Well-Defined, Shelf-Stable (NHC)Ag(CF2H) Complexes for Difluoromethylation

Article abstract of DOI:10.1021/acs.organomet.5b00350

The preparation of the thermally stable, well-defined NHC-ligated difluoromethylated silver complexes 1a,b is described. The complexes were fully characterized, and the structural assignments were ambiguously further confirmed by single-crystal X-ray diffraction. Reactions of [(SIPr)Ag(CF₂H)] with a variety of activated electrophiles such as diaryliodonium salts, vinyl(aryl)iodonium salts, aryldiazonium salts, and acid chlorides in the presence or absence of CuI occurred smoothly at room temperature to generate difluoromethylated compounds in good to excellent yields. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.organomet.5b00350

Article
pubs.acs.org/Organometallics
Well-Defined, Shelf-Stable (NHC)Ag(CF2H) Complexes for
Difluoromethylation
Yang Gu,† Dalu Chang,† Xuebing Leng,† Yucheng Gu,‡ and Qilong Shen*,†
†Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, People’s Republic of China
‡Syngenta, Jealott’s Hill International Research Centre Bracknell, Berkshire RG42 6EY, U.K.
S
* Supporting Information
ABSTRACT: The preparation of the thermally stable, well-
defined NHC-ligated difluoromethylated silver complexes 1a,b is
described. The complexes were fully characterized, and the
structural assignments were ambiguously further confirmed by
single-crystal X-ray diffraction. Reactions of [(SIPr)Ag(CF2H)]
with a variety of activated electrophiles such as diaryliodonium
salts, vinyl(aryl)iodonium salts, aryldiazonium salts, and acid
chlorides in the presence or absence of CuI occurred smoothly at
room temperature to generate difluoromethylated compounds in
good to excellent yields.
Mechanistically, an in situ generated [Cu(CF2H)] was
proposed to form by mixing a copper salt with TMSCF2H or
n-Bu3SnCF2H in the presence of an activator. [Cu(CF2H)]
then reacts with the electrophiles to form the difluoromethy-
lated products. However, the intermediate [Cu(CF2H)] was
not stable enough to be isolated. It has been well documented
that difluoromethylated coinage-metal species in low oxidation
states are unstable at room temperature.10 For example, Eujen
reported that [Ag(CF2H)2]− decomposed at −50 °C to give
tetrafluoroethane and silver11a and [Cu(CF2H)2]− dispropotio-
nated to tetrakis(difluoromethyl)cuprate(III) [Cu(CF2H)4]−
and metallic copper above 0 °C.11b Burton reported that a
solution of [Cu(CF2H)] in DMF formed by the reaction of
(HCF2)CdX with CuBr or CuCl at −50 to −60 °C reacted
quickly with allyl halides to form difluoromethylated products
in good yields. However, in the absence of electrophiles, the in
situ formed complex decomposed rapidly at −30 °C to
generate tetrafluoroethane and cis-difluoroethylene.12 Thus,
investigations of well-defined, stable difluoromethylated coin-
age-metal complexes and an understanding of the fundamental
reactivities of these complexes are vital to our ability to design
new catalytic difluoromethylation processes.
INTRODUCTION
■
In recent years, incorporation of fluoroalkyl groups into
druglike molecules has become a powerful and widely
employed tactic in the process of drug design because of the
well-known beneficial effects of the fluoroalkyl moiety, such as
improved lipophilicity and increased metabolic stability.1
Among many fluoroalkyl groups, the difluoromethyl group
(CF2H) is an intriguing structural motif with great potential,
since it is well-known that it is a bioisostere of a hydroxyl or
thiol group and can act as lipophilic hydrogen bond donor to
improve the binding selectivity.2 Hence, the development of
methods for direct difluoromethylation of small molecules
under mild conditions is highly desirable.3
In sharp contrast to the tremendous recent success of the
transition-metal-catalyzed trifluoromethylation reactions of aryl
substrates,4 far fewer methods for the direct formation of the
difluoromethylated compounds have been reported.5 In 2012,
Hartwig and co-workers described a copper-mediated method
for direct difluoromethylation of aryl and vinyl iodides with
TMSCF2H using CsF as the activator.6 In the presence of 1.0
equiv of CuI, electron-rich aryl iodides were difluoromethylated
in high yields, while reactions of electron-poor aryl iodides only
generated the protonated side products. Prakash and co-
workers improved the scope of the reaction to cover both
electron-rich and electron-poor aryl iodides by employing n-
Bu3SnCF2H as the nucleophilic difluoromethylating reagent.7
More recently, Qing discovered that the copper-mediated
difluoromethylation reaction could be conducted at room
temperature when KOtBu was used as the activator.8 In 2015,
Goossen and co-worker described a Sandmeyer-type difluor-
omethylation process for direct conversion of (hetero)-
arenediazonium salts into the corresponding difluoromethy-
lated (hetero)arenes under mild conditions.9
In 2014, we discovered that the N-heterocyclic carbene
(NHC) ligated difluoromethylated silver complex [(SIPr)Ag-
(CF2H)] (SIPr = 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-
ylidene) is not sensitive to air or moisture over a period of 1
week in the solid state. On the basis of this discovery, we
developed a cooperative bimetallic Pd/Ag catalyst for direct
difluoromethylation of aryl bromides and iodides.13 More
recently, we have extended the method to the difluoromethy-
Received: April 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.5b00350
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
lation of vinyl bromides, triflates, tosylates, and nonaflates in
the presence of a palladium catalyst by using [(SIPr)Ag-
(CF2H)] as the difluoromethyl source.14
In a continuation of our efforts on the development of
efficient methods for late-stage introduction of the difluor-
omethyl group into small molecules, we report herein the
details of the preparation of the N-heterocyclic carbene15
(NHC) ligated difluoromethylated silver complex [(SIPr)Ag-
(CF2H)] and its analogue [(IPr)Ag(CF2H)].16 More impor-
tantly, we discovered that reactions of [(SIPr)Ag(CF2H)] with
activated electrophiles such as diaryliodonium salts, vinyl(aryl)-
iodonium salts, aryldiazonium salts, and acid chlorides in the
presence or absence of CuI occurred smoothly at room
temperature to give the corresponding difluoromethylated
compounds in good to excellent yields.
