Cobalt/diamine-catalyzed 1,1-difluoroethylation and 2,2,2-trifluoroethylation of aryl Grignard reagents with corresponding fluoroalkyl halides

Article abstract of DOI:10.1016/j.jfluchem.2016.03.007

Cobalt/diamine-catalyzed 1,1-difluoroethylation and 2,2,2-trifluoroethylation of aryl Grignard reagents with 1,1-difluoroethyl and 2,2,2-trifluoroethyl halides were investigated. With regard to the 1,1-difluoroethylation, 1,2-bis(dimethylamino)-2-methylpropane, which has been rarely used in the cross-coupling reactions, gave the highest yield among the diamine ligands tested. In the 2,2,2-trifluoroethylation, trans-1,2-bis(dimethylamino)cyclohexane provided the desired products in satisfactory yields with not only 2,2,2-trifluoroethyl iodide but also chloride. This Co/diamine catalyst was also effective for the coupling with other partially fluorinated alkyl halides in the presence of appropriate diamine ligands.

Full text of DOI:10.1016/j.jfluchem.2016.03.007

Accepted Manuscript
Title: Cobalt/diamine-Catalyzed 1,1-Difluoroethylation and
2,2,2-Trifluoroethylation of Aryl Grignard Reagents with
Corresponding Fluoroalkyl Halides
Author: Yuhki Ohtsuka Tetsu Yamakawa
PII:
S0022-1139(16)30059-8
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.03.007
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Revised date:
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14-3-2016
16-3-2016
Please cite this article as: Yuhki Ohtsuka, Tetsu Yamakawa, Cobalt/diamine-
Catalyzed 1,1-Difluoroethylation and 2,2,2-Trifluoroethylation of Aryl Grignard
Reagents with Corresponding Fluoroalkyl Halides, Journal of Fluorine Chemistry
http://dx.doi.org/10.1016/j.jfluchem.2016.03.007
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Cobalt/diamine-Catalyzed 1,1-Difluoroethylation and 2,2,2-Trifluoroethylation of Aryl Grignard
Reagents with Corresponding Fluoroalkyl Halides
Yuhki Ohtsuka, Tetsu Yamakawa*
1Sagami Chemical Research Institute, Hayakawa 2743-1, Ayase, Kanagawa 252-1193, Japan
*Corresponding author. Tel.: + 81 467769268; Fax: +81 467774113
E-mail address: t_yamakawa@sagami.or.jp
- 1 -

Graphical Abstract (pictogram)
Synopsis
The combined use of Co/diamine catalyzed 1,1-difluoroethylation and 2,2,2-trifluoroethylation of
aryl Grignard reagents with 1,1-difluoroethyl and 2,2,2-trifluoroethyl halides, providing the desired
products in satisfactory yields.
- 2 -

Highlights
・1,1-Difluoroethylation and 2,2,2-trifluoroethylation of ArMgBr proceeded smoothly.
・Co/diamine-catalyst showed the satisfactory activity in this reaction.
・The choice of diamine ligand and solvent are very important for excellent yields.
Abstract
Cobalt/diamine-catalyzed 1,1-difluoroethylation and 2,2,2-trifluoroethylation of aryl Grignard
reagents with 1,1-difluoroethyl and 2,2,2-trifluoroethyl halides were investigated. With regard to
the 1,1-difluoroethylation, 1,2-bis(dimethylamino)-2-methylpropane, which has been rarely used in
the cross-coupling reactions, gave the highest yield among the diamine ligands tested. In the
2,2,2-trifluoroethylation, trans-1,2-bis(dimethylamino)cyclohexane provided the desired products
in satisfactory yields with not only 2,2,2-trifluoroethyl iodide but also chloride. This Co/diamine
catalyst was also effective for the coupling with other partially fluorinated alkyl halides in the
presence of appropriate diamine ligands.
Keywords: 1,1-difluoroethylation; 2,2,2-trifluoroethylation; cobalt catalyst; diamine ligand
- 3 -

