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
NBS (6.0)
NIS (12.0)
NCS (10.0)
1
PdCl2
1.0
1.0
1.0
1.0
1.0
1.5
1.0
1.5
2.0
2.2
2.5
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
17 h
17 h
17 h
17 h
17 h
17 h
17 h
30 min
10 min
10 min
10 min
34[b]
2
3
4
[{PdCl(allyl)}2]
[Pd(dba)2]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
45[b]
41 (30)
35
46
57
47
[a] Reaction conditions: 1 (1 equiv), [Pd] (10 mol%), NXS (6 to
12 equiv), solvent (0.125m), under argon, 17 h. Yield determined by
1H NMR spectroscopy. Yield of isolated product given within parenthe-
ses.
5[c]
6
7
8[d]
9[d]
10[d]
11[d]
62
71 (44)
70 (50)
63 (47)
icidal potential of halogenated aryltetrazine of the Clofente-
zine family [3,6-bis-(2-chlorophenyl)-1,2,4,5-tetrazine (4b);
see the Supporting Information], which overcomes the
resistance developed by pests to classical organophosphorous
pesticides.[11] By using our method, Clofentezine was synthe-
sized and isolated in 35% yield in a single step by using
5 equivalents of NCS with 1, thus providing a valuable
alternative to traditional multistep pathways employed.
[a] Reaction conditions: 3,6-diphenyl-1,2,4,5-tetrazine 1 (1 equiv), [Pd]
(10 mol%), NFSI (1–2.5 equiv), solvent (0.125m), 1108C, under argon.
Yield determined by 1H and 19F NMR spectroscopy. Yield of isolated
product given within parentheses. [b] Chlorination product was detected.
[c] [Pd2(dba)3] (20 mol%). [d] [Pd(dba)2] (20 mol%), microwave (MW)
200 W, under air.
À
Based on these results we also examined direct C H
fluorination reactions. We were especially eager to test
tetrafluorination of
1
to provide the acaracide
B
(Scheme 1), which was isolated in 13% yield from a multistep
synthesis involving large amounts of hazardous PCl5 and
hepatotoxin CCl4.[5] In addition, with regard to catalyzed
fluorination reactions, a fast conversion time is an important
parameter for potential radiolabeling involving the radiative
isotope 18F, which has a short half-life (t1/2 = 110 min).[12]
Scheme 3. Tetrafluorination of 3,6-diphenyl-1,2,4,5-tetrazine (1) and
3,6-bis(2-fluorophenyl)-1,2,4,5-tetrazine (6b). NFSI (8–12 equiv) was
used.
À
Examples of C H bond activation using N-containing direct-
ing groups have been reported, and generally involves a single
directing group.[13,14] We have here the opportunity for easy
polyfluorination, which is potentially useful for obtaining
higher radiochemical yields.
tively, upon isolation. The lower yield of the isolated product
is a result of stability issues during chromatography on silica.
To further demonstrate the interest of such a straightfor-
ward method to obtain fluorinated tetrazines, we tested their
ability to undergo cycloaddition reaction with pristine 1.
Electron-deficient diene tetrazines can react with electron-
rich dienophiles to form a Diels–Alder adduct (inverse
electron-demand Diels–Alder reaction; iEDDA), which is
then converted into a pyridazine upon extrusion of N2.
Because of its fast reactivity and bioorthogonal nature, this
reaction has already been utilized for bioconjugation in vitro
and in vivo, and has also been applied successfully in polymer
and materials science.[15] We tested the iEDDA reaction with
the starting materials 1 and 6b. The bicyclononyne 8a, used
(Scheme 4) for iEDDA reactions, contains a terminal dioxo-
pyrroldinyl ester which allows easy modification with many
biochemical products from peptide coupling.[16] Strain-pro-
moted [4+2] cycloaddition of 1,2,4,5-tetrazines (1 or 6b) with
8a was monitored by UV/Vis spectroscopy with examination
of the decay of the absorption band at l = 540 nm for 6b (to
give 9) and l = 550 nm for 1 (see Figure S1). The reaction
The reaction between 1 and 1 equivalent of N-fluoroben-
zenesulfonimide (NFSI) was conducted in nitromethane at
1108C, using 10 mol% of [Pd(dba)2]. The monofluorinated
compound 6a was isolated in 30% yield, with a corresponding
conversion of 1 at around 41% over 17 hours (Table 3, lines
1–7). The reaction time was reduced to 30 minutes upon using
microwave irradiation (entries 8–11), 20 mol% of [Pd(dba)2],
and trifluoromethylbenzene (PhCF3) as a solvent at 1108C in
the presence of air (entry 8). The amount of NFSI was crucial
to achieve full conversion of 1. By using 2.5 equivalents of
NFSI, 1 was fully converted into the mono- and difluorinated
species 6a, 6b, and 6c (3-(2,6-difluorophenyl)-6-phenyl-
1,2,4,5-tetrazine) in a 63:27:9 ratio (entry 11). A 77:18:5
ratio with a 91% conversion of 1 and 50% yield of the
isolated 6a was achieved by using 2.2 equivalents of NFSI
(entry 10).