RESULTS AND DISCUSSION
■
Figure 1. ORTEP diagram of 1a. Ellipsoids are shown at the 50%
probability level. Selected bond distances (Å) and angles (deg) for 1a:
Ag−C1, 2.090(3); Ag−C28, 2.076(4); C1−Ag−C28, 177.14(17);
N1−C1−N2, 108.5(2); N1−C1−Ag, 126.1(4); N2−C1−Ag,
125.2(4).
Preparation of the NHC-Ligated Difluoromethylated
Silver Complexes [(SIPr)Ag(CF2H)] and [(IPr)Ag(CF2H)].
The NHC-ligated difluoromethylsilver complex [(SIPr)Ag-
(CF2H)] (1a; SIPr = 1,3-bis(2,6-diisopropylphenyl)-
imidazolin-2-ylidene) was prepared in 82% yield by the
reaction of [(SIPr)AgCl] with 2.0 equiv of TMSCF2H in
THF at room temperature in the presence of 2.0 equiv of
NaOtBu (eq 1). [(IPr)Ag(CF2H)] (1b; IPr = 1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene) was prepared in 35%
yield by an analogous reaction using KOtBu as the activator (eq
1). Complexes 1a,b were isolated as white crystalline solids and
were characterized by 1H, 13C, and 19F NMR spectroscopy and
elemental analysis. The structural assignments were ambigu-
ously further confirmed by single-crystal X-ray diffraction
(Figures 1 and 2). Complexes 1a,b, to our knowledge, are the
first examples of isolable difluoromethylated silver(I) com-
plexes.
The solid-state structures of 1a,b comprise a silver atom
coordinated by a carbene and a difluoromethyl group in a linear
geometry. The Ag−C(NHC) bonds in both complexes
(2.090(3) and 2.092(4) Å, respectively) are of similar length.
The Ag−C(CF2H) bond length in complex 1b (2.104 (5) Å) is
slightly longer (by 0.028 Å) than those in complex 1a
(2.076(4) Å), likely due to the weaker σ-donating ability of
IPr in comparison to that of SIPr. The C−N−C and C−Ag−C
bond angles in complex 1a are larger than those in complex 1b
by roughly 4 and 1°, respectively.
Complex 1a is much more stable than complex 1b in the
solid state. Complex 1a is air-stable and light-insensitive in the
solid state. No decomposition was observed after 24 h at room
temperature when it was left in a vial on the bench.
Furthermore, complex 1a is stable at room temperature
under an argon atmosphere in the dark for over 1 month
without decomposition. In contrast, complex 1b turned black
after exposure to light for 1 h.
Figure 2. ORTEP diagram of 1b. Ellipsoids are shown at the 50%
probability level. Selected bond distances (Å) and angles (deg) for 1b:
Ag−C1, 2.092(4); Ag−C28, 2.104(5); C1−Ag−C28, 176.2(2); N1−
C1−N2, 104.4(4); N1−C1−Ag, 128.7(7); N2−C1−Ag, 126.7(7).
Complexes 1a,b are soluble in aprotic solvents, such as THF,
CH2Cl2, and CHCl3, and insoluble in less polar solvents, such
as benzene and hexane. In solution, both complexes were stable
for at least 24 h in the dark on dissolution in CH2Cl2 or THF
but completely decomposed after 24 h when exposured to light.
Room-temperature 19F NMR spectra of 1a,b (CD2Cl2)
displayed doublets at −113.01 (dd, 2J
= 64.0 Hz,
109Ag−F
2
2J
2J
= 56.4 Hz, JH−F = 45.1 Hz) and −112.76 ppm (dd,
107Ag−F
109Ag−F
2
2
107Ag−F
= 63.9 Hz, J
= 56.2 Hz, JH−F = 41.4 Hz),
respectively. These patterns were not dependent on the
concentration of the complexes, indicating that the complexes
were not in equilibrium with the ionic form [(NHC)2Ag]+[Ag-
(CF2H)2]−.
