Two Ligands Transfer from Ag to Pd: En Route to (SIPr)Pd(CF2H)(X) and Its Application in One-Pot C-H Borylation/Difluoromethylation

Article abstract of DOI:10.1021/acs.joc.9b03296

A process for the concurrent transfer of both the NHC ligand and the difluoromethyl group from [(SIPr)Ag(CF₂H)] to PdX₂ (X = Cl, OAc, and OPiv) for the preparation of [(SIPr)Pd(CF₂H)X] complexes is described. These complexes were air-stable and easily underwent transmetalation with aryl pinacol boronate/reductive elimination to generate ArCF₂H in high yields. Based on this discovery, the first one-pot C-H borylation and difluoromethylation process for the preparation of difluoromethylated (hetero)arenes was developed.

Full text of DOI:10.1021/acs.joc.9b03296

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Article
Two ligands transfer from Ag to Pd: En Route to (SIPr)Pd(CF2H)(X)
and its Application in One-pot C-H Borylation/Difluoromethylation
Haiwei Zhao, Simon Herbert, Tom Kinzel, Wei Zhang, and Qilong Shen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03296 • Publication Date (Web): 23 Jan 2020
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Two ligands transfer from Ag to Pd: En Route to (SIPr)Pd(CF2H)(X) and its
Application in One-pot C-H Borylation/Difluoromethylation
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Haiwei Zhao,† Simon Herbert,‡ Tom Kinzel,§ Wei Zhang and Qilong Shen†,*
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†Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy
of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
P. R. China
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‡Bayer AG, Research & Development, Pharmaceuticals, 178 Müllerstraße, Berlin,
13342, Germany
§Bayer Pharmaceuticals, Open Innovation Center China, Bayer Center, Bei Dong
San Han 27, Beijing 100020, P. R. China
Centre for Green Chemistry and Department of Chemistry, University of
Massachusetts Boston, 100 Morrissey Boulevard, Boston, Massachusetts 02125,
United States
ABSTRACT: A process for the concurrent transfer of both the NHC ligand and
difluoromethyl group from [(SIPr)Ag(CF2H)] to PdX2 (X = Cl, OAc and OPiv) for the
preparation [(SIPr)Pd(CF2H)X] complexes is described. These complexes were air-
stable and easily underwent transmetalation with aryl pinacol boronate/reductive
elimination to generate ArCF2H in high yields. Based on this discovery, the first one-
pot C-H borylation and difluoromethylation for the preparation of difluoromethylated
(hetero)arenes was developed.
Introduction
Mainly due to its unique physicochemical properties, the difluoromethyl group (-CF2H)
is generally considered by medicinal chemists as one of the privileged functional
groups that may bring beneficial effects to the pharmacological and pharmacokinetic
properties of lead compounds.1 1) The proton in the difluoromethyl group is slightly
acidic, which is able to act as hydrogen bonding donor to interact with the targeted
protein.2 It is now commonly accepted that the difluoromethyl group is an isosteric and
isopolar functional group to hydroxyl (OH) and thiol (SH) units in drug design;3 2) The
Hammett constant (p) of the difluoromethyl group is 0.32, which is slightly lower than
that of an ester (p = 0.45) but much higher than that of a hydroxy (p = -0.37) or thiol
groups (p = 0.15),4 suggesting that the difluoromethyl group is a moderate electron-
withdrawing group. Thus, replacement of hydroxy or thiol groups with difluoromethyl
in a drug molecule may effectively decrease its overall electron density potentially
preventing its oxidation by cytochrome P450, and consequently, improving the drug
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molecule’s metabolic stability. These beneficial effects of the difluoromethyl group
have promoted organic chemists to develop efficient methods for its incorporation. As
a result, in the past few years, numerous difluoromethylative methods for the
preparation of difluoromethylated arenes have emerged, especially those mediated
with transition metal catalysis (Figure 1).5
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Difluoromethylarenes via transition metal-medianted cross-coupling reactions
Cu or Pd or Ni
(M = Zn or Sn)
Pd
TMSCF2H
or MCF2H
+
ArX
Ar(B(OH)2
+
CF2
Ar CF2H
H
Cu
Pd or Ni or Fe
Het
+
TMSCF2H
+
HCF2X
ArM
(M = BR2 or Zn)
This work
(SIPr)Ag(CF2H) + PdX2
(SIPr)Pd(CF2H)(X) + AgX
X = OAc (1), Cl (2), OPiv (3)
R1
R1
R1
H
Bpin
CF2H
[Ir]/B2pin2
2
R2
R2
R2
Figure 1. Methods for preparation of difluoromethylarenes via transition metal catalysis.
Among these methods, transition metals including copper,6 nickel7 or palladium8-
mediated or -catalyzed coupling of an aryl halide with a nucleophilic difluoromethyl
reagent represents an attractive strategy, with potentially broad applications. For
example, in 2014, we reported the first transition metal-catalyzed direct
difluoromethylation of aryl bromides/iodides with TMSCF2H by employing a
cooperative bimetallic Pd/Ag catalyst, which could be easily applied in the preparation
of many bioactive difluoromethylated arene derivatives.8a In addition, by using the key
intermediate [(SIPr)Ag(CF2H)] (SIPr = 1,3-bis(2,6-diisopropyl-phenylimidazolin-2-
ylidene) as a nucleophilic difluoromethylating reagent, we further developed several
Pd-catalyzed difluoromethylation protocols that are able to difluoromethylate a broad
scope of aryl electrophiles including aryl chlorides and triflates,9 heteroaryl chlorides,
bromides and iodides.10 Nevertheless, these methods typically required the use of
prefunctionalized arene substrates that limits their applications in the late-stage
modification of drug candidates for structure-activity studies. A more efficient and
atom-economical difluoromethylation method that could direct convert the arene C-H
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bond to C-CF2H bond under certain conditions, is thus highly desirable. Previously,
Qing and coworkers reported a copper-mediated C-H difluoromethylation of
heteroarenes. Nevertheless, the scope of substrates was limited to heteroarenes.11
Results and Discussion
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During the studies of Pd(OAc)2-catalyzed C-H bond activation/difluoromethylation
of 2-phenylpyridine with [(SIPr)Ag(CF2H)], we discovered that even though the desired
C-H difluoromethylative product can be observed in about 10% yield, a new species
with a chemical shift at -88.0 ppm in 19F NMR spectroscopy was also detected. Further
studies showed that this species was [(SIPr)Pd(CF2H)(OAc)], which was resulted from
concurrently transferring both difluoromethyl group and N-heterocyclic carbene ligand
SIPr from Ag to Pd. In addition, not only Pd(OAc)2 but also PdCl2 or Pd(OPiv)2 (OPiv
= pivalate) also reacted similarly to give [(SIPr)Pd(CF2H)(X)]2 (X = Cl or OPiv) in high
yield. We also discovered that these new complexes could serve as efficient
difluoromethylating reagents when reacted with aryl boronic acids or their derivatives
under basic conditions. Based on these findings, we developed a one-pot C-H
borylation difluoromethylation protocol for the preparation of difluoromethylated
arenes and heteroarenes. Herein, we report these discoveries.
Initially, we investigated direct C-H difluoromethylation by examining the reaction
of 2-phenylpyridine with [(SIPr)Ag(CF2H)] using 10 mol% Pd(OAc)2 as the catalyst in
the presence of various oxidants such as AgOAc, Ag2CO3, Cu(OAc)2, 1,4-
benzoquinone (BQ) or oxygen.12,13 Interestingly, while the desired difluoromethylated
product 2-(2-(difluoromethyl)phenyl)pyridine was generated in 1-14% yield, a new
signal which is a doublet with a chemical shift at -88.0 ppm in 19F NMR spectroscopy
appeared. We suspected that the new signal was a difluoromethylated palladium
complex (Eq. 1). Since we were unable to improve the yield of the C-H
difluoromethylated product by optimizing the reaction parameters such as the solvent,
the reaction temperature and the oxidant, we speculated that the unknown
difluoromethylated species observed in various reaction conditions might serve as a
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dormant palladium catalyst or a palladium catalyst reservoir. We then decided to
isolate this species to probe whether our speculation was correct.
After a quick screen of the reaction conditions, we identified a high-yielding method
for the preparation of the target difluoromethylated palladium complex. Stoichiometric
reaction of [(SIPr)Ag(CF2H)] with Pd(OAc)2 in THF at 80 oC overnight generated the
identical signal in 19F NMR spectroscopy as the catalytic reaction in 80% yield (Eq. 2).
