A general, regiospecific synthetic route to perfluoroalkylated arenes via arenediazonium salts with RFCu(CH3CN) complexes

Article abstract of DOI:10.1002/ejoc.201402820

A mild method of converting arylamines into perfluoroalkylated arenes is described. Relatively stable R_FCu(CH₃CN) complexes are used as perfluoroalkylating agents, which react smoothly with arenediazonium salts to produce various perfluoroalkylarenes in good yields. Based on the results of clock trapping experiments with diallyl ether, a radical process might be involved in the reaction.

Full text of DOI:10.1002/ejoc.201402820

FULL PAPER
DOI: 10.1002/ejoc.201402820
A General, Regiospecific Synthetic Route to Perfluoroalkylated Arenes via
Arenediazonium Salts with RFCu(CH3CN) Complexes
Dong-Fang Jiang,[a] Chao Liu,*[a] Yong Guo,[a] Ji-Chang Xiao,[a] and Qing-Yun Chen*[a]
Keywords: Alkylation / Fluorine / Copper / Solvent effects / Regioselectivity / Radical reactions
A mild method of converting arylamines into perfluoroalk-
ylated arenes is described. Relatively stable RFCu(CH3CN)
perfluoroalkylarenes in good yields. Based on the results of
clock trapping experiments with diallyl ether, a radical pro-
complexes are used as perfluoroalkylating agents, which re- cess might be involved in the reaction.
act smoothly with arenediazonium salts to produce various
Perfluoroalkylarenes have become increasingly indispens-
able for material, pharmaceutical and agrochemical indus-
tries.[1] McLoughlin and Thrower accomplished their cre-
ative work of Ullmann perfluoroalkylation of aryl iodides.[2]
Later, (perfluoroalkyl)copper species, especially trifluoro-
methylcopper species, and their properties were extensively
studied.[3] Remarkable process has been achieved in the area
of radical perfluoroalkylation of arenes (Scheme 1).[4] How-
ever, all these methods may result in regioselectivity prob-
lems in many cases. A general and regiospecific perfluoro-
alkylation of arenes under mild conditions has long been
desired, and some progress has been achieved (Scheme 1).
Scheme 1. Strategies of introducing perfluoroalkyl groups into
Daugulis et al. reported cross-coupling reactions of iodoar-
enes and RFH under alkaline conditions in the presence of
a catalytic amount of cuprous chloride.[5] Shen and Lu et
al. achieved copper-mediated coupling of arylboronic acids
and perfluoroalkyl iodides to give perfluoroalkylarenes in
good yields.[6] Hartwig and co-workers reported that 1,10-
phenanthroline-ligated (perfluoroalkyl)copper agents re-
acted with haloarenes or arylboronate esters to obtain per-
fluoroalkylarenes.[3d,7] Grushin and co-workers realized the
highly efficient perfluoroethylation of aryl halides with
C2F5H in the presence of CuCl and tBuOK.[8]
Arenediazonium salts, due to their higher reactivity and
availability from economical arylamines, are very useful and
important alternatives to aryl halides and can be converted
into numerous valuable compounds under mild condi-
tions.[9] Recently, such compounds have been utilized by
Fu,[10] Wang,[11] and Gooßen,[12] to realize aryl trifluoro-
methylation or trifluoromethylthiolation. In light of these
advances, we envisaged that perfluoroalkylated arenes may
arenes.
be accessed via their respective arenediazonium salts by
using RFI and suitable copper salts. Herein, we present the
results.
Initially, we selected 4-methylbenzenediazonium tetra-
fluoroborate as aryl precursor, copper powder (freshly pre-
pared from CuSO4·5H2O and Zn powder) as reductant,
Cl(CF2)4I as fluoroalkylating agent, and acetonitrile as sol-
vent. To our delight, the target product was detected in 31%
yield by 19F NMR spectroscopic analysis, and its identity
was confirmed by GC–MS analysis. 1-Iodo-4-methylbenz-
ene was identified as the main by-product and a trace
amount of 4,4Ј-dimethyl-1,1Ј-biphenyl was also detected
[Equation (1)]. It should be mentioned that no reaction oc-
curred with the C–Cl bond of Cl(CF2)4I.