Then, the synthesis of B was achieved starting from either
1 or its difluorinated derivative 6b (Scheme 3). The one step
synthesis of B from 1 and 6b was achieved in 74 and 87%
conversions, respectively, and in 36 and 46% yield, respec-
Angew. Chem. Int. Ed. 2016, 55, 5555 –5559
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5557

Angewandte
Communications
Chemie
ˇ
ˇ
5805; Angew. Chem. 2014, 126, 5915; b) J. Yang, J. Seckute˙, C. M.
Cole, N. K. Devaraj, Angew. Chem. Int. Ed. 2012, 51, 7476;
Angew. Chem. 2012, 124, 7594; c) G. Budin, K. S. Yang, T.
Reiner, R. Weissleder, Angew. Chem. Int. Ed. 2011, 50, 9378;
Angew. Chem. 2011, 123, 9550; d) N. K. Devaraj, S. A. Hilder-
brand, R. Upadhyay, R. Mazitschek, R. Weissleder, Angew.
Chem. Int. Ed. 2010, 49, 2869; Angew. Chem. 2010, 122, 2931;
e) N. K. Devaraj, R. Upadhyay, J. B. Haun, S. A. Hilderbrand, R.
Weissleder, Angew. Chem. Int. Ed. 2009, 48, 7013; Angew. Chem.
2009, 121, 7147; f) N. K. Devaraj, R. Weissleder, S. A. Hilder-
brand, Bioconjugate Chem. 2008, 19, 2297; g) M. L. Blackman,
M. Riyzen, J. M. Fox, J. Am. Chem. Soc. 2008, 130, 13518.
[3] For selected applications related to photophysical, electrochem-
ical, energetic, and coordination properties of tetrazines, see:
a) J. Malinge, C. Allain, A. Brosseau, P. Audebert, Angew. Chem.
Int. Ed. 2012, 51, 8534; Angew. Chem. 2012, 124, 8662; b) D. E.
Chavez, S. K. Hanson, J. M. Veauthier, D. A. Parrish, Angew.
Chem. Int. Ed. 2013, 52, 6876; Angew. Chem. 2013, 125, 7014;
c) Z. Li, J. Ding, N. Song, J. Lu, Y. Tao, J. Am. Chem. Soc. 2010,
132, 13160; d) D. E. Chavez, M. A. Hiskey, R. D. Gilardi, Angew.
Chem. Int. Ed. 2000, 39, 1791; Angew. Chem. 2000, 112, 1861;
e) M. A. Withersby, A. J. Blake, N. R. Champness, P. Hubber-
stey, W.-S. Li, M. Schrçder, Angew. Chem. Int. Ed. Engl. 1997, 36,
2327; Angew. Chem. 1997, 109, 2421.
[4] a) E. Jullien-Macchi, V. Alain-Rizzo, C. Allain, C. Dumas-
Verdes, P. Audebert, RSC Adv. 2014, 4, 34127; b) Q. Zhou, P.
Audebert, G. Clavier, F. Miomandre, J. Tang, RSC Adv. 2014, 4,
7193; c) P. Audebert, S. Sadki, F. Miomandre, G. Clavier, M.-C.
Verni›res, M. Saoud, P. Hapiot, Chem. Eur. J. 2005, 11, 5667;
d) P. Audebert, S. Sadki, F. Miomandre, G. Clavier, M.-C.