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1H NMR spectroscopic study of the isolated complex showed that the complex
bears an SIPr ligand, an acetate and a difluoromethyl group, which indicates that the
structure of the complex is [(SIPr)Pd(OAc)(CF2H)] 1 in which the acetate group
coordinated in κ2-binding modes. The structure was further ambiguously confirmed by
X-ray diffraction of its single crystals (Figure 2). In addition, other Pd(II) complexes
such as PdCl2 or Pd(OPiv)2 also reacted with [(SIPr)Ag(CF2H)] to give crystalline
solids [(SIPr)Pd(Cl)(CF2H)]2 2 and [(SIPr)Pd(OPiv)(CF2H)] 3 in 70% and 82% yield,
respectively (See SI for their single crystal structures). In all cases, we observed that
both NHC ligand the difluoromethyl group were transferred from Ag to Pd.14
Figure 2. ORTEP diagram of complex [(SIPr)Pd(OAc)(CF2H)] 1. Ellipsoids are shown
at the 30% probability level.
With these complexes in hand, we then subjected them to the palladium-catalyzed
arene C-H difluoromethylation conditions. The formation of C-H difluoromethylation
product 2-(2-(difluoromethyl)phenyl)pyridine was not observed when the three
complexes were used as catalysts. These observations confirm our initial assumption
that the difluoromethylated complexes were dormant palladium complexes that
suppressed the catalytic reaction.
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Scheme 1. Rapid Optimization of Conditions for Reaction of Quinoline-3-boronic
Acid Pinacol Ester with Complexes 1-3a
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aReaction conditions: quinoline-3-boronic acid pinacol ester (0.05 mmol), [(SIPr)Pd(CF2H)(X)] 1-3 (0.05
b
mmol) and K2CO3 (0.1 mmol) in specified solvent (1.0 mL). Yields were determined by 19F NMR
analysis of the crude reaction mixture with benzotrifluoride as an internal standard.
The lack of success in the development of the Pd-catalyzed arene C-H
difluoromethylation method promoted us to seek an alternative protocol. Previously,
Hartwig, Marder, Smith, Maleczka and co-workers have independently reported an
efficient iridium-catalyzed borylation of arene C-H bonds and they have demonstrated
that the borylated products can be efficiently converted to other functionalized arenes
such as aryl halides, phenol or amine derivatives and trifluoromethylated arenes in
high yields.15 We therefore envisaged that if the aryl pinacol boronates resulting from
the Ir-catalyzed C-H borylation could react with complexes 1-3, a tandem C-H
activation borylation/difluoromethylation protocol would be developed. This would
provide a method for late-stage difluoromethylation, with previously inaccessible
regioselectivity, which could be applied to drug-like molecules. The key for such a
strategy is the successful difluoromethylation of aryl pinacol boronates with complexes
1-3 which we next quickly examined. It was found that reaction of quinoline-3-boronic
acid pinacol ester with complexes 1-3 occurred smoothly at 80 oC after 12 h to give 3-
difluoromethylquinoline in 10-76% yield, whereas [(SIPr)Pd(CF2H)Cl]2 2 showed
higher reactivity than [(SIPr)Pd(CF2H)(OAc)] 1 and [(SIPr)Pd(CF2H)(OPiv)] 3 was
much less reactive. Further optimizations showed that DMF was a better solvent than
THF or toluene.
With the optimized conditions for the difluoromethylation of aryl pinacol boronates
in hand, the tandem reaction of 1,3-disubstituted arenes or heteroarenes to the
corresponding difluoromethyl (hetero)arenes was studied, as shown in Scheme 2.
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Scheme 2. Scope of One-Pot C-H Borylation/Difluoromethylationa
1. [Ir(COD)(OMe)]2 (0.25 mol%)
dtbpy (0.5 mol%)
6
7
B2Pin2 (0.7 equiv.)
THF, 80 oC, 24 h
R1
R1
H
CF2H
evaporation of volatile materials
8
9
2. [(SIPr)Pd(CF2H)Cl]2 2 (0.5 equiv.)
K2CO3 (2.0 equiv.)
DMF, 80 oC, 12 h
R2
R2
4a-y
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tBu
tBu
MeO2C
CO2Me
CF3
CO2Me
Me
CO2Me
Me
OPiv
NC
CF3
CF2H
CF2H
CF2H
CF2H
4d, 64%
CF2H
CF2H
4a, 71%
4b, 79%
4c, 72%
4e, 46%
4f, 61%
O
O
O
NC
Me
Me
Me
Me
N
MeO
OMe
Cl
OMe
Et
NEt2
CF2H
CF2H
CF2H
CF2H
CF2H
CF2H
4g, 68%
4j, 59%
4h, 50%
4i, 62%
4k, 64%
4l, 26%
F
OMe
CF2H
CF2H
O
MeO
OMe
Me
Me
NC
CF2H
HF2C
O
N
N
tBu
tBu
N
N
Boc
CF2H
CF2H
4p, 60%
4q, 53%b
4r, 47%b
4m, 63%
4o, 66%
4n, 68%
CF2H
CF2H
N
CF2H
Me
CF2H
MeO
CF2H
CF2H
N
N
N
N
N
N
N
N
N
Boc2N
N
N
NC
BocN
4y, 47%c
4s, 59%b
4t, 56%b
4u, 39%c
4v, 44%c
4x, 41%c
aIsolated yields; [Ir(cod)OMe]2 (1.0 mol%) and dtbpy (2.0 mol%) were used; [Ir(COD)(OMe)]2 (3.0
b
c
mol%) and Me4Phen (6.0 mol%) were used.
Generally, we conducted the well-known process of borylation of 1,3-disubstituted
arenes or heteroarenes with 0.7 equivalents of bis(pinacolato)diboron (B2pin2) in the
presence of 0.25 mol% of [Ir(COD)OMe]2 (COD = 1,5-cyclooctadiene) and 0.54 mol%
o
of di-tert-butylbipyridine (dtbpy) in THF at 80 C for 24 h. After evaporation of the
volatile materials, [(SIPr)Pd(CF2H)Cl]2 2, K2CO3 and DMF were sequentially added
o
and the resulting mixture was heated at 80 C for another 12 h. Using this one-pot
protocol, a variety of 5-difluoromethylated 1,3-disubstituted (hetero)arenes were
obtained in moderate to high yields, as summarized in Scheme 1. In general, arenes
containing esters (4b-d), protected phenolic hydroxy (4e), cyano (4f-g), enolizable
ketone (4h), amide (4i) and tertiary amine (4j) were compatible with the reaction
conditions. However, bromine and iodine are not tolerated since the halogenated
arenes further reacted with aryl pinacol boronates. Chlorinated substrate (4l) was
successfully difluoromethylated, albeit in slightly lower yield. Heteroarenes, including
protected indole (4o), pyridine (4p-r) and quinoline (4s-t) were successfully
difluoromethylated, even though slightly higher loadings of [Ir-(COD)OMe]2 and dtbpy
were required. Reactions of pyrimidine derivatives, however, required the use a more
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reactive catalyst, generated by using Me4Phen (3,4,7,8-tetramethyl-1,10-
phenanthroline) as the ligand. Under these conditions, a few pyrimidine derivatives
successfully underwent the one-pot C-H borylation/difluoromethylation to give the
corresponding difluoromethylated pyrimidine derivatives in moderate yields (4u-x).
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Finally,
to
demonstrate
the
applicability
of
the
the
one-pot
borylation/difluoromethylation
protocol,
we attempted
late-stage
difluoromethylation of drug and agrochemical derivatives (Scheme 3). For example,
Vitamin B3 and Guaiazulene,16 a cosmetic color additive, were successfully
difluoromethylated in 64% and 62% yields, respectively, under the standard protocol
conditions (Eqs. 3-4). In addition, Metalaxyl,17 a marketed fungicide used in mixtures
as a foliar spray for tropical and subtropical crops and as a seed treatment to control
downy mildews was successfully difluoromethylated in gram-scale in 62% yield (Eq
5). Furthermore, two other drug molecules Neostigmine,18 a medication to
treat myasthenia gravis and ogilvie syndrome, and Rivastigmine,19 a drug used
to treat confusion related to Alzheimer/Parkinson's disease, were also successfully
difluoromethylated in 46-50% yield, respectively (Eqs. 6-7). Considering the
importance of the difluoromethyl group in medicinal chemistry which often is
considered as a bioisostere of the hydroxy or thio group,2 these examples exhibit great
potential of the one-pot C-H borylation/difluoromethylation protocol in the preparation
of more complicated drug-like molecules.
