Regiocontrolled Heptafluoroisopropylation of Aromatic Halides by Copper(I) Carboxylates with Heptafluoroisopropyl-Zinc Reagents

Article abstract of DOI:10.1021/acs.orglett.8b04147

Copper(I)-mediated heptafluoroisopropylation of aryl halides (ArX: X = I, Br) is demonstrated using copper(I) carboxylates and a bis(heptafluoroisopropyl)zinc reagent Zn(i-C₃F₇)₂(dmf)₂, prepared from heptafluoroisopropyl iodide and diethylzinc. The air-tolerant solid heptafluoroisopropylzinc reagent is advantageous to conduct simple synthetic operations and successful to give the corresponding heptafluoroisopropyl arene derivatives via transmetalation to copper(I) center. The newly developed copper(I)-mediated heptafluoroisopropylation process can be advanced to the copper(I)-catalysis by silver carboxylate salts and complementary to the precedent radical-based processes.

Full text of DOI:10.1021/acs.orglett.8b04147

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regiocontrolled Heptafluoroisopropylation of Aromatic Halides by
Copper(I) Carboxylates with Heptafluoroisopropyl-Zinc Reagents
Soichiro Ono, Yuki Yokota, Shigekazu Ito, and Koichi Mikami*
Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology,
O-okayama, Meguro-ku, Tokyo 152-8552, Japan
S
* Supporting Information
ABSTRACT: Copper(I)-mediated heptafluoroisopropylation of aryl hal-
ides (ArX: X = I, Br) is demonstrated using copper(I) carboxylates and a
bis(heptafluoroisopropyl)zinc reagent Zn(i-C3F7)2(dmf)2, prepared from
heptafluoroisopropyl iodide and diethylzinc. The air-tolerant solid
heptafluoroisopropylzinc reagent is advantageous to conduct simple
synthetic operations and successful to give the corresponding heptafluor-
oisopropyl arene derivatives via transmetalation to copper(I) center. The newly developed copper(I)-mediated
heptafluoroisopropylation process can be advanced to the copper(I)-catalysis by silver carboxylate salts and complementary
to the precedent radical-based processes.
n synthetic organofluorine chemistry, the introduction of
fluoroalkyl functional groups into lead/sead organic
Scheme 1. Aromatic Heptafluoroisopropylations
I
compounds poses a long-standing challenge due to unique
fluoroalkyl functionalities.1 Among them, heptafluoroisopropyl
arenes have attracted current interests in agrochemical2a,b and
organocatalysis2c fields. For instance, flubendiamide and
pyrifluquinazon are in market as insecticides with excellent
activity against a broad spectrum of pests. As for organo-
catalysis, hetero-Diels−Alder reactions can be catalyzed by
heptafluoroisopropylated binaphthyl bis-sulfonimide to give
high enantioselectivities. In addition, heptafluoroisopropyl
compounds have also been applied as liquid crystals.2d
Fluoroalkyl groups should be directly introduced into target
molecular units both on early (starting) and very late (last)
stages.3 However, the methods for heptafluoroisopropylation
were rarely of precedence (Scheme 1). For instance,
McLoughlin and Ishikawa reported Ullmann-type heptafluor-
oisopropylations separately (eq 1).4 The reaction can be
performed only at high (125 °C) temperature and with large
excess (7.0 equiv) of copper powder. Nihon Nohyaku Co., Ltd.
reported radical-type heptafluoroisopropylations leading to
flubendiamide (eq 2).5 The reaction requires substrates
containing strongly electron-donating amino groups and
proceeds only at para-position. Recently, Wu and Gong
reported oxidative heptafluoroisopropylations using aryl
boronic acids (eq 3).6 They require excess reagents (2.0
equiv of Ag salt and 1.0 equiv of Cu salt). Burton et al.
attempted heptafluoroisopropylation with heptafluoroisoprop-
yl cadmium complex7 that afforded heptafluoroisopropyl
copper complex via transmetalation. However, this process
has not been employed for synthesis of heptafluoroisopropyl
arene products.
iodide with bis(trifluoromethyl)zinc in N,N′-dimethylpropyle-
neurea (DMPU).8 The catalytic reaction provides moderate-
to-high yields of trifluoromethyl products from aromatic
halide.