[a] Key Laboratory of Organofluorine Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. China
E-mail: chenqy@sioc.ac.cn
chaoliu@sioc.ac.cn
http://chenqingyun.sioc.ac.cn/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402820.
(1)
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FULL PAPER
Further screening of cuprous salts such as CuCl, CuI, desired product was not steady and by-product per-
and copper(I) thiophene-2-carboxylate (CuTC) achieved no fluorobutyric acid always appeared even though the reac-
better results than achieved with copper powder under air tion system was carefully degassed. By checking the
conditions (Table 1, entries 1–4). Interestingly, the yield of amounts of reagents used, we found that extra tBuONO
the desired product slightly increased when zinc powder was had a negative effect on the reaction and led to more by-
added in the reaction (entry 5), but zinc was not necessary product and lower yield of the desired product (entries 4
when copper powder was used immediately after prepara- and 5). However, hydroquinone could be employed as a re-
tion. Solvents played an important role in the reaction. ductant to remove the extra tBuONO after the diazotiza-
Acetonitrile was the optimal medium among solvents scre- tion of arylamines without affecting the reaction, and the
ened. No desired reaction took place in toluene, tetra- 19F NMR yield of the desired product was improved to
hydrofuran (THF), or CH2Cl2 (entries 6–8). In methanol, 78% on average at a stable level (entry 6). Finally, addition
only 11% of the desired product and 46% yield of Cl- of nitrogen-containing ligands did not improve the yield
(CF2)4H by-product were observed (entry 9), whereas the (see the Supporting Information).
use of acetone as solvent provided the desired product in
19% yield (entry 10). It was found that about 30–40% water
Table 2. Exploring the effect of counterions of arenediazonium
salts with the one-pot method.[a]
by volume in acetonitrile promoted the reaction and im-
proved the yield to 47% at 0 °C (entry 11). The use of
2.0 equiv. of copper improved the yield further to 56% (en-
try 12). In most of the above cases, Cl(CF2)3COOH,[13]
·
which may be attributed to partial quenching of Cl(CF2)4
radical by oxygen,[14] was observed as a by-product; this
process could be suppressed if the system was carefully de-
gassed, although the yield of the product remained un-
changed. In addition, a number of additives were checked,
but no better results were obtained (see the Supporting In-
formation).
Entry HX
tBuONO
[equiv.]
Yield [%][b]
p-CH3OC6H4(CF2)4F
C[c]
[d]
1
2
3
4
HCl
1.2
1.2
1.2
1.2
1.0
1.2
47
58
61
65
69
78
–
–
–
[d]
HPF6
H3PO4
H2SO4
H2SO4
H2SO4
Table 1. Exploring the reaction conditions.[a]
[d]
27
3
0
5
6[e]
[a] Reaction conditions: 1a (0.4 mmol), HX (0.48 mmol), tBuONO
(0.48 mmol), F(CF2)4I (0.2 mmol), copper (0.8 mmol), CH3CN/
H2O (3:2 v/v), –20 °C to room temp., 30 min, under N2 atmosphere.
[b] Yields were determined by 19F NMR analysis using trifluorotol-
uene as internal standard. [c] C = F(CF2)3COOH. [d] Not detected.
[e] Hydroquinone (20 mmol-%) was added after diazotization.
