Palladium-Catalyzed Negishi Cross-Coupling Reaction of Aryl Halides with (Difluoromethyl)zinc Reagent

Article abstract of DOI:10.1021/acs.orglett.6b01734

The palladium-catalyzed Negishi cross-coupling reaction of aryl iodides and bromides with (difluoromethyl)zinc reagent bearing a diamine such as TMEDA is achieved to provide the difluoromethylated aromatic compounds in good to excellent yields. The advantages of (difluoromethyl)zinc reagent are that (1) the derivatives, which possess different stability and reactivity, can be readily prepared via ligand screening and (2) transmetalation of a difluoromethyl group from the zinc reagent to palladium catalyst efficiently proceeds without an activator.

Full text of DOI:10.1021/acs.orglett.6b01734

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Negishi Cross-Coupling Reaction of Aryl Halides
with (Difluoromethyl)zinc Reagent
Kohsuke Aikawa, Hiroki Serizawa, Koki Ishii, 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: The palladium-catalyzed Negishi cross-coupling
reaction of aryl iodides and bromides with (difluoromethyl)zinc
reagent bearing a diamine such as TMEDA is achieved to provide
the difluoromethylated aromatic compounds in good to excellent
yields. The advantages of (difluoromethyl)zinc reagent are that
(1) the derivatives, which possess different stability and reactivity,
can be readily prepared via ligand screening and (2) transmetalation of a difluoromethyl group from the zinc reagent to palladium
catalyst efficiently proceeds without an activator.
ecently, interest in aromatic compounds bearing a
difluoromethyl (−CF2H) group, which can be regarded
DMF and DMPU but also diamine ligands (Scheme 1). We
found that the preparation of (DMF)2Zn(CF2H)2 (1b) and
R
as a bioisostere of alcohols and thiols, has grown in the
pharmaceutical and agrochemical industries.1 As part of a direct
and regiospecific synthetic method for difluoromethylated
aromatic compounds, Hartwig and Prakash independently
disclosed the copper-mediated difluoromethylations of aryl
iodides with TMSCF2H and nBu3SnCF2H as difluoromethyl
sources.2,3 However, to the best our knowledge, the catalytic
difluoromethylation of aryl halides with difluoromethyl reagents
is still conspicuously limited, in sharp contrast to the
a
Scheme 1. Preparation of (Difluoromethyl)zinc Reagents
4
corresponding synthetic methods for the CF3 and CF2R5
groups.6 In 2014, the first catalytic difluoromethylation of aryl
halides with TMSCF2H was demonstrated by Shen using the
cooperative dual palladium/silver catalyst system.7 Moreover,
Vicic succeeded in the nickel-catalyzed difluoromethylation of
aryl halides by employment of (DMPU)2Zn(CF2H)2.8 In the
preceding paper, we reported the copper-catalyzed difluor-
omethylation of aryl iodides with (DMPU)2Zn(CF2H)2 as an
organozinc reagent.9 The reaction proceeded efficiently
through the ligand/activator-free operation, providing the
difluoromethylated aromatic compounds in moderate to high
yields. However, the fundamental drawback of the reaction is
that only aryl iodides bearing electron-withdrawing substituents
can be utilized, and thus, aryl iodides possessing electron-
donating substituents are not applicable. Herein, we report the
palladium-catalyzed Negishi cross-coupling reaction with a
(difluoromethyl)zinc reagent that occurs with aryl halides
bearing not only electron-withdrawing substituents but also
electron-donating substituents.10
a
Yield and ratio of a/b were determined by 19F NMR spectroscopy.