1. Introduction
Because trifluoromethyl and difluoromethyl groups directly bound to aromatic rings give
unique bio-active character, numerous syntheses of aromatic compounds containing these
functional groups have been reported [1,2]. In a similar manner, other fluoroalkyl groups,
particularly partially fluorinated alkyl groups, have received much attention for medical and
agricultural compounds [3]. Recently, the remarkable bioactivity of heteroaromatic compounds and
nucleobases featuring the 1,1-difluoroethyl (CH3CF2) group, which mimics the steric and electronic
features of methoxy group [4b-e], has been explored [4]. Thus far, aromatic compounds having
CH3CF2 group have been synthesized via fluorination of functional groups on aromatic rings with
various fluorinating reagents. Fluorination of the ethynyl group in phenylacetylene using
HF-organic
base
provides
1,1-difluoroethylbenzene
[5].
Deoxo-Fluor
(bis(2-methoxyethyl)aminosulfur trifluoride) [6] or phenylsulfur chlorotetrafluoride [7] converts
the acetyl group in acetophenone to CH3CF2 group, yielding 1,1-difluoroethylbenzene. Similarly,
3-acetylindoles were converted to 3-(1,1-difluoroethyl)indoles with DAST (N,N-diethylaminosulfur
trifluoride) [8]. The use of Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate)) [9] or uranium hexafluoride [10] gives 1,1-difluoroethylbenzenes from
2-methyl-2-phenyl-1,3-dithiolane or 2-aryl-1,3-dithianes. The methylene hydrogen atoms in
ethylbenzenes can be selectively substituted with fluorine atoms by using Selectfluor or Selectfluor
II (4-fluoro-1-methyl-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) in the presence of a
catalytic amount of xanthone [11a] or Na2S2O8 [11b,c]. Very recently, fluorination of
(1-chloroethenyl)benzene
or
1-bromo-4-(1-chloroethenyl)benzene
with
HF
to
(1,1-difluoroethyl)benzene or 1-bromo-4-(1,1-difluoroethyl)benzene, respectively, was reported in
a patent [12]. This method appears to be more practical than the other ones, because HF is the most
inexpensive fluorinating reagent.
On the other hand, 1,1-difluoroethylation of aromatic compounds via cross-coupling using
1,1-difluoroethyl halides [13] or their metal reagents has not been reported to the best of our
knowledge, although it requires no toxic and expensive fluorination reagents. In particular, the
- 4 -

cross-coupling of 1,1-difluoroethyl halides and arylmetal reagents can be a practical and usable
process because of its availability of substrates.
With regard to 2,2,2-trifluoroethylation, which furnishes bioactive aromatic compounds
possessing the 2,2,2-trifluoroethyl (CF3CH2) group [14], several examples of palladium-catalyzed
cross-couplings of 2,2,2-trifluoroethyl iodide or triflate and arylboronic acids or their esters have
been reported [15]. However, they require a large amount of palladium, expensive ligands such as
2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl and optionally CuCl. Xu and co-workers
reported the Cu-promoted coupling of aryliodides 2,2,2-trifluoroethyl iodide [16]. Although this
reaction proceeds without any ligands and bases, the excess amount of Cu powder and the long
reaction time, 55 h, are necessary. Recently, Ackermann and co-workers showed
2,2,2-trifluoroethylation with CF3CH2I through C-H bond activation with a catalyst consisting of
[(dimethoxyethane)NiCl2] and bis(2-dimethylaminoethyl)ether [17], though the substrates of this
reaction were limited to benzamides and 2,2,2-trifluoroethylation occurred only at the ortho
position of an amide group. In addition, the radical 2,2,2-trifluoroethylation of aromatic C-H bond
with zinc (2,2,2-trifluoroethyl)sulphinate afforded only 15% yields [18].
We began our investigation with the aim of realizing a more general and practical
cross-coupling process for partially fluorinated alkylation. Therefore, we focused on a catalyst
consisting of cobalt and a diamine ligand that catalyzes the cross-coupling of aryl Grignard
reagents and alkyl halides [19] or arylzinc reagents and ethyl bromodifluoroacetate [20]. As a result,
we found that 1,1-difluoroethylation and 2,2,2-trifluoroethylation proceeded smoothly with readily
available 1,1-difluoroethyl iodide (CH3CF2I), 1,1-difluoroethyl bromide (CH3CF2Br) or
2,2,2-trifluoroethyl iodide (CF3CH2I) and aryl Grignard reagents in the presence of a Co/diamine
catalyst. Interestingly, 2,2,2-trifluoroethylation also occurred by the use of corresponding chloride
(CF3CH2Cl), which should be rather inactive. Based on the other partially fluorinated alkylation by
the use of partially fluorinated alkyl halides possessing three or four carbons, we revealed that the
yields largely depended on the diamine ligand.
- 5 -