Reaction of [(NHC)Ag(CF2H)] Complexes with Diary-
liodonium Salts. With the NHC-ligated difluoromethylsilver
complexes [(SIPr)Ag(CF2H)] (1a) and [(IPr)Ag(CF2H)]
(1b) in hand, we then studied their reactions with 4-tert-
butylphenyl iodide in the presence of copper salts such as CuX
(X = Cl, Br, I), Cu(OAc)2, and copper(I) thiophene-2-
B
DOI: 10.1021/acs.organomet.5b00350
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
carboxylate (CuTc). Nevertheless, less than 5% of the desired
difluoromethylated arenes was observed even at 80 °C in
several solvents such as THF, DMF, MeCN, and acetone. The
main products observed were HCF2CF2H and an unidentified
species with a chemical shift of −115 ppm in 19F NMR
spectroscopy. Interestingly, when the more reactive Ar2IOTf
(Ar = p-tert-butylphenyl)17 was reacted with [(SIPr)Ag-
(CF2H)] (1a) or [(IPr)Ag(CF2H)] (1b) in the presence of
1.0 equiv of CuI in CH3CN for 30 min at room temperature,
the desired difluoromethylated 4-tert-butylbenzene was ob-
Scheme 2. Scope for CuI-Promoted Difluoromethylation of
Diaryliodonium Salts with [(SIPr)Ag(CF2H)]
a
served in 60% and 52% yield, respectively, as determined by 19
F
NMR spectroscopy with an internal standard. Since [(SIPr)-
Ag(CF2H)] (1a) is more stable than [(IPr)AgCF2H] (1b), we
further optimized the reaction conditions by employing
[(SIPr)Ag(CF2H)] (1a) as the nucleophilic difluoromethylat-
ing reagent. It was determined that the counterion of the diaryl
hypervalent iodine was crucial for the conversion of the
reaction. The reaction of diaryl hypervalent iodine with OTf as
the counterion gave the highest yield, while compounds with
other counterions such as BF4, NO3, and Br took place in much
lower yields (Scheme 1, entries 1−4). Likewise, the addition of
a
Reaction conditions: diaryliodonium salt (0.5 mmol), [(SIPr)Ag-
(CF2H)] (1.0 mmol), and copper salt (1.0 mmol) in CH3CN (2.5
mL) at room temperature for 30 min. Yields were determined by 19F
NMR spectroscopy with trifluoromethoxybenzene as an internal
Scheme 1. Optimization Conditions for Reaction of
a
Diaryliodonium Salts with [(SIPr)Ag(CF2H)]
b
standard. Isolated yield.
substituted diaryliodonium salt also reacted with [(SIPr)Ag-
(CF2H)] to give the corresponding difluoromethylated arene in
69% yield (Scheme 2, 3m). The main side products of these
reactions were aryl iodides that can be separated and reused for
the preparation of diaryliodonium salts.
To better understand the reactivity of the aryl group in the
diaryliodonium salt with [(SIPr)Ag(CF2H)] (1a), (2,4,6-
trimethylphenyl)(phenyl)iodonium triflate (2n) was prepared
and subjected to the standard reaction conditions. The reaction
occurred smoothly after 30 min at room temperature to full
conversion to give a mixture of 2-(difluoromethyl)-1,3,5-
trimethylbenzene and difluoromethylbenzene in overall 70%
yield with a ratio of 1/2, as determined by 19F NMR
spectroscopy and GC-MS (eq 2). The less hindered aryl
group is slightly favored over the more hindered aryl group.
a
Reaction conditions: diaryliodonium salt (0.05 mmol), [(SIPr)Ag-
(CF2H)] (0.05 mmol), and copper salt (0.05 mmol) in CH3CN (0.5
b
mL) at room temperature for 30 min; The yields were determined by
19F NMR spectroscopy with trifluoromethoxybenzene as an internal
c
d
standard. 5.0 equiv of CuI was used. 2.0 equiv of (SIPr)Ag(CF2H)
and 2.0 equiv of CuI were used.
CuI was important to the reaction and none of the desired
difluoromethylated product was observed in the absence of
CuI. Reactions in the presences of other copper salts such as
CuCl, CuBr, CuTc, and Cu(OAc)2 occurred in lower yields
(Scheme 1, entries 5−9). Finally, when 2.0 equiv of
[(SIPr)Ag(CF2H)] was used, the yield of the reaction was
improved to 85% (Scheme 1, entry 11).
We next applied this room temperature difluoromethylation
protocol to a variety of different diaryliodonium triflates. As
shown in Scheme 2, diaryliodonium triflates bearing electron-
donating and -withdrawing substituents underwent difluor-
omethylation in good to excellent yields under these
conditions. This protocol is compatible with a variety of
common functional groups such as chloride, bromide, and
esters (Scheme 2, 3e,f,h). The presence of chloride or bromide
in the products is very useful for further synthetic
manipulations. Substrates containing ortho substituents also
underwent efficient difluoromethylation under these optimized
conditions (Scheme 2, 3k,l). A more hindered 2,6-dimethyl-
Reaction of [(SIPr)Ag(CF2H)] Complex with Vinyl-
(phenyl)iodonium Salts. Encouraged by the excellent results
for the reaction of [(NHC)Ag(CF2H)] complexes with
diaryliodonium salts, we next turned our attention to the
copper-mediated difluoromethylation of vinyl(phenyl)-
iodonium salts. The selective formation of difluoromethylal-
kenes was expected, since it is well-known that the aryliodonio
group is one of the best leaving groups and a vinyliodonium salt
is generally considered as an equivalent of a vinylic cation.18
Indeed, the reaction of styrenyl(phenyl)iodonium triflates with
1.5 equiv of [(SIPr)Ag(CF2H)] (1a) in the presence of 1.5
equiv of CuI in CH3CN occurred smoothly after 30 min at
room temperature to generate β-difluoromethylstyrene in 94%
yield.