First, we tried to synthesize9 stable but reactive bis-
(heptafluoroisopropyl)zinc reagents prepared from diethylzinc
and heptafluoroisoropyl iodide (Table 1). In hexane, the
desired zinc reagent was obtained but in low yields (entry 1−
Herein, we report copper(I)-mediated aromatic heptafluor-
oisopropylation with heptafluoroisopropylzinc reagents under
mild reaction conditions (eq 4). Recently, we reported
trifluoromethylation of aryl iodides catalyzed by copper(I)
Received: December 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04147
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Table 1. Preparation of Bis(heptafluoroisopropyl)zinc
Reagents*
Table 2. Copper(I)-Mediated Heptafluoroisopropylation of
Ethyl 2-Iodobenzoate
a
a
entry
cosolvent (Solv)
solvent
temp
time
yield (%)
entry
bc
Cu salt
solvent
DMF
DMF
toluene
1,4-dioxane
DMPU
DCE
THF
diglyme
DMI
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
temp
yield (%)
,
1
2
3
DMF
DMPU
DME
DMF
DMF
hexane
hexane
hexane
CH2Cl2
CH2Cl2
−20
−20
−20
−20
0
48
48
48
48
3
22
20
18
71
96
1
2
3
4
5
6
7
8
9
CuI
70
70
70
70
70
70
70
70
70
80
90
100
80
90
90
70
0
20
0
43
0
36
20
36
4
47
47
32
69
81
60
82
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuTC
CuTC
CuTC
CuTC
b
c
4
5
*
Conditions: Diethylzinc (5.0 mmol), i-C3F7I (12.5 mmol), cosolvent
(Solv) (10 mmol) in solvent (10 mL). Isolated yield. 1.0 equiv of
a
b
c
DME was used. 5.0 equiv of i-C3F7I was used.
10
11
12
13
14
15
16
3). Although Zn(i-C3F7)2(dmpu)2 1b was air-sensitive at room
temperature, the DMF- and DME-coordinated zinc complexes
showed almost no decomposition in air at room temperature.
However, Zn(i-C3F7)2(dme)2 1c could not be purified by
crystallization, and further investigation with DMPU and DME
was not carried out. In dichloromethane including DMF as a
cosolvent, Zn(i-C3F7)2(dmf)2 1a was isolated in higher yields
(entry 4−5). The DMF-coordinated zinc complex 1a was
obtained after workup procedures with >97% purity (19F
NMR). Crystalline 1a showed slight instability to moisture but
could be stored at −30 °C under inert atmosphere at least one
month.
b
bd
,
*
Conditions: 2a (0.10 mmol), 1a (0.20 mmol), Cu salt (0.15 mmol)
a
in solvent (0.30 mL). Yields based on 2a were determined by 19F
b
NMR analysis by using BTF as an internal standard. 1.0 equiv of zinc
reagents 1a was used. 1.0 equiv of Cu salt was used. Reaction time
c
d
was 48 h.
Thermal stability of 1a was examined by 19F NMR
spectroscopic analysis (Table S1). In DMF, 1a was
decomposed at 70 and 90 °C in 20 and 10 min, respectively.
In the decomposition process, hexafluoropropene via fluoride
elimination was not observed, but heptafluoropropane was
detected together with unidentified byproducts. However, in
1,4-dioxane, 1a showed relatively high stability as compared in
DMF, and only small amount of hexafluoropropene and
heptafluoropropane were observed upon heating at 90 °C for 1
h.
Scheme 2. Scope of Substrates*
Compound 1a showed melting point (decomp.) of 78 °C,
which is lower than Zn(i-C3F7)2(CH3CN)2 (121 °C).9 Thus,
the lower thermal stability of 1a might correspond to the useful
reactivity for aromatic heptafluoroisopropylation (vide infra).
No report on Zn(i-C3F7)2(CH3CN)2 has been known in
synthetic application.
*
Conditions: 2 (0.10 mmol), 1a (0.10 mmol), CuTC (0.15 mmol) in
1,4-dioxane (0.3 mL). Yields based on 2 were determined by 19F
NMR analysis by using BTF as an internal standard. Isolated yields
are shown in parentheses. 1.0 mmol scale experiment. 1.0 mmol scale
a
The copper(I)-mediated heptafluoroisopropylation of aryl
iodides was executed with the zinc reagent 1a (Table 2). A
stoichiometric amount of copper(I) iodide was first employed
for the reaction of ethyl 2-iodobenzoate (2a) as a model
substrate with 1a in DMF at 70 °C for 18 h. Unfortunately,
heptafluoroisopropyl product was not obtained (entry 1).
However, by employing copper(I) acetate, the product (3a)
was obtained in a low yield (entry 2). This finding encouraged
us to optimize the reaction conditions. Entries 3−9 examined
the solvents, and 1,4-dioxane gave higher yields (entry 4).