2. Results and discussion
2.1 1,1-Difluoroethylation
Scheme 1 illustrates the reaction of 4-methoxyphenyl Grignard reagent and CH3CF2I
with CoCl2 as a cobalt precursor and trans-1,2-bis(dimethylamino)cyclohexane (ligand a) or
N,N,N’,N’-tetramethylethylenediamine (TMEDA) as a diamine ligand; these diamine ligands were
used in the previously reported cobalt-catalyzed cross-coupling [19, 20]. The desired product was
obtained in 40% and 80% 19F NMR yield, respectively. This result indicated that the cobalt/diamine
catalyst could be used for the target reaction and that surveying the reaction conditions to obtain the
higher yields was worthwhile.
First, the reaction with 4-methoxyphenyl Grignard reagent was examined with various
cobalt precursors and diamine ligands. CH3CF2Br was used in this examination instead of the
iodide, because (i) it is less expensive than the iodide, and (ii) the differences derived from the
precursors and ligands could be clearer owing to its lower reactivity compared to the iodide. Taking
into account the low boiling point (14 ºC) of CH3CF2Br, the reactions were carried out with a THF
solution of the bromide. Table 1 lists the results obtained using various cobalt precursors with
ligand a that gave the higher yield in Scheme 1. As anticipated from the reactivity of the bromide,
the yield with CoCl2 decreased to 62%, which was lower than that with the bromide, 80% (entry 1).
Of the cobalt halides tested, CoI2 provided the highest yield of the desired product (entry 3). Both
divalent and trivalent fluoride salts were inactive (entries 4 and 5). A divalent acetate precursor
gave a moderate yield (entry 6). With regard to acetylacetonate precursors, both divalent and
trivalent precursors provided moderate yields (entries 7 and 8). When 0.05 mmol of CoI2, CoBr2 or
CoCl2 and ligand a were used, all the yields decreased (entries 9-11) and a satisfactory yield, 74%,
was obtained only with CoI2. Based on the results in Table 1, 0.10 mmol of CoCl2 was chosen as
the precursor hereinafter, because it gave a satisfactory yield and was readily available.
- 6 -

Figure 1 shows the 19F NMR yields of 1-(1,1-difluoroethyl)-4-methoxybenzene from
CH3CF2Br and 4-methoxyphenyl Grignard reagent with CoCl2 and various diamines featuring an
N,N,N’,N’-tetramethylethylenediamine backbone as a ligand. Although the yield with ligand a was
larger than that with TMEDA, each ligand afforded a lower yield than Scheme 1. This is readily
anticipated by the lower reactivity of bromide than iodide. Interestingly, only
1,2-bis(dimethylamino)-2-methylpropane (ligand b) gave a higher yield than ligand a (89% vs.
62%) among the diamines tested. This compound is known as a catalyst in polyurethane synthesis
[21] and is one of the ligands in LiNEt2-catalyzed hydroamination [22]. However, it has never been
used in cross-coupling reactions to the best of our knowledge. All of the other diamine ligands also
afforded lower yields than ligands a and b. In addition, bis(2-dimethylaminoethyl)ether, which was
used in the nickel-catalyzed 2,2,2-trifluoroethylation through C-H bond activation afforded no
desired product at all.
Based on the results in Table
1
and Figure 1, we chose ligand
a
(trans-1,2-bis(dimethylamino)cyclohexane), which has been used previously in the
cobalt-catalyzed cross-coupling, and ligand b (1,2-bis(dimethylamino)-2-methylpropane), which
revealed its availability in cross-coupling reactions in the present investigation, for the survey of
the reaction conditions.
Next, we examined the use of oligoethers as a solvent for CoCl2 and the ligand in the
coupling of CH3CF2Br and 4-methoxyphenyl Grignard reagent. Table 2 lists the 19F NMR yields
using ligands a and b in ethylene glycol dimethylether (DME), diglyme and triglyme solvents. In
the reactions with ligand a, the yield rose up to 92% in diglyme solvent (entry 3), while the use of
DME and triglyme as a solvent afforded similar yields to THF (entry 1 vs. 2 and 4). Diglyme is
well known to enhance the nucleophilicity of a Grignard reagent through bidentate coordination to
magnesium [23]. Therefore, it is reasonable that the activation of 4-methoxyphenyl Grignard
reagent brought about the excellent yield. In contrast, the yields obtained using ligand b were lower
with each oligoethers. It is well known that oligoethers also act as polydentate ligands to cobalt
[24]. Thus far, the syntheses of several kinds of Co(II) complexes featuring the oligoethers in Table
- 7 -