C
DOI: 10.1021/acs.organomet.5b00350
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Likewise, several substituted styenyl(phenyl)iodonium salts
also reacted with [(SIPr)Ag(CF2H)] (1a) to give the
corresponding difluoromethylated styrene derivatives in high
yields (Scheme 3). Since the copper-mediated difluoromethy-
A variety of aryldiazonium salts were then treated with
[(SIPr)Ag(CF2H)] (1a) in acetonitrile at room temperature,
and the corresponding difluoromethylated azo compounds
were obtained in high yields (Scheme 4). In general, reactions
Scheme 3. CuI-Promoted Difluoromethylation of
Vinyl(phenyl)iodonium Triflate with [(SIPr)Ag(CF2H)]
Scheme 4. Difluoromethylation of Aryldiazonium Salts with
[(SIPr)Ag(CF2H)]
a b
,
ab
,
a
Reaction conditions: vinyl(phenyl)iodonium salt (1.0 mmol),
[(SIPr)Ag(CF2H)] (1.5 mmol), and CuI (1.5 mmol) in CH3CN
b
(5.0 mL) at room temperature for 30 min. Isolated yield.
lation of aryl iodides with TMSCF2H or nBu3SnCF2H typically
requires high temperature, the current method represents an
alternative and complementary method for the formation of
difluoromethylated alkenes under relatively mild conditions.
Reaction of [(SIPr)Ag(CF2H)] with Aryldiazonium Salts.
The Sandmeyer reaction is one of the most fundamental
functional group transformations routinely practiced in organic
laboratories and applied industry.19 Under Sandmeyer reaction
conditions, the amino group is efficiently tranformed into other
functional groups such as halogen (F, Cl, Br, I), hydroxyl,
cyano, and boryl groups.20 Very recently, Sandmeyer-type
trifluoromethylations21 and trifluoromethylthiolations22 of
aryldiazonium salts have also been successfully developed.
Inspired by these recent advances, we envisaged that a similar
Sandmeyer difluoromethylation reaction of aryldiazonium salts
with [(SIPr)Ag(CF2H)] (1a) might be realized.
With this in mind, we initially studied the reaction of (4-tert-
butylphenyl)diazonium tetrafluoroborate with [(SIPr)Ag-
(CF2H)] (1a) in the presence of 1.0 equiv of a copper salt
in acetonitrile (eq 3). Interestingly, less than a 40% yield of the
expected 1-(difluoromethyl)-4-tert-butylbenzene was observed
when different CuX (X = Cl, Br, I, CN) species were used as
the catalysts. Instead, a compound with a new doublet having a
chemical shift at −104.61 ppm in the 19F NMR spectrum was
observed in more than 40% yield. The yield for the new
product was even higher (89%) when the reaction was
conducted in the absence of the copper salt (eq 3). After
isolation and purification, the new compound was determined
to be 1-(4-tert-butylphenyl)-2-(difluoromethyl)diazene (5a) by
1H, 13C, and 19F NMR spectroscopy and mass spectroscopy.
Obviously, the direct nucleophilic substitution reaction was
faster than the denitrogenative Sandmeyer reactions under the
reaction conditions.
a
Reaction conditions: aryldiazonium salt (1.0 mmol) and [(SIPr)Ag-
(CF2H)] (1.0 mmol) in CH3CN (10 mL) at room temperature for 30
b
min. Isolated yield.
of aryldiazonium salts with electron-donating groups or
electron-withdrawing groups also gave high yields. In addition,
a variety of functional groups such as bromo, iodo, cyano, ester,
and enolizable ketone were compatible with the reaction
conditions. These azo compounds are not air- and moisture-
sensitive. No decomposition was observed after the compounds
were left in a vial on the bench for 1 month. We further tried to
convert the azo compounds to difluoromethylarenes by heating
under reflux with CuI or photolysis in MeCN at 80 °C for 8 h.
However, no formation of difluoromethylarenes was observed
by 19F NMR spectroscopy.
Reaction of [(SIPr)Ag(CF2H)] with Acid Chlorides. To
further expand the reaction scope of [(SIPr)Ag(CF2H)] (1a),
we studied the reaction of acid chlorides with [(SIPr)Ag-
(CF2H)] (1a). It was found that acid chlorides were more
reactive than diaryliodonium triflates. One equivalent of
[(SIPr)Ag(CF2H)] was required for the reaction of acid
chlorides for full conversion to generated difluoromethylated
ketones in excellent yields (Scheme 5). The reaction was
compatible with a variety of functional groups such as bromide,
cyano, and ester (Scheme 5, 6c−e). The reaction of
benzo[b]thiophene-2-carboxylic acid with [(SIPr)Ag(CF2H)]
in the presence of 5 mol % of CuI and 1,10-phenanthroline
generated the heteroaryl difluoromethyl ketone in 92% yield
(Scheme 5, 6g). Likewise, under the same conditions,
cinnamoyl chloride was converted into the difluoromethylated
ketone in 71% yield (Scheme 5, 6h). Aliphatic carboxylic acid
chlorides were also reacted with [(SIPr)Ag(CF2H)] to give the
corresponding difluoromethylated ketone, albeit in moderate
yields (Scheme 5, 6i,j). Previous methods for the preparation of
difluoromethyl ketone typically require multiple steps.23
D
DOI: 10.1021/acs.organomet.5b00350
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
diisopropylphenyl)imidazolidin-2-yl)(difluoromethyl)silver, [(SIPr)-
Ag(CF2H)] (1a), as a white solid (698 mg, 82%). Crystals suitable
for X-ray analysis were obtained by laying a solution of complex 1a in
Scheme 5. Scope for CuI-Catalyzed Difluoromethylation of
Acid Chlorides with [(SIPr)Ag(CF2H)]