However, the yield was not substantially improved even at
higher temperatures (entries 10−12). To our delight, the use
of copper(I) thiophene-2-carboxylate (CuTC) improved the
yield dramatically (entries 13−16). We concluded that the
conditions with CuTC at 70 °C in 1,4-dioxane should be
employed for further studies (entry 16).
experiment.
carbonyl substituents at ortho-position, such as ester, ketone,
and amide, afforded the heptafluoroisopropyl products (3a−
3c) in good yields. However, the absence of ortho-carbonyl
substituent reduced the yields of heptafluoroisopropyl
products (3d, 3g), suggesting that the ortho-carbonyl groups
might facilitate the oxidative addition via intramolecular
coordination on copper(I) center.10 Thiophene and bithio-
phene iodides also gave products (3e, 3f) in moderate to good
yields.
The reaction was further examined with low yielding para-
ethoxycarbonyl substrate 2g (Table 3). In 1,4-dioxane at 70
and 90 °C, the reaction resulted in low yields. However, the
small amount of product 3g in entries 1 and 2 prompted us to
optimize the reaction conditions. In diglyme, the yields
remained low (entries 3, 4). In DMF, the reaction gave an
Under the optimized conditions in 1,4-dioxane, the substrate
scope was investigated (Scheme 2). Aryl iodides bearing
B
DOI: 10.1021/acs.orglett.8b04147
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As for thiophene derivatives, the products were obtained in
moderate yields. Even aryl bromides were also applicable to
give good yields (3h, 3k, 3l). It should be noted here that the
use of just 0.5 equiv of 1a led to excellent yield (3g, 90%),
equally high to that obtained with 1.0 equiv of 1a (92%).
In order to develop Cu-catalyzed reaction system (vide
infra), we employed silver(I) carboxylate salt (Scheme 4). The
Table 3. Copper(I)-Mediated Heptafluoroisopropylation of
Ethyl 4-Iodobenzoate*
a
entry
solvent
temp
yield (%)
b
1
1,4-dioxane
1,4-dioxane
diglyme
diglyme
DMF
DMF
DMF
DMF
DMF
70
90
90
120
80
8
Scheme 4. Catalytic Reactions*
2
3
4
5
6
7
8
16
10
16
22
38
22
7
90
100
120
90
c
9
92
*
Conditions: 2g (0.10 mmol), 1a (0.10 mmol), CuTC (0.15 mmol)
a
in solvent (0.30 mL). Yields based on 2g were determined by 19F
NMR analysis by using BTF as an internal standard. Reaction time
was 48 h. 2g (0.30 mmol), 1a (0.30 mmol), CuTC (0.45 mmol) in
b
c
*
Conditions: 2 (0.10 mmol), 1a (0.10 mmol), CuI (0.01 mmol),
DMF (0.60 mL), using oven-dried glassware, reaction time was 7 h.
silver(I) acetate (0.15 mmol) in 1,4-dioxane (0.30 mL). Yields based
on 2 were determined by 19F NMR analysis by using BTF as an
a
b
increased (38%) yield at 90 °C (entry 6). Using oven-dried
glassware and higher concentration [0.50 mol/L], the reaction
reproductively gave the product 3g in 92% yield (entry 9). We
concluded that the conditions in DMF at 90 °C for 7 h should
be employed for further studies (entry 9).
Under the optimized conditions in DMF, the substrate
scope was investigated (Scheme 3). Aryl iodides bearing
internal standard. 1.0 equiv of silver(I) acetate was used. 0.6 equiv
c
of silver(I) acetate was used. 2f (1.0 mmol), 1a (1.0 mmol), CuTC
(0.1 mmol), silver(I) acetate (1.5 mmol) in 1,4-dioxane (3.0 mL).
heptafluoroisopropyl products (3a, 3b, 3f) were obtained in
good to excellent (73−98%) yields with a catalytic amount of
copper(I) iodide or thiophenecarboxylate (10 mol %) and
1.0−1.5 equiv of silver(I) acetate. The heptafluoroisopropyl
silver(I) complex6 was not observed in the reaction of 1a and
silver(I) acetate in 1,4-dioxane.