2, DME [24a-c], diglyme [24c-e] and triglyme [24f] and a chloride ligand were reported. This
suggests that the decrease in the yields with ligand b may be due to the change in the cobalt species
through the substitution of ligand b with the oligoethers. Therefore, we noted the colors of the
solutions of each reaction in Figure 1 and Table 2. The solutions of each reaction in Figure 1,
except bis(2-dimethylaminoethyl)ether, were dark blue, indicating that bidentate coordination of
each
diamine
ligands
to
Co(II)
[25].
The
reaction
solution
containing
bis(2-dimethylaminoethyl)ether was purple, which was consistent with the report that
[Co(bis(2-dimethylaminoethyl)ether)Cl2] was purple [26]. The solutions of each reaction in Table 2
were also dark blue. On the other hand, the color of the isolated Co(II) complexes featuring the
oligoethers, which ranges between blue and purple [22], is very similar to that of Co(II) complexes
coordinated with TMEDA derivatives. Therefore, it is difficult to estimate the change in the cobalt
species by observing the colors of the reaction solutions.
Next we attempted the reaction using 1,1-difluoroethyl chloride (CH3CF2Cl), which is
generally less active than CH3CF2Br (Table 3). Indeed, the yield with CH3CF2Cl was remarkably
lower than with CH3CF2Br using ligand a (entry 1). Keeping the reaction solution at 40 ºC during
the addition of the THF solution of the Grignard reagent and the use of diglyme improved the yield
to 60% (entry 3), which was almost the same as entry 1 in Table 1 (62%). Ligand b afforded a
lower yield with CH3CF2Cl than with CH3CF2Br (entry 4) even when the reaction was performed at
40 ºC.
Table 4 lists the yields of 1,1-difluroethylation of various aryl Grignard reagents with
CH3CF2Br. Both ligand a in diglyme and b in THF provided the desired products from each
substrate in satisfactory yields except 2-methoxyphenyl Grignard reagent (entry 3). In particular,
4-(1,1-difluoroethyl)biphenyl was obtained quantitatively with both ligands (entry 7). The yields in
entries 1 and 6 with electron-donating substituents and those in entries 8 and 9 with
electron-withdrawing substituent were all satisfactory. In addition, the reactions with phenyl
Grignard reagent also gave the similar yields (entry 4). This suggests that the electronic character of
- 8 -

substituents did not affect the yield. The rather low yield in entry 3 is presumably due to steric
hinderance by the methoxy group at the ortho position.
All the products in Table 4 could be isolated by the general procedure (see 4.2. Reaction
procedure). The isolated yields in Table 4 except entry 5 and 7 were rather lower than the 19F NMR
yields presumably due to volatility derived from the existence of fluorine atoms. In particular,
drastic decline in the isolated yield was observed with 1,1-difluoroethylbenzene that has small
molecular weight (entry 4) and 1-(1,1-difluoroethyl)-4-trufluoromethylbenzene that has five
fluorine atoms (entry 9).
2.2 2,2,2-Trifluoroethylation
First, the coupling of CF3CH2I and 4-methoxyphenyl Grignard reagent using CoCl2 and
ligand a or b was investigated; the use of 2,2,2-trifluoroethyl bromide is legally prohibited. The
results are listed in Table 5. The yield with ligand a under the same conditions as entry 3 in Table 2,
in diglyme, was 72% yield (entry 1). When the reaction temperature was lowered to 0 ºC, the yield
was slightly improved (entry 2). Interestingly, the yield at 0 ºC reached 92% in THF (entry 3). This
is in remarkable contrast to the result in difluoroethylation. The 62% yield of entry 1 in Table 1, in
THF, decreased drastically to 7% at 0 ºC. The yield with ligand b was also higher at 0 ºC than at
room temperature (entry 4 vs. 5), though it was lower than with ligand a. Similar satisfactory yields
to those obtained with ligand b were obtained with TMEDA and 1,2-bis(dimethylamino)propane
which afforded low yields in the reactions with CH3CF2Br (Figure 1).
Next, we examined the 2,2,2-trifluoroethylation using CF3CH2I and 2,2,2-trifluoroethyl
chloride (CF3CH2Cl) with various aryl Grignard reagents. Each substrate gave the desired product
in a satisfactory yield (Table 6). We found two differences between 1,1-difluoroethylation and
2,2,2-trifluoroethylation in the results in Table 6. One is the satisfactory yield with
4-(dimethylamino)phenyl Grignard reagent (entry 6), which afforded no product in the
1,1-difluoroethylation. The other is the unexpected high reactivity of CF3CH2Cl. While all of the
yields obtained in 2,2,2-trifluoroethylation with the chloride were slightly lower than those with the
- 9 -