a b
,
1
THF (70 μL)/pentane (3.5 mL) at −30 °C. H NMR (400 MHz,
3
3
THF-d8): δ 7.36 (t, JH−H = 8.0 Hz, 2 H), 7.26 (d, JH−H = 8.0 Hz, 4
2
3
H), 5.90 (td, JH−F = 43.6, JH−H =14.0 Hz, 1 H), 4.04 (s, 4 H), 3.15
3
3
(hept, JH−H = 6.8 Hz, 4 H), 1.34 (d, JH−H = 7.2 Hz, 12 H), 1.32 (d,
3JH−H = 7.2 Hz, 12 H). 19F NMR (376 MHz, THF-d8): δ −113.66 (dd,
2
2
2J
= 62.4 Hz, J
= 54.5 Hz, JH−F = 43.6 Hz). 13C NMR
109Ag−F
107Ag−F
(101 MHz, CDCl3): δ 24.11, 25.76, 28.96, 124.55, 129.78, 134.80,
1
1
109
107
146.76, 153.67 (dt, 1J
= 260.6 Hz, J
= 225.2 Hz, JC−F =
Ag−C
Ag−C
1
1
109
109
280.8 Hz), 211.41 (d, J Ag−C = 151.5 Hz, J Ag−C = 131.3 Hz) ppm.
Anal. Calcd for C28H39AgF2N2: C, 61.20; H, 7.15; N, 5.10. Found: C,
60.91; H, 6.87; N, 4.78.
Preparation of [(IPr)Ag(CF2H)] (1b). To a solution of [(IPr)-
AgCl] (552 mg, 1.00 mmol) and KOtBu (225 mg, 2.00 mmol) in THF
(90 mL) was added TMSCF2H (250 μL 3.00 mmol) in THF (10 mL),
and the resulting mixture was stirred for 4 h at ambient temperature.
The mixture was filtered through a short plug of Celite, and the
solvent was evaporated under vacuum to give an off-white solid. The
solid was recrystallized from THF/pentane to give (1,3-bis(2,6-
diisopropylphenyl)-2,3-dihydro-1H-imidazol-2-yl)(difluoromethyl)sil-
ver [(IPr)Ag(CF2H)] (1b) as a white solid (189 mg, 35%). Crystals
suitable for X-ray analysis were obtained by laying a solution of
a
1
Reaction conditions: acid chloride (0.5 mmol), [(SIPr)Ag(CF2H)]
(1.0 mmol), CuI (0.025 mmol), and 1,10-phenanthroline (0.025
complex 1a in THF (70 μL)/pentane (3.5 mL) at −30 °C. H NMR
(400 MHz, CDCl3): δ 7.48 (t, 3JH−H = 7.6 Hz, 2 H), 7.28 (d, 3JH−H
=
b
7.6 Hz, 4 H), 7.14 (s, 2 H), 6.25 (td, 2JH−F = 43.2, 3JH−H = 16.0 Hz, 1
H), 2.53 (hept, 3JH−H = 7.2 Hz, 4 H), 1.26 (d, 3JH−H = 6.8 Hz, 12 H),
mmol) in CH3CN (5.0 mL) at room temperature for 2 h. Isolated
yield.
3
1.20 (d, JH−H = 6.8 Hz, 12 H). 19F NMR (376 MHz, CDCl3) δ
2
2
107
−112.76 (dd, J Ag−F = 63.5 Hz, J Ag−F = 54.9 Hz, 2JH−F = 43.2 Hz).
109
CONCLUSION
■
13C NMR (126 MHz, CDCl3): δ 23.94, 24.54, 28.68, 123.23, 124.10,
In summary, we have shown the preparation and character-
ization of the first thermally stable and well-defined (NHC)-
AgI(CF2H) complexes. It was discovered that [(SIPr)Ag-
(CF2H)] can efficiently difluoromethylate various activated
electrophiles such as diaryliodonium salts, vinyl(phenyl)-
iodonium salts, aryldiazonium salts and acid chlorides in the
presence or absence of CuI under mild conditions. Further
explorations in ligand and reagent design and an understanding
of the mechanism of the copper-mediated difluoromethylation
with [(NHC)Ag(CF2H)] are ongoing in our laboratory.
125.03, 130.39, 134.67, 145.61, 155.00 (dt, 1J
= 262.6 Hz,
109Ag−C
1
Ag−C = 227.3 Hz, 1JC−F = 281.5 Hz), 188.66 (d, 1JAg−C = 142.6 Hz)
107
J
ppm. Anal. Calcd for C28H37AgF2N2: C, 61.43; H, 6.81; N, 5.12.
Found: C, 61.32; H, 6.88; N, 4.99.
General Procedure for the Difluoromethylation of Ar2IOTf.
Anhydrous MeCN (2.5 mL) was added to a mixture of Ar2IOTf (0.5
mmol, 1.0 equiv), CuI (0.19 g, 1.0 mmol, 2.0 equiv), and
[(SIPr)Ag(CF2H)] (550 mg, 1.00 mmol, 2.0 equiv) in a 20 mL vial
in a glovebox under an argon atmosphere. The vial was sealed and
moved out of the glovebox. The mixture was stirred for 30 min. The
dark solution was diluted with CH2Cl2 (15 mL). The mixture was
filtered through a short plug of Celite and washed with CH2Cl2 (20
mL × 3). The organic layers were combined and washed with brine
(20 mL × 3). The filtrate was dried over MgSO4, filtered, and
concentrated under vacuum. The crude product was purified by
column chromatography on silica gel with pentane or a pentane/Et2O
mixture as the eluent to give the product.
General Procedure for the Difluoromethylation of Vinyl-
(phenyl)iodonium. Anhydrous MeCN (5.0 mL) was added to a
mixture of Ar2IOTf (1.0 mmol, 1.0 equiv), CuI (0.29 g, 1.5 mmol, 1.5
equiv), and [(SIPr)Ag(CF2H)] (825 mg, 1.5 mmol, 1.5 equiv) in a 20
mL vial in a glovebox under an argon atmosphere. The vial was sealed
and moved out from the glovebox. The mixture was stirred for 30 min.