Scheme 3. Scope of Substrates*
In order to clarify the reaction mechanism, transmetalation
of the heptafluoroisopropyl group from the zinc reagent 1a to
copper(I) salts such as CuI, CuOAc, and CuTC was
monitored by 19F NMR spectroscopic analysis (Scheme 5,
Scheme 5. Transmetalation to Copper(I) Salts from Zinc
Reagent 1a
Table S2). Transmetalation to copper(I) iodide was not
observed at all in a wide range of temperatures (50−90 °C)
and either 1,4-dioxane or DMF. However, copper(I)
carboxylates gave monoheptafluoroisopropyl copper(I) com-
plex7 4a at 70 °C in 1,4-dioxane. The mixture containing 4a in
1,4-dioxane was reacted with aryl iodide 2a to give the
heptafluoroisopropyl product 3a. In DMF, the reaction of a
copper(I) carboxylate and 1a gave mainly bis-heptafluoroiso-
propyl copper(I) complex 4b at room temperature. The
mixture did not react with 2g at room temperature. On heating
the mixture at 90 °C, the amount of monoheptafluoroisopropyl
copper(I) complex 4a was increased and the reaction with 2g
proceeded to afford the heptafluoroisopropyl product 3g (see
Table S3). It is thus likely that 4b is not reactive11 but a
*
Conditions: Aryl iodides 2 (0.30 mmol), 1a (0.30 mmol), CuTC
(0.45 mmol) in DMF (0.6 mL). Yields based on 2 were determined
by 19F NMR analysis by using BTF as an internal standard. Isolated
a
b
yields are shown in parentheses. 0.5 equiv of 1a was used. Aryl
c
bromides 2′ were used instead of aryl iodides 2. 0.6 mmol scale
experiment.
electron-withdrawing substituents in para- and meta-positions,
such as ester, cyano, nitro, and trifluoromethyl, afforded the
products in excellent yields. Electron-donating substituents in
para- and meta-position, such as methoxy and tert-butyl groups,
also afforded excellent yields. Electron-withdrawing and
-donating substituents in ortho-position gave moderate yields.
C
DOI: 10.1021/acs.orglett.8b04147
Org. Lett. XXXX, XXX, XXX−XXX

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reservoir of 4a that can react with 2 affording 3. Significantly,
both 4a and 4b were found to be stable even at 90 °C.
On the basis of these NMR studies, the proposed
mechanism of the catalytic cycle is visualized in Scheme 6
n-perfluoroalkyl derivatives,14,15 installation of iso-heptafluor-
opropyl substituents to quaterthiophene would be advanta-
geous in term of easy fabrication based on high solubility.
In summary, we have succeeded in the first copper(I)-
catalyzed heptafluoroisopropylation of aryl halides with the
organozinc reagent Zn(i-C3F7)2(dmf)2 1a, prepared from
heptafluoroisopropyl iodide and diethylzinc. The air-tolerant
zinc reagent is applicable to develop easy synthetic operations
for various heptafluoroisopropyl aryl products. The copper(I)-
mediated heptafluoroisopropylation should thus be comple-
mentary to the radical processes. Material developments are in
progress for demand installation of heptafluorooisopropyl and
other fluoro-functional units.
Scheme 6. Plausible Reaction Mechanisms
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b04147.
Experimental procedures, compound characterization
data and DFT calculation data(PDF)
NMR data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mikami.k.ab@m.titech.ac.jp.
ORCID
with energy profiles (by DFT calculations; see SI). The cycle
starts from transmetalation12 of 1a to copper(I) carboxylates
affording monoheptafluoroisopropyl 4a together with bis-
heptafluoroisopropyl 4b. Compound 4a would react with 2 via
oxidative addition. The Cu(III) intermediate could cause
reductive elimination to give the heptafluoroisopropyl product
3 and copper(I) iodide. Although copper(I) iodide is inert to
transmetalation, anion exchange with silver(I) carboxylates
provides the copper(I) carboxylates, which would close the
catalytic cycle.
In 1,4-dioxane, 4a shows low reactivity, but ortho-carbonyl
coordinated heptafluoroisopropyl copper(I) complex has
higher reactivity10 (by DFT calculations; see SI). Therefore,
the substrate scope was limited only on coordinating/
activating substrates. In DMF, 4a has higher reactivity because
DMF coordinated on the copper(I) center.13 Therefore, the
heptafluoroisopropylation in DMF realizes wide substrate
scope.
Koichi Mikami: 0000-0002-7093-2642
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Nippon Soda Co., Ltd. for generous gift of
heptafluoroisopropyl iodide. This research was supported by
the Japan Science and Technology Agency (JST) (ACT-C:
Creation of Advance Catalytic Transformation for the
Sustainable Manufacturing at Low Energy, Low Environmental
Load).
REFERENCES
■
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D
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