Entry
Solvent
Metal
Yield [%][b]
p-MeC6H4(CF2)4Cl A[c]
B[d]
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
CH2Cl2
THF
CH3OH
acetone
CH3CN/H2O
CH3CN/H2O
Cu
CuCl
CuI
31
0
2
0
6
0
0
0
8
0
0
0
0
0
CuTC
Cu/Zn
Cu/Zn
Cu/Zn
Cu/Zn
Cu/Zn
Cu/Zn
Cu/Zn
Cu
9
0
38
0
3
0
With the optimized conditions in hand (Table 2, entry 6),
we investigated the substrate scope of the reaction. As
shown in Table 3, a range of arylamines with either elec-
tron-donating or -withdrawing groups were subjected to the
reaction conditions, to provide the desired perfluorobut-
ylarenes in acceptable yields. It should be mentioned that
the main by-products of the reactions were the correspond-
ing aryl iodides, which complicated the purification. How-
ever, the substrates with alkyloxy or phenyl groups could
be successfully purified by exhausting silica gel column
chromatography. Importantly, most substrates, if not ex-
0
0
0
79
46
0
3
1
9
11[c]
19
47
56
11
[e]
10
11[f]
12[g]
–
9
11
[a] Reaction conditions: 4-methylbenzenediazonium tetrafluoro-
borate (0.4 mmol), [Cu] (0.4 mmol), Zn (0.2 mmol, if added),
Cl(CF2)4I (0.2 mmol), solvent, in air, r.t., 30 min. [b] Yields were
determined by 19F NMR spectroscopic analysis with trifluorotol-
uene as internal standard. [c] A
= Cl(CF2)4H. [d] B = Cl-
(CF2)3COOH. [e] Complex mixture. [f] Reaction performed at 0 °C. clusive, afforded the desired products without detectable re-
[g] Cu (0.8 mmol) was used.
gioisomers. For example, the structure and purity of prod-
ucts 3a, 3b, and 3f were confirmed by GC–MS and 1H
NMR analyses, and no regioisomers were observed. The
Further study indicated that the counterions of arenedia- regiospecific reactivity of diazonium salts[12a,15] is in con-
zonium salts played an important role in the reaction trast to the reported direct perfluoroalkyl radical addition
–
(Table 2). HSO4 provided a better result than other anions to arenes, for which a lack of regioselectivity was a common
(entries 1–5). However, it was noted that the yield of the issue (Scheme 2).[4f,16]
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A General Regiospecific Synthesis of Perfluoroalkylated Arenes
Table 3. Substrate scope.[a]
[a] Reaction conditions: 1 (0.4 mmol), H2SO4 (0.48 mmol), tBuONO (0.48 mmol), F(CF2)4I (0.2 mmol), CH3CN/H2O (3:2 v/v), hydro-
quinone (0.08 mmol), copper (0.8 mmol), under N2 atmosphere, –20 °C to room temp., 30 min. [b] Yields were determined by 19F NMR
spectroscopic analysis with trifluorotoluene as internal standard. [c] Isolated yield in parentheses.
possible to improve the reaction further. It was reported
that arenediazonium salts in general tend to react through
an aryl radical process.[9a] Initially, a radical clock (diallyl
ether) was added to the reaction, to identify possible radical
species [Equation (2)]. Addition of diallyl ether (1.0 equiv.)
led to a clear reduction in the yield, and traces of various
radical-initiated cyclization products 4–7 were detected.
Based on these preliminary results, we assumed that per-
fluorobutylcopper “F(CF2)4Cu” species might be the key
intermediate in the reaction, and that the reaction might
Scheme 2. Examples of regioselectivity of direct radical perfluoro-
alkylation of arenes.
proceed through a radical process. As shown in Scheme 3,
an aryl radical produced by a SET process of the arenedi-
azonium salt may abstract the iodine atom from a per-
A preliminary mechanistic investigation was carried out fluorobutyl iodide to release the perfluorobutyl radical.
on this reaction and, as a result, the new findings made it The latter may be captured by Cu to form the “F(CF2)4Cu”
(2)
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D.-F. Jiang, C. Liu, Y. Guo, J.-C. Xiao, Q.-Y. Chen
FULL PAPER
intermediate, which may subsequently react with arene- [Equation (5)]. When TEMPO (2.0 equiv.) was introduced
diazonium salt to generate the target product in a SET pro- to a mixture of 9 and 4-methoxybenzenediazonium in
cess.
CH3CN/H2O, the yield decreased about 40%, giving 12%
8 and a trace amount of 10 [Equation (6)]. The direct reac-
tion of F(CF2)4Cu(CH3CN) complex with TEMPO re-
sulted in the formation of 8 [Equation (7)], which was sim-
ilar to the reported result.[11] We also found that CuI salts
could induce the reactions (see the Supporting Infor-
mation). These results supported the conclusion that inter-
mediate I (Scheme 3) had a longer lifetime than the perfluo-
robutyl radical. It was reported that arenediazonium salts
have a stronger oxidizing ability than TEMPO,[17] so we
proposed that F(CF2)4Cu(CH3CN) reacted with arene-
diazonium salt in a SET process to form aryl radical and
intermediate I, the cross-coupling of which finally produced
the desired product (Scheme 3).[18]
Scheme 3. Proposed mechanism for the reactions of arenediazon-
ium salts with RFI mediated by copper.