Scheme 3. Late-stage difluoromethylation of drug and agrochemical derivatives
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MeO2C
H
MeO2C
CF2H
standard conditions
(3)
(4)
4
5
6
7
8
9
N
N
HCF2-Vitamin B3, 5, 64%b
Vitamin B3
H
CF2H
Me
Me
standard conditions
Me
Me
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Me
Me
Me
HCF2-Guaiazulene 6, 62%
Me
Guaiazulene
MeO
MeO
O
OMe
N
MeO
MeO
O
OMe
N
standard conditions
(5)
H
CF2H
Me
Me
Metalaxyl (977 mg, 3.5 mmol)
HCF2-Metalaxyl, 7, 62%
Me2N NMe2
O
Me2N NMe2
O
standard conditions
standard conditions
(6)
(7)
O
O
CF2H
HCF2-Norneostigmine, 8, 46%
H
Norneostigmine
Me
Me
N
Me
Me
N
Me
O
Me
O
N
N
Me
O
Me
Me
O
Me
CF2H
HCF2-Rivastigmine, 9, 50%
H
Rivastigmine
In summary, we reported a concurrent ligand transfer process that transfers both
NHC ligand and CF2H group from [(SIPr)Ag(CF2H)] to PdX2 (X = Cl, OAc, OPiv) for
the preparation [(SIPr)Pd(CF2H)X] complexes. These complexes were then applied in
one-pot Ir-catalyzed C-H borylation and difluoromethylation access 5-
difluoromethylated 1,3-difunctionalized (hetero)arenes in high yields. Even though a
stoichiometric amount of difluoromethylated palladium complex was used as the
difluoromethylating reagent, from the viewpoint of medicinal chemists, this protocol
represents an efficient method for the direct late-stage preparation of previously
inaccessible difluoromethylated arenes and heteroarenes. Studies toward the use of
complex 1-3 as the catalyst for catalyzed difluoromethylation are undergoing currently
in our laboratory.
Experimental Section
General information. All solvents were purified by standard method. 1H, 19F and 13C
NMR spectra were acquired on 400 MHz; 376 MHz; 101, 126, 151 MHz spectrometer
(400 MHz for 1H ; 376 MHz for 19F; 101, 126 151 MHz for 13C). 1 H NMR and 13C NMR
chemical shifts were determined relative to internal standard TMS at δ 0.0 ppm and
19F NMR chemical shifts were determined relative to CFCl3 as inter standard.
Chemical shifts (δ) are reported in ppm, and coupling constants (J) are in hertz (Hz).
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The following abbreviations were used to explain the multiplicities: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet. All reactions were monitored by TLC or
19F NMR. Flash column chromatograph was carried out using 300-400 mesh silica gel
at medium pressure.
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Materials. All reagents were received from commercial sources. Solvents were freshly
dried and degassed according to the purification handbook Purification of Laboratory
Chemicals before using.
Synthesis of [(SIPr)Pd(CHF2)(OAc)] 1. In a glovebox, Pd(OAc)2 (448 mg, 2.00 mmol,
1.00 equiv.) and (SIPr)Ag(CF2H) (1.1 g, 2.0 mmol, 1.0 equiv.) were placed in a 250
mL sealed tube that was equipped with a stirrer. Then 20 mL of anhydrous THF was
o
added and the reaction mixture was stirred at 80 C in an oil bath overnight. The
mixture was then filtered through a short plug of Celite. The solvent was removed
under vacuum. The residue was purified by flash chromatography on silica gel
(petroleum / ethyl acetate = 20/1) to give [(SIPr)Pd(CF2H)(OAc)] as a white solid (973
mg, 80%). Colorless crystals of 1 suitable for single-crystal X-ray diffraction study were
obtained by standing its THF solution at room temperature via slow evaporation of
THF. 1H NMR (400 MHz, CDCl3) δ 7.42 (t, J = 7.7 Hz, 2 H), 7.28 (m, 4 H), 5.87 (t, J =
52.8 Hz, 1 H), 4.01 (s, 3 H), 3.23 (m, 4 H), 1.45 (d, J = 6.6 Hz, 12 H), 1.26 (d, J = 6.8
Hz, 12 H); 19F NMR (376 MHz, CDCl3) δ -87.95 (d, J = 52.8 Hz); 13C{1H} NMR (151
MHz, CDCl3) δ 198.7 (t, J = 9.8 Hz), 187.5, 147.4, 134.8, 129.6, 124.8, 120.2 (t, J =
304.2 Hz), 53.8, 28.8, 26.5, 23.6, 23.4 ppm. Anal. Calcd for C30H42PdO2F2N2: C, 59.35;
H, 6.97; N, 4.61. Found: C, 59.74; H, 7.24; N, 4.42.
Synthesis of [(SIPr)Pd(CHF2)Cl]2 2. In a glovebox, Pd(CH3CN)2Cl2 (520 mg, 2.00
mmol, 1.00 equiv.) and (SIPr)Ag(CF2H) (1.1 g, 2.0 mmol, 1.0 equiv.) were placed in a
250 mL sealed tube that was equipped with a stirrer. Then 20 mL of anhydrous THF
was added and the reaction mixture was stirred at 80 oC in an oil bath overnight. The
mixture was then filtered through a short plug of Celite. The solution was reduced to a
minimum volume of THF, and a white solid (817 mg, 70%) was precipitated by the
addition of ether to the concentrated solution. Colorless crystals of 2 suitable for single
crystal X-ray diffraction study were obtained by diffusing n-pentane into its THF
solution at room temperature. 1H NMR (400 MHz, CDCl3) δ 7.34 (t, J = 7.6 Hz, 2 H),
7.21 (m, 4 H), 5.53 (t, J = 52.8 Hz, 1 H), 3.84 (d, J = 3.9 Hz, 4 H), 3.19 (m, 4 H), 1.33
(d, J = 6.3 Hz, 12 H), 1.21 (d, J = 6.1 Hz, 6 H), 1.10 (d, J = 5.8 Hz, 6 H); 19F NMR (376
MHz, CDCl3) δ -85.05 (d, J = 52.8 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 200.1 (t, J =
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12.9 Hz), 147.6, 146.8, 135.6, 129.0, 124.6, 124.4, 120.8 (t, J = 304.0 Hz), 28.9, 28.1,
27.0, 26.8, 24.1, 24.0 ppm. Anal. Calcd for C33H48PdO2F2N2: C,61.06; H, 7.45; N, 4.32.
Found: C, 60.66; H, 7.41; N, 3.46.
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Synthesis of [(SIPr)Pd(CHF2)(OPiv)] 3. In a glovebox, Pd(OPiv)2 (154 mg, 0.500
mmol, 1.00 equiv.) and (SIPr)Ag(CF2H) (275 mg, 0.500 mmol, 1.00 equiv.) were
placed in a 25 mL sealed tube that was equipped with a stirrer. Then 5 mL of
anhydrous THF was added and the reaction mixture was stirred at 80 oC in an oil bath
overnight. The mixture was then filtered through a short plug of Celite. The solvent
was removed under vacuum. The residue was purified by flash chromatography on
silica gel (petroleum / ethyl acetate = 20/1) to give [(SIPr)Pd(CF2H)(OPiv)] as a white
solid (533 mg, 82%). Colorless crystals of 3 suitable for single-crystal X-ray diffraction
study were obtained by standing its THF solution at room temperature via slow
evaporation of THF. 1H NMR (400 MHz, CDCl3) δ 7.42 (t, J = 7.7 Hz, 2 H), 7.28 (m, 4
H), 5.87 (t, J = 52.8 Hz, 1 H), 4.01 (s, 4 H), 3.23 (m, 4 H), 1.45 (d, J = 6.6 Hz, 12 H),
1.26 (d, J = 6.8 Hz, 12 H), 0.86 (s, 9 H); 19F NMR (376 MHz, CDCl3) δ -87.95 (d, J =
52.8 Hz); 13C{1H} NMR (151 MHz, CDCl3) δ 198.7 (t, J = 9.8 Hz), 187.5, 147.4, 134.8,
129.6, 124.8, 120.2 (t, J = 304.2 Hz), 53.8, 28.8, 26.5, 23.6 ppm. Anal. Calcd for
C56H78Pd2Cl2F4N4: C,57.64; H, 6.74. Found: C, 57.64; H, 6.81.
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General procedure for one-pot C-H borylation/difluoromethylation.