idodide, 1,1-difluoroethylation with CH3CF2Cl required a higher reaction temperature than with
CH3CF2Br to obtain satisfactory yields (Table 1 vs. Table 3). Similar to the products in Table 4, the
compounds bearing 2,2,2-trifluoroethyl group are certainly volatile, resulting in low isolated yields.
Since it is generally recognized that cobalt-catalyzed cross-coupling with alkyl halides
involves alkyl radical formation from the corresponding halides [27], the difference between
2,2,2-trifluoroethylation and 1,1-difluoroethylation should be derived from the difference in the
property between 2,2,2-trifluoroethyl radical and 1,1-difluoroethyl radical. We now investigate the
properties of the radicals from the standpoints of difficulty in generation, stability, reactivity and
other factors using various partially fluorinated alkyl halides.
2.3 Other partially fluorinated alkylation
Finally, we attempted the cobalt/diamine-catalyzed coupling of 2,2-difluoroethyl-,
2,2,3,3-tetrafluoro-n-propyl- or 2,2,3,3,3-pentafluoro-n-propyl iodide and 4-methoxyphenyl
Grignard reagent. Table 7 shows the diamine ligands that provided the highest and the second
highest yields for each iodide in screening of diamine ligands in THF. The results revealed that (i)
2,2-difluoroethylation
proceeded
more
smoothly
with
1-[(1-methylpyrrolidine-2-yl)methyl]piperidine, which afforded
a
rather poor yield in
1,1-difluoroethylation (Figure 1), than with ligand a (entry 1 vs. 2), (ii) the highest yields with the
latter two iodides were obtained with ligand a (entries 4 and 6), and (iii) TMEDA also provided the
satisfactory yields from latter two iodides despite slightly lower than ligand a. Surprisingly, ligand
b afforded lower yields with any of the iodides than these diamine ligands. These results indicate
that the choice of diamine ligand is very important in the present reaction, including
1,1-difluoroethylation and 2,2,2-trifluoroethylation. The isolated yields of products in Table 7 are
also rather lower than 19F NMR yield due to their volatility as well as those in Table 4 and 6.
3. Conclusion
In this study, we revealed that the cobalt/diamine-catalyzed 1,1-difluoroethylation and
- 10 -

2,2,2-trifluoroethylation of aryl Grignard reagents proceeded smoothly with the corresponding
halides. Moreover, other partially fluorinated alkylations provided the desired products with the
cobalt/diamine catalyst. The choice of diamine ligand and solvent are very important for excellent
yields. Because the present method is simple and uses an inexpensive catalyst, we believe that it
has a potential as a practical process.
4. Experimental
4.1. General techniques
1H, 13C and 19F NMR spectra were recorded in CDCl3 on a Bruker DRX-500 (13C 125
MHz) and a DRX-250 (1H 250 MHz, 19F 235 MHz) spectrometers using tetramethylsilane as an
internal reference for 1H and 13C NMR, and fluorotrichloromethane as an external reference for 19
F
NMR. The chemical shifts are expressed in ppm (δ). The multiplicities are indicated as brs (broad
singlet), d (doublet), t (triplet), q (quartet), dt (doublet of triplet), tt (triplet of triplet) and m
(multiplet). The 19F NMR yields were calculated using benzotrifluoride as an internal standard. IR
and high-resolution mass spectroscopy (HR-MS) were measured using a HORIBA FT-720 and a
JMS-T100LP AccTOF LC-plus 4G, respectively. IR spectra were obtained in the reflective mode.
All of the commercially available reagents were used without further purification. According to a
literature method [28], CH3CF2I was synthesized from 1,1-difluoroethylene and
trifluoromethanesulfonic acid as starting materials.
4.2. Reaction procedures
The procedure for the synthesis of 1-(1,1-difluoroethyl)-4-methoxybenzene (entry 1 in
Table 1) is used as a representative example. A 2.0 mL THF solution containing 13.0 mg of CoCl2
(0.10 mmol) and 17.0 mg of trans-1,2-bis(dimethylamino)cyclohexane (0.10 mmol) was prepared.
This solution was added to 1.0 mL of a 1.0 mol/L 1,1-difluoroethyl bromide in THF (1.0 mmol) in
a reaction vessel under an argon atmosphere and the mixture was stirred for 15 min at room
temperature. To this reaction mixture, 4.2 mL of a 0.36 mol/L bromo(4-methoxyphenyl)magnesium
- 11 -