The dark solution was diluted with CH2Cl2 (15 mL). The mixture was
filtered through a short plug of Celite and washed with CH2Cl2 (20
mL × 3). The organic layers were combined and washed with brine
(20 mL × 3). The filtrate was dried over MgSO4, filtered, and
concentrated under vacuum. The crude product was purified by
column chromatography on silica gel with pentane or a pentane/Et2O
mixture as the eluent to give the product.
EXPERIMENTAL SECTION
■
General Information. All manipulations were conducted under an
inert atmosphere with an argon-filled glovebox unless otherwise noted.
All reactions were conducted in oven-dried 4.0 or 20.0 mL vials fitted
with a Teflon-lined screw cap under an atmosphere of argon unless
otherwise noted (the preparation of diaryliodonium salts Ar2IOTf was
conducted in air). The diaryliodonium salts Ar2IOTf were prepared
following known procedures.24−26 The vinyl(phenyl)iodonium salts
were prepared following known procedures.27 The aryldiazonium salts
were prepared following known procedures.9 The carbonyl chlorides
were obtained from commercial sources, except for 6g. m-CPBA was
dried under high vacuum at 23 °C for 4 h.28 All solvents were purified
by standard methods.
1H, 13C, and 19F NMR spectra were acquired on 400, 100, and 376
1
MHz spectrometers (400 or 300 MHz for H; 100 or 125 MHz for
13C; 282 or 376 MHz for 19F). Chemical shifts are reported in ppm
and referenced to residual solvent peaks, and 19F spectra were
referenced to CFCl3 set to 0. Coupling constants are reported in hertz.
The following abbreviations are used to explain the multiplicities: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.
Preparation of [(SIPr)Ag(CF2H)] (1a). To a solution of
[(SIPr)AgCl] (831 mg, 1.50 mmol) and NaOtBu (285 mg, 3.00
mmol) in THF (30 mL) was added TMSCF2H (375 uL, 3.00 mmol).
The resulting mixture was stirred for 1.5 h at ambient temperature.
The mixture was filtered through a short plug of Celite, and the
solvent was evaporated under vacuum to give an off-white solid. The
solid was recrystallized from THF/pentane to give (1,3-bis(2,6-
General Procedure for the Difluoromethylation of Vinyl-
(phenyl)iodonium. Anhydrous MeCN (10 mL) was added to a
mixture of ArN2BF4 (1.0 mmol, 1.0 equiv) and , [(SIPr)Ag(CF2H)]
(550 mg, 1.0 mmol, 1.0 equiv) in a 20 mL vial in a glovebox under an
argon atmosphere. The vial was sealed and moved out from the
glovebox. The mixture was stirred for 30 min. The dark solution was
diluted with CH2Cl2 (15 mL). The mixture was filtered through a
short plug of Celite and washed with CH2Cl2 (20 mL × 3). The
organic layers were combined and washed with brine (20 mL × 3).
E
DOI: 10.1021/acs.organomet.5b00350
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
The filtrate was dried over MgSO4, filtered, and concentrated under
vacuum. The crude product was purified by column chromatography
on silica gel with pentane or a pentane/Et2O mixture as the eluent to
give the product.
6679−6687. (f) Besset, T.; Schneider, C.; Cahard, D. Angew. Chem.,
Int. Ed. 2012, 51, 5048−5050.
́
(5) (a) Dolbier, W. R., Jr.; Medebielle, M.; Ait-Mohand, S.
Tetrahedron Lett. 2001, 4811−4814. (b) Fujikawa, K.; Fioka, Y.;
Kobayashi, A.; Amii, H. Org. Lett. 2011, 13, 5560−5563. (c) Fujiwara,
Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.; Dixon, D. D.; Collins,
M. R.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc. 2012, 134,
1494−1497. (d) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder, E. D.;
General Procedure for the Difluoromethylation of vinyl-
(phenyl)iodonium. Anhydrous MeCN (5.0 mL) was added to a
mixture of RCOCl (0.5 mmol, 1.0 equiv), CuI (4.8 mg, 0.025 mmol,
0.05 equiv), 1,10-phenanthroline (4.5 mg, 0.025 mmol, 0.05 equiv),
and [(SIPr)Ag(CF2H)] (550 mg, 0.5 mmol, 1.0 equiv) in a 20 mL vial
in a glovebox under an argon atmosphere. The vial was sealed and
moved out from the glovebox. The mixture was stirred for 30 min. The
dark solution was diluted with CH2Cl2 (15 mL). The mixture was
filtered through a short plug of Celite and washed with CH2Cl2 (20
mL × 3). The organic layers were combined and washed with brine
(20 mL × 3). The filtrate was dried over MgSO4, filtered, and
concentrated under vacuum. The crude product was purified by
column chromatography on silica gel with pentane or a pentane/Et2O
mixture as the eluent to give the product.
́
Dixon, D.; Rodriguez, R. A.; Baxter, R. D.; Herle, B.; Sach, N.; Collins,
M. R.; Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95−99. (e) Li, Z.-J.;
Cui, Z.-L.; Liu, Z.-Q. Org. Lett. 2013, 15, 406−409. (f) Xia, J.-B.; Zhu,
C.; Chen, C. J. Am. Chem. Soc. 2013, 135, 17494−17500. (g) Mizuta,
S.; Stenhagen, I. S. R.; Duill, M. O.; Wolstenhulme, J.; Kirjavainen, A.