Procedure A. In an argon-filled glove box, arene (0.3 mmol) and B2pin2 (53 mg, 0.21
mmol) were placed into a sealed tube. To this tube was added anhydrous THF (1.5
mL) containing [Ir(COD)(OMe)]2 (0.25 mol%) and dtbpy (0.54 mol%). The reaction was
stirred at 80 oC in an oil bath and monitored by TLC until the disappearance of the
arene (24 h). After evaporation of volatile materials under vacuum, K2CO3 (83 mg,
0.60 mmol), [(SIPr)Pd(CF2H)Cl]2 (175 mg, 0.150 mmol) and dry DMF (3.0 mL) were
added under argon. The mixture was stirred at 80 oC in an oil bath overnight. The
solution was diluted with Et2O (5.0 mL), and filtered through a short plug of silica gel,
washed with Et2O (20.0 mL). The organic layer was washed with water (20.0 mL × 3),
dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel.
Procedure B. In an argon-filled glove box, arene (0.3 mmol) and B2pin2 (53 mg, 0.21
mmol) were placed into a sealed tube. To this tube was added anhydrous THF (1.5
mL) containing [Ir(COD)(OMe)]2 (1.0 mol%) and dtbpy (2.0 mol%). The reaction was
stirred at 80 oC in an oil bath and monitored by TLC until the disappearance of the
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arene (24 h). After evaporation of volatile materials under vacuum, K2CO3 (83 mg,
0.60 mmol), [(SIPr)Pd(CF2H)Cl]2 (175 mg, 0.150 mmol) and dry DMF (3.0 mL) were
added under argon. The mixture was stirred at 80 oC in an oil bath overnight. The
solution was diluted with Et2O (5.0 mL), and filtered through a short plug of silica gel,
washed with Et2O (20.0 mL). The organic layer was washed with water (20.0 mL × 3),
dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel.
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Procedure C. In an argon-filled glove box, arene (0.3 mmol) and B2pin2 (53 mg, 0.21
mmol) were placed into a sealed tube. To this tube was added anhydrous THF (1.5
mL) containing [Ir(COD)(OMe)]2 (3.0 mol%) and Me4Phen (6.0 mol%). The reaction
was stirred at room teperature and monitored by TLC until the disappearance of the
arene (24 h). After evaporation of volatile materials under vacuum, K2CO3 (83 mg,
0.60 mmol), [(SIPr)Pd(CF2H)Cl]2 (175 mg, 0.150 mmol) and dry DMF (3.0 mL) were
added under argon. The mixture was stirred at 80 oC in an oil bath overnight. The
solution was diluted with Et2O (5.0 mL), and filtered through a short plug of silica gel,
washed with Et2O (20.0 mL). The organic layer was washed with water (20.0 mL × 3),
dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel.
1,3-Di-tert-butyl-5-(difluoromethyl)benzene 4a. The general procedure A
conducted with 1,3-di-tert-butylbenzene (57 mg, 0.30 mmol) in dry THF (1.5 mL) and
then in dry DMF (3.0 mL) gave 51 mg (71%) product as a yellow oil. Eluent: petroleum
ether, Rf = 0.3. 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1 H), 7.33 (s, 2 H), 6.63 (t, J =
56.7 Hz, 1 H), 1.34 (s, 18 H); 19F NMR (376 MHz, CDCl3) δ -109.42 (d, J = 56.7 Hz);
13C{1H} NMR (126 MHz, CDCl3) δ 151.4, 133.6 (t, J = 21.5 Hz), 124.9, 119.7 (t, J =5.67
Hz), 115.6 (t, J = 238.4 Hz), 35.0, 31.4 ppm. The physical and spectral data were
consistent with those previously reported.8b
Dimethyl 5-(difluoromethyl)isophthalate 4b. The general procedure A conducted
with dimethyl isophthalate (58 mg, 0.30 mmol) in dry THF (1.5 mL) and then in dry
DMF (3.0 mL) gave 58 mg (79%) product as a yellow solid. Mp: 60.8-62.2 oC. Eluent:
ethyl acetate/petroleum ether (1/20), Rf = 0.2. 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1
H), 8.38 (s, 2 H), 6.74 (t, J = 55.9 Hz, 1 H), 3.98 (s, 6 H); 19F NMR (376 MHz, CDCl3)
δ -111.78 (d, J = 55.9 Hz); 13C NMR (126 MHz, CDCl3) δ 165.38, 135.35 (t, J = 23.1
Hz), 132.74, 131.42, 130.92 (t, J = 6.0 Hz), 113.47 (t, J = 240.4 Hz), 52.70 ppm. MS
(EI): 213 (100), 244 (19.38); HRMS (EI-TOF) m/z: [M]+ Calcd for C11H10O4F2: 244.0553;
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Found: 244.0547. IR (KBr): max = 2956, 1723, 1617, 1434, 1384, 1328, 1242, 1207
cm-1.
Methyl 3-(difluoromethyl)-5-(trifluoromethyl)benzoate 4c. The general procedure
A conducted with methyl 3-(trifluoromethyl)benzoate (61 mg, 0.30 mmol) in dry THF
(1.5 mL) and then in dry DMF (3.0 mL) gave 54 mg (72%) product as a yellow oil.
Eluent: ethyl acetate/petroleum ether (1/20), Rf = 0.5. 1H NMR (400 MHz, CDCl3) δ
8.40 (d, J = 16.9 Hz, 2 H), 7.97 (s, 1 H), 6.75 (t, J = 55.8 Hz, 1 H), 3.99 (s, 3 H); 19F
NMR (376 MHz, CDCl3) δ -63.01 (s, 3 F), -112.32 (d, J = 55.8 Hz, 2 F); 13C{1H} NMR
(101 MHz, CDCl3) δ 164.8, 135.9 (t, J = 23.5 Hz), 132.4 – 131.3 (m), 130.0 (t, J = 6.1
Hz), 128.6, 128.6, 126.6 (dt, J = 9.5, 4.8 Hz), 123.1 (q, J = 272.8 Hz), 113.1 (t, J =
240.8 Hz), 52.8 ppm. MS (EI): 223 (100), 254 (43.79). HRMS (EI-TOF) m/z: [M]+ Calcd
for C10H7O2F5: 254.0366; Found: 254.0371. IR (KBr): max = 2960, 1731, 1617, 1439,
1345, 1255, 1131, 1039, 988, 767, 720 cm-1.
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Methyl 3-(difluoromethyl)-5-methylbenzoate 4d. The general procedure A
conducted with methyl 3-methylbenzoate (45 mg, 0.30 mmol) in dry THF (1.5 mL) and
then in dry DMF (3.0 mL) gave 38 mg (64%) product as a colorless oil. Eluent: ethyl
acetate/petroleum ether (1/20), Rf = 0.5. 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 2 H),
7.52 (s, 1 H), 6.65 (t, J = 56.3 Hz, 1 H), 3.93 (s, 3 H), 2.45 (s, 3 H); 19F NMR (376 MHz,
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CDCl3) δ -111.20 (d, J = 56.3 Hz); C{1H} NMR (151 MHz, CDCl3) δ 166.5, 139.3,
134.9 (t, J = 22.5 Hz), 132.6, 130.9, 130.6 (t, J = 5.5 Hz), 124.3 (t, J = 6.3 Hz), 114.4
(t, J = 239.3 Hz), 52.4, 21.4 ppm. MS (EI): 169 (100), 200 (75.44). HRMS (EI) m/z:
[M]+ Calcd for C10H10O2F2: 200.0649; Found: 200.0653. IR (KBr): max = 2956, 1723,
1612, 1437, 1386, 1311, 1221, 1171, 1028, 881, 766 cm-1.
3-(Difluoromethyl)-5-methylphenyl pivalate 4e. The general procedure A
conducted with methyl m-tolyl pivalate (58 mg, 0.30 mmol) in dry THF (1.5 mL) and
then in dry DMF (3.0 mL) gave 33 mg (46%) product as a colorless oil. Eluent: ethyl
acetate/petroleum ether (1/20), Rf = 0.3. 1H NMR (400 MHz, CDCl3) δ 7.17 (s, 1 H),
7.00 (d, J = 12.5 Hz, 2 H), 6.59 (t, J = 56.4 Hz, 1 H), 2.40 (s, 3 H), 1.36 (s, 9 H);19F
NMR (376 MHz, CDCl3) δ -111.20 (d, J = 56.4 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ
177.1, 151.3, 140.4, 135.7 (t, J = 22.4 Hz), 124.7, 123.6 (t, J = 6.0 Hz), 116.1 (t, J =
6.1 Hz), 114.2 (t, J = 239.1 Hz), 39.2, 27.2, 21.4 ppm. MS (EI): 116 (100), 167 (99.81),
242 (1.99). HRMS (EI-TOF) m/z: [M]+ Calcd for C13H16O2F2: 242.1118; Found:
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242.1125. IR (KBr): max = 2976, 1752, 1600, 1463, 1371, 1273, 1110, 1029, 888, 741
cm-1.
