Stable but reactive perfluoroalkylzinc reagents: Application in ligand-free copper-catalyzed perfluoroalkylation of aryl iodides

Article abstract of DOI:10.1002/chem.201405677

The aromatic perfluoroalkylation catalyzed by a copper(I) salt with bis(perfluoroalkyl)zinc reagents Zn(R_F)₂(DMPU)₂, which were prepared and then isolated as a stable white powder from perfluoroalkyl iodide and diethylzinc, was accomplished to provide the perfluoroalkylated products in good-to-excellent yields. The advantages of this reliable and practical catalytic reaction are 1) airstable and easy-to-handle bis(perfluoroalkyl)zinc reagents can be utilized, 2) the reagent is reactive and hence the operation without activators and ligands is simple, and 3) not only trifluoromethylation but also perfluoroalkylation can be attained.

Full text of DOI:10.1002/chem.201405677

DOI: 10.1002/chem.201405677
Communication
&
Synthetic Methods
Stable but Reactive Perfluoroalkylzinc Reagents: Application in
Ligand-Free Copper-Catalyzed Perfluoroalkylation of Aryl Iodides
Kohsuke Aikawa, Yuzo Nakamura, Yuki Yokota, Wataru Toya, and Koichi Mikami*[a]
methyl-copper reagents and its application to trifluoromethyl-
Abstract: The aromatic perfluoroalkylation catalyzed by
ation reactions. In sharp contrast, the copper-catalyzed per-
a
copper(I) salt with bis(perfluoroalkyl)zinc reagents
fluoroalkylation of aryl halides is still undeveloped.[3] Recently,
the copper-catalyzed perfluoroalkylation of aryl iodides has
been disclosed for the first time, by using perfluoroalkylzinc re-
agents in situ pre-generated from TMP2Zn and 1H-perfluoroal-
kanes.[11] The fundamental drawback of this method is that
TMP2Zn is extremely water- and air-sensitive. Therefore, the de-
velopment of more reliable and practical method for catalytic
perfluoroalkylation reactions on aromatic system is strongly
desirable.[3] Herein, we report the ligand-free copper-catalyzed
direct incorporation of not only trifluoromethyl but also per-
fluoroalkyl groups into aromatic moieties (Scheme 1). The ad-
Zn(RF)2(DMPU)2, which were prepared and then isolated as
a stable white powder from perfluoroalkyl iodide and di-
ethylzinc, was accomplished to provide the perfluoroalky-
lated products in good-to-excellent yields. The advantages
of this reliable and practical catalytic reaction are 1) air-
stable and easy-to-handle bis(perfluoroalkyl)zinc reagents
can be utilized, 2) the reagent is reactive and hence the
operation without activators and ligands is simple, and 3)
not only trifluoromethylation but also perfluoroalkylation
can be attained.
In synthetic organic chemistry, the introduction of fluoroalky-
lated functional groups into organic molecules continues to be
a long-standing challenge due to unique property of fluorine.[1]
Generally, fluoroalkylated compounds can be synthesized by
using fluoroalkyl-containing building blocks[2] or fluoroalkylat-
ing reagents.[3] The former utilizes available fluoroalkyl-contain-
ing building blocks on early stage, thus playing an important
role in catalytic asymmetric synthesis of optically active fluo-
roalkylated compounds.[2] The latter employs nucleophilic, elec-
trophilic, and radical fluoroalkylations reactions by available
fluoroalkylating reagents to directly introduce fluoroalkyl
groups into target molecules not only on early stage but also
late stage. Particularly, a considerable progress has been ach-
ieved on the transition-metal-mediated or -catalyzed trifluoro-
methylation of aromatic compounds by treatment of trifluoro-
methylating reagents.[3] The trifluoromethylation of aryl chlo-
ride[4] and aromatic CÀH bond by directing group[5] could be
catalyzed by unique palladium catalysts. On the other hand,
Amii and co-workers reported that the trifluoromethylation of
aryl iodides could be catalyzed by copper(I) salt through the
addition of 1,10-phenanthroline as a ligand.[6] This finding trig-
gered the development of the various stoichiometric and cata-
lytic trifluoromethylation of aromatic system by copper(I)
salt.[7,8] Especially, Hartwig[9] and Grushin[10] groups have inde-
pendently reported the preparation and isolation of trifluoro-
Scheme 1. This work: copper-catalyzed perfluoroalkylation reactions.