(DMF)2Zn(CF2H)I (1a) (82:18) according to the previous
procedure9 followed by the ligand exchange between DMF and
diamines, such as TMEDA and diamine 5, could produce the
corresponding zinc reagents, LZn(CF2H)2 (3b and 4b) in high
yields as major products, respectively. The structure of 4b was
defined by X-ray crystallography as having tetrahedral geometry
at zinc (Figure 1).15,16 With regard to the stability of zinc
reagents in DMF solution, we found that diamine ligands can
thermally stabilize the zinc reagents. In fact, although
(TMEDA)Zn(CF2H)2 almost decomposed at 60 °C after 24
h, the decomposition rate was slower than that of counterparts
bearing monodentate ligands. Moreover, LZn(CF2H)2 (L = 5)
was more stable at 60 °C, and 51% of the zinc reagent remained
even after 24 h.15
Next, transmetalation of the CF2H group to palladium from
zinc was examined by 19F NMR spectroscopy (Table 1). The
addition of (DMPU)2Zn(CF2H)2 to (DPPF)Pd(Ph)I (6)
proceeded smoothly at room temperature to afford (DPPF)-
We have previously provided synthetic protocols involving
(trifluoromethyl)-,11,12 (perfluoroalkyl)-,11,12d,13 and (difluoro-
methyl)zinc8,9,14 reagents. The advantage of these zinc reagents
is that derivatives possessing different stability and reactivity
depending on the ligands can be readily prepared through the
screening. Therefore, we sought to investigate (difluoromethyl)
zinc reagents bearing not only monodentate ligands such as
Received: June 15, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01734
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Organic Letters
Letter
a
Table 2. Catalytic Difluoromethylation of Aryl Iodide
c
reaction
conditions
yield
(%)
b
entry
1
Zn reagent
P-ligand
DPPF
(DMF)2Zn(CF2H)l
(DMF)2Zn(CF2H)2
(DMPU)2Zn(CF2H)2
(TMEDA)Zn(CF2H)2
(5)Zn(CF2H)2
1,4-dioxane,
5
Figure 1. X-ray structure of 4b. Selected hydrogen atoms are shown.
Angles: C1−Zn−C2, 132.41°; N1−Zn−N2, 83.09°. Bond lengths:
C1−Zn, 2.028 Å; C2−Zn, 2.031 Å; N1−Zn, 2.140 Å; N2−Zn, 2.133
Å.
80 °C, 12 h
2
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPE
DPPP
BINAP
1,4-dioxane,
80 °C, 12 h
1,4-dioxane,
80 °C, 12 h
1,4-dioxane,
80 °C, 12 h
1,4-dioxane,
80 °C, 12 h
toluene,
80 °C, 12 h
DMF, 80 °C,
12 h
35
57
73
58
71
65
67
76
81
3
4
Table 1. Transmetalation of CF2H Group
5
6
(TMEDA)Zn(CF2H)2
(TMEDA)Zn(CF2H)2
(TMEDA)Zn(CF2H)2
(TMEDA)Zn(CF2H)2
(TMEDA)Zn(CF2H)2
(TMEDA)Zn(CF2H)2
(TMEDA)Zn(CF2H)2
(TMEDA)Zn(CF2H)2
(TMEDA)Zn(CF2H)2
7
8
THF, 80 °C,
12 h
9
1,4-dioxane,
100 °C, 6 h
1,4-dioxane,
120 °C, 6 h
1,4-dioxane,
120 °C, 6 h
1,4-dioxane,
120 °C, 6 h
b
yield (%) of
a
entry
Zn reagent
reaction conditions
1,4-dioxane, rt, 1 h
[7/8/9]
10
11
12
13
14
d
1
2
3
(DMF)2Zn(CF2H)2
49/0/11
94/0/1
(TMEDA)Zn(CF2H)2 1,4-dioxane, 50 °C, 1 h 22/8/0
(0/91/0)
93/0/3
(74)
(DMPU)2Zn(CF2H)2 1,4-dioxane, rt, 1 h
11
c
17
51
15
4
5
(5)Zn(CF2H)2
1,4-dioxane, rt, 1 h
d
1,4-dioxane,
120 °C, 6 h
(DMF)2Zn(CF2H)l
1,4-dioxane,
rt to 100 °C, 12 h
0/0/0
P(1-Ad)2nBu 1,4-dioxane,
120 °C, 6 h
a
LZn(CF2H)2 and (DMF)2Zn(CF2H)I prepared according to the
methods shown in Scheme and our previous report (ref 9) were
a
b
employed, respectively. Yield was determined by 19F NMR
Conditions: 10a (0.1 mmol), zinc reagent (∼0.5 M 1,4-dioxane
solution: 0.2 mmol), Pd(dba)2 (5 mol %), and P-ligand (10 mol %).