3-(Difluoromethyl)-5-(trifluoromethyl)benzonitrile 4f. The general procedure A
conducted with 3-(trifluoromethyl)benzonitrile (51 mg, 0.30 mmol) in dry THF (1.5 mL)
and then in dry DMF (3.0 mL) gave 40 mg (61%) product as a colorless oil. Eluent:
ethyl acetate/petroleum ether (1/10), Rf = 0.4. 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1
H), 8.01 (s, 2 H), 6.75 (t, J = 55.5 Hz, 1 H); 19F NMR (376 MHz, CDCl3) δ -63.29 (s, 3
F), -113.40 (d, J = 55.5 Hz, 2 F); 13C{1H} NMR (126 MHz, CDCl3) δ 136.5 (t, J = 23.7
Hz), 132.5 (dd, J = 68.2, 33.3 Hz), 132.1 (t, J = 6.0 Hz), 130.6, 126.5 – 126.2 (m),
121.9 (q, J = 273.2 Hz), 116.0, 114.0, 111.8 (t, J = 241.8 Hz) ppm. MS (EI): 152 (100),
221 (86.84). HRMS (EI-TOF) m/z: [M]+ Calcd for C9H4NF5: 221.0264; Found:
221.0260. IR (KBr): max = 2240, 1617, 1462, 1386, 1281, 1225, 1136, 1114, 1044,
899, 748 cm-1.
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3-(Difluoromethyl)-5-methylbenzonitrile 4g. The general procedure A conducted
with 3-methylbenzonitrile (35 mg, 0.30 mmol) in dry THF (1.5 mL) and then in dry DMF
(3.0 mL) gave 34 mg (68%) product as a colorless oil. Eluent: ethyl acetate/petroleum
ether (1/10), Rf = 0.4. 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1 H), 7.58 (s, 1 H), 7.55
(s, 1 H), 6.63 (t, J = 55.7 Hz, 1 H), 2.46 (s, 3 H); 19F NMR (376 MHz, CDCl3) δ -112.26
(d, J = 55.7 Hz); 13C{1H} NMR (151 MHz, CDCl3) δ 140.4, 135.8 (t, J = 23.1 Hz), 134.8,
130.7 (t, J = 5.6 Hz), 126.6 (t, J = 6.3 Hz), 118.1, 113.4 (t, J = 240.5 Hz), 113.2, 21.3
ppm. MS (EI): 116 (100), 167 (79.18). HRMS (EI-TOF) m/z: [M]+ Calcd for C9H7NF2:
167.0547; Found: 167.0546. IR (KBr): max = 2926, 2235, 1604, 1464, 1376, 1293,
1175, 1093, 1033, 874, 730 cm-1.
1-(3-(Difluoromethyl)-5-methylphenyl)propan-1-one 4h. The general procedure A
conducted with 1-(m-tolyl)propan-1-one (44 mg, 0.30 mmol) in dry THF (1.5 mL) and
then in dry DMF (3.0 mL) gave 30 mg (50%) product as a yellow oil. Eluent: ethyl
acetate/petroleum ether (1/30), Rf = 0.2. 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 2 H),
7.51 (s, 1 H), 6.66 (t, J = 56.2 Hz, 1 H), 3.01 (q, J = 7.2 Hz, 2 H), 2.46 (s, 3 H), 1.23 (t,
J = 7.2 Hz, 3 H); 19F NMR (376 MHz, CDCl3) δ -110.97 (d, J = 56.2 Hz); 13C{1H} NMR
(151 MHz, CDCl3) δ 200.2, 139.4, 137.6, 135.0 (t, J = 22.3 Hz), 130.9, 130.5 (t, J =
5.8 Hz), 122.6 (t, J = 6.2 Hz), 114.4 (t, J = 239.3 Hz), 32.1, 21.5, 8.3 ppm. MS (EI):
169 (100), 198 (10.17). HRMS (EI-TOF) m/z: [M]+ Calcd for C11H12OF2: 198.0856;
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Found: 198.0859. IR (KBr): max = 2980, 2942, 1688, 1605, 1350, 1184, 1165, 1026,
880, 806, 739 cm-1.
3-(Difluoromethyl)-N,N-diethyl-5-methylbenzamide 4i. The general procedure A
conducted with N,N-diethyl-3-methylbenzamide (57 mg, 0.30 mmol) in dry THF (1.5
mL) and then in dry DMF (3.0 mL) gave 45 mg (62%) product as a yellow oil. Eluent:
ethyl acetate/petroleum ether (1/4), Rf = 0.3. 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 1
H), 7.30 (s, 2 H), 6.62 (t, J = 56.3 Hz, 1 H), 3.55 (s, 2 H), 3.24 (s, 2 H), 2.42 (s, 3 H),
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1.25 (s, 3 H), 1.11 (s, 3 H); F NMR (376 MHz, CDCl3) δ -111.24 (d, J = 56.3 Hz);
13C{1H} NMR (151 MHz, CDCl3) δ 170.5, 139.2, 138.0, 134.7 (t, J = 22.7 Hz), 129.3,
126.9 (t, J = 6.1 Hz), 120.7 (t, J = 6.2 Hz), 114.4 (t, J = 239.3 Hz), 43.4, 39.4, 21.4,
14.3, 13.0 ppm. MS (ESI): 242.1 [M+H]+; HRMS (ESI-Orbitrap) m/z: [M+H]+ Calcd for
C13H17ONF2: 242.1351; Found: 242.1349. IR (KBr): max = 2976, 2934, 2874, 1626,
1430, 1383, 1318, 1255, 1218, 1171, 1085, 1021, 875, 811, 758, 729 cm-1.
4-(3-(Difluoromethyl)-5-methylphenyl)morpholine 4j. The general procedure A
conducted with 4-(m-tolyl)morpholine (53 mg, 0.30 mmol) in dry THF (1.5 mL) and
then in dry DMF (3.0 mL) gave 40 mg (59%) product as a pale green oil. Eluent: ethyl
acetate/petroleum ether (1/10), Rf = 0.4. 1H NMR (400 MHz, CDCl3) δ 6.84 (s, 1 H),
6.82 (s, 2 H), 6.56 (t, J = 56.7 Hz, 1 H), 3.91 – 3.82 (m, 4 H), 3.23 – 3.13 (m, 4 H),
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2.36 (s, 3 H); F NMR (376 MHz, CDCl3) δ -110.42 (d, J = 56.7 Hz); C{1H} NMR
(126 MHz, CDCl3) δ 151.7, 139.7, 135.3 (t, J = 21.9 Hz), 118.6, 117.9 (t, J = 6.1 Hz),
115.2 (t, J = 238.8 Hz), 109.7 (t, J = 6.1 Hz), 67.0, 49.2, 21.8 ppm. MS (EI): 169 (100),
227 (47.59). HRMS (EI-TOF) m/z: [M]+ Calcd for C12H15NOF2: 227.1122; Found:
227.1132. IR (KBr): max = 2966, 2860, 2824, 1602, 1450, 1388, 1263, 1121, 1089,
1014, 844, 728 cm-1.
1-(Difluoromethyl)-3,5-dimethoxybenzene 4k.5f The general procedure A
conducted with 1,3-dimethoxybenzene (41 mg, 0.30 mmol) in dry THF (1.5 mL) and
then in dry DMF (3.0 mL) gave 36 mg (64%) product as a colorless oil. Eluent: ethyl
acetate/petroleum ether (1/100), Rf = 0.4. 1H NMR (400 MHz, CDCl3) δ 6.64 (s, 2
H),6.56 (t, J = 56.5 Hz, 1 H), 6.54 (s, 1 H), 3.82 (s, 6 H); 19F NMR (376 MHz, CDCl3)
δ -110.90 (d, J = 56.5 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 161.0, 136.4 (t, J = 22.4
Hz), 114.5 (t, J = 239.1 Hz), 103.4 (t, J = 6.5 Hz), 102.7, 55.5 ppm. The physical and
spectral data were consistent with those previously reported.