vantages of our catalytic reaction are: 1) utilization of air-stable
and easy-to-handle bis(perfluoroalkyl)zinc reagents; 2) a simple
operation without the addition of ligands and fluoride activa-
tors, in sharp contrast to that of perfluoroalkylsilanes (RFSiMe3),
such as Ruppert–Prakash reagent; and 3) application to not
only trifluoromethylation but also perfluoroalkylation under
the relatively mild conditions.
Recently, we have reported the trifluoromethylation of aryl
iodides catalyzed by copper(I) salt with trifluoromethylzinc in
situ pre-generated from trifluoromethyl iodide (CF3I) and Zn
dust in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(DMPU).[12] The catalytic reaction gave moderate-to-high yields
of the trifluoromethylated products under the mild reaction
conditions. We envisaged the development of reliable and
practical catalytic method not only for trifluoromethylation but
also perfluoroalkylation by using bis(perfluoroalkyl)zinc re-
agents without halide, which can be isolated as air-stable and
easy-to-handle solid due to the intrinsic drawback that gas-
eous CF3I (boiling point À22.58C) is hard to handle due to the
development of reactions in regular laboratories: thus, general
synthetic applications are restricted. Naumann and co-workers
have already reported Zn(CF3)2Ln (L: glyme n=1, diglyme n=1,
pyridine n=2) complexes prepared by treatment of CF3I with
dialkylzinc in the presence of Lewis base (L) in CCl3F as a sol-
vent.[13,14] However, these reagents have never been utilized
[a] Dr. K. Aikawa, Y. Nakamura, Y. Yokota, W. Toya, Prof. Dr. K. Mikami
Department of Applied Chemistry, Tokyo Institute of Technology
O-okayama, Meguro-ku, Tokyo 152-8552 (Japan)
Fax: (+81)3-5734-2776
E-mail: mikami.k.ab@m.titech.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405677.
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Scheme 2. Preparation of bis(perfluoroalkyl)zinc reagents.
successfully in catalytic reactions to the best of our knowledge.
On the other hand, Zn(C2F5)2(DMPU)2 but not Zn(CF3)2(DMPU)2
reagent prepared by a combination of C2F5H and TMP2Zn in
DMPU as a solvent is also a known compound, which structure
was confirmed by X-ray crystallography, was isolated by Dau-
gulis and co-workers.[11,15] Referring to these previous reports,
we investigated the synthetic methods improved for prepara-
tion and isolation of air-stable and easy-to-handle various bis-
(perfluoroalkyl)zinc reagents. After a survey on the various zinc
reagents, Lewis bases, and reaction conditions, it was found
that the reaction with perfluoroalkyl iodides (2.5–5.0 equiv), di-
ethyl zinc, and DMPU (2 equiv) in hexane below 08C gave effi-
Scheme 4. Copper-catalyzed trifluoromethylation of aryl iodides. Conditions:
3 (0.1 mmol), 1a (0.2 mmol), and CuI (0.01 mmol) in DMPU (0.2 mL) at 508C
for 24 h. Yields were determined by 19F NMR analysis by using BTF as an in-
ternal standard. [a] By using CuI (2 mol%). [b] Isolated yield. [c] By using 1a
(1.6 equiv). [d] By using 1a (4 equiv). [e] By using CuTC (1.0 equiv) instead of
CuI.
transmetallation was found to be much faster than that with
CuI (Eq. [2] in Scheme 3). Interesting is that not the formation
of cuprate
A with iodide but neutral CuCF3 (C: dF =
À27.3 ppm),[7,10] which was clarified to be reactive species in
various trifluoromethylation reactions, was confirmed to be ob-
tained in 15% yield after five minutes, along with cuprate B in
28% yield.
ciently Zn(RF)2(DMPU)2 reagents
1
on gram scale
(Scheme 2a).[16] Reagents 1 existed as air-stable white solids,
except for 1a, which was slightly moisture sensitive and slowly
decomposed in air at room temperature, but was stable for at
least one month under argon atmosphere.[17] Additionally, the
combination of 1a and tetramethylethylenediamine (TMEDA;
1 equiv) in DMF underwent the ligand exchange to give the
air-stable Zn(CF3)2(TMEDA) (2; Scheme 2b). The structure of
complex 2, which is characterized by tetrahedral geometry of
the Zn center, was undoubtedly determined by X-ray analysis
of the single crystal.