Verni›res, M. Saoud, P. Hapiot, New J. Chem. 2004, 28, 387; e) L.
Pellegatti, E. Vedrenne, J.-M. Leger, C. Jarry, S. Routier, J.
Comb. Chem. 2010, 12, 604.
[5] J. Hajimichael, S. Botar, E. Bleicher, L. Pap, I. Szekely, K.
Marmarosi, J. Ori, Eur. Pat. Appl. EP 635499 A2 19950125, 1995.
[6] V. M. Tsefrikas, S. Arns, P. M. Merner, C. C. Warford, B. L.
Merner, L. T. Scott, G. J. Bodwell, Org. Lett. 2006, 8, 5195.
[7] a) Z. Novµk, A. Kotschy, Org. Lett. 2003, 5, 3495; b) N. Leconte,
A. Keromnes-Wuillaume, F. Suzenet, G. Guillaumet, Synlett
2007, 2004.
Scheme 4. Cycloadditions of 1 and 6b.
went to completion in less than 1 hour with 6b, and a slightly
longer reaction time was needed for 1. Such a result shows
that although the presence of the fluorine atoms did not
preclude cycloaddition, they favorably influence the electron
density of the dieneophile and thus increase the rate of the
reaction (for kinetic curves see Figure S3: rate for 6b
cycloaddition kapp = 0.0755 minÀ1 vs. 0.0355 minÀ1 for 1). As
a definitive proof-of-concept illustrating a bioconjugation
scenario, 8a was conjugated with l-glutamic acid to afford 8b,
which was subsequently efficiently reacted with 6b to afford
the pyridazine 10b. Further work is ongoing regarding the
radiofluorination transfer.[17]
À
In summary, we reported the ortho-C H activation of
s-tetrazines, a reaction which allows the introduction of
various functional groups to the tetrazine core. A new and
efficient methodology was developed for electrophilic ortho-
fluorination of tetrazines, using NFSI and microwave irradi-
ation, in only ten minutes when open to air. Hence, this work
provides an efficient and practical entry to access highly
substituted tetrazine derivatives, and will facilitate the devel-
opment of ortho-functionalized aryltetrazines as useful pre-
cursors to materials and bioactive compounds which are
difficult to obtain by using the typical Pinner-like syntheses.
[8] a) S. Maji, B. Sarkar, S. Patra, J. Fiedler, S. M. Mobin, V. G.
Puranik, W. Kaim, G. K. Lahiri, Inorg. Chem. 2006, 45, 1316.
À
[9] For selected reviews on the ligand-directed C H bond activa-
tion, see: a) K. Hirano, M. Miura, Top. Catal. 2014, 57, 878; b) N.
Kuhl, M. N. Hopkinson, J. Wencel-Delord, F. Glorius, Angew.
Chem. Int. Ed. 2012, 51, 10236; Angew. Chem. 2012, 124, 10382;
c) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147; d) L.
Ackermann, Top. Organomet. Chem. 2007, 24, 35.
Acknowledgments
This work was supported by the UniversitØ de Bourgogne
(MESR PhD grant for CT), the RØgion Bourgogne (PARI II
CDEA program), and the CNRS (3MIM-P4 program). We
thank ChemaTechꢀ for generous gift of bicyclononyne. We
are thankful for specific support from the Institut Universi-
taire de France IUF (JCH) and CNRS (RD).
[10] Palladium-catalyzed halogenation with N-halosuccinimides:
a) D. Kalyani, A. R. Dick, W. Q. Anani, M. Sanford, Org. Lett.
2006, 8, 2523; b) D. Sarkar, F. S. Melkonyan, A. V. Gulevich, V.
Gevorgyan, Angew. Chem. Int. Ed. 2013, 52, 10800; Angew.
Chem. 2013, 125, 11000; c) B. Du, X. Jiang, P. Sun, J. Org. Chem.
2013, 78, 2786; d) X. Sun, G. Shan, Y. Sun, Y. Rao, Angew. Chem.
Int. Ed. 2013, 52, 4440; Angew. Chem. 2013, 125, 4536.