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Methyl 3-chloro-5-(difluoromethyl)benzoate 4l. The general procedure A
conducted with 1-chloro-3-methoxybenzene (43 mg, 0.30 mmol) in dry THF (1.5 mL)
and then in dry DMF (3.0 mL) gave 17 mg (26%) product as a colorless oil. Eluent:
petroleum ether (1/100), Rf = 0.3. 1H NMR (400 MHz, CDCl3) δ 7.08 (s, 1 H), 6.99 (s,
1 H), 6.92 (s, 1 H), 6.56 (t, J = 56.1 Hz, 1 H), 3.83 (s, 3 H); 19F NMR (376 MHz, CDCl3)
δ -111.77 (d, J = 56.1 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 160.7, 136.9 (t, J = 22.8
Hz), 135.6, 118.2 (t, J = 6.4 Hz), 116.7, 113.8 (t, J = 240.3 Hz), 109.8 (t, J = 6.3 Hz),
55.8 ppm. MS (EI): 192 (100). HRMS (EI-TOF) m/z: [M]+ Calcd for C8H7OF2Cl:
192.0153; Found: 192.0156. IR (KBr): max = 2972, 2840, 1583, 1466, 1435, 1368,
1279, 1170, 1106, 1031, 947, 843, 732 cm-1.
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5-(Difluoromethyl)-2-fluoro-1,3-dimethoxybenzene 4m. The general procedure A
conducted with 2-fluoro-1,3-dimethoxybenzene (47 mg, 0.30 mmol) in dry THF (1.5
mL) and then in dry DMF (3.0 mL) gave 39 mg (63%) product as a colorless oil. Eluent:
ethyl acetate/petroleum ether (1/100), Rf = 0.4. 1H NMR (400 MHz, CDCl3) δ 6.75 (d,
J = 6.8 Hz, 2 H), 6.57 (t, J = 56.6 Hz, 1 H), 3.91 (s, 6 H); 19F NMR (376 MHz, CDCl3)
δ -109.76 (dd, J = 56.6, 3.1 Hz, 2 F), -154.59 (tt, J = 6.8, 3.4 Hz, 1 F); 13C{1H} NMR
(126 MHz, CDCl3) δ 148.8 (d, J = 9.2 Hz), 143.8 (dt, J = 248.6, 2.1 Hz), 129.7 (td, J =
22.6, 5.0 Hz), 114.4 (t, J = 239.4 Hz), 103.4 (t, J = 6.3 Hz), 56.7 ppm. MS (EI): 206
(100). HRMS (EI-TOF) m/z: [M]+ Calcd for C9H9O2F3: 206.0555; Found: 206.0550. IR
(KBr): max = 2976, 1619, 1522, 1466, 1426, 1380, 1341, 1244, 1130, 1020, 974, 841,
733 cm-1.
5-(Difluoromethyl)-2-methoxy-1,3-dimethylbenzene 4n. The general procedure A
conducted with 2-methoxy-1,3-dimethylbenzene (41 mg, 0.30 mmol) in dry THF (1.5
mL) and then in dry DMF (3.0 mL) gave 38 mg (69%) product as a yellow oil. Eluent:
ethyl acetate/petroleum ether (1/20), Rf = 0.4. 1H NMR (400 MHz, CDCl3) δ 7.17 (s, 2
H), 6.54 (t, J = 56.7 Hz, 1 H), 3.74 (s, 3 H), 2.32 (s, 6 H). 19F NMR (376 MHz, CDCl3)
δ -110.16 (d, J = 56.7 Hz). 13C{1H} NMR (126 MHz, CDCl3) δ 159.0, 131.7, 129.8 (t, J
= 22.2 Hz), 126.2 (t, J = 5.7 Hz), 115.0 (t, J = 237.9 Hz), 59.8, 16.3 ppm. MS (EI): 186
(100). HRMS (EI-TOF) m/z: [M]+ Calcd for C10H12OF2: 186.0856; Found: 186.0858. IR
(KBr): max = 2940, 1611, 1487, 1371, 1228, 1150, 1089, 1006, 881, 782, 756 cm-1.
tert-Butyl 3-(difluoromethyl)-1H-indole-1-carboxylate 4o. The general procedure
B conducted with tert-butyl 1H-indole-1-carboxylate (65 mg, 0.30 mmol) in dry THF
(1.5 mL) and then in dry DMF (3.0 mL) gave 53 mg (66%) product as a yellow solid.
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Mp: 66.0-67.5 oC. Eluent: ethyl acetate/petroleum ether (1/30), Rf = 0.3. 1H NMR (400
MHz, CDCl3) δ 8.18 (d, J = 8.3 Hz, 1 H), 7.81 (t, J = 2.3 Hz, 1 H), 7.72 (d, J = 7.8 Hz,
1 H), 7.42 – 7.36 (m, 1 H), 7.31 (td, J = 7.8, 1.0 Hz, 1 H), 6.89 (t, J = 55.6 Hz, 1 H),
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1.68 (s, 9 H); F NMR (376 MHz, CDCl3) δ -110.65 (dd, J = 55.6, 2.4 Hz); C{1H}
NMR (126 MHz, CDCl3) δ 149.4, 135.7, 126.5, 125.6 (t, J = 8.9 Hz), 125.5, 123.5,
120.1, 115.6, 115.3 (t, J = 25.9 Hz), 112.4 (t, J = 234.0 Hz), 84.8, 28.3 ppm. MS (EI):
57 (100), 267 (13.64). HRMS (EI-TOF) m/z: [M]+ Calcd for C14H15NO2F2: 267.1071;
Found: 267.1077. IR (KBr): max = 2982, 1740, 1452, 1396, 1345, 1259, 1155, 1094,
1016, 852, 746 cm-1.
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2,6-Di-tert-butyl-4-(difluoromethyl)pyridine 4p. The general procedure A
conducted with 2,6-di-tert-butylpyridine (57 mg, 0.30 mmol) in dry THF (1.5 mL) and
then in dry DMF (3.0 mL) gave 43 mg (60%) product as a yellow oil. Eluent: ethyl
acetate/petroleum ether (1/10), Rf = 0.3. 1H NMR (400 MHz, CDCl3) δ 7.19 (s, 2 H),
6.58 (t, J = 56.1 Hz, 1 H), 1.36 (s, 18 H); 19F NMR (376 MHz, CDCl3) δ -114.17 (d, J =
56.1 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 169.0, 142.3 (t, J = 22.4 Hz), 114.2 (t, J =
240.3 Hz), 111.9 (t, J = 6.0 Hz), 38.0, 30.2 ppm. MS (EI): 226 (100), 241 (25.92).
HRMS (EI-TOF) m/z: [M]+ Calcd for C14H21NF2: 241.1642; Found: 241.1651. IR (KBr):

max = 2959, 1608, 1577, 1479, 1420, 1374, 1207, 1099, 1043, 901, 875, 729 cm-1.
3-(Difluoromethyl)-5-(1,3-dioxolan-2-yl)pyridine 4q.10 The general procedure B
conducted with 3-(1,3-dioxolan-2-yl)pyridine (45 mg, 0.30 mmol) in dry THF (1.5 mL)
and then in dry DMF (3.0 mL) gave 32 mg (53%) product as a yellow oil. Eluent: ethyl
acetate/petroleum ether (1/2), Rf = 0.4. 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1 H),
8.72 (s, 1 H), 7.92 (s, 1 H), 6.70 (t, J = 55.7 Hz, 1 H), 5.87 (s, 1 H), 4.69 – 3.78 (m, 4
H); F NMR (376 MHz, CDCl3) δ -112.59 (d, J = 55.7 Hz, 2 F); C{1H} NMR (126
MHz, CDCl3) δ 150.5 (t, J = 1.9 Hz), 147.7 (t, J = 6.6 Hz), 134.0, 131.5 (t, J = 5.6 Hz),
129.8 (t, J = 23.1 Hz), 113.2 (t, J = 239.7 Hz), 101.3, 65.5 ppm. The physical and
spectral data were consistent with those previously reported.
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5-(Difluoromethyl)nicotinonitrile 4r.10 The general procedure B conducted with
nicotinonitrile (31 mg, 0.30 mmol) in dry THF (1.5 mL) and then in dry DMF (3.0 mL)
o
gave 21 mg (47%) product as a yellow solid. Mp: 58.1-59.4 C. Eluent: ethyl
acetate/petroleum ether (1/2), Rf = 0.4. 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1 H),
8.93 (s, 1 H), 8.11 (s, 1 H), 6.75 (t, J = 55.3 Hz, 1 H); 19F NMR (376 MHz, CDCl3) δ -
113.91 (d, J = 55.3 Hz, 2 F); 13C{1H} NMR (126 MHz, CDCl3) δ 154.3 (t, J = 1.7 Hz),
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150.4 (t, J = 6.4 Hz), 136.7 (t, J = 5.8 Hz), 130.5 (t, J = 23.9 Hz), 115.6, 112.0 (t, J =
241.8 Hz), 110.4 ppm. The physical and spectral data were consistent with those
previously reported.