Having established a method for the preparation of perfluo-
roalkylzinc reagents 1 as an air-stable solid, we explored the
reliable and practical method for the copper-catalyzed trifluo-
romethylation and perfluoroalkylation to various aromatic
rings. Initially, bis(trifluoromethyl)zinc 1a was applied to the tri-
fluoromethylation of aryl iodides 3 in catalytic amount of CuI
(10 mol%; Scheme 4). After surveying a wide range of ligands
and solvents, it was found that the reaction without ligand in
DMPU at 508C was the most suitable. Under the optimized re-
action conditions, aryl iodides with the electron-withdrawing
substituents, such as ester, ketone, nitro, and nitrile, showed
good-to-excellent yields (4a–d). Heteroaromatic compounds,
pyridine 4e–f, pyrazine 4g, pyrimidine 4h, quinoline 4i, isoqui-
noline 4j, 1,3,5-triazine 4k, and purine riboside 4l were also
formed by the catalytic reaction in good-to-excellent yields.
Even when the amount of CuI was decreased to 2 mol%, 4h
could be obtained in quantitative yield. The reaction could be
performed on a gram scale without a decrease in yield. How-
ever, aryl iodide bearing the electron-donating methoxy sub-
stituents extremely decreased the reactivity to give almost vir-
tually no product 4m even in the presence of each 1.0 equiv
of CuI and 1,10-phenanthroline. In sharp contrast, the use of
1.0 equivalent of CuTC, which could generate neutral CuCF3,
resulted in 74% yield of 4m, whereas the pentafluoroethylated
by-product was provided in 15% yield.
The transmetallation reaction of CF3 group to copper from
zinc in DMPU using the zinc reagent 1a was investigated by
19F NMR spectroscopy (Scheme 3). Even at room temperature,
the transmetallation proceeded to give two singlets of the
cuprate species, [Cu(CF3)I]À (A: dF =À29.1 ppm)[18] and
[Cu(CF3)2]À (B: dF =À31.9 ppm)[18] in 19 and 9% yields, respec-
tively (Eq. [1] in Scheme 3). Upon replacement with CuTC, the
Scheme 3. Transmetallation to copper of CF3 group on zinc. Yields based on
CuI or CuTC were determined by 19F NMR analysis by using benzotrifluoride
(BTF) as an internal standard (CuTC=copper(I)-thiophene-2-carboxylate).
The monitoring by 19F NMR spectroscopy was performed to
observe the formation of cuprate (A and B) prepared with CuI
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Table 1. Transmetallation to copper of perfluoroalkyl groups.
RF =C2F5 (1b)
RF =nC3F7 (1c)
RF =nC6F13 (1d)
T
[8C]
t
A/B
T
t
A/B
T
t
A/B
[min] [%][a]
[8C] [min] [%][a]
[8C] [min] [%][a]
50
70
60
5
30
5
16/5
40/19 70
49/31
39/19 90
51/31
50
60
5
60
5
13/5
14/7
29/24
33/18 90
46/38
50
70
60
5
60
5
<1/<1
<1/<1
13/5
23/10
37/30
90
30
30
30
[a] Yields based on CuI were determined by 19F NMR analysis by using
BTF as an internal standard.
Scheme 6. Copper-catalyzed perfluoroalkylation reactions of aryl halides.
Conditions: 3 (0.2 mmol), 1c–e (0.2 mmol), and CuI (0.02 mmol) in DMPU
(0.4 mL) at 908C for 72 h. Yields were determined by 19F NMR analysis by
using BTF as an internal standard. [a] Conditions: 908C for 24 h. [b] Condi-
tions: 1008C for 60 h. [c] Aryl bromides instead of aryl iodides were used.
[d] By using 1c–d (0.7 equiv). [e] Isolated yield.