solution in THF (1.5 mmol) was added dropwise at a rate of 2.1 mL/h for 2 h at room temperature.
The mixture was further stirred for 1 h at room temperature. After the reaction, saturated NH4Cl
aqueous solution (2.5 mL) and H2O (2.5 mL) were added to the obtained mixture and the product
was extracted with diethyl ether (3 mL × 3). 19F NMR analysis of the diethyl ether layer with
benzotrifluoride
as
an
internal
standard
revealed
that
the
yield
of
1-(1,1-difluoroethyl)-4-methoxybenzene was 92% based on the charged amount of
1,1-difluoroethyl bromide. The isolation of the product was performed through the following
procedure. After the addition of a saturated NaCl aqueous solution (5 mL), the diethyl ether layer
was dried with anhydrous Na2SO4. Na2SO4 was removed by filtration, and the filtrate was
concentrated in vacuo. The obtained crude product was purified by the use of silica gel column
chromatography
(eluent
hexane/ethyl
acetate
=
15/1),
providing
1-(1,1-difluoroethyl)-4-methoxybenzene as a colorless oil in 61% yield (105 mg).
4.3 Characterization of products
Following 5 compounds are new and NMR (1H, 13C and 19F), IR and HR-MS data of
them are shown below. The other compounds are known and the characterization data of 1H, 13C or
19F NMR agreed with the reported data.
4.3.1. 1-(1,1-difluoroethyl)-3-methoxybenzene
1
colorless oil. H NMR (CDCl3) δ 1.91 (t, JHF = 18.1 Hz, 3H), 3.84 (s, 3H), 6.93-6.98 (m, 1H),
7.02-7.05 (m, 1H), 7.06-7.11 (m, 1H), 7.30-7.36 (m, 1H). 13C NMR (CDCl3)  25.8 (t, JCF = 29.9
Hz), 55.1, 110.3 (t, JCF = 6.3 Hz), 115.1, 116.8 (t, JCF = 6.1 Hz), 121.6 (t, JCF = 239.1 Hz), 129.6,
139.6 (t, JCF = 26.6 Hz), 159.6. 19F NMR (CDCl3) δ –87.6 (q, JFH = 18.1 Hz). IR (neat) 1587, 1456,
1302, 1234, 1173, 1045, 926, 783, 698 cm-1. HR-MS: calcd for C9H11F2O (M+H): 173.0772; found:
173.0801.
4.3.2. 1-(1,1-difluoroethyl)-4-methylbenzene
colorless oil. 1H NMR (CDCl3) δ 1.91 (t, JHF = 18.1 Hz, 3H), 2.38 (s, 3H), 7.22 (d, J = 8.0 Hz, 2H),
7.39 (d, J = 8.0 Hz, 2H). 13C NMR (CDCl3) 21.2, 25.9 (t, JCF = 30.2 Hz), 122.0 (t, JCF = 238.4
Hz), 124.5 (t, JCF = 6.1 Hz), 129.1, 135.4 (t, JCF = 26.6 Hz), 139.6. 19F NMR (CDCl3) δ –86.9 (q,
- 12 -

JFH = 18.1 Hz). IR (neat) 1383, 1296, 1173, 1111, 1088, 914, 818, 721 cm-1. HR-MS: calcd for
C9H11F2 (M+H): 157.0823; found: 157.0836.
4.3.3. 1-(2,2-difluoroethyl)-4-methoxybenzene
colorless oil. 1H NMR (CDCl3) δ 3.07 (dt, J = 4.6 Hz, JHF = 17.4 Hz, 2H), 3.80 (s, 3H), 5.87 (tt, J =
4.6 Hz, JHF = 56.7 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H). 13C NMR (CDCl3)
39.9 (t, JCF = 21.8 Hz), 55.1, 114.0, 116.8 (t, JCF = 241.2 Hz), 124.4 (t, JCF = 6.0 Hz), 130.8, 159.0.
19F NMR (CDCl3) δ –115.0 (dt, JFH = 56.7, 17.4 Hz). IR (neat) 1614, 1514, 1248, 1180, 1111, 1020,
820, 773 cm-1. HR-MS: calcd for C9H11F2O (M+H): 173.0772; found: 173.0805.
4.3.4. 1-(2,2,3,3-tetrafluoropropyl)-4-methoxybenzene
colorless oil. 1H NMR (CDCl3) δ 3.22 (t, JHF = 17.9 Hz, 2H), 3.81 (s, 3H), 5.68 (tt, JHF = 3.4, 53.7
Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H). 13C NMR (CDCl3)  35.9 (t, JCF = 22.7
Hz), 55.1, 110.0 (tt, JCF = 249.4, 39.0 Hz), 114.1, 116.6 (tt, JCF = 247.4, 28.2 Hz), 121.9 (t, JCF = 3.5
Hz), 131.6, 159.3. 19F NMR (CDCl3) δ –115.9 (dt, JFH = 3.4, 17.9 Hz, 2F), –136.5 (d, JFH = 53.7
Hz, 2F). IR (neat) 1614, 1514, 1248, 1099, 1034, 837, 777, 661 cm-1. HR-MS: calcd for C10H11F4O:
223.0741; found: 223.0761.
4.3.5. 1-(2,2,3,3,3-pentafluoropropyl)-4-methoxybenzene
1
colorless oil. H NMR (CDCl3) 3.26 (t, JHF = 18.3 Hz, 2H), 3.81 (s, 3H), 6.89 (d, J = 8.6 Hz, 2H),
7.20 (d, J = 8.6 Hz, 2H). 13C NMR (CDCl3) 36.2 (t, JCF = 22.3 Hz), 55.1, 114.0, 114.6 (tq, JCF
=
251.9, 36.9 Hz), 119.3 (qt, JCF = 285.7, 36.3 Hz), 121.0 (t, JCF = 2.2 Hz), 131.7, 159.6. 19F NMR
(CDCl3) δ –84.6 (s, 3F), –117.2 (t, JFH = 18.3 Hz, 2F). IR (neat) 1614, 1516, 1244, 1188, 1026, 791,
696 cm-1. HR-MS: calcd for C10H10F5O: 241.0652; found: 241.0634.
- 13 -