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3-(Difluoromethyl)-6-methylquinoline 4s. The general procedure B conducted with
6-methylquinoline (43 mg, 0.30 mmol) in dry THF (1.5 mL) and then in dry DMF (3.0
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mL) gave 34 mg (59%) product as a yellow solid. Mp: 41.6-43.0 C. Eluent: ethyl
acetate/petroleum ether (1/4), Rf = 0.3. 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1 H),
8.19 (s, 1 H), 8.05 (d, J = 9.1 Hz, 1 H), 7.63 (d, J = 3.6 Hz, 2 H), 6.86 (t, J = 55.9 Hz,
1 H), 2.55 (s, 3 H); F NMR (376 MHz, CDCl3) δ -111.47 (d, J = 55.9 Hz); C{1H}
NMR (101 MHz, CDCl3) δ 147.8, 146.3 (t, J = 5.3 Hz), 137.8, 133.5, 133.3 (t, J = 6.7
Hz), 129.2, 127.4, 127.2, 127.0, 113.9 (t, J = 239.3 Hz), 21.7 ppm. MS (EI): 193 (100).
HRMS (EI-TOF) m/z: [M]+ Calcd for C11H9NF2: 193.0703; Found: 193.0701. IR (KBr):
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
max = 3024, 1614, 1573, 1440, 1383, 1333, 1181, 1027, 919, 829 cm-1.
3-(Difluoromethyl)-6-methoxyquinoline 4t. The general procedure B conducted
with 6-methoxyquinoline (48 mg, 0.30 mmol) in dry THF (1.5 mL) and then in dry DMF
(3.0 mL) gave 35 mg (56%) product as an orange oil. Eluent: ethyl acetate/petroleum
ether (1/2), Rf = 0.5. 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1 H), 8.20 (s, 1 H), 8.06 (d,
J = 9.2 Hz, 1 H), 7.46 (dd, J = 9.2, 2.6 Hz, 1 H), 7.14 (d, J = 2.5 Hz, 1 H), 6.87 (t, J =
55.5 Hz, 1 H), 3.95 (s, 3 H); 19F NMR (376 MHz, CDCl3) δ -109.89 (d, J = 55.5 Hz);
13C{1H} NMR (151 MHz, CDCl3) δ 158.7, 145.5, 144.8 (t, J = 5.3 Hz), 132.6 (t, J = 6.4
Hz), 131.1, 128.3, 127.6 (t, J = 22.8 Hz), 124.1, 113.9 (t, J = 239.7 Hz), 105.7, 55.8
ppm. MS (EI): 209 (100). HRMS (EI-TOF) m/z: [M]+ Calcd for C11H9NOF2: 209.0652;
Found: 209.0657. IR (KBr): max = 2954, 2926, 1613, 1504, 1379, 1235, 1221, 1027,
916, 837, 731 cm-1.
5-(Difluoromethyl)pyrimidine-2-carbonitrile 4u.10 The general procedure C
conducted with pyrimidine-2-carbonitrile (32 mg, 0.30 mmol) in dry THF (1.5 mL) and
then in dry DMF (3.0 mL) gave 18 mg (39%) product as a yellow oil. Eluent: ethyl
acetate/petroleum ether (1/3), Rf = 0.3. 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 2 H),
6.85 (t, J = 56.4 Hz, 1 H); 19F NMR (376 MHz, CDCl3) δ -115.91 (d, J = 56.4 Hz, 2 F);
13C{1H} NMR (126 MHz, CDCl3) δ 150.6(t, J = 7.5 Hz), 141.3(t, J = 2.5 Hz), 124.8 (t, J
= 30.0 Hz), 109.8, 105.8 (t, J = 243.2 Hz) ppm. The physical and spectral data were
consistent with those previously reported.
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5-(Difluoromethyl)-2-(pyrrolidin-1-yl)pyrimidine 4v.10 The general procedure C
conducted with 2-(pyrrolidin-1-yl)pyrimidine (45 mg, 0.30 mmol) in dry THF (1.5 mL)
and then in dry DMF (3.0 mL) gave 26 mg (44%) product as a yellow solid. Mp: 71.2-
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72.0 C. Eluent: ethyl acetate/petroleum ether (1/2), Rf = 0.3. H NMR (400 MHz,
CDCl3) δ 8.41 (s, 2 H), 6.56 (t, J = 56.4 Hz, 1 H), 3.60 (t, J = 6.0 Hz, 4 H), 2.01 (m, 4
H); 19F NMR (376 MHz, CDCl3) δ -109.45 (d, J = 56.4 Hz, 2 F); 13C NMR (126 MHz,
CDCl3) δ 161.0, 155.8 (t, J = 5.0 Hz), 115.5 (t, J = 23.8 Hz), 113.8 (t, J = 235. 5 Hz),
46.8, 25.4 ppm. The physical and spectral data were consistent with those previously
reported.
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tert-Butyl-N-tert-butoxycarbonyl-N-[5-(difluoromethyl)pyrimidin-2-yl]carbamate
4x.10
The
general
procedure
C
conducted
with
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butoxycarbonyl)amino)pyrimidine (88 mg, 0.30 mmol) in dry THF (1.5 mL) and then in
o
dry DMF (3.0 mL) gave 42 mg (41%) product as a yellow solid. Mp: 67.0-68.1 C.
Eluent: ethyl acetate/petroleum ether (1/8), Rf = 0.3.1H NMR (400 MHz, CDCl3) δ 8.86
(s, 2 H), 6.77 (t, J = 56.4 Hz, 1 H), 1.48 (s, 18 H); 19F NMR (376 MHz, CDCl3) δ -113.82
(d, J = 56.4 Hz, 2 F); 13C{1H} NMR (126 MHz, CDCl3) δ 160.2, 156.4 (t, J = 6.3 Hz),
150.4, 125.4, 111.9 (t, J = 239.2 Hz), 84.0, 27.8 ppm. The physical and spectral data
were consistent with those previously reported.
tert-Butyl 4-(5-(difluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate 4y. The
general procedure C conducted with tert-butyl 4-(pyrimidin-2-yl)piperazine-1-
carboxylate (79 mg, 0.30 mmol) in dry THF (1.5 mL) and then in dry DMF (3.0 mL)
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gave 44 mg (47%) product as a white solid. Mp: 62.9-64.6 C. Eluent: ethyl
acetate/petroleum ether (1/3), Rf = 0.3. 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 2 H),
6.57 (t, J = 56.0 Hz, 1 H), 3.92 – 3.81 (m, 4 H), 3.55 – 3.44 (m, 4 H), 1.49 (s, 9 H); 19F
NMR (376 MHz, CDCl3) δ -110.11 (d, J = 56.0 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ
162.4, 156.1 (t, J = 5.5 Hz), 154.9, 116.7 (t, J = 24.3 Hz), 113.6 (t, J = 237.0 Hz), 80.3,
43.8, 28.6 ppm. MS (ESI): 337.1 [M+Na]+; HRMS (ESI-Orbitrap) m/z: [M+H]+ Calcd for
C14H20O2N4F2: 315.1627; Found: 315.1625. IR (KBr): max = 2977, 2868, 1681, 1610,
1526, 1236, 1167, 1122, 1076, 955, 742 cm-1.
Methyl 5-(difluoromethyl)nicotinate 5. The general procedure B conducted with
tert-butyl 4-(pyrimidin-2-yl)piperazine-1-carboxylate (41 mg, 0.30 mmol) in dry THF
(1.5 mL) and then in dry DMF (3.0 mL) gave 36 mg (66%) product as a yellow solid.
Mp: 94.6-96.3 oC. Eluent: ethyl acetate/petroleum ether (1/3), Rf = 0.4. 1H NMR (400
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MHz, CDCl3) δ 9.30 (s, 1 H), 8.90 (s, 1 H), 8.43 (s, 1 H), 6.76 (t, J = 55.5 Hz, 1 H),
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3.97 (s, 3 H); F NMR (376 MHz, CDCl3) δ -112.95 (d, J = 55.5 Hz); C{1H} NMR
(126 MHz, CDCl3) δ 165.0, 152.9, 150.8 (t, J = 6.11 Hz), 134.6 (t, J = 5.9 Hz), 130.2
(t, J = 23.6 Hz), 126.2, 112.9 (t, J = 240.4 Hz), 52.8 ppm. MS (EI): 156 (100), 187
(81.97). HRMS (EI-TOF) m/z: [M]+ Calcd for C8H7NO2F2: 187.0445; Found: 187.0451.