LZn(CF2H)2 and (DMF)2Zn(CF2H)I prepared according to the
c
d
spectroscopy. Reaction time was 24 h. (DPPF)Pd(CF2H)I was
b
observed in 20−40% yields.
methods shown in Scheme 1 and our previous report (ref 9) were
c
employed, respectively. Yield was determined by 19F NMR spectros-
d
copy. Reaction time was 3 h.
Pd(Ph) (CF2H) (7) in 94% yield. The use of (DMF)2Zn-
(CF2H)2, in contrast, resulted in the formation of 7 and
(DPPF)Pd(CF2H)2 (9) in 49% and 11% yields, respectively
(Table 1, entries 1 vs 2). Complex 9 was found to be
catalytically inactive. Transmetalation of 6 using (TMEDA)-
Zn(CF2H)2 required higher temperature (Table 1, entry 3) and
provided (difluoromethyl)benzene (8) in addition to 7 (entry
3). Indeed, Shen has already reported that complex 7 can
undergo reductive elimination at 47 °C, providing 8 in high
yield.7a In contrast, LZn(CF2H)2 (L = 5) bearing diamine
efficiently underwent transmetalation even at room temper-
ature (entry 4). To our surprise, (DMF)2Zn(CF2H)I did not
cause the desirable transmetalation even at 100 °C, and
(DPPF)Pd(CF2H)I was observed in 20−40% yields at the
same time as decomposition of the zinc reagent in the 19F
NMR spectrum (entry 5).
With preparation of (difluoromethyl)zinc reagents and
observation of the transmetalation, our research was focused
on the catalytic difluoromethylation of aryl halides (Table 2).
We tested various zinc reagents, phosphine ligands, solvents,
and reaction temperature. Initially, the reactions were
conducted with 4-iodobenzonitrile (10a) and (DMF)2Zn-
(CF2H)I or (DMF)2Zn(CF2H)2 in the presence of Pd(dba)2/
2DPPF in 1,4-dioxane at 80 °C to provide the desired product
(11a), but yields were low (entries 1 and 2). Although
(DMPU)2Zn(CF2H)2 gave moderate yield under the same
conditions (entry 3), we were delighted to find that use of
(TMEDA)Zn(CF2H)2 could lead to 11a in 73% yield (entry
4). However, LZn(CF2H)2 (L = 5) decreased the yield (entry
5). Other solvents, such as toluene, DMF, and THF, also
initiated the reaction but did not enhance the yields (entries 6−
8). Higher temperature (120 °C) led to higher yield (entry 10),
while the reaction proceeded smoothly even at 80 °C (entry 4).
Bidentate ligands, such as DPPE, DPPP, and BINAP, led to a
significant drop in yields (entries 10 vs 11−13). No
improvement of yields was observed even by bulky
monodentate ligand (entry 14).
The nature of the phosphine ligands had a large impact on
the yields of the reactions. For example, the stoichiometric
examination of Pd(dba)2/2DPPF and 10a in the presence of
(TMEDA)Zn(CF2H)2 could provide the difluoromethylated
product (11a) in 97% yield, along with a slight amount of
(DPPF)Pd(CF2H)2 (9) (Scheme 2, eq 1). In sharp contrast,
employment of bulky monodentate ligand P(1-Ad)nBu2 also
furnished 11a in 42% yield. In this case, however, (TMEDA)-
Pd(CF2H)2 (12) was provided as a major product (67% yield)
in a ligand-exchange reaction and was found to be inactive in
the catalytic cycle (Scheme 2, eq 2). These results indicate that
relatively electron-donating bidentate ligands, which can
suppress the production of the inert complex 12, are suitable
for the present catalytic system.