K.; Forsback, S. J.; Tredwell, M.; Sandford, G.; Moore, P. R.; Huiban,
M.; Luthra, S. K.; Passchier, J.; Solin, O.; Gouverneur, V. Org. Lett.
2013, 15, 2648−2651. (h) Xu, P.; Guo, S.; Wang, L.-Y.; Tang, P.-P.
Angew. Chem., Int. Ed. 2014, 53, 5955−5958. (i) Fujikawa, K.; Fujioka,
Y.; Kobayashi, A.; Amii, H. Synlett 2012, 3015−3018. (j) Sun, X.-Y.;
Yu, S.-Y. Org. Lett. 2014, 16, 2938−2941. (k) Su, Y.-M.; Hou, Y.; Yin,
F.; Xu, Y.-M.; Li, Y.; Zheng, X.-Q.; Wang, X.-S. Org. Lett. 2014, 16,
2958−2961.
ASSOCIATED CONTENT
■
S
* Supporting Information
(6) (a) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524−
5527. (b) Ge, S.; Chaładaj, W.; Hartwig, J. F. J. Am. Chem. Soc. 2014,
136, 4149−4152.
Text, figures, and CIF files giving details of all syntheses, NMR
spectra of the isolated products, and X-ray crystallographic data
for complexes 1a,b. The Supporting Information is available
free of charge on the ACS Publications website at DOI:
10.1021/acs.organomet.5b00350.
(7) Prakash, G. K. S.; Ganesh, S. K.; Jones, J. P.; Kulkarni, A.;
Masood, K.; Swabeck, J. K.; Olah, G. A. Angew. Chem., Int. Ed. 2012,
51, 12090−12094.
(8) Jiang, X.-L.; Chen, Z.-H.; Xu, X.-H.; Qing, F.-L. Org. Chem. Front.
2014, 1, 774−776.
AUTHOR INFORMATION
■
(9) Matheis, C.; Jouvin, K.; Goossen, L. J. Org. Lett. 2014, 16, 5984−
5987.
Corresponding Author
*E-mail for Q.S.: shenql@sioc.ac.cn.
(10) Difluoromethyl-ligated transition-metal complexes: (a) Blake, D.
M.; Winkeman, A.; Chung, Y.-L. Inorg. Chem. 1975, 14, 1326−1332.
(b) Schultz, A. J.; Khare, G. P.; McArdle, J. V.; Eisenberg, R. J. Am.
Chem. Soc. 1973, 95, 3434−3436. (c) Schultz, A. J.; McArdle, J. V.;
Khare, G. P.; Eisenberg, R. J. Organomet. Chem. 1974, 72, 415−423.
(d) Brothers, P. J.; Burrell, A. K.; Clark, G. R.; Rickard; Clifton, E. F.;
Roper, W. R. J. Organomet. Chem. 1990, 394, 615−642. (e) Burrell, A.
K.; Clark, G. R.; Jeffrey, J. G.; Rickard, C. E. F.; Roper, W. R. J.
Organomet. Chem. 1990, 388, 391−408. (f) Huang, D.-J.; Caulton, K.
G. J. Am. Chem. Soc. 1997, 119, 3185−3186. (g) Huang, D.-J.; Koren,
P. R.; Folting, K.; Davidson, E. R.; Caulton, K. G. J. Am. Chem. Soc.
2000, 122, 8916−8931.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the financial support from
the National Basic Research Program of China
(2012CB821600), the National Natural Science Foundation
of China (21172245/21172244/21372247/21421002), the
Syngenta Ph.D. fellowship (Y.G.), and the SIOC. We also
thank Dr. John Clough of Syngenta at Jealott’s Hill Interna-
tional Research Centre for proof-reading of the manuscript.
(11) (a) Eujen, R.; Hoge, B.; Brauer, D. J. Inorg. Chem. 1997, 36,
3160−3166. (b) Eujen, R.; Hoge, B.; Brauer, D. J. J. Organomet. Chem.
1996, 519, 7−20.
REFERENCES
(12) (a) Hartgraves, G. A.; Burton, D. J. J. Fluorine Chem. 1988, 39,
425−430. (b) Burton, D. J.; Hartgraves, G. A. J. Fluorine Chem. 2007,
128, 1198−1125.
■
(1) (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis,
Reactivity, Applications; Wiley-VCH: Weinheim, Germany, 2004.
(b) Hiyama, T. Organofluorine Compounds: Chemistry and Properties;
Springer-Verlag: Berlin, 2000. (c) Uneyama, K. Organofluorine
Chemistry; Blackwell: Oxford, U.K., 2006. (d) O’Hagan, D. Chem.
Soc. Rev. 2008, 37, 308−319. (e) Ma, J.-A.; Cahard, D. Chem. Rev.
2004, 104, 6119−6146. (f) Ma, J.-A.; Cahard, D. Chem. Rev. 2008,
108, PR1−PR43. (g) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem.
Rev. 2011, 111, 455−529. (h) Leroux, F.; Jeschke, P.; Schlosser, M.
Chem. Rev. 2005, 105, 827−856.
(13) Gu, Y.; Leng, X.-B.; Shen, Q. Nat. Commun. 2014, 5, 5405.
(14) Chang, D.-L.; Gu, Y.; Shen, Q. Chem. - Eur. J. 2015, 21, 6074−
6078.
(15) Reviews on N-heterocyclic carbene (NHC) ligated silver
complexes: (a) Arnold, P. L. Heteroat. Chem. 2002, 13, 534−539.
(b) Carrison, J. C.; Youngs, W. Chem. Rev. 2005, 105, 3978−4008.