[11] a) J. H. Parsons, Eur. Pat. Appl. A-5912, 1979; b) P. J. Brooker,
J. H. Parsons, J. Reid, P. J. West, Pestic. Sci. 1987, 18, 179; c) J. H.
Parsons, Eur. Pat. Appl. A-5912, 1979; d) R. Nauen, N. Stumpf,
A. Elbert, C. P. W. Zebitz, W. Kraus, Pest Manage. Sci. 2001, 57,
253.
À
Keywords: C H activation · fluorine · halogenation ·
heterocycles · palladium
How to cite: Angew. Chem. Int. Ed. 2016, 55, 5555–5559
Angew. Chem. 2016, 128, 5645–5649
[12] a) P. W. Miller, N. J. Long, R. Vilar, A. D. Gee, Angew. Chem.
Int. Ed. 2008, 47, 8998; Angew. Chem. 2008, 120, 9136; b) R.
Littich, P. J. H. Scott, Angew. Chem. Int. Ed. 2012, 51, 1106;
Angew. Chem. 2012, 124, 1132.
[13] a) K. L. Hull, W. Q. Anani, M. S. Sanford, J. Am. Chem. Soc.
2006, 128, 7134; b) X. Wang, T.-S. Mei, J.-Q. Yu, J. Am. Chem.
Soc. 2009, 131, 7520; c) K. S. L. Chan, M. Wasa, X. Wang, J.-Q.
[1] a) G. Clavier, P. Audebert, Chem. Rev. 2010, 110, 3299; b) N. K.
Devaraj, R. Weissleder, Acc. Chem. Res. 2011, 44, 816; c) R. P.
Singh, R. D. Verma, D. T. Meshri, J. M. Shreeve, Angew. Chem.
Int. Ed. 2006, 45, 3584; Angew. Chem. 2006, 118, 3664; d) W.
Kaim, Coord. Chem. Rev. 2002, 230, 127.
[2] For bioorthogonal innovative applications, see: a) H. Wu, J.
ˇ
ˇ
˙
Yang, J. Seckute, N. K. Devaraj, Angew. Chem. Int. Ed. 2014, 53,
5558
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 5555 –5559

Angewandte
Communications
Chemie
Yu, Angew. Chem. Int. Ed. 2011, 50, 9081; Angew. Chem. 2011,
Fox, D. S. Johnson, J. Am. Chem. Soc. 2015, 137, 11461; b) Y.
123, 9247; d) S.-J. Lou, D.-Q. Xu, A.-B. Xia, Y.-F. Wang, Y. Liu,
X.-H. Du, Z.-Y. Xu, Chem. Commun. 2013, 49, 6218; e) S.-J. Lou,
Q. Chen, Y.-F. Wang, D.-Q. Xu, X.-H. Du, J.-Q. He, Y.-J. Mao,
Z.-Y. Xu, ACS Catal. 2015, 5, 2846.
Sun, X. Ma, K. Cheng, B. Wu, J. Duan, H. Chen, L. Bu, R. Zhang,
X. Hu, Z. Deng, L. Xing, X. Hong, Z. Cheng, Angew. Chem. Int.
Ed. 2015, 54, 5981; Angew. Chem. 2015, 127, 6079.
[17] Application patent was deposited for this methodology: J.-C.
Hierso, J. Roger, C. Testa, R. DecrØau, US Pat. Appl. US 62/
260,741, 2015.
[14] C. Testa, J. Roger, S. Scheib, P. Fleurat-Lessard, J.-C. Hierso,
Adv. Synth. Catal. 2015, 357, 2913.
[15] a) A.-C. Knall, C. Slugovc, Chem. Soc. Rev. 2013, 42, 5131; b) W.
Chen, D. Wang, C. Dai, D. Hamelberg, B. Wang, Chem.
Commun. 2012, 48, 1736; c) F. Liu, Y. Liang, K. N. Houk, J.
Am. Chem. Soc. 2014, 136, 11483.
[16] a) H. E. Murrey, J. C. Judkin, C. W. am End, T. E. Ballard, Y.
Fan, K. Riccardi, L. Di, E. R. Guilmette, J. W. Schwartz, J. M.
Received: January 30, 2016
Revised: February 23, 2016
Published online: March 24, 2016
Angew. Chem. Int. Ed. 2016, 55, 5555 –5559
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5559