B
DOI: 10.1021/acs.orglett.6b01734
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Organic Letters
Letter
a
ester, and chloride, were found to undergo the difluoromethy-
lation in good to high yields (11b−d). Significantly, substrates
bearing electron-donating substituents and a phenyl group also
reacted smoothly to give the desired products 11e−g in high
yields. In addition, the reaction employing meta- and ortho-
substituted aryl iodides could be converted to the difluor-
omethylated arenes (11h,i), but ortho-disubstituted arene and
isoquinoline led to diminished reactivity (11j,k). Purine
riboside was compatible with the present catalytic reaction
(11l). The introduction of the CF2H group was also found to
be applicable to corannulene backbone (11m). Aryl bromides
with electron-withdrawing substituents in the para-position
underwent the reaction to afford the products 11b,c in good
yields. Furthermore, by using XPhos instead of DPPF, the
reaction of aryl bromides bearing electron-donating and
withdrawing substituents in the para- and meta-positions
resulted in the formation of the products 11e,n in high yields,
respectively. Vinylic substrate was also compatible with the
present reaction (11o). The reaction of aryl chloride with an
electron-withdrawing substituent occurred to give the corre-
sponding product (11b), albeit in 39% yield.
Scheme 2. Stoichiometric Examination
a
Yield was determined by 19F NMR spectroscopy. (TMEDA)Zn-
(CF2H)2 prepared according to the method shown in Scheme 1 was
employed.
Scheme 3 summarizes the scope of the aromatic difluor-
omethylation with various aryl and heteroaryl iodides and
bromides under the reaction conditions optimized in Table 2.
In general, aryl iodides possessing electron-withdrawing
substituents in the para-position of the ring, such as nitro,
In summary, an efficient and practical palladium-catalyzed
Negishi cross-coupling reaction of aryl iodides and bromides
was developed with (TMEDA)Zn(CF2H)2 as an organozinc
reagent. Transmetalation of the CF2H group from zinc reagents
to palladium catalyst proceeded efficiently without an activator,
in contrast to the counterparts employing TMSCF2H and
nBu3SnCF2H as difluoromethyl sources.2,3,7 This difluorome-
thylation protocol was carried out with aryl iodides and
bromides bearing not only electron-withdrawing but also
electron-donating substituents, affording the difluoromethy-
lated arenes in good to excellent yields. To demonstrate the
efficiency and versatility of a palladium catalytic system which
can be easily optimized depending on substrates, development
of the palladium-catalyzed difluoromethylations with various
(hetero)aryl bromides, triflates, and chlorides with (difluor-
omethyl)zinc reagents is now underway in our laboratory.
Scheme 3. Substrate Scope and Functional-Group
Tolerance
a
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01734.
Experimental procedures and compound characterization
data (PDF)
X-ray crystallographic data for 4b (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mikami.k.ab@m.titech.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
a
Conditions: 10 (0.3 mmol), (TMEDA)Zn(CF2H)2 (∼0.5 M 1,4-
This research was supported by JST (ACT-C: Advanced
Catalytic Transformation program for Carbon utilization) and
JSPS KAKENHI Grant No. 26620078. We thank Dr. Kenji
Yoza (Bruker AXS) for valuable help with the X-ray crystal-
structure analysis. We are also grateful to Prof. John F. Hartwig
(University of California Berkeley) for his useful discussions.
dioxane solution: 0.6 mmol), Pd(dba)2 (5 mol %), and DPPF (10 mol
%) in 1,4-dioxane (2 mL). Yield was determined by 19F NMR
spectroscopy. (TMEDA)Zn(CF2H)2 prepared according to the
method shown in Scheme 1 was employed. Reaction was carried
out at 80 °C for 12 h. Pd(dba)2 (2 mol %) and DPPF (4 mol %) were
b
c
d
used. XPhos instead of DPPF was used.
C
DOI: 10.1021/acs.orglett.6b01734
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Organic Letters
Letter
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DOI: 10.1021/acs.orglett.6b01734
Org. Lett. XXXX, XXX, XXX−XXX