To test our hypothesis, we attempted to synthesize the
“F(CF2)4Cu” complex according to a reported procedure.[2]
However, we found that ligandless “F(CF2)4Cu” decom-
posed instantly once the solvent was evaporated.
Fortunately, we noted that acetonitrile could stabilize
“F(CF2)4Cu” species by forming
a
relative stable
(5)
F(CF2)4Cu(CH3CN) complex, which was separated and
characterized by elemental and 1H NMR spectroscopic
analyses. Interestingly, acetonitrile protons in F(CF2)4-
Cu(CH3CN) complex are shifted downfield by 0.3 ppm
compared with that of free acetonitrile in 1H NMR
spectra [Equation (3)]. 4-Methoxybenzenediazonium and
F(CF2)4Cu(CH3CN) complex were then mixed together in
CH3CN/H2O and 57% of the desired product was achieved
[Equation (4)]. This result may also explain why acetonitrile
acts as such an effective solvent.
(3)
(6)
(7)
Considering the problems associated with purification of
the product in the presence of aryl iodides and to avoid the
(4)
We then included 2,2,6,6-tertramethylpiperidine-N-oxyl use of an excess of arylamine in the reaction of arenedi-
(TEMPO; 2.0 equiv.), a radical scavenger, to quench the re- azonium salts with stable F(CF2)4Cu(CH3CN) complex, we
action under standard conditions, and observed that tried to use this complex as perfluorobutylating agent di-
TEMPO-(CF2)4F (8) was formed in 38% 19F NMR yield rectly in acetonitrile. To our delight, the reaction proceeded
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A General Regiospecific Synthesis of Perfluoroalkylated Arenes
Table 4. Scope of the perfluoroalkylation of arenes by the reaction of arenediazonium tetrafluoroborates with RFCu(CH3CN) complex-
es.[a,b]
[a] Reaction conditions: 2 (0.4 mmol), RFCu(CH3CN) (0.44–0.48 mmol), CH3CN (4.0 mL), 30 min, under N2. [b] Isolated yield.
smoothly and arenediazonium tetrafluoroborates with vari- mation of aryl iodide by-products. The method thus pro-
ous functional groups were effectively converted into the vides a convenient way of introducing perfluoroalkyl
corresponding perfluoroalkylated arenes in good yields un- groups to various arenes in late-stage procedures.
der mild conditions. Substrates with either electron-donat-
ing or electron-withdrawing groups gave similar high yields
(Table 4). Many functionalities such as alkyl, alkyloxy, ester,
acyl, acylamino, cyano, nitro, and halo (Cl, Br, I) were tol-
Experimental Section
General: NMR spectra were obtained with an Agilent 400M NMR
system using CDCl3 or [D6]acetone as deuterated solvents, with
1H, 13C, and 19F resonances at 400, 101, and 376 MHz, respectively.
Chemical shifts were reported in parts per million (ppm) relative
to TMS as an internal standard (δ = 0 ppm) for 1H and 13C NMR
spectra and CFCl3 as an external standard (negative for upfield)
for 19F NMR spectra. GC–MS (EI) data were determined with
an Agilent 5975C. HRMS (EI) data were obtained with a Water
Micromass GCT Premier. Element analysis data were determined
with an Elementar VARIO EL apparatus. Acetonitrile was distilled
from CaH2. All the other solvents or reagents were used as com-
mercial sources without purification. All reactions were performed
in standard Schlenk tubes and monitored by TLC or 19F NMR
spectroscopy. Flash column chromatography was carried out by
erated in the reaction. In addition, the reaction could also
be extended to include perfluoropropyl, perfluorohexyl,
and perfluoroisopropyl groups.
Conclusions
We have developed a convenient and efficient method of
converting various arylamines into perfluoroalkylarenes un-
der mild conditions. In view of the preliminary mechanism
study, relatively stable RFCu(CH3CN) were successfully
prepared and used as perfluoroalkylating agents to react
with a variety of arenediazonium salts to provide the corre-
sponding perfluoroalkylarenes in high yields without for- using 300–400 mesh silica gel.