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- 16 -

MgBr
in THF (0.36 mol/L)
4.2 mL (1.5 mmol)
MeO
CoCl2 0.10 mmol
+
ligand 0.10 mmol
dropwise (0.75 mmol/h)
F
F
rt
THF2 mL, rt, 15 min
Br
Me
in THF (1.0 mol/L)
1.0 mL (1.0 mmol)
F F
Me
rt, 1 h
MeO
Me
Me2N
Me Me
tBu
NMe2 Me2N
39%
NMe2 Me2N
NMe2
21%
NMe2
Me2N
NMe2 Me2N
NMe2
89%
62%
29%
Me2N
Me
Me2N
NMe2 Me2N
NMe2 Me2N
33%
NMe2
22%
57%
29%
O
Me2N
NMe2
N
Me
N
Me
N
NMe2
N
0%
Me NMe2
26%
10%
35%
Figure 1 19F NMR yields of 1-(1,1-difluoroethyl)-4-methoxybenzene obtained through coupling
of CH3CF2Br and 4-methoxyphenyl Grignard reagent with CoCl2 and various diamine
ligands
- 17 -

MgBr
in THF (0.5 mol/L)
4.0 mL (2.0 mmol)
MeO
CoCl2 0.05 mmol
+
ligand 0.05 mmol
dropwise (1.0 mmol/h)
F F
Me
1.0 mmol
rt
THF 1 mL, rt, 15 min
I
F F
Me
rt, 1 h
MeO
Me2N
NMe2
Me2N
ligand a
80% 19F NMR yield
NMe2
TMEDA
40% 19F NMR yield
Scheme 1 Cobalt/diamine catalyzed coupling of CH3CF2I and 4-methoxyphenyl Grignard reagent
- 18 -

Table 1
Cobalt/diamine-catalyzed coupling of CH3CF2Br and 4-methoxyphenyl Grignard reagent with
various Co precursors
Co precursor 0.10 mmol
+
MgBr
in THF (0.36 mol/L)
4.2 mL (1.5 mmol)
MeO
0.10 mmol
dropwise (0.75 mmol/h)
F F
Me
Me2N
NMe2
rt
THF 2 mL, rt, 15 min
Br
in THF (1.0mol/L)
1.0 mL (1.0 mmol)
F F
Me
rt, 1 h
MeO
entry
Co precursor
CoCl2
yield / %a
1
2
3
4
5
6
7
62
67
79
2
CoBr2
CoI2
CoF2
CoF3
3
Co(OAc)2
Co(acac)2
55
58
8
Co(acac)3
CoCl2
40
52
9b
10b
11b
CoBr2
CoI2
54
74
aDetermined by 19F NMR.
bCo precursor 0.05 mmol, ligand 0.05 mmol
- 19 -

Table 2
Effect of oligoethers as a solvent in the cobalt/diamine catalyzed coupling of CH3CF2Br and
4-methoxyphenyl Grignard reagent
MgBr
in THF (0.36 mol/L)
4.2 mL (1.5 mmol)
MeO
CoCl2 0.10 mmol
+
dropwise (0.75 mmol/h)
F F
Me
ligand 0.10 mmol
solvent 2 mL,
rt, 15 min
rt
Br
in THF (1.0 mol/L)
1.0 mL (1.0 mmol)
F F
Me
rt, 1 h
MeO
yield / %a
ligand a
entry
solvent
ligand b
89
1
2
3
4
THF
DME
62
56
92
67
80
diglyme
triglyme
63
60
aDetermined by 19F NMR.
Me Me
Me2N
NMe2
Me2N
NMe2
liganda
b
ligand
- 20 -