(c) Lin, J. C. Y.; Huang, R. T. W.; Lee, C. S.; Bhattacharyya, A.;
Hwang, W. S.; Lin, I. J. B. Chem. Rev. 2009, 109, 3561−3598.
́
(d) Dıez-Gonzal
́
ez, S.; Marrion, N.; Nolan, S. P. Chem. Rev. 2009, 109,
(2) (a) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619−8683.
(b) Shimizu, M.; Hiyami, T. Angew. Chem., Int. Ed. 2005, 44, 214−231.
(c) Hu, J.-B.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465−7478.
(3) (a) Markovski, L. N.; Pahinnik, V. E.; Kirsanov, A. V. Synthesis
1973, 787−789. (b) Kuroboshi, M.; Hiyama, T. Synlett 1991, 909−
910.
(4) Recent reviews on transition-metal-catalyzed trifluoromethylation
of arene substrates: (a) Burton, D. J.; Yang, Z.-Y. Tetrahedron 1992,
48, 189−275. (b) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45,
5432−5446. (c) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473,
470−477. (d) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011,
111, 4475−4521. (e) Liu, T.; Shen, Q. Eur. J. Org. Chem. 2012, 34,
3612−3676.
(16) Pioneering works on N-heterocyclic carbene (NHC) stabilized
coinage-metal fluorinated or fluoroalkylated complexes: (a) Dubinina,
G. G.; Fururachi, H.; Vicic, D. A. J. Am. Chem. Soc. 2008, 130, 8600−
8601. (b) Dubinina, G. G.; Ogikubo, J.; Vicic, D. A. Organometallics
2008, 27, 6233−6235. (c) Zhang, C. P.; Vicic, D. A. Organometallics
2012, 31, 7812. (d) Akana, J. A.; Bhattacharyya, K. X.; Muller, P.;
̈
Sadigha, J. P. J. Am. Chem. Soc. 2007, 129, 7736−7737.
(17) (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299−
5358. (b) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48,
9052−9070.
F
DOI: 10.1021/acs.organomet.5b00350
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(18) (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 1996, 96, 1123−
1178. (b) Pirkuliev, N. S.; Brel, V. K.; Zeforov, N. S. Russ. Chem. Rev.
2000, 69, 105−120. (c) Stang, P. J. Angew. Chem., Int. Ed. 1992, 31,
274−285.
(19) (a) Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 1633−1635.
(b) Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 2650−2653.
(20) For reviews on functionalization of aryldiazonium salts, see:
(a) Hodgson, H. H. Chem. Rev. 1947, 40, 251−277. (b) Roglans, A.;
̌
Pla-Quintana, A.; Moreno-Manas, M. Chem. Rev. 2006, 106, 4622−
4643. (c) Mo, F.-Y.; Dong, G.-B.; Zhang, Y.; Wang, J.-B. Org. Biomol.
Chem. 2013, 11, 1582−1593. (d) Hari, D. P.; Konig, B. Angew. Chem.,
Int. Ed. 2013, 52, 4734−4743.
(21) (a) Wang, X.; Xu, Y.; Mo, F.-Y.; Ji, G.; Qiu, D.; Feng, J.; Ye, Y.;
Zhang, S.; Zhang, Y.; Wang, J.-B. J. Am. Chem. Soc. 2013, 135, 10330−
10333. (b) Dai, J.-J.; Fang, C.; Xiao, B.; Yi, J.; Xu, J.; Liu, Z.-J.; Lu, X.;
Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 8436−8439. (c) Danoun,
G.; Bayamagnai, B.; Grunberg, M. F.; Gooßen, L. J. Angew. Chem., Int.
̈
Ed. 2013, 52, 7972−7972. (d) Tlili, A.; Billard, T. Angew. Chem. Int.
Ed. 2013, 52, 6818−6819.
(22) (a) Adams, D. J.; Goddard, A.; Clark, J. H.; Macquarrie, D. J.
Chem. Commun. 2000, 987−988. (b) Danoun, G.; Bayarmagnai, B.;
Gruenberg, M. F.; Gooßen, L. J. Chem. Sci. 2014, 5, 1312−1315.
(c) Bayarmagnai, B.; Matheis, C.; Risto, E.; Gooßen, L. J. Adv. Synth.
Catal. 2014, 356, 2343−2348.
(23) Previous methods for the formation of difluoromethyl ketone:
(a) Wagner, P. J.; Thomas, M. J.; Puchalski, A. E. J. Am. Chem. Soc.
1986, 108, 7739−7744. (b) Zupan, M.; iskra, J.; Stavber, S. J. Org.
Chem. 1995, 60, 259−260. (c) Peng, W.; Shreeve, J. J. Org. Chem.
2005, 70, 5760−5763. (d) Kirij, N. V.; Babadzhanova, L. A.; Movchun,
V. N.; Yagupolskii, Y. L.; Tyrra, W.; Naumann, D.; Fischer, H.;
Scherer, H. J. Fluorine Chem. 2008, 129, 14−21.
(24) Zhu, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134,
10815−10818.
(25) Bielawski, M.; Zhu, M.; Olofsson, B. Adv. Synth. Catal. 2007,
349, 2610−2618.
(26) Zhu, M.; Jalalian, N.; Olofsson, B. Synlett. 2008, 4, 592−596.
(27) Skucas, E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 134,
9090−9093.
(28) Gademann, K.; Jana, C. K.; Neuburger, M.; Thommen, C. Org.
Lett. 2013, 15, 1390−1393.
G
DOI: 10.1021/acs.organomet.5b00350
Organometallics XXXX, XXX, XXX−XXX