Eur. J. Org. Chem. 2014, 6303–6309
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D.-F. Jiang, C. Liu, Y. Guo, J.-C. Xiao, Q.-Y. Chen
FULL PAPER
Typical Procedures for Perfluoroalkylation of Arenediazonium Salts
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Procedure A: To a solution of arylamine (0.4 mmol) in CH3CN/
H2O (3:2 v/v, 2.0 mL), H2SO4 (12 n, 40 μL, 0.48 mmol) and
tBuONO (54.9 mg, 0.48 mmol) were added sequentially under
cooling with an ice-water bath. The reaction mixture was kept for
15 min, then hydroquinone (8.8 mg, 0.08 mmol), F(CF2)4I
(69.3 mg, 0.2 mmol), and freshly prepared copper (50.8 mg,
0.8 mmol) were sequentially added under a nitrogen atmosphere.
The reaction mixture was stirred at r.t. for 30 min, diluted with
ethyl acetate (20 mL) and filtered through a pad of Celite. The or-
ganic layer was collected and washed with water (20 mL) and the
aqueous layer was further extracted with ethyl acetate (2ϫ 20 mL).
The combined organic layer was dried with MgSO4 for 30 min,
filtered, and concentrated. The residue was purified by flash
chromatography (petroleum ether/ethyl acetate) to obtain the cor-
responding perfluoralkylated arene.
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Procedure B
(1) Preparation of F(CF2)4Cu(CH3CN) Complex. Typical Pro-
cedure:[2] All the operations were performed under a nitrogen atmo-
sphere. A 200 mL Schlenk tube was charged with copper (1.6 g,
25 mmol), F(CF2)4I (3.75 g, 11 mmol) and anhydrous DMSO
(15 mL). The reaction mixture was kept at 110 °C for 1.5 h. After
cooling to room temperature, the mixture was poured into diethyl
ether (50 mL) and degassed water (30 mL). The organic layer was
collected and washed with degassed water (5ϫ 30 mL), dried with
MgSO4, and filtered to give colorless solution. Acetonitrile
(5.0 mL) was added and the resulting solution was evaporated in
vacuo for 2 h to give the desired complex as a clear pale-amber oil,
which could be stored under an N2 atmosphere at 4 °C for several
months.
[4]
(2) Preparation of Arenediazonium Tetrafluoroborates. General Pro-
cedure:[19] To a solution of arylamine (1.0 mmol) in THF (2.0 mL),
BF3·Et2O (213 mg, 1.5 mmol) was added slowly under cooing with
an ice-water bath. tBuONO (137 mg, 1.2 mmol) was then added
dropwise. The reaction mixture was stirred for 15 min, then diethyl
ether (10 mL) was added. The precipitate formed was filtered,
washed with diethyl ether, and dried in vacuo for 30 min to afford
the desired arenediazonium salt.
(3) Reaction of RFCu(CH3CN) with Arenediazonium Salts. General
Procedure: A Schlenk tube was charged with RFCu(CH3CN) com-
plex (0.44–0.48 mmol) and acetonitrile (2.0 mL) under a nitrogen
atmosphere. Freshly prepared arenediazonium tetrafluoroborate
(0.4 mmol) was dissolved in acetonitrile (2.0 mL) and the resulting
solution was injected into the above reaction mixture dropwise un-
der cooling with an ice-water bath. After stirring for 30 min at
room temperature, the reaction mixture was diluted with ethyl acet-
ate (20 mL) and filtered through a pad of Celite. The filtrate was
collected and concentrated. The resulting residue was purified by
flash chromatography (petroleum ether/ethyl acetate) to obtain the
corresponding perfluoralkylated arene.
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cle): Reaction optimization, mechanism experiments, characteriza-
1
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Acknowledgments
The authors thank the National Natural Science Foundation of
China (NSFC) (grant numbers 21032006, 21302207) and the 973
Program of China (grant number 2012CB821600) for financial sup-
port.
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Received: June 26, 2014
Published Online: August 15, 2014
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