Trifluoromethylation of 1-aryl-3,3-diisopropyltriazenes

Article abstract of DOI:10.1002/adsc.201201040

A new method for the trifluoromethylation of functionalized aromatic diisopropyltriazenes is described. In a facile two-step, one-pot synthesis, various functionalized trifluoromethyl-substituted arenes are accessible in mostly good yields by using methyl iodide as iodination agent and the trifluoromethylation system (trifluoromethyl)trimethylsilane/potassium fluoride/copper iodide. This concept could be expanded to perfluoroethylation as well as ethoxycarbonyldifluoromethylation reactions. Copyright

Full text of DOI:10.1002/adsc.201201040

UPDATES
DOI: 10.1002/adsc.201201040
Trifluoromethylation of 1-Aryl-3,3-diisopropyltriazenes
Andreas Hafnera and Stefan Brꢀsea,b,*
a
Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax : (+49)-721-6084-8581; phone: (+49)-721-6084-2903; e-mail: braese@kit.edu
Institute of Toxicology and Genetics, Karlsruhe Institute of Technonolgy (KIT), Hermann-von-Helmholtz-Platz 1, 76344
b
Eggenstein-Leopoldshafen, Germany
Received: November 23, 2012; Revised: January 12, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201201040.
Abstract: A new method for the trifluoromethyla-
tion of functionalized aromatic diisopropyltriazenes
is described. In a facile two-step, one-pot synthesis,
various functionalized trifluoromethyl-substituted
arenes are accessible in mostly good yields by using
methyl iodide as iodination agent and the trifluoro-
methylation system (trifluoromethyl)trimethylsi-
lane/potassium fluoride/copper iodide. This concept
could be expanded to perfluoroethylation as well as
ethoxycarbonyldifluoromethylation reactions.
group can be directly introduced via radical,[3] nucleo-
philic[4] or electrophilic[5] CF3 sources. While CF3 radi-
cals react under simple conditions with aromatic com-
pounds there is often a lack of selectivity. Therefore,
nucleophilic or electrophilic trifluoromethylation re-
actions are still favoured for the selective introduction
of the CF3 moiety. In most common protocols aromat-
ic boronic acids[6] or halides[7] (especially iodides or
bromides) are selectively trifluoromethylated using
easy to handle liquids like (trifluoromethyl)trimethyl-
silane (TMS-CF3) or (trifluoromethyl)triethylsilane
(TES-CF3). While TES-CF3 is often used in copper[7e]
or palladium[7d] catalysed trifluoromethylation reac-
tions of aryl halides due to the increased stability
against the formation of difluorocarbenes, TMS-CF3
has still the advantage of being more affordable.[8] In
contrast to TES-CF3, the lower stability of TMS-CF3
Keywords: copper; perfluoroethylation; triazenes;
trifluoromethylation
Over the last years, a lot of effort has been made to leads to reduced yields or more perfluoroethylated
find new methods that allow the direct insertion of by-product when used under catalytic conditions. In
the trifluoromethyl moiety into organic compounds. some cases these drawbacks of TMS-CF3 in copper-
Since many pharmaceutical and agrochemical com- catalysed trifluoromethylation can be avoided by
pounds possess aromatic CF3-groups (Figure 1), adding stoichiometric amounts of AgF.[7c] Neverthe-
arenes are the major target of trifluoromethylation re- less, when TMS-CF3 is used as CF3 source, stoichio-
actions.[1]
metric amounts of copper together with KF are still
Fluorine-containing groups like the CF3 group show the method of choice for the trifluoromethylation of
an increased stability against metabolization com- aryl halides.[9]
pared to other electron-withdrawing groups (e.g.,
Our group has been working on triazenes and their
other halides, carbonyl substituents, etc.). This is one applications in solid-phase synthesis as well as “solu-
reason why they are interesting in terms of bioiso- tion” chemistry for years.[10] Aromatic triazenes are
steric replacement.[2] To date, the trifluoromethyl easily accessible via a simple one-step procedure
Figure 1. Examples for CF3-containing drugs and agrochemicals.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

Andreas Hafner and Stefan Brꢀse
UPDATES
Table 1. Catalytic and stoichiometric trifluoromethylation.[a]
starting from commercially available aniline deriva-
tives.[11] They are versatile intermediates in organic
synthesis as they can be converted into a whole series
of different functionalities.[12] On the other hand, they
tolerate several reaction conditions such as cross-cou-
pling reactions and thus allow for the generation of
complex structures.[13] Until now, no conversion of
this useful group into the corresponding CF3 moiety is
known in literature. Herein, we present a novel and
facile two-step, one-pot protocol for the transforma-
tion of 1-aryl-3,3-diisopropyltriazenes into the corre-
sponding CF3-arenes.
Method CF3 source
(equiv.)
CuI
(equiv.)
Additive
(equiv.)
Yield of
2a
At first, we tested the direct trifluoromethylation of
the triazene group. In general, the triazene moiety is
cleaved by using a reactive electrophile (e.g., H+ or
Lewis acids) to generate the corresponding diazonium
salt which can then be further reacted. These condi-
tions were not suitable for trifluoromethylation reac-
tions using a nucleophilic CF3 source since acids also
protonate the CF3 nucleophile to fluoroform (pKa =
28), which is inert to further conversions under the re-
action conditions used. Therefore, we looked for an
alternative reaction pathway. It is known that the tri-
A
B
C
TES-CF3
(2.00)
TMS-CF3
(2.00)
TMS-CF3
(1.20)
0.10
0.10
1.50
phen (0.10)
phen (0.10)
–
95%[b]
23%[c]
>99%
[a]
Reaction conditions: 1a (0.40 mmol), MeI (2.40 mmol),
1108C, 5 h, then under argon atmosphere: CuI, CF3
source, KF (mmol equal to the CF3 source), additive,
NMP (1.50 mL), 608C, 16 h. Yields determined by
19F NMR using ortho-fluoronitrobenzene as internal stan-
dard.
Conversion was quantitative but 4% perfluoroethylated
by-product was observed.
4% perfluoroethylated by-product was also observed.
ACHTUNGTRENNUNGazene moiety can be used as a masked iodide
group.[14] So we proposed a transformation based on
a simple two-step, one-pot procedure. The first step
should be the iodination of the triazene group fol-
lowed by direct trifluoromethylation under known
conditions.
[b]
[c]
Starting from triazene 1a, we first tested different hand we synthesized other aromatic triazenes and
iodination reactions and it was possible to achieve functionalized them by using MeI and the trifluoro-
quantitative conversion using methyl iodide at 1108C methylation system TMS-CF3/CuI/KF to the corre-
for 5 h. The remaining methyl iodide was removed sponding CF3-arenes (Table 2). Most interestingly,
under reduced pressure and we tested the trifluoro- electron-poor substrates like 1b and 1d showed no
methylation conditions without further purification. conversion at all, but when an additional electron-do-
We investigated stoichiometric as well as catalytic nating group was available, quantitative conversion
transformation protocols[7e] starting from triazene 1a. was observed as in case of 2a and 2c. This shows one
With catalytic amounts of CuI and TES-CF3 as CF3 drawback of this reaction. On the one side, electron-
source quantitative conversion was observed, but be- rich triazenes reacted smoothly with MeI to furnish
sides the desired product 2a, perfluoroethylated by- iodoarenes in quantitative yields, while electron-poor
product (~4%) was detected, too (Table 1, A). As ex- triazenes are less reactive or do not react at all.
pected, the yields as well as the selectivity of the cata-
On the other side, trifluoromethylation of aromatic
lytic trifluoromethylation dropped down (23%) when halides is favoured for electron-poor arenes. These
we changed the CF3 source to TMS-CF3 (Table 1, B). considerations as well as the steric hindrance of ortho
Lastly, when stoichiometric amounts of CuI together substituents explain the conversions observed. None-
with TMS-CF3 were used under our optimized condi- theless, most aromatic triazenes could be trifluorome-
tions, product 2a was synthesized in quantitative thylated in good yields.
yields (Table 1, C).
Copper-mediated perfluoroethylation as well as
The results of methods A and C are comparable to ethoxycarbonyldifluoromethylation are also known in
known trifluoromethylation protocols starting from the literature.[9a,15] Therefore, we wondered whether
iodoarenes, which indicates a quantitative generation such transformations are also possible under our con-
of ammonium salts in the first step, that neither affect ditions. When we tested the perfluoroethylation using
the selectivity nor the yields of the following trifluoro- CuI/TMS-C2F5/KF in DMF (in NMP only poor con-
methylation reaction. Therefore, both reaction proto- versions were observed) triazene 1a as well as 1c
cols are suitable for this conversion, but because of could be converted into their corresponding C2F5-
the less expensive TMS-CF3 we tested further conver- products (Table 3, left), but with reduced yields com-
sions with method C. With our reaction conditions in pared to the trifluoromethylation protocol. In 2011,
2
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Trifluoromethylation of 1-Aryl-3,3-diisopropyltriazenes
Table 2. Trifluoromethylation of functionalized aromatic triazenes.
[a]
Reaction was conducted with 0.40 mmol of triazene 1. Yields determined by
19F NMR using ortho-fluoronitrobenzene as internal standard. Yields in parenthe-
ses are isolated yields.
Table 3. Perfluoroethylation and ethoxycarbonyldifluoromethylation of functionalized aro-
matic triazenes.[a]
[a]
Reaction was conducted with 0.40 mmol of triazene 1. Isolated yields are given.
Amii and co-workers reported the ethoxycarbonyldi- low yields were obtained, despite the fact that stoi-
fluoromethylation of aromatic iodides.[15] Thus we chiometric equivalents of copper were used (Table 3,
tested this reaction under similar conditions starting right).
from aromatic triazenes 1a and 1c. In both cases only
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

Andreas Hafner and Stefan Brꢀse
UPDATES
In conclusion, we have shown that the trifluorome- General Procedure for Ethoxycarbonyldifluorometh-
thylation of the triazene moiety is possible with ylation of the Triazene Moiety
a facile two-step, one-pot synthesis in mostly good
The procedure as well as the equivalents werethe same as in
yields. This transformation can also be used for per-
the general procedure for the trifluoromethylation reactions,
fluoroethylation as well as ethoxycarbonyldifluorome-
thylation.
except for the solvent (DMSO instead of NMP) and the
TMS-agent (TMS-CF2COOEt instead of TMS-CF3).
Experimental Section
Acknowledgements
General
We thank the Landesgraduiertenfçrderung Baden-Wꢀrttem-
berg for financial support. We also want to thank Steffen
Styra for taking care of the 19F NMR measurement.
NMR spectra were recorded on a Bruker AM 400, a Bruker
Avance 300 or a Bruker DRX 500 spectrometer as solutions.
Chemical shifts are expressed in parts per million (ppm, d)
downfield from tetramethylsilane (TMS) and are referenced
to residual solvent peaks. All coupling constants (J) are ab-
solute values and J values are expressed in Hertz (Hz). The
description of signals includes: s=singlet, d=doublet, t=
triplet, q=quartet and m=multiplet. The spectra were ana-
lyzed according to first order. The signal structure in
13C NMR was analyzed by DEPT and is described as fol-
lows: + =primary or tertiary C-atom (positive signal), À=
secondary C-atom (negative signal) and Cquart =quaternary
C-atom (no signal). MS (EI) (electron impact mass spec-
trometry) was performed by using a Finnigan MAT 90
(70 eV). In cases where no (EI) mass spectra could be mea-
sured due to the high volatility of the compound, the GC-
MS was used for characterization. IR (infrared spectrosco-
py) was recorded on a FT-IR Bruker alpha. Solvents, re-
agents and chemicals were purchased from Aldrich, ABCR
and Acros. All solvents, reagents and chemicals were used
as purchased unless stated otherwise.
References
[1] O. Tomashenko, V. V. Grushin, Chem. Rev. 2011, 111,
4475–4521.
[2] a) R. Filler, Y. Kobayashi, Y. L. Yagupolskii, Organo-
fluorine Compounds in Medicinal Chemistry and Bio-
logical Applications, Elsevier, Amsterdam, 1993; b) P.
Kirsch, Modern Fluoroorganic Chemistry, Wiley-VCH,
Weinheim, 2004.
[3] a) D. A. Nagib, D. W. C. MacMillan, Nature 2011, 480,
224–228; b) Y. Ye, S. A. Kꢂnzi, M. S. Sanford, Org.
Lett. 2012, 14, 4979–4981; c) Y. Ye, M. S. Sanford, J.
Am. Chem. Soc. 2012, 134, 9034–9037; d) Y. Ji, T.
Brueckl, R. D. Baxter, Y. Fujiwara, I. B. Seiple, S. Su,
D. G. Blackmond, P. S. Baran, Proc. Natl. Acad. Sci.
USA 2011, 108, 14411–14415; e) A. Hafner, S. Brꢀse,
Angew. Chem. 2012, 124, 3773–3775; Angew. Chem.
Int. Ed. 2012, 51, 3713–3715; f) T. Kino, Y. Nagase, Y.
Ohtsuka, K. Yamamoto, D. Uraguchi, K. Tokuhisa, T.
Yamakawa, J. Fluorine Chem. 2010, 131, 98–105; g) Y.
Li, A. Studer, Angew. Chem. 2012, 124, 8345–8348;
Angew. Chem. Int. Ed. 2012, 51, 8221–8224; h) Y. Yasu,
T. Koike, M. Akita, Angew. Chem. 2012, 124, 9705–
9709; Angew. Chem. Int. Ed. 2012, 51, 9567–9571;
i) review: A. Studer, Angew. Chem. 2012, 124, 9082–
9090; Angew. Chem. Int. Ed. 2012, 51, 8950–8958.
[4] a) O. A. Tomashenko, E. C. Escudero-Adan, M. M.
Belmonte, V. V. Grushin, Angew. Chem. 2011, 123,
7797–7801; Angew. Chem. Int. Ed. 2011, 50, 7655–7659;
b) P. Novak, A. Lishchynskyi, V. V. Grushin, Angew.
Chem. 2012, 124, 7887–7890; Angew. Chem. Int. Ed.
2012, 51, 7767–7770; c) H. Kondo, M. Oishi, K. Fujika-
wa, H. Amii, Adv. Synth. Catal. 2011, 353, 1247–1252;
d) A. Hafner, S. Brꢀse, Adv. Synth. Catal. 2011, 353,
3044–3048; e) H. Morimoto, T. Tsubogo, N. D. Litvinas,
J. F. Hartwig, Angew. Chem. 2011, 123, 3877–3882;
Angew. Chem. Int. Ed. 2011, 50, 3793–3798; f) T.
Knauber, F. Arikan, G.-V. Rçschenthaler, L. J. Gooßen,
Chem. Eur. J. 2011, 17, 2689–2697; g) X. Mu, S. Chen,
X. Zhen, G. Liu, Chem. Eur. J. 2011, 17, 6039–6042;
h) X. Mu, T. Wu, H.-Y. Wang, Y.-L. Guo, G. Liu, J.
Am. Chem. Soc. 2012, 134, 878–881; i) L. Chu, F.-L.
Qing, J. Am. Chem. Soc. 2012, 134, 1298–1304.
General Procedure for Trifluoromethylation of the
Triazene Moiety
A vial equipped with a pressure-resistant crimp top and
a stirring bar was charged with 0.40 mmol of the triazene.
The reaction vessel was closed and 0.15 mL methyl iodide
(340 mg, 2.40 mmol) was added via syringe under an argon
atmosphere. The suspension was stirred at 1108C. After 5–
16 h the suspension was cooled to room temperature and re-
maining methyl iodide was removed under reduced pres-
sure. Now, 113 mg (0.60 mmol) copper iodide and 35 mg
(0.60 mmol) potassium fluoride were added. Then, 1.50 mL
dry NMP and 0.07 mL (68 mg, 0.48 mmol) TMS-CF3 were
added under argon and the suspension was heated to 608C
for another 16 h. The solution was diluted with diethyl ether
and washed with NH3 solution and 2M HCl. The organic
layer was dried over MgSO4. Finally, the solvent was re-
moved under vacuum and the crude product purified by
flash column chromatography.
General Procedure for Perfluoroethylation of the
Triazene Moiety
The procedure as well as the equivalents were the same as
in the general procedure for the trifluoromethylation reac-
tions, except for the solvent (DMF instead of NMP) and the
TMS-agent (TMS-C2F5 instead of TMS-CF3).
[5] a) X.-G-. Zhang, H.-X. Dai, M. Wasa, J.-Q. Yu, J. Am.
Chem. Soc. 2012, 134, 11948–11951; b) T. Liu, X. Shao,
4
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Trifluoromethylation of 1-Aryl-3,3-diisopropyltriazenes
Y. Wu, Q. Shen, Angew. Chem. Int. Ed. 2011, 50, 540–
543; c) C.-P. Zhang, Z.-L. Wang, Q.-Y. Chen, C.-T.
Zhang, Y.-C. Gu, J.-C. Xiao, Angew. Chem. 2011, 123,
1936–1940; Angew. Chem. Int. Ed. 2011, 50, 1896–1900;
d) X. Wang, L. Truesdale, J.-Q. Yu, J. Am. Chem. Soc.
2010, 132, 3648–3649; e) M. S. Wiehn, E. V. Vinogrado-
va, A. Togni, J. Fluorine Chem. 2010, 951–957.
[9] For example: a) H. Urata, T. Fuchikami, Tetrahedron
Lett. 1991, 32, 91–94; b) T. Kitazume, S. Nakayima, J.
Fluorine Chem. 2004, 125, 1447–1449.
[10] a) S. Brꢀse, Acc. Chem. Res. 2004, 37, 805–816;
b) M. E. P. Lormann, C. H. Walker, T. Mꢂller, M. Es-
Sayed, S. Brꢀse, Chem. Commun. 2002, 1296–1297;
c) R. Reingruber, S. Vanderheiden, A. Wagner, M.
Nieger, M. Es-Sayed, S. Brꢀse, Eur. J. Org. Chem. 2008,
3314–3327.
[11] M. Dçbele, S. Vanderheiden, N. Jung, S. Brꢀse, Angew.
Chem. 2010, 122, 6122–6125; Angew. Chem. Int. Ed.
2010, 49, 5986–5988.
[12] Review: D. B. Kimball, M. M. Haley, Angew. Chem.
2002, 114, 3484–3498; Angew. Chem. Int. Ed. 2002, 41,
3338–3351.
[13] For example: a) C.-Y. Liu, P. Knochel, Org. Lett. 2005,
7, 2543–2546; b) see ref.[3e]; c) review: see ref.[10]
[14] J. S. Moore, E. J. Weinstein, Z. Wu, Tetrahedron Lett.
1991, 32, 2465–2466.
[15] a) K. Fujikawa, Y. Fujioka, A. Kobayashi, H. Amii,
Org. Lett. 2011, 13, 5560–5563; b) K. Fujikawa, A. Ko-
bayashi, H. Amii, Synthesis 2012, 44, 3015–3018.
[6] a) X. Jiang, L. Chu, F.-L. Qing, J. Org. Chem. 2012, 77,
1251–1257; b) T. D. Senecal, A. T. Parsons, S. L. Buch-
wald, J. Org. Chem. 2011, 76, 1174–1176; c) L. Chu, F.-
L. Qing, Org. Lett. 2010, 12, 5060–5063.
[7] a) G. G. Dubinina, H. Furutachi, D. A. Vicic, J. Am.
Chem. Soc. 2008, 130, 8600–8601; b) F. Cottet, M.
Marull, O. Lefebvre, M. Schlosser, Eur. J. Org. Chem.
2003, 1559–1568; c) Z. Weng, R. Lee, W. Jia, Y. Yuan,
W. Wang, X. Feng, K.-W. Huang, Organometallics 2011,
30, 3229–3232; d) E. J. Cho, T. D. Senecal, T. Kinzel, Y.
Zhang, D. A. Watson, S. L. Buchwald, Science 2011,
328, 1679–1681; e) M. Oishi, H. Kondo, H. Amii,
Chem. Commun. 2009, 1909–1911.
[8] Price per mol: ~2000 E (TMS-CF3) vs. ~16000 E (TES-
CF3). Source: http://www.sigmaaldrich.com.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

UPDATES
6 Trifluoromethylation of 1-Aryl-3,3-diisopropyltriazenes
Adv. Synth. Catal. 2013, 355, 1 – 6
Andreas Hafner, Stefan Brꢀse*
6
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!