IR (KBr): max = 3057, 1721, 1587, 1442, 1374, 1298, 1216, 1111, 1084, 1036, 925,
901, 768, 726 cm-1.
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2-(Difluoromethyl)-7-isopropyl-1,4-dimethylazulene 6. The general procedure C
conducted with Guaiazulene (60 mg, 0.30 mmol) in dry n-hexane (1.5 mL) at 100 oC
and then in dry DMF (3.0 mL) gave 46 mg (62%) product as a blue oil. Eluent:
petroleum ether, Rf = 0.4. 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1 H), 7.51 (d, J = 10.5
Hz, 1 H), 7.40 (s, 1 H), 7.11 (t, J = 55.9 Hz, 1 H), 7.10 (d, J = 9.8 Hz, 1 H),3.18 – 3.05
(m, 1 H), 2.86 (s, 3 H), 2.70 (s, 3 H), 1.39 (d, J = 6.9 Hz, 6 H). 19F NMR (376 MHz,
CDCl3) δ -109.80 (d, J = 55.8 Hz). 13C{1H} NMR (126 MHz, CDCl3) δ 147.3, 141.3,
139.3 – 138.7 (m), 137.0, 136.4, 135.4, 126.4, 122.4 (t, J = 5.7 Hz), 113.8 (t, J = 235.0
Hz), 110.4 (t, J = 5.8 Hz), 38.4, 24.84, 24.3, 10.5 ppm. MS (EI): 233 (100), 248 (79).
HRMS (EI-TOF) m/z: [M]+ Calcd for C16H18F2: 248.1377; Found: 248.1368. IR (KBr):

max = 2960, 2924, 2870, 1560, 1461, 1361, 1126, 1031, 819, 793 cm-1.
Gram-scale synthesis of HCF2-Metalaxyl 7. In an argon-filled glove box, Metalaxyl
(977 mg, 3.50 mmol) and B2pin2 (630 mg, 2.48 mmol) were placed into a sealed tube.
To this tube was added anhydrous THF (10 mL) containing [Ir(COD)(OMe)]2 (5.8 mg,
0.25 mol%) and dtbpy (6.4 mg, 0.50 mol%). The reaction was stirred at 80 oC in an oil
bath and monitored by TLC until the disappearance of Metalaxyl (24 h). After
evaporation of volatile materials under vacuum, K2CO3 (966 mg, 7.00 mmol),
[(SIPr)Pd(CF2H)Cl]2 (2.04 g, 1.75 mmol) and dry DMF (35 mL) were added under
argon. The mixture was stirred at 80 oC in an oil bath overnight. The solution was
diluted with Et2O (50 mL), and filtered through a short plug of silica gel, washed with
Et2O (100 mL). The organic layer was washed with water (100 mL × 3), dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel
column chromatography (ethyl acetate/petroleum ether = 1/3, v/v) to afford HCF2-
Metalaxyl (714 mg, 62%). 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 2 H), 6.55 (t, J = 56.2
Hz, 1 H), 4.46 (q, J = 7.4 Hz, 1 H), 3.74 (s, 3 H), 3.53 (d, J = 15.4 Hz, 1 H), 3.41 (d, J
= 15.4 Hz, 1 H), 3.27 (s, 3 H), 2.46 (s, 3 H), 2.15 (s, 3 H), 0.94 (d, J = 7.4 Hz, 3 H); 19F
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NMR (376 MHz, CDCl3) δ -111.02 (d, J = 56.2 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ
172.7, 169.8, 139.9, 138.6, 137.8, 135.1 (t, J = 22.4 Hz), 126.7 (t, J = 5.7 Hz), 125.9
(t, J = 5.5 Hz), 114.1 (t, J = 239.5 Hz), 70.7, 59.5, 55.4, 52.4, 18.8, 18.5, 14.8 ppm.
MS (ESI): 330.1 [M+H]+; HRMS (ESI-Orbitrap) m/z: [M+H]+ Calcd for C16H21O4NF2:
330.1511; Found: 330.1508. IR (KBr): max = 2988, 2952, 1747, 1673, 1454, 1381,
1200, 1171, 1091, 1024, 881, 742 cm-1.
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3-(Difluoromethyl)-5-(dimethylamino)phenyl dimethylcarbamate 8. The general
procedure A conducted with Norneostigmine (62 mg, 0.30 mmol) in dry THF (1.5 mL)
and then in dry DMF (3.0 mL) gave 35 mg (46%) product as a brown oil. Eluent: ethyl
1
acetate/petroleum ether (1/4), Rf = 0.4. H NMR (400 MHz, CDCl3) δ 6.64 (s, 1 H),
6.59 (s, 1 H), 6.56 (t, J = 56.7 Hz, 1 H), 6.52 (s, 1 H), 3.09 (s, 3 H), 3.01 (s, 3 H), 2.97
(s, 6 H). 19F NMR (376 MHz, CDCl3) δ -111.14 (d, J = 56.7 Hz). 13C{1H} NMR (126
MHz, CDCl3) δ 154.9, 152.8, 151.7, 136.0 (t, J = 22.1 Hz), 114.8 (t, J = 239.5 Hz),
107.8, 106.9 (t, J = 5.9 Hz), 106.1 (t, J = 6.2 Hz), 40.6, 36.8, 36.6 ppm. MS (ESI):
259.1 [M+H]+; HRMS (ESI-Orbitrap) m/z: [M+H]+ Calcd for C12H17O2N2F2: 259.1253;
Found: 259.1255. IR (KBr): max = 2927, 1718, 1615, 1497, 1373, 1238, 1159, 1088,
877, 756, 741 cm-1.
(S)-3-(Difluoromethyl)-5-(1-(dimethylamino)ethyl)phenyl
ethyl(methyl)
carbamate 9. The general procedure A conducted with Rivastigmine (75 mg, 0.30
mmol) in dry THF (1.5 mL) and then in dry DMF (3.0 mL) gave 45 mg (50%) product
as a yellow oil. Eluent: dichloromethane/methanol (20/1), Rf = 0.4. 1H NMR (400 MHz,
CDCl3) δ 7.28 (s, 1 H), 7.20 (m, 2 H), 6.62 (t, J = 56.5 Hz, 1 H), 3.41 (m, 3 H), 3.03 (d,
J = 29.5 Hz, 3 H), 2.22 (s, 6 H), 1.38 (d, J = 6.6 Hz, 3 H), 1.20 (m, 3 H).19F NMR (376
MHz, CDCl3) δ -110.96 (d, J = 56.4, rotamer 1), -110.98 (d, J = 56.4, rotamer 2).13C{1H}
NMR (126 MHz, CDCl3) δ 154.2 (rotamer 1), 154.0 (rotamer 2), 151.7 (d, J = 4.1 Hz),
146.9 (d, J = 10.9 Hz), 135.4 (t, J = 22.7 Hz), 123.1 (d, J = 8.5 Hz), 121.2 (q, J = 6.2
Hz), 117.7 (t, J = 6.1 Hz), 114.2 (t, J = 239.5 Hz), 65.5, 44.1, 43.2, 34.3 (rotamer 1),
33.8 (rotamer 2), 20.0, 13.2 (rotamer 1), 12.4 (rotamer 2) ppm. MS (ESI): 301.2 [M+H]+;
HRMS (ESI-Orbitrap) m/z: [M+H]+ Calcd for C15H23O2N2F2: 301.1722; Found:
301.1724. IR (KBr): max = 2979, 2770, 1721, 1453, 1376, 1278, 1164, 1089, 1027,
968, 883, 755 cm-1.
ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications
website. 1H, 19F and 13C NMR spectra of complexes 1-3, 4a-y and 5-7 (PDF); cif files
of for single crystals of complexes 1-3 (cif)
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AUTHOR INFORMATION
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Corresponding Author
*shenql@sioc.ac.cn
Author Contributions
The manuscript was written through contributions of all authors. All authors have given
approval to the final version of the manuscript.
ACKNOWLEDGMENT
The authors gratefully acknowledge the financial support from National Natural
Science Foundation of China (21625206, 21632009, 21572258, 21421002) and the
Strategic Priority Research Program of the Chinese Academy of Sciences
(XDB20000000).
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Table of Content
MeO
MeO
O
O Me
N
MeO
MeO
O
O Me
N
1. [Ir]/B2pin2
H
CF2H
2. [(SIPr)Pd(CF2H)Cl]2
Me
Me
Metalaxyl (977 mg)
HCF2-Metalaxyl, 62%
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