Table 3
Cobalt/diamine-catalyzed coupling of CH3CF2Cl and 4-methoxyphenyl Grignard reagent
MgBr
in THF (0.36 mol/L)
4.2 mL (1.5 mmol)
MeO
CoCl2 0.10 mmol
+
ligand 0.10 mmol
dropwise (0.75 mmol/h)
F F
Me
in THF (1.5mol/L)
temperature
F F
Me
solvent 2 mL,
rt, 15 min
Cl
0.65 mL (1.0 mmol)
rt, 1 h
MeO
entry
ligand
solvent
THF
temperature
rt
yield / %a
1
2
3
4
11
32
60
50
a
a
a
b
THF
40 ºC
40 ºC
40 ºC
diglyme
THF
aDetermined by 19F NMR.
Me Me
Me2N
NMe2
Me2N
NMe2
liganda
b
ligand
- 21 -

Table 4
Cobalt/diamine-catalyzed coupling of CH3CF2Br and various aryl Grignard reagents
MgBr
R
in THF
CoCl2 0.10 mmol
+
ligand 0.10 mmol
dropwise (0.75 mmol/h)
F F
Me
in THF (1.0 mol/L)
rt
solvent 2 mL,
rt, 15 min
Br
F F
Me
1.0 mL (1.0 mmol)
R
rt, 1 h
yield / %a
entry
ligand a in diglymeb
ligand b in THF
1
2
92 (61)
89 (57)
74 (49)
86 (55)
3
4
5
21 (8)
86 (28)
50 (41)
17 (9)
86 (20)
44 (38)
6
7
8
9
75 (38)
96 (93)
60 (33)
77 (22)
89 (21)
98 (95)
90 (32)
89 (22)
aDetermined by 19F NMR.
bIsolated yields were shown in parentheses.
Me Me
Me2N
NMe2
Me2N
NMe2
liganda
ligandb
- 22 -

Table 5
Cobalt/diamine-catalyzed coupling of CF3CH2I and 4-methoxyphenyl Grignard reagent
MgBr
in THF (0.36 mol/L)
4.2 mL (1.5 mmol)
MeO
CoCl2 0.10 mmol
+
dropwise (0.75 mmol/h)
ligand 0.10 mmol
I
CF3
solvent 2 mL,
rt, 15 min
T1
in THF (1.0 mol/L)
1.0 mL (1.0 mmol)
CF3
T2, 1 h
MeO
entry
ligand
solvent
diglyme
diglyme
THF
T1
T2
rt
yield / %a
1
2
3
4
5
6
rt
72
77
92
39
76
77
a
0 ºC
0 ºC
rt
0 ºC
0 ºC
rt
a
a
THF
b
b
THF
0 ºC
0 ºC
0 ºC
0 ºC
TMEDA
THF
7
THF
0 ºC
0 ºC
78
aDetermined by 19F NMR.
Me Me
Me2N
NMe2
Me2N
NMe2
liganda
b
ligand
- 23 -

Table 6
Cobalt/diamine-catalyzed coupling of CF3CH2I or CF3CH2Cl and various aryl Grignard reagents
Co precursor 0.10 mmol
MgBr
in THF
+
R
0.10 mmol
NMe2
dropwise (0.75 mmol/h)
Me2N
X
CF3
THF2 mL, rt,
15 min
0℃
CF3
in THF (1.0mol/L)
1.0 mL (1.0 mmol)
R
0 ℃, 1 h
yield / %a
entry
X = Ib
X = Cl
91 (53)
1
2
92 (46)
71 (41)
65 (42)
3
4
5
83 (25)
71 (30)
77 (32)
83 (32)
69 (21)
71 (22)
6
Me2N
86 (29)
78 (34)
aDetermined by 19F NMR.
bIsolated yields were shown in parentheses.
- 24 -

Table 7
Cobalt/diamine-catalyzed coupling of various partially-fluorinated alkyl iodides and
4-methoxyphenyl Grignard reagents
MgBr
in THF(0.36 mol/L)
4.2 mL (1.5 mmol)
MeO
CoCl 0.10 mmol
2
+
dropwise (0.75 mmol/h)
ligand 0.10 mmol
I
Rf
THF 2 mL,
rt, 15 min
0 ℃
in THF(1.0 mol/L)
1.0 mL (1.0 mmol)
Rf
0 ℃, 1 h
MeO
entry
Rf
ligand
yield / %a
89
1
2
-CF2H
-CF2H
-CF2H
a
N
94 (62)b
N
Me
3
TMEDA
a
85
96 (58)b
83
4
-CF2CF2H
-CF2CF2H
-CF2CF3
5
TMEDA
a
6
75 (52)b
72
7
-CF2CF3
TMEDA
aDetermined by 19F NMR.
bIsolated yields were shown in parentheses.
Me2N
NMe2
liganda
- 25 -