(48 h). This is in sharp contrast to the trifluoromethylation by
using 1a, in which the decomposition of 1a occurred even at
508C to give extremely low yield on the electron-rich sub-
strates (Scheme 4).
Perfluoroalkylation reactions with zinc reagent 1c–e were
also examined as the coupling reactions by using other kind of
aryl halide (Scheme 6). In a similar manner to the pentafluoro-
ethylation, aryl iodides with both the electron-withdrawing
and -donating substituents gave good-to-excellent yields (6a–
d, 7a–d). Aryl bromides, such as o-ester, caffeine, and azulene,
also underwent the reaction to give the corresponding prod-
ucts (6e,g,h, 7e,g,h, and 8g). Uracil derivative was also com-
patible with the reaction (6–8 f).
Scheme 5. Copper-catalyzed pentafluoroethylation of aryl iodides. Condi-
tions: 3 (0.2 mmol), 1b (0.14 mmol), and CuI (0.02 mmol) in DMPU (0.4 mL)
at 708C for 12–48 h. Yields were determined by 19F NMR analysis by using
BTF as an internal standard. [a] By using 1b (0.5 equiv). [b] By using 1b
(1.0 equiv). [c] p-Nitrophenyl bromide was used instead of p-nitrophenyl
iodide; reaction temperature was 908C.
The vinylic substrates were also applicable to the copper-
catalyzed perfluoroalkylation reactions (Scheme 7). The use of
and 1b–d as a perfluoroalkyl source in DMPU (Table 1). At
508C, the generation of cuprate A and B was observed. After
the reaction mixture was gradually warmed up, the best yields
were achieved at 908C after 30 minutes, respectively. Conse-
quently, it was elucidated that longer chain perfluoroalkyl
groups showed slower transmetallation to copper from zinc.
Next, the pentafluoroethylation reaction of aryl iodides 3
was scrutinized as a coupling reaction on the aromatic system
(Scheme 5). The reaction of p-nitrophenyl iodide even by treat-
ment with 0.7 equivalent of zinc reagent 1b proceeded
smoothly at 708C to give the pentafluoroethylated product 5a
in 93% yield, indicating that the second pentafluoroethyl
group can transfer to copper. Although the use of 1.0 equiva-
lent of 1b led to quantitative yield, 0.5 equivalent of 1b de-
creased yield (78%). Additionally, p-nitrophenyl bromide was
also applicable to the present reaction in spite of moderate
yield (48%). Under the optimized reaction conditions by using
0.7 equivalent of 1b, aryl iodides with the electron-withdraw-
ing substituents and 2-iodopyridine gave excellent yields (91–
>99%) of the products 5b–e. Interestingly, the electron-rich
substrates could also lead to the corresponding products 5 f–h
in high-to-excellent yields despite the prolonged reaction time
Scheme 7. Copper-catalyzed perfluoroalkylation reactions of vinyl iodides.
Conditions: 9 (0.1 mmol, 9a: R=Ph, E/Z 20:1; 9b: R=nC6H13, E/Z>20:1), 1b
or d (0.1 mmol), and CuI (0.01 mmol) in DMPU (0.2 mL) at 90 or 1208C for
24 or 48 h. Yields were determined by 19F NMR analysis by using BTF as an
internal standard. [a] The corresponding vinyl bromide (E/Z 11:1) instead of
vinyl iodide 9a was used.
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10 mmol) was then added dropwise at À608C. After stirring at
À208C for 48 h, unreacted trifluoromethyl iodide and hexanes
were removed in vacuo. The solid obtained was washed with Et2O
(15 mL) three times and dried under vacuum to give
Zn(CF3)2(DMPU)2 (1a) as a white powder (4.15 g, 90% yield).
1H NMR (300 MHz, CDCl3): d=3.27 (t, J=6.0 Hz, 8H), 2.98 (s, 12H),
1.97 ppm (quint, J=6.0 Hz, 4H); 13C NMR (75 MHz, [D7]DMF): d=
157.3, 146.2 (qq, JCF =4.8, 359.2 Hz, CF3), 48.0, 35.4, 22.2 ppm;
19F NMR (282 MHz, CDCl3): d=À43.5 (s, 6F); HRMS (ESI-TOF) calcd
for C13H24F3N4O2Zn [MÀCF3]+: 389.1143; found: 389.1126; elemental
analysis calcd for C14H24F6N4O2Zn: C 36.58, H 5.26, N, 12.19; found:
C 35.99, H 4.97, N 12.01.
vinyl iodide 9a (E/Z 20:1) promoted the reaction to produce
the corresponding (E)-10a and 11 a in high yields and regiose-
lectivities (93–97%, E/Z>20:1) (Scheme 7a). Furthermore, the
corresponding vinyl bromide (E/Z 11:1) could also lead to the
perfluoroalkylated products 10a and 11 a in moderate yields
(67–73%, E/Z 13–14:1). Aliphatic vinyl iodide 9b could be uti-
lized as an available substrate. In the case of vinyl iodide 9c
(E/Z 1:17), the retention of geometry was observed (E/Z 1:17)
to give good yields (Scheme 7b).
The mechanism of the present copper-catalyzed perfluoro-
alkylation reactions by using zinc reagents can be visualized by
the following catalytic cycle (Scheme 8). During the first step,
General procedure for trifluoromethylation of aryl iodide by
using Zn(CF3)2(DMPU)2 (1a; Scheme 4): To a test tube equipped
with a magnetic stir bar was added Zn(CF3)2(DMPU)2 (1a; 92 mg,
0.2 mmol), CuI (1.9 mg, 0.01 mmol, 10 mol%), DMPU (0.2 mL), and
aryl iodide 3 (0.1 mmol) at RT under argon atmosphere. After stir-
ring at 508C for 24 h, the reaction mixture was quenched with HCl
(5 mL), and then Et2O (5 mL) was added. The organic layer was sep-
arated, and the aqueous layer was extracted with Et2O (5 mLꢁ3).
The combined organic layer was washed with brine (10 mL), dried
over Na2SO4, and evaporated under reduced pressure. The result-
ing crude product 4 was purified by silica-gel column chromatog-
raphy.
Acknowledgements
Scheme 8. Proposed reaction mechanism.
This research was supported by JST (ACT-C: Advanced Catalytic
Transformation program for Carbon utilization) and the Nogu-
chi Institute. We thank TOSOH F-TECH, INC for generous gift of
CF3I and C2F5I. We thank Dr. Kenji Yoza (Bruker AXS) for valua-
ble help in X-ray crystal-structure analysis.
the rate of transmetallation of perfluoroalkyl group to CuI from
Zn(RF)2(DMPU)2 critically depends on the length of RF to give
the cuprate [Cu(RF)I]À and Zn(RF)I(DMPU)2, which readily causes
Schlenk equilibrium to Zn(RF)2(DMPU)2 and ZnI2.[14] Subsequent-
ly, the oxidative addition of aryl iodide to copper species
([Cu(RF)I]À or neutral CuRF generated by the dissociation of
iodide from the cuprate), and finally the reductive elimination
provides the desired perfluoroalkylated products.
Keywords: copper · perfluoroalkylation · perfluoroalkylzinc ·
transmetallation · synthetic methods
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Experimental Section
Preparation of bis(trifluoromethyl)zinc reagent Zn(CF3)2(DMPU)2
(1a; Scheme 2a): To an oven-dried 50 mL two-neck round-bot-
tomed flask equipped with a magnetic stir bar were added n-
hexane (15 mL) and DMPU (2.41 mL, 20 mmol) under argon atmos-
phere. Trifluoromethyl iodide (ca. 9.8 g, 50 mmol) was bubbled
into the solution at À608C. Diethylzinc (1.0m in hexanes, 10 mL,
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Received: October 16, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Synthetic Methods
K. Aikawa, Y. Nakamura, Y. Yokota,
W. Toya, K. Mikami*
&& – &&
Homogeneous catalysis: The aromatic
perfluoroalkylation catalyzed by copper
with Zn(RF)2(DMPU)2 reagents (DMPU=
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone) was accomplished to pro-
vide the products in good-to-excellent
yields. The advantages of this reliable
and practical catalytic reaction are given
in the scheme.
Stable but Reactive Perfluoroalkylzinc
Reagents: Application in Ligand-Free
Copper-Catalyzed Perfluoroalkylation
of Aryl